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diff --git a/old/60822-0.txt b/old/60822-0.txt deleted file mode 100644 index ade1933..0000000 --- a/old/60822-0.txt +++ /dev/null @@ -1,12978 +0,0 @@ -The Project Gutenberg EBook of Studies on Epidemic Influenza, by -University of Pittsburgh School of Medicine - -This eBook is for the use of anyone anywhere in the United States and -most other parts of the world at no cost and with almost no restrictions -whatsoever. You may copy it, give it away or re-use it under the terms -of the Project Gutenberg License included with this eBook or online at -www.gutenberg.org. If you are not located in the United States, you'll -have to check the laws of the country where you are located before using -this ebook. - - - -Title: Studies on Epidemic Influenza - Comprising Clinical and Laboratory Investigations - -Author: University of Pittsburgh School of Medicine - -Release Date: December 1, 2019 [EBook #60822] - -Language: English - -Character set encoding: UTF-8 - -*** START OF THIS PROJECT GUTENBERG EBOOK STUDIES ON EPIDEMIC INFLUENZA *** - - - - -Produced by Richard Tonsing and the Online Distributed -Proofreading Team at http://www.pgdp.net (This file was -produced from images generously made available by The -Internet Archive) - - - - - - - - - -PUBLICATIONS FROM THE UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE - - -[Illustration] - - - - - _Studies on Epidemic Influenza_ - COMPRISING - CLINICAL AND LABORATORY INVESTIGATIONS - - - BY - - MEMBERS OF THE FACULTY - OF THE - SCHOOL OF MEDICINE - - UNIVERSITY OF PITTSBURGH - - 1919 - - - - - TABLE OF CONTENTS - - - Page - - History and Epidemiology of Epidemic Influenza 9–33 - - James I. Johnston, M.D., F.A.C.P., - Assistant Professor of Medicine. - - A Clinical Description of Influenza as It Appeared in the - Epidemic of 1918–19 35–63 - - J. A. Lichty, Ph.M., M.D., - Associate Professor of Medicine. - - The Urine and Blood in Epidemic Influenza 65–79 - - P. I. Zeedick, M.D., - Demonstrator in Medicine. - - The Treatment of Influenza 81–95 - - W. W. G. Maclachlan, M.D., C.M., - Assistant Professor of Medicine. - - The Prevention of Epidemic Influenza with Special Reference to - Vaccine Prophylaxis 97–153 - - S. R. Haythorn, M.D., - Director of the Singer Memorial Research - Laboratories. - - Physiological and Physiological Chemical Observations in - Epidemic Influenza 155–160 - - C. C. Guthrie, Ph.D., M.D., - Professor of Physiology. - - The Bacteriology of Epidemic Influenza with a Discussion of B. - Influenzæ as the Cause of This and Other Infective Processes 161–205 - - W. L. Holman, B.A., M.D., - Professor of Bacteriology. - - The Pathology of Epidemic Influenza 207–293 - - Oskar Klotz, M.D., C.M., - Professor of Pathology. - - - - - PREFACE - - -This report is based upon a series of investigations carried on during -the epidemic of influenza at Pittsburgh. This epidemic reached -Pittsburgh about the last week of September, 1918, rapidly spreading -through the community during the first days of October. Pittsburgh had -been warned of its coming through the experience of Boston, where the -epidemic made its appearance during the late days of August. To a -certain extent the warning from the East permitted the making of -preparations to control its ravages. But even with the attempt for the -protection of public health the epidemic advanced with all its -virulence, rapidly picking out the susceptible individuals and leading -to a high death rate. - -At the time of the coming of the epidemic there were stationed at -Pittsburgh two military camps, comprising about 7,000 men. It was with -the presence of the disease among these men that our investigations were -chiefly concerned. The men at their respective camps (on the campus of -the University of Pittsburgh and at the Carnegie School of Technology) -were housed in barracks which had been erected only a short time -previously. These barracks contained large dormitories, in which the -individuals freely mingled with each other. In them there was no -opportunity of complete isolation, and by this means of housing good -opportunity was available for the propagation of any communicable -infectious disease. The ordinary sanitary arrangements for these groups -were well provided. The first cases of recognized influenza made their -appearance on October 2. On this day two men were found with the disease -and were isolated. On the following day there were four, and on the -third day eight. It was soon recognized that the increasing number of -the infected cases was growing so rapidly that definite arrangements for -their segregation and care had to be undertaken. This was provided for -on October 4, when the Elizabeth Steel Magee Hospital was in part taken -over by the military authorities and wards were rapidly adapted for the -coming epidemic. For the foresight in making the adequate arrangements -for its control and management we shall always remain indebted to Major -E. W. Day. His indefatigable work in the early days of the epidemic will -always be remembered, and the fact that the epidemic was kept within -reasonable bounds of control was the result of his stringent quarantine -regulations along with the organization of his medical forces. Working -under his direction, Capt. H. H. Hendershott undertook the management of -the hospital and rendered most efficient service. The capacity of the -hospital was soon overburdened, so that from a normal 150–bed -institution it was on the sixth day of its conversion into an emergency -hospital carrying more than 300 cases of influenza. This hospital in -itself was unable to accommodate all of the cases falling ill, and -provision for these had to be made in some of the municipal -institutions. On October 5, 1918, the Medical School of the University -of Pittsburgh undertook to provide the laboratory facilities for the -emergency Military Hospital. It was at first intended to equip only -those laboratory departments which were deemed essential for the -clinical care of the patients in the wards. Inasmuch, however, as the -epidemic of influenza was spreading with alarming rapidity throughout -the city, it was deemed advisable to close the Medical School and to -place at the disposal of the Military Hospital all the laboratory -facilities which could in any way be of use in the care and study of the -influenza patients. This permitted the establishment of departments in -pathology, bacteriology, physiology, physiological-chemistry and -clinical microscopy. The following workers partook in the investigations -which were here carried out: Dr. Oskar Klotz, director of laboratories; -physiology, Dr. C. C. Guthrie (chief), Dr. A. Rhode, Dr. M. Menten, Mrs. -C. C. Macklin, Miss S. Waddell and Miss M. Lee; bacteriology, Dr. W. L. -Holman (chief), Miss A. Thorton, Miss C. Prudent and Miss R. Jackson; -pathology, Dr. Oskar Klotz (chief), Mr. A. D. Frost, Mr. J. L. Scott and -Miss A. Totten; clinical microscopy, Miss R. Thompson, Mr. M. Marshall -and Mr. H. Mock; records, Miss H. Turpin. Intensive work was undertaken -by each over a period of about five weeks, when the epidemic was again -on the road to disappearance and few new cases were being admitted. -These laboratories discontinued their work at the Military Hospital on -November 9. - -The clinical observations which are contained in this report were made -at the Mercy Hospital. This institution set aside upward of 100 beds for -the care of the overflow which could not be accommodated at the Military -Hospital. It is unfortunate that the clinical observations and the -laboratory findings contained in this report were not made upon the same -cases. With the number of cases suddenly thrust upon the medical staff -of the army, it was not possible for them to devote detailed attention -to clinical investigation. Furthermore, during the progress of the -epidemic these medical officers were transferred to new posts, so that -it was impossible to obtain a summary of the clinical findings at the -Military Hospital by any of the officers who had but recently been -detailed to the work. We were fortunate, however, that the clinical -investigations were carried out on a similar group of cases to those -studied by the laboratory, and it might be said that their clinical -findings on the patients housed at the Mercy Hospital are parallel with -those observed in other institutions. Necessarily the researches carried -out during such an epidemic were intensive, and all the workers in the -various branches feel that if they had to live through another such -plague they would be much better prepared to approach their problem. -During the heat of such investigations valuable time is often lost in -perfecting methods of technique, and one sorrowfully finds oneself -without available material when the technical work has been accomplished -but the epidemic has passed by. In the studies in bacteriology we were -fortunate in having some of the technical difficulties for the isolation -of the B. influenzæ previously solved. It may be that this in part -explains the broad success which Dr. Holman has had in isolating the B. -influenzæ from so many cases. In other fields the road was less broken, -and it was not until late in the course of the epidemic that results -were obtained in the investigation which seemed to point to valuable -leads. - -Dr. S. R. Haythorn, director of the Singer Memorial Laboratory, early in -the epidemic became interested in the protection of individuals against -the infection. In certain quarters much was claimed for the immunity -which could be conferred by vaccination, either by the inoculation of -pure B. influenzæ vaccines or by mixed vaccines. Hoping for some results -by the use of such vaccines, Dr. Haythorn undertook the preparation of -these materials. The value of this procedure could only be estimated -after the lapse of some time and at a period when the epidemic was again -waning. - -The clinical work at Mercy Hospital was carried on under the direction -of Dr. J. A. Lichty, and assisted by Dr. W. W. G. Maclachlan, Dr. P. I. -Zeedick, Dr. F. Klein and Dr. W. J. Fetter. By the close co-operation of -the members of this group it was possible to put the clinical findings -of one or other member to severe test, so that the recorded observations -and deductions are of the greater value and less flavored by the -personal element. This is of the more value, since, with the great -amount of work which had to be done at the time of the height of the -epidemic, it was often not possible for the same individual to bestow -the amount of time upon each and all cases as he desired. - -We are much indebted to Dr. Ogden M. Edwards, dean of the School of -Medicine, for making available the facilities for carrying out the work, -and for encouraging the publication of the reports. - - OSKAR KLOTZ. - - _Pittsburgh_, June, 1919. - - - - - HISTORY AND EPIDEMIOLOGY OF INFLUENZA - - By JAMES I. JOHNSTON, M. D. - - -The history of epidemic influenza extends back with definite -authenticity to the Middle Ages, with a fair amount of assurance to the -beginning of the Christian Era and with presumptive reliability even -before that period. Beyond this statement, nothing definite can be said -until the first epidemic reported by Short and found in the English -Annals in the year 1510. This, the first reliable record, presented some -features not unlike those occurring in the present epidemic. Two or -three striking things stand out in this record—namely, the presence of -nose bleed, pneumonia and the very great danger to gravid women. Here, -for the first time, the meteorological conditions were elaborately -studied and persistently dwelt upon. One other impressive thing, also -reported by Short, was that in 1580 the disease showed a tendency to -return after a period of quiescence. Attention is called to this because -the epidemic, while it was exceedingly prevalent in the months of August -and September, became pandemic in October and November. Another feature -was that during the years intervening between 1580 and 1658 sporadic -cases of this disease were frequently reported. During the latter year -another epidemic appeared in the month of April. In 1657 and 1658 at -London the summer was very warm, the winter came on early, there was -much snow and the spring was very moist. - -The prevailing opinion at this time, and the first stated by Willis, was -that the widespread disease was due to the weather influences on the -circulation, poisoning the blood of the patients, and “not blasts of -malignant air.” The disease prevailed in the large cities, recurring -again in the autumn in an extensive form through the villages and -country. Sydenham, in his communication on the epidemic in 1675, wrote -emphatically on the influence of the infection on pregnant women, and -here used the term “tussis epidemicus” as a name for the disease. The -summer of 1675 was wet with an inconstant autumn. La Grippe prevailed in -France and Germany, according to Atmuller. In England in 1676, the -autumn was pleasant, but suddenly became cold and moist. La Grippe then -started in Germany during September after a summer and a beginning -autumn which was very rainy. Molyneux in his description of the epidemic -of 1693 in Dublin called attention to a feature, very striking to the -recent pandemic, that the aged to a great extent escaped the infection. -This would seem a somewhat unique feature until that epidemic is -compared with the present one. In 1729 Morgagni and others stated that -over all Europe the winter of 1728 was very rigorous, the spring was -cold and the summer and autumn very variable, while January and February -of that year were very moist. Huxham in his record of 1729, the fifth -extensive one on record in the English Annals, which extended into 1733, -stated from his study at Plymouth that the epidemic was exceedingly mild -in the year 1733, and, with the exception of infants and consumptive old -people, the mortality was very low. Like many of his predecessors, he -emphasized greatly the conditions of the weather at the time and -presented an elaborate study of it. The epidemic of 1732 was one of the -longest and most persistent, extending up to 1737. All authors do not -hesitate to attribute as a cause the very frequent variations of -temperature which characterized this period. Of this epidemic Arbuthnot -also emphasized the importance of the air, assigning the prevalence and -widespread features of the disease to the thick and frequent fogs. From -November, 1732, until March, 1733, this disease spread from Germany to -Italy and thence to England. He called attention to a very striking -feature—namely, that people in prisons and in hospitals escaped the -disease. This, as we know, where such institutions are placed under -preventive quarantine, is not such a unique feature during this present -scourge. He, more than former writers, devoted pages to the elaborate -and accurate description of instruments for meteorological observation -and their findings, which meteorological records were published in -detail, covering the whole period of a year—June, 1732, to June, -1733—with almost daily regularity. Huxham in 1737 in his record first -used the term “epidemic catarrhal fever”—a name often used subsequently -to describe this disease. Here attention was first called to the -prostration which characterized the convalescents, and his belief that -consumption frequently followed the disease. The next epidemic, which -occurred in 1742 and 1743, was also reported by Huxham, who stated that -the weather was very rigorous. This disease, according to his -description, extended over all Europe, and the term “influenza” seems to -have been first used by him during this time. The cases were mild in -England, but more severe in Southern Europe. Whytt in his record of the -epidemic of 1758 was the first who did not consider that the air -condition or the seasons had the significance attributed to them by -former writers, since the weather conditions during the prevalence of -the disease were generally mild and dry. In Edinburgh at this time not -even one out of seven escaped. Nevertheless, he did not hesitate to -express his opinion that the disease did not spread by contagion from -one person to another. One other observation of his is worthy of note, -which is: that frequent relapses occurred when patients were re-exposed -too soon after the first infection and such relapses were much more -severe than the original disease. - -The epidemic of 1762 called forth the opinion of Baker, emphasizing an -opinion already expressed by Whytt, that the origin of epidemic disease -is not due to changeable winds nor to their nature or character as -recorded by the barometer. This epidemic also prevailed over all Europe -and appears to have begun following sharp alterations of cold and -moisture. In 1766 in Spain, France and other parts of Europe the -epidemic appears to have begun after a warm summer, followed by an -autumn moist and cold. In 1767 Heberden placed on record his -observations during this period, but nothing new was reported. In 1775 -the disease began in Germany in the summer after a dry and warm spring -and spread over all Europe. During the prevalence of the disease in 1775 -a questionnaire was sent to the leading English physicians, and letters -from Fothergill, Sir John Pringle, Heberden, Reynolds and others seemed -to express a consensus of opinion that weather conditions had nothing to -do with the prevalence or spread of the disease, and that the cause and -reason for its spread were unknown. Following sharp alterations in -temperature in 1780, the disease appeared in France and then throughout -the world. The epidemic of 1782 began in Russia, starting January 2 at -St. Petersburg. The thermometer underwent a variation of 40 degrees and -the same day 4,000 were afflicted with La Grippe. It reached Koenigsburg -in March, Copenhagen in April, London in May, France in June and July, -Italy in July and August, Spain and Portugal in August and September, -and then reached America. Edward Gray, writing of the epidemic of 1782 -for the first time, expressed emphatically his opinion on the -contagiousness of the disease and stated what we now know—that close -contact is necessary. To him also is attributed the opinion first -mentioned by him, that there is a possibility of carriers in this -disease. During this time Dr. Hamilton, in a published letter, protested -against venesection in influenza, a practice long prevalent, and Hogarth -called attention to the fact that the disease began in cities and -villages first and that it was brought to these places by visitors from -without. - -The first American writer on this subject was Noah Webster in 1647 and -1655. Following him was Warren, writing of the epidemic of 1789 and -1790, just 100 years before the last and greatest epidemic which -preceded the present one. Rush and Drake also reported this epidemic. -During that epidemic which prevailed in America from September to -December, 1789, and appeared again in the spring of 1790, President -Washington suffered a very severe attack. The year before, in 1788, when -the epidemic prevailed abroad, the summer temperature in Paris was very -variable, variations of 8, 10 and 12 degrees occurring on various days. -La Grippe predominated all the time. The same variations were true in -Vienna. At the end of the year 1799 the epidemic struck Russia, -following very cloudy, misty weather, was prevalent in Lithuania in -January of the year 1800 and in Poland during February. - -The next great epidemic occurred in 1802 and 1803, was very general, -beginning in France and coinciding with a cold and moist autumn -following a very dry summer. It was of six months’ duration in England. -Many schools, jails, asylums and workhouses, although located in the -area swept by this plague, at first escaped. As mentioned before, this -striking feature has not been so unique in subsequent epidemics. One -feature noticed here and commented upon freely was that elsewhere -throughout the country there seemed to arise endemic foci. During this -time there was also the prevailing belief that the disease was followed -by phthisis. One other observation made here, which was accurate, -lasting and is accepted today, was that no family was affected _en -masse_, but always one individual case occurred first, to be followed by -general infection of the others. At this time early bleeding was still -adhered to. The French spoke of seven varieties of the disease, but one -can only see in the classification emphasis laid on certain individual -symptoms in this disease of complex symptomatology. During this epidemic -pneumonia is said to have been very infrequent. The disease was -particularly fatal to pregnant women, and the patients suffering from -pulmonary tuberculosis were hurried off by the influenza. - -Burns, writing of the epidemic of 1831, mentioned that in 1810 the -disease was very widespread in China and Manila, and also emphasized the -fact mentioned in many works that certain epidemics prevailed among -animals at the same time, stating that in 1831 these diseases were of -choleric nature. This epidemic began in 1830 in the East, reached Paris -in the summer of 1831, reappeared in Europe in 1833, following the same -route that cholera had taken in 1832. In the epidemic of 1833, Hingeston -also laid great stress on the fact that horses were often affected. -These features, as mentioned by Burns and Hingeston, are frequently -quoted by authors, and such observations seem to have been widely -accepted. - -One of the greatest epidemics of influenza began in 1836 and extended -until 1837, and was called at this time epidemic catarrh. It began in -England in January, spread to France, and during all the time that it -was in Paris there were continual penetrating rains with cold and -humidity. At Montpelier on February 20, 1837, the thermometer passed -from 12 to 15 degrees above to 2 and 3 degrees below zero, and it was -then that La Grippe appeared suddenly. In reply to the circular letter -sent out by the Council of the Provincial Medical Association of -England, comprising 18 questions, the following opinions prevailed. The -disease was greatest from September to February; the great prevalence of -the epidemic in all parts of the kingdom was recognized—attacks were -irrespective of age, sex or temperament; it was milder in children, and -the aged suffered most from it. Further, the disease was extensive in -all neighborhoods; the mortality was 1 in 50, old age predisposed to -fatal termination, and the duration of the disease occupied two periods, -one terminating in 4 or 5 days and one in 5 to 14 days. Also relapses -were frequent; those exposed to employment in the open air were not more -liable to the disease than others; there was no proof of the disease -being communicated from one person to another, and influenza aggravated -an existent pneumonia or pulmonary phthisis. And finally previous -attacks of influenza offered no protection; the symptoms were uniform; -the most common of unusual symptoms were those of meningitis, -inflammation of the lungs and syncope, and aside from ordinary care and -treatment, general venesection was not endorsed. Evidence of fine -weather and good telluric conditions were at this time also appended. -The same symptoms and complications, particularly those of the lungs, -occurred irrespective of seasons, civilization or place. It was believed -and stated that the plague described in Homer was probably influenza. -For the first time there is noticed here a point well worth -consideration—the association of other epidemics with influenza, either -anticipating, following or superseding. That some such association may -follow the present pandemic is not to be entirely ignored. For example, -cholera is already reported as prevailing abroad, following an earlier -influenza outbreak. During the period, as if anticipating bacteriology, -one writer explained the epidemic in an article called “The Dust of -Regular Winds,” and Groves (1850) wrote on “Epidemics Examined, or -Living Germs as a Source of Disease.” - -In 1846 and 1847 a slight epidemic occurred in London, Paris, Nancy and -Geneva. In France during the last week of 1857, and extending into -January and February, 1858, there was a mild epidemic. During this -period there alternated frequent frosts with soft weather, misty and -humid. Among the numerous small epidemics between 1837 and 1889, one -occurred on the continent of Europe in 1860, but little of value or -interest was noted. In Paris in March, after great and sharp variations -in temperature, a series of epidemics extended from 1870 to 1875. These -were unimportant. Atmospheric modifications occupied first rank in the -minds of some as a cause for the outbreaks. Rapid changes from hot to -cold or from cold to hot were given weight. Other undetermined -modifications of conditions were probably important. - -In a recent article published by Loy McAfee (J. A. M. A., 1917, 72, 445) -he discussed the confusion which existed between the diagnosis of -cerebro-spinal meningitis and epidemic influenza in 1863. These were -believed the same by some—that is, the same disease of varying degree. -There was a great diversity of opinion among clinicians at this time, -and the American Medical Association appointed a committee to make an -investigation. McAfee quotes from the Medical and Surgical History of -the War of the Rebellion that in 1861 and 1862 an epidemic existed among -the troops called epidemic catarrh, which was afterward changed to read -acute bronchitis. In September, 1861, there existed an epidemic of -influenza in one of the regiments which lasted more than two weeks, and -in another camp there was a similar epidemic at the same time. It is -stated that there were in all 168,715 cases among the white troops, with -a mortality of 650, and 22,648 among the negro troops, with a mortality -of 255, making about 4 per thousand, and over 11 per thousand, -respectively. - -The next great epidemic, and the last until the present, occurred in the -years 1889 and 1892, and was pandemic in its nature. The death rate -during this time was lower in the cities than in the country. This was -probably due to the fact that the greatest mortality was among children -and old people, and as old people were generally left in the country, -this explains the observation. The highest number of deaths was among -males, believed to be due to the exposure and fatigue of work. Forty per -cent. of the world’s population was said to have been attacked during -this period. The yearly or seasonal repetition, as shown in this -pandemic, had occurred in other epidemics. In the great pandemic of 1889 -and 1890, five decades after the last important epidemic, it was stated -that the medical profession found itself confronted by a new disease of -which it had knowledge through medical history, so also in our time few -physicians recognized at first the reappearance of influenza. This 1889 -epidemic is extensively reported in the literature, and has been -elaborately worked out by many observers. One important feature has been -emphasized by Leichtenstern, which, although recognized by the -profession after the last epidemic had been fully reported and recorded, -is not appreciated by the profession during the present epidemic—namely, -that while shortly after the last epidemic there were smaller -relightings of the infection throughout various parts of the country, -those diseases which we erroneously call grippe or influenza, occurring -commonly in the spring and fall, are in no way connected with the -disease with which we are dealing, and which occurs at rather long -intervals. Any speculation in regard to these periods, which history has -shown to be fairly wide apart, has very little basis. This pandemic, -like many of former days, is believed to have originated in Asia, and -from there to have spread over Europe and hence over the world. The -disease spread rapidly over countries, affected probably about 40 per -cent. of the world’s population, disappeared rapidly after several -weeks, was thought to have had nothing to do with weather conditions, -had a great morbidity but small mortality, and affected all ages and -occupations. There is no doubt, as stated by some, that the development -of traffic and travel was a large factor in the rapid and extensive -spread of influenza during this pandemic. The course which the disease -followed, springing from its supposed beginning in Asia, has been fully -and amply described by writers after that period, but the great rapidity -of its dissemination over all countries is the most remarkable feature -in the epidemiology of any disease. This, during 1889, made many -prominent physicians disregard the opinion that influenza spread by -contagion and accept again the opinion expressed by observers of -epidemics in former ages, that miasma as a pathogenic agent was -responsible for its distribution; but anyone who reads closely the -history of this epidemic, and in the light of modern medical science, -must feel that the rapidity of distribution was nowhere greater than the -most speedy means of transportation. This very necessary close -connection was demonstrated also in regard to the mode of spread of the -disease; the large cities and the commercial centers were affected -earlier, smaller and country districts followed later, railroad towns -were more frequently attacked than isolated villages, and even from -jails, prisons and workhouses, where quarantine was immediately -attempted, as well as from remote villages where the disease had been -brought, there could be traced a zone of infection spreading into the -country. One interesting point was raised at this time—namely, that in -some places it seemed to spread by leaps and bounds, and at other places -radiating as stated above. - -The old controversy of whether influenza is distributed in a radiating -manner or in so-called leaps and bounds is believed to be settled by -consensus of opinion that it occurs in both ways. An opinion expressed -by the study at this time as to whether influenza spreads more rapidly -than any other infectious disease is found in the statement that the -contagion is markedly virulent, the micro-organisms are easily conveyed -from their original seat in the mucous membrane by coughing, sneezing -and expectoration, the great number of persons who, though slightly -affected, carried on their ordinary way of life without hindrance, the -probable longevity of the organisms in convalescents, the brief period -of incubation of two or three days, the susceptibility of all people of -every age and vocation, and the possibility of carrying the contagion by -merchandise and even through short distances in the air, are all -suggestive reasons for this. No one at present accepts the so-called -miasmatic nature of the contagion. Proofs are ample to show that one -case must be present in a locality or even family, although it may be -frequently overlooked, from which the epidemic spreads. During this -period of 1889 and 1890 the duration of the actual epidemic period in -different localities in Europe was from four to six weeks. This was -subsequently shown to be consistent with the recorded reports from the -various cities in the United States. Following this pandemic in the -first part of the year in 1891 there were numerous epidemic outbreaks in -various parts of America, including New Orleans, Chicago, Boston, and -simultaneously in England. Strange to say, at this time neither Germany -nor France had such epidemics, although both were exposed by travelers, -particularly from England and America. The question was raised at that -time whether the Germans, French or other continental nations were more -immune than Americans and English. In the fall of 1891 and the entire -winter of 1892 the disease was extensively prevalent both in Europe and -Northern America. In these later epidemics there was no definite -direction of spread. They probably would come more clearly under the -so-called radiation from numerous rural districts. In almost every case -at the point of its origin in these countries the epidemic developed and -spread slowly, lasting months and with very varying morbidity and -mortality. They had none of the explosive characteristics of the -pandemic. The general diminished morbidity of the later epidemic, the -diminished geographic distribution of the disease and the scarcely -recognizable character of its contagion, its slow development and -extension over several months, the continuous diminution in frequency -and in intensity since its onset in 1889, have been explained by -presumptive successive lessening of susceptibility of the population, -possibly due to acquired immunization. Observers at that time, as well -as ourselves, could question this last statement. - -There was observed one noteworthy thing about seasons. While the great -pandemic of 1889 and 1890 had no definite connection with seasons, the -epidemic types which followed in 1891 and 1892 seemed to show a lighting -up in either spring or fall, remaining dormant in the summer months. It -has also been shown by the history of former epidemics that almost all -the pandemics started from Russia in the fall, winter and spring months. -Such was the case in 10 of the great pandemics of 1729 to 1889. This, no -doubt, was the reason so many of the former historical writers were -impressed by seasons and meteorological conditions. The statement made -by observers during the epidemic that influenza presented two phases, -one pandemic and the other endemic, and that each follows different -epidemiological rules, seems possible. The question raised during the -last epidemic of the spread of the disease in families, the disease -occurring at high altitudes and even at sea, we know does not interfere -with the recognition of its spread by direct contagion. Definite -examples of families or villages being infected by a returned member of -such family or citizen from abroad are reported frequently, and even the -appearance of the disease in isolated places has often been traced and -verified from a definite source, to say nothing of the question of -carriers and those supposed to be suffering from other diseases. - -Striking examples are shown also in this epidemic that many -institutions, frequently those isolated from the world, were markedly -exempt until, through servants or outside visitors, the disease gained -access to them. This gave a most favorable field for the study of -invasion, spread and decline of the disease. Observations made at this -time in regard to hospitals seemed to suggest that certain institutions -were more or less exempt, although not closed institutions, while others -suffered from the first. These two types of hospital invasion are hard -to reconcile. - -Great stress was laid in this epidemic upon the very great morbidity and -the low mortality. Simple, uncomplicated influenza at this time was -looked upon as a disease that was rarely dangerous to life. Studies have -shown that after this period there seemed to have been lessened -morbidity. As previously stated, nearly all the numerous pandemics at -various times have had their origin in Russia and arose in the late -autumn or winter months. This pandemic of 1889 and the succeeding severe -epidemics in Europe and North America in the years of 1891 and 1892 -occurred almost exclusively in the cold weather, the summer remaining -free. It is generally believed now, and was at the end of that pandemic, -that atmospheric or telluric conditions had nothing to do with the -spread. The origin of epidemics following the pandemics seemed to be -influenced in their recurrence by the season of the year. It was -conceded by observers in that pandemic also that contagion might be -carried by merchandise and even flies and healthy individuals. - - - _1918 Epidemic in Large Cities_ - -In the city of Boston during the week ending August 28, at the Naval -Station at the Commonwealth Pier, 50 cases of influenza occurred and -within the next two weeks more than 2,000 were reported in the naval -forces of the First Naval District. Of these 5 per cent. developed -broncho-pneumonia with a mortality of more than 60 per cent. From here -it probably spread to Camp Devens and thence ran rapidly over the -country. There can hardly be a question that it spread along the lines -of traffic. Up to November 9 there were reported 3,339 cases among the -civilian population of Boston. There were 3,430 deaths from influenza, -the presumption being that these were due to bronchial pneumonia, -although not reported as such. The deaths from all forms of pneumonia -were reported as 942, making in all 4,372 deaths from September 7 to -November 9. This discrepancy—that is more deaths than reported cases of -influenza—is due to the fact that influenza was not made a reportable -disease until the date of October 4, fully a month from the time the -epidemic appeared. The weather conditions were generally fair and no -noted abnormality is recorded as compared with other years. The -statement of the Health Department of this city was that, after a -practical disappearance of influenza in October, there was a slight -recurrence in November and a more pronounced recurrence about the first -of December, since which time the cases have slowly but steadily -decreased, until at present—December 21—the fatalities attributable to -influenza are about 20 daily. - -In the city of New York the epidemic first appeared September 18. Up to -and including December 27 there were reported to the Department of -Health 136,061 cases of influenza and 21,388 cases of pneumonia. The -number of deaths since September 18 was 11,725 attributed to influenza -in the death certificates filed in the Health Department and 11,601 -attributed to pneumonia. The epidemic reached its peak during the week -of October 19, slowly subsided and was practically at an end on November -9. While the epidemic is reported as ending on this date, the mortality -rate from influenza and pneumonia is still very much above normal. No -particular features concerning the meteorological conditions were noted, -except that in this city the weather was clear and delightful during the -months of September and October when the epidemic was rampant. - -In the city of Philadelphia on July 22 the Health Department issued its -first health bulletin on so-called Spanish influenza, announcing the -possible spread of this disease into the United States. On September 18 -a warning was issued against an epidemic, the department starting a -public campaign against coughing, sneezing and spitting. On September 21 -the Bureau of Health made influenza a reportable disease. At this time -the authorities stated an epidemic of influenza was recognized as -existing among the civil population of similar type to that found in the -naval stations and cantonments; that a large percentage of cases was -accompanied by pneumonia; that patients should be isolated and -attendants wear masks; that isolation be practiced for a period of ten -days after recovery to prevent carriers; that patients be guarded -against relapse and that the public be cautioned against large -assemblages and crowded places, as well as to avoid coughing, sneezing -and spitting. On October 3 the churches, saloons and theatres were -closed, funerals were made private and food handlers were required to -protect their wares. The number of cases reported from September 23 to -November 8 was 48,131, but the Bureau states, from a rough estimate, the -number of cases was probably 150,000. The total number of deaths -reported was 7,915 from influenza and 4,772 from pneumonia in all its -forms, the presumption being that the deaths during this period were due -to influenzal pneumonia. The weather condition during this time is -recorded as mild and fair. - -The influenza cases began to be reported in Cleveland on October 5, and -up to December 20, 22,703 cases had been recorded. Certificates -recording deaths due to influenza alone numbered 2,497, while pneumonia -amounted to 833. The epidemic was at its height in the latter half of -October and the weather was spoken of as pleasant fall weather. During -the week of October 26 the epidemic reached its greatest height, abated -in the week ending November 23, increased later, but showed a drop for -the week ending December 21. - -The epidemic first reached Chicago on September 21, and from that date -on it rapidly increased throughout the city for a period of 26 days -until October 17, when it reached its maximum both in the number of -deaths from influenza and from pneumonia. On that day the total number -of deaths from influenza and from pneumonia reported was 2,395. From -September 21 until November 16 there were reported 37,921 cases of -influenza and 13,109 cases of pneumonia. On September 8 at the Great -Lakes Naval Training Station, which is 32 miles north of the city, an -extensive outbreak of influenza occurred. This was 13 days before the -outbreak in the city of Chicago itself. Camp Grant, located at Rockford, -92 miles northwest of the city, suffered an outbreak on September 21. A -suggestion of the likelihood that influenza was prevalent in this -country in a mild and unrecognized form in the spring of this year is -shown by the fact that numerous local outbreaks of acute respiratory -diseases were brought to the attention of the Health Department of -Chicago. These occurred especially in large office buildings and in -industrial departments. The total number of deaths from influenza and -pneumonia during 14 weeks was 51,915. This would indicate that a very -great number of cases were not reported to the Bureau of Health until -they died or else there must have been a large number of deaths due to -lobar pneumonia. One naturally obtains from these figures the impression -that the disease was not recognized for a long time, that the pneumonia -must have been called lobar pneumonia, and that the actual figures -gathered by this city, as well as others, must have been greatly -confused at the onset of the epidemic. It is not unlikely that records -from many of the army cantonments and naval stations may be considered -from the same viewpoint. Weather conditions were considered normal at -the height of the epidemic, the weather being dry. There has been a -flare-up of influenza recently, but not in sufficient numbers to justify -calling it epidemic. - -In the city of Louisville, Ky., the epidemic started September 26, and -the total number of cases up to December 21 is reported as being 9,445. -Out of this number 772 deaths occurred from pneumonia. No distinction is -made here between broncho-pneumonia and lobar pneumonia, but the -presumption from the records of other cities at this time is that these -were cases of broncho-pneumonia following influenza. The weather was -described as being delightful fall weather. The statement is made by the -authorities that while the epidemic is still prevalent, it is confined -largely to children and is rapidly abating. - -The first case in the city of St. Louis was reported about October 7, -and up to December 23 there had been 31,531 cases reported to the Bureau -of Health. They recorded 1,920 deaths with influenza given as a -contributing cause. Preceding the time when the epidemic was at its -height the weather was fair and warm, and the statement is made that, -“without going into the matter exactly, we have been of the opinion that -damp, rainy weather has been a help in controlling the disease.” The -opinion was expressed by the Commissioner of Health that the disease had -now abated. - -No information could be obtained as to when the epidemic first reached -the city of New Orleans, but during the months of October and November -43,954 cases of influenza were recorded. Of this number 2,188 died from -a combination of influenza and pneumonia. They stated in their health -report that during the period from January 1 to December 31 there were -239 deaths attributable to broncho-pneumonia. The weather was mild and -on December 24 the epidemic was stated to have abated. - -The city of Minneapolis recorded its first case on October 7, but the -authorities expressed their belief that a few cases had appeared before -that date. Up to December 21, 15,000 cases had been reported to the -Bureau of Health and of these there had been 735 deaths from -broncho-pneumonia. They had in their city a late, rainy fall and up to -that period they had had no cold weather. - -The record obtained from the city of San Francisco stated that the -epidemic first appeared September 23 and that it was very widespread in -that city early in October. There were two invasions and 53,260 cases -reported. At the height of the epidemic more than 2,000 cases were -reported in one week; 188 deaths occurred from influenzal pneumonia. The -following week, after the institution of mask wearing, in which between -80 and 90 per cent. of the population concurred, it was stated that the -number of cases decreased to about 200. It was stated that the weather -was generally very fair during the epidemic. - -From the city of Portland, Oregon, the following information was -obtained: The epidemic first appeared October 11, with a second one -toward the end of the year. There were 8,079 cases reported, with 658 -deaths from influenza and 250 from pneumonia. Weather conditions were -stated to be varied, but the health officer believed that during the -worst wave the weather was clear and dry, with easterly wind. He -believed that a decrease in influenza was noticed immediately after a -Chinook wind and warm rain. Similar observations were made by Coutant in -Manila. - -A weather comparison of 12 large cities, well distributed over the -United States, studied during this pandemic of influenza and checked -with normal weather during that of many years, shows: Boston, fair with -no abnormality; New York, clear and delightful, no abnormality; -Philadelphia, mild and fair; Pittsburgh, mild and cloudy; Cleveland, -pleasant fall weather; Chicago, normal and dry; Louisville, delightful -fall weather; St. Louis, fair and warm-damp, rainy weather later seemed -to control the epidemic; New Orleans, mild; Minneapolis, a rainy fall -and no cold weather, which is unusual there; San Francisco, generally -fair, and Portland, Oregon, clear and dry. - - - _The Epidemic in Universities and Colleges_ - -At Bryn Mawr College, in Pennsylvania, an institution devoted to the -higher education of women, located within 10 miles of the city of -Philadelphia, the epidemic occurred at the beginning of the college -year—October 1. This college at the time had an enrollment of 465 -students. There were 85 cases of influenza, with an additional 25 who -suffered from influenza in their homes. There were no deaths from -pneumonia. The weather conditions were clear and warm, and since -November 29 there have been no new cases occurring in the college and -only three or four of the students have been ill at their homes since -that time. - -[Illustration: - - DATES OF THE APPEARANCE OF INFLUENZA ENDEMIC IN VARIOUS CITIES OF THE - UNITED STATES - 1918. -] - -The enrollment at Smith College, Northampton, Mass., was 2,103, and the -first case of influenza appeared with the arrival of the students on -September 18 and reached its height on September 30. All group -gatherings indoors were stopped from October 3 to October 18, and the -epidemic was over by October 20. A recurrence began November 15 and -continued until December 17. There were 182 cases in the first epidemic -and 100 cases in the second. There were only two deaths from influenza -pneumonia. During the rise of the epidemic the weather was rainy, -followed by good, clear weather. The change in weather conditions seemed -to make no difference. The second epidemic was still prevalent when the -students left for their holidays. - -In Wellesley College, where there were enrolled 1,593 students, the -epidemic first appeared on September 18. Up to the middle of December -they had had 280 cases. During six weeks of the epidemic 265 cases were -reported and only one death occurred from broncho-pneumonia. For the -most part, bright and sunny days were present, with only a few cloudy -and rainy days. This college has not been without cases since September, -but the epidemic lasted only about six weeks. - -In a communication from Columbia University it is stated that the -epidemic appeared during the week beginning September 22. No records -were available for the student body at the time of inquiry, but in the -Student Army Training Corps of 2,200 men between 8 and 9 per cent. had -the disease during the period from October 1 to December 14. In this -army group during this period two deaths from influenza and pneumonia -occurred. The weather conditions in the city during this time were -considered normal for fall weather—that is, mostly clear, with high -winds. The opinion expressed was that the epidemic was still prevalent -and increasing, and that a return wave seemed to be more virulent and -affected the children of the city more than had the first one in the -early fall. - -There were enrolled at Harvard on October 1, 3,193 students. The first -case of influenza occurred on September 20. There were 227 cases of -influenza reported; of these there were 46 cases of broncho-pneumonia, -with five deaths. There were two waves to the epidemic; the first wave -height was in October and the second the last of November. The weather -conditions were not severe nor particularly unfavorable at either time. -The epidemic abated at the university largely because of the -demobilization of the Student Army Training Corps. At that time it was -still prevalent in Cambridge and Greater Boston. - -At Yale University the disease first appeared in the New Haven Hospital -on September 21. There were registered in all departments of the -university 2,265 students. Up to the date of December 24, 1,013 cases -have been treated. The number of deaths from broncho-pneumonia has been -249. At the height of the epidemic, which occurred in the third week of -October, typical fall weather prevailed. An unusually clear, dry October -with very little rain, much sunshine and rather low humidity was the -weather report. - -During the period of the epidemic at Princeton that university had 1,050 -students, and the first cases appeared shortly after the opening of the -college term on September 24. As a precautionary measure, every case, -when even only suspicious, was sent to the infirmary. In all, there were -about 70 cases in the university and about 45 cases from the United -States School of Military Aeronautics. Only one member in the latter -school died of pneumonia. There were no deaths among the students at the -university. In this part of the country the weather was most delightful -all autumn, being warm and dry, very little rain having occurred since -the end of July. At the date of the inquiry the epidemic had -disappeared—that is, about December 21—there being only two very mild -cases under suspicion. In the town of Princeton, outside of the -university, the conditions were much more serious than in the university -itself. Influenza appeared in the homes of many of the poor people of -the immigrant class, so that it was not uncommon for four or five -members of one family to be infected at once. In one family of seven, -five serious cases of pneumonia developed. An emergency hospital was -opened by the authorities and 40 cases of pneumonia were treated. Of -these approximately one-half died. At the time this report was furnished -the epidemic seemed to have disappeared. - -The number of students enrolled at the University of Virginia was 957. -The first cases occurred as early as September 24. There were 290 of -these in number, and three died of broncho-pneumonia. The epidemic was -reported as having abated on December 15, but a few cases appeared after -that date. - - - _1918 Epidemic at Pittsburgh_ - -At the Army General Hospital No. 24, located at Hoboken, a few miles -outside of the city of Pittsburgh, on September 28 two soldiers were -taken ill and, with the disease unrecognized, they were removed to the -cantonment hospital at Point Breeze, within the city proper. The men -were found a few days later to be suffering from influenza, and from -this presumable source an epidemic spread rapidly among the troops and -student soldiers located here. - -From September 28 until November 20, 1,392 cases of influenza occurred -among the enlisted men. How the infection reached the first two cases at -Hoboken is not known. The command here consisted of the Student Army -Training Corps of the University of Pittsburgh, and Carnegie Institute -of Technology, Motor Mechanics of the University of Pittsburgh and the -Ordnance and Quartermasters’ Department on detached service. The -strength of this command was approximately 7,000. The first case -appeared on September 30 and the diagnosis was made on the following -day. Beginning October 13, all soldiers of this group were inoculated -with two 1 cc. doses of vaccine, obtained from the New York State Board -of Health. At the height of the epidemic there were about 840 soldier -patients in the several hospitals of the city at one time. Cubicles were -used in the hospitals, and in the barracks a floor space of 50 square -feet was allowed to each man. The men slept alternately head to foot, -with paper screens intervening, which were changed daily. In company -formation they were instructed to gargle their throats and clean their -teeth morning and night under the supervision of their officers. Strict -military quarantine was maintained throughout the entire camp, no -congregating was allowed, classes were suspended and only open-air -drills were permitted. For the entire command there were 220 cases of -pneumonia, with 99 deaths, an average mortality of 44 per cent. The -dishes were boiled in the hospitals, and sanitary dishwashers were used -in all mess halls. The kitchen help and personnel were inoculated with -influenza vaccine, with apparently good results. The Magee Hospital, -with 375 beds, was under strict military control. When this was full, -all others were treated in the civilian hospitals. - -In the city of Pittsburgh the disease was not made reportable until -October 5. However, one case was reported on October 1, and it was known -that there were a few isolated cases in Pittsburgh previous to that -date. During the months of October, November and up to December 21 there -were 23,268 cases of influenza reported, and the deaths were 1,374 from -lobar pneumonia and 678 from broncho-pneumonia. We cannot but feel that -most of the deaths reported during the period of the epidemic as lobar -pneumonia were broncho-pneumonia associated with influenza. It was well -known among civilians that true lobar pneumonia was exceedingly rare and -has remained so up to the present time. This is especially noticeable, -as this is the time of the year when lobar pneumonia is usually -widespread in Western Pennsylvania. This district was particularly -favored with a mild fall and winter. On October 1 the first case was -reported, on October 15 the epidemic reached its peak—on that day 957 -persons being reported ill with the disease. From October 16 until -October 28 it maintained an average of 600 cases daily; from October 29 -until October 31 there was a sharp decline from 600 cases daily down to -200 cases daily. From November 1 until December 21 the decline has been -uniform, and on this latter date 58 cases of influenza and 7 of -pneumonia were reported. The height of the epidemic was reached between -October 15 and October 29. During the period of the epidemic in -Pittsburgh, from October 1 until December 15, 62 days were recorded as -cloudy, or partially cloudy, and only 14 days as clear, although the -cloudy days seemed distributed and not in decided groups. The mean -temperature for October was 58 degrees, with normal 54.9; for November, -44 degrees, normal 42.9; for December, 41 degrees, normal 34.7. The -precipitation in October was 3.08, as against a normal of 2.36; in -November, 1.79, with normal 2.55; and in December, 3.50, normal 2.73. -From a study of these weather reports we see that the epidemic occurred -during a period of abnormally warm, cloudy and slightly more moist -autumnal season than usual, but these variations were relatively slight -and far from decided. The confusion of diagnosis between lobar pneumonia -and broncho-pneumonia, associated with or following influenza, occurred -in the Pittsburgh health reports as well as in other cities. The -presumption that almost all, if not all, of the cases reported as -pneumonia of different types were really cases of influenzal pneumonia, -seems justified. - - - _Epidemic Incidents in Institutions and Towns of Western Pennsylvania_ - -During the time the epidemic was at its height in Pittsburgh the Western -Pennsylvania Institution for the Blind was in session. This school is -located in the heart of the educational center and was surrounded by the -barracks of the Student Army Training Corps of the University of -Pittsburgh and the Carnegie Institute of Technology. When the influenza -was recognized as epidemic in this neighborhood, the attending physician -at this institution advised a quarantine against the public. The -children were refused visitors in the buildings, and the usual week-end -trips home were forbidden. This school was continuously in session from -September 24 until November 30. During this time there was not a single -case of influenza in the school and the children were free from any -infectious disease. On December 1 the pupils returned to school after -the Thanksgiving holiday, and one week later, on December 8, the first -case of influenza appeared. In a period of five days following 15 cases -developed. It was considered wise to close the school, and all well -children were sent to their homes. The institution was kept closed until -January 1, since which time no cases have developed. Very few of these -children had influenza at home, and only one death occurred. - -A reliable report, subsequently confirmed by the health officer, stated -that in Masontown, Pa., the start and course of the epidemic were very -striking. A dance was held in the town and the musicians were brought -from nearby cities. One of the musicians employed was not very well upon -his arrival, and became so ill that after the dance he was put to bed in -the hotel. He was found to be suffering from influenza when examined the -following day, and from him as the primary case the town was swept by -the epidemic. - -In Mercer, Pa., the physician to the Board of Health reported that -during September they had a general epidemic of coryza and sneezing, -with slight fever, which lasted for three or four days. This was looked -upon by the people as hay fever. In the midst of this, or about -September 16, a man, 74 years of age, who had been away from home, -developed true influenza, followed by pneumonia, from which he recovered -about October 10. Another man, employed in Greenville, a nearby town, -where influenza was already prevalent, returned to his family here -suffering from the disease. The whole family and all who were exposed to -this family were infected. From this family as a focus the disease -spread rapidly in every direction. There were about 350 cases in the -town of 2,000 inhabitants, and there were 9 deaths. Sporadic cases have -occurred since, ranging in number from one to a dozen at a time. These -numbers do not include scores of cases called colds by the people, but -it seems that all these cases had an influenza element. - -In the town of New Castle it was not possible to trace the onset of the -influenza epidemic to a definite case. As the health officer stated, -several cases were reported at once. - -The first case of influenza in Indiana, Pa., of which there was any -definite knowledge occurred on September 15. A clothing merchant who had -just arrived from New York, where he had been buying stock for his -store, was the first case identified. The next case occurred several -weeks later, the disease being contracted at the mining town of Coal -Run, in Indiana County. - -A man resident in Sharpsburg who had suffered from influenza visited -friends in Fraser Township, Allegheny County, to convalesce. Previous to -his coming that section had been free from the disease. He was still -coughing at the time, and, moreover, he is said to have been a great -talker and visited largely among the neighbors of his host. Threshings -in that part of the township were going on and these he also attended. -The date of his coming was October 13. By October 15 his hostess was -taken ill. By October 16 some of the threshers were affected, and by -October 17 enough were sick to break up the work of threshing. -Eventually all the men engaged became ill, and 11 families were infected -from this source. - - - _Summary_ - -Reviewing the history of former epidemics and pandemics, I have gained -the impression, as have many others, that we are not dealing with any -new disease. Further, our knowledge of this pandemic with its high -incidence of broncho-pneumonia shows that it is in no way markedly -different from that of former manifestations of influenza. One is -impressed by the fact that in different outbreaks of this disease of -complex symptomatology certain symptoms or complications have been -prominent, overshadowing others, and making such complications the -striking feature at the time. The failure to recognize that these -varying features are merely different manifestations of one disease has -resulted in much confusion. The observation made in the last -epidemic—and one which can be endorsed during the present plague—is that -influenza has been and is the most widespread, rapid and extensive of -all diseases. One thing also that attracts attention at the present time -is the long period existing between the several pandemics. Whether, as -one observer during the present pandemic has stated, it requires a long -period for the infection to become active and easily carried, or whether -any possible reason can be suggested for these phenomena, admits of no -satisfactory explanation. The outstanding feature during this epidemic -is the complication of broncho-pneumonia, and yet, from very early -times, this complication has been repeatedly spoken of as a striking -characteristic. Reviewing the health reports from the large cities of -deaths from pneumonia, the presumptive opinion seems justified that -almost all, if not all, pneumonias reported as associated with influenza -were of the broncho-pneumonia type. The infrequent presence, indeed the -rare finding, of lobar pneumonia during this period in Pittsburgh seems -to verify the aforesaid opinion. The great frequency and the high -mortality of broncho-pneumonia were particularly noted during the -present epidemic. During the present epidemic the great mortality among -pregnant women was another striking feature, and yet this is by no means -new, having been recorded by some of the earliest writers. Such also may -be said of the recurrence of the disease in the same patient. One -important observation brought out in the study of the pandemic of 1889 -to 1892 was that the ordinary infections occurring in the spring and -fall known as grippe or La Grippe are in no way connected with the -pandemics which have occurred. There seems to be a consensus of opinions -among the records of the more recent epidemics, as well as during the -present pandemic, that weather conditions in no way influence the spread -of the disease. Furthermore, a study of weather conditions throughout -the United States, and particularly those of our own city, seem to bear -out the truth of this observation. While clinicians during other -epidemics expressed their belief in the incident of a primary case -producing infection, it has only been during the present one that such -an opinion has not been assailed. The large number of military training -camps and cantonments have undoubtedly offered splendid opportunity for -the spread of influenza. The futility of attempting to control it even -under normal conditions is still questionable. Consistent with former -reported invasions of the disease, the present epidemic lasted a -definite period. This period was about six weeks in most of our large -cities, colleges and institutions, extending approximately from October -1 to November 15. - -It is imperative to note the accurate clinical observations recorded -from the numerous epidemics of the past by men with far less data to go -upon than is available at the present day. The high morbidity among the -personnel of many of our hospitals and institutions where the infection -occurred and the relatively low mortality deserve attention. This may be -partly explained by the methods of treatment of those infected, but not -entirely. The great likelihood of carriers of influenza, who either are -not ill or who are suffering from very mild infection, is an observation -also noted by former writers which cannot be ignored. The value of the -masks has not been established, although they have been extensively used -in many parts of the country. Frequent throat lavage was generally -accepted as a rational preventive measure. Relightings of the disease -have been noted in most of our cities after the subsidence of the -epidemic. Vaccination against influenza is fully discussed in Dr. -Haythorn’s paper in this series. - -The presence of influenza in San Quentin prison, California, in April, -1918 (Public Health Reports, May 9, 1919); an epidemic of respiratory -disease in Chicago in the spring of 1918; the report of Soper of -influenza in our army camps in March and April, 1918; the occurrence of -influenza in Porto Rico in June; influenza on a United States Army -transport from San Francisco, as reported by Coutant, seem to point to -the possibility that influenza had a footing in America long before the -disease became pandemic. The view held by some that the beginning of -influenza was in America, subsequently being transferred to Europe and -then reimported here, is worthy of consideration. Coutant believed the -disease originated in Manila, others that it traveled from “a permanent -endemic focus in Turkestan,” and there are many other theories which -attempt to discover the original source of the disease. The question is -today an unsettled one. The pandemic of influenza in its severest form -swept so suddenly over the world that before the profession realized it -or had become stabilized it had changed its character and the great -plague was gone. The consequence has been that we have really learned -little that is new and have done scarcely more than establish on a firm -basis many of the opinions formed after the great outbreak of some 30 -years ago. Because transportation is today more rapid than it was at -that time, so the spread of the disease has been correspondingly swift. -Our modern life, the congregating crowds in theatres, moving-picture -houses and in lecture halls, as well as of the men in our training -camps, the development of street cars and the more frequent traveling by -train—these and many more changes in our mode of living have served to -aggravate the conditions favoring the widespread distribution of the -infecting agent. A higher proportion of the population was, therefore, -attacked than in any previous pandemic, and the period during which the -disease was widely prevalent has for the same reason been relatively -much shorter. - -The characters differed somewhat in different regions, but the evidence -shows clearly that we are not dealing with any new disease. It will be -years before we are able to fully analyze the data that have been -collected from such wide sources and by so large a body of trained men, -so that important epidemiological facts may still be forthcoming from -the material already at hand. We are too close to the events to get the -most helpful perspective, and the object of this report has been to add, -in however small a degree, to the general knowledge of this great -pandemic as it has appeared to us in Pittsburgh and its surroundings. - - - - - A CLINICAL DESCRIPTION OF INFLUENZA AS IT APPEARED IN THE EPIDEMIC OF - 1918–1919 - - By J. A. LICHTY, M. D. - - -The epidemics of influenza which have been recorded from time to time -during the past few centuries have always contributed an interesting -chapter to the history of medicine. The protean character of the disease -with its many complications is always an excuse for another attempt at -the description of the clinical manifestations of a recent epidemic. -This is not, however, the only incentive at the present time for -describing the clinical aspect of the disease as it appeared in the -epidemic through which we have just passed. The study of the disease -from other aspects, such as the pathological, the bacteriological and -the physiological, by well-organized groups of workers has made it -necessary to co-ordinate, if possible, the clinical findings in every -detail with these apparently basic principles. It would be interesting -to review here the peculiarly fortunate circumstances which have led to -the investigations. On account of the great war many temporary -laboratory organizations which otherwise would not have existed were in -operation, and these organizations, moreover, were keen to undertake any -laboratory problem which might arise. The present epidemic presented the -opportunity, and that the work was taken up with great enthusiasm is -evidenced by the reports coming from the various army hospitals, base -hospitals and civilian hospitals throughout the world. The permanent -laboratories connected with medical schools and with institutions for -medical research took up the problems with equal endeavor. This brief -reference is made only to call attention to the fact that from such -organizations a great mass of information has come which must be -critically reviewed and coordinated before it can add to the permanent -fund of our knowledge of the disease under consideration. - -The material upon which the following clinical observations have been -made is peculiarly adapted to review because it consists of two distinct -groups of patients which were admitted to the Mercy Hospital. One group -of 153 men was composed of soldiers between the ages of 18 and 23, which -had been recently inducted into the Student Army Training Corps, and -were living in barracks in the immediate vicinity of the hospital. -Another group consisted of civilians (394), ranging from youth to old -age, which came from various parts of the city and surrounding towns and -country. The first group came to the hospital early, or as soon as the -disease was recognized; the second group came usually after several days -of illness had elapsed, or when a complication had already arisen. Many -of this group had been ambulatory cases for the first part of the -disease. The entire number of patients admitted to the Mercy Hospital -from the first admission, September 21 to December 1, the end of the -quarantine, was 547. After December 1 very few simple influenza cases -were admitted. These 547 cases form the basis of the observations which -will be referred to in this paper. - -From the last great epidemic or pandemic of influenza, that of 1889 and -1890, have come clinical descriptions which should be reviewed before -speaking of the clinical manifestations which have characterized the -present epidemic as shown in the two groups studied. - -One of the best descriptions of that epidemic was given by Dr. O. -Leichtenstern in Nothnagel’s Encyclopedia of Practical Medicine. This -contribution, among many others, describing the epidemic of 1889 and -1890 is one of the first to refer to the Pfeiffer bacillus as being -etiologically associated with the disease. It differs, therefore, -greatly from descriptions of previous epidemics. Leichtenstern says: -“The typical influenza consists of a sudden pyrexia of from one to -several days duration, commencing with a rigor, and accompanied by -severe headache, generally frontal, with the pains in the back and -limbs, by prostration quite out of proportion to other symptoms and -marked loss of appetite.” He continues by saying that to these -characteristic symptoms may be added the catarrhal phenomena arising -from the affection of the respiratory tract, particularly the upper -(coryza) and “occasionally” the lower, the trachea and bronchi. This -description is so in accord with the symptoms of uncomplicated influenza -as found in the present epidemic that very little need be added. Any -difference which may occur in the description of the disease is likely -to be accounted for by the peculiarity of onset, whether in the upper or -lower respiratory tract, and by the different ways of interpreting -complications which may have arisen. It is evident from this description -that the upper respiratory tract was affected more generally than the -lower in the epidemic of 1889 and 1890. In the present epidemic it can -safely be said that the reverse was the usual state of affairs. It was a -rather unusual occurrence when the affection was limited only to the -nose, pharynx, larynx, trachea and larger bronchi. A very large number, -no doubt, had a peculiar œdema, a so-called “wet lung,” which we shall -discuss later; others went on to a capillary bronchitis or a -bronchiolitis, and a large number had broncho-pneumonia. This sequence -we shall attempt to show in the statistics at hand. In some cases the -lesion in the lower respiratory tract seemed to be primary, there having -been no initial coryza. At least none was observed and no history was -obtained. - - - _Prodromal Stage and Communicability_ - -The length of the prodromal stage—the stage from the time of contact to -the earliest onset of symptoms—has always led to interesting -observations and discussion. In this epidemic we have rather definite -information bearing upon this subject. - -A young married farmer living in a rural community where no influenza -had occurred up to the time of the present experience went to a city -about 40 miles distant. On the train he sat in the same seat with a man -who was apparently ill, and who was sneezing and coughing. He was in the -city only a few hours, and was not in any place of congregation except -the railway train. Forty-eight hours after his return to his home he -noticed the first symptoms and began a mild course of influenza. About -50 hours later his wife was taken with the same symptoms, and in two -days more their only child was afflicted. Other members of the household -were also afflicted, and one of them died of pneumonia. - -It might be interesting to quote a similar observation made by Macdonald -and Lyth, of York, England, published in a recent issue of the British -Medical Journal (November 2, 1918, p. 488), which corroborates this -experience. They say: “We traveled from London together on Thursday, -October 3, by train, leaving King’s Cross at 5.30 P. M., arriving in -York at 9.30, and as we were leaving the carriage a young flying -officer, who had come the whole way with us and was coughing and -sneezing at intervals, informed us that he was ill and had had influenza -for several days. On Saturday, October 5, we both became ill and had -developed typical attacks of influenza. With both of us the illness -developed suddenly with laryngitis; in both the first signs were a -severe attack of coughing; and in both the time was noted fairly -accurately as being between 2 and 2.30 P. M. One case was quite mild, -the temperature never over 101. The other was more severe; the -temperature arose to 104½ and the catarrh extended to the bronchi. His -wife and two children also developed influenza, and in their case the -symptoms showed suddenly, about 2 P. M., on Monday, October 7. Now we -are convinced that we became infected from our traveling companion -during the train journey—more likely toward the end of the journey; and -if we take the time of infection as 9.30, this fixes the incubation -period for both of us at a minimum of 41 hours, with a maximum margin of -error of 4 hours. The three cases developing in the family of one of us -point to a similar incubation period, as their illness started almost -exactly 48 hours after his, and as it is likely that the infection would -not take place until a few hours after the first symptom, the incubation -period in these three cases must have been nearly the same as our own -two. - -“It can be readily understood that we were in no position to conduct -extensive bacteriological examinations, but a culture taken from the -posterior nares of one of us on October 10 with a guarded swab showed -colonies of Pfeiffer’s bacillus and of micrococcus catarrhalis.” - -This observation is so convincing, I have quoted it at length and in -full. - -The communicability of influenza has been observed by all, and the ease -with which it passes from one individual to another noted. One -observation made by us was of considerable interest. In a house where a -patient lay sick with a severe attack of influenza for nearly three -weeks several members of the household passed the door of the sick room -a number of times daily, and yet they did not contract the disease. This -is in marked contrast with the immediate contact between the two -physicians and the young flying officer, who sat in the same railway -carriage compartment for four hours. The same observation was made in -the hospital among nurses in direct contact with patients. A large -number of these contracted the disease, while those not immediately -associated with influenza patients almost invariably escaped. This -speaks strongly against the idea that the epidemic was a so-called -“plague,” or that it passed without intermediate means through the air -and pervaded all places. - -From information thus far at hand it seems, therefore, that the -prodromal stage, or stage of incubation, is one which covers about 48 -hours, and that it is usually without symptoms unless it be a peculiar -prostration which had been described by some patients. It would also -appear from the experiences just narrated that it was necessary to be in -rather close contact with a patient, so that there could be an exchange -of respired air before infection could take place. - - - _Duration of the Disease_ - -In all descriptions of the disease the duration is spoken of as “several -days, more or less,” “a three-day fever,” or “a seven-day fever.” -Because of the careful supervision under which the soldiers were kept -while in the barracks an excellent opportunity was afforded to note the -duration of uncomplicated cases. The shortest time observed was 1 day, -and the longest 10 days. The average duration of temperature among 87 -soldiers without inflammation of the lungs or other certain -complications was 6⅓ days. Among the civilians the shortest time of -pyrexia was a few hours only, while the longest in 73 male patients was -14 days, and in 84 female patients was 16 days. The average length of -pyrexia in the males was 4⅝ days, and in the females was 5¼ days. - -While the very definite clinical description of the former epidemics of -a so-called uncomplicated influenza seems to have served satisfactorily -to the present time, the laboratory studies and the possibly more -thorough clinical observations which have been carried out recently in -this epidemic make it necessary to present anew the whole disease -picture of influenza, with the hope of suggesting a classification more -in accord with our present knowledge of the disease. - - - _Forms and Varieties of Influenza_ - -A few words as to “forms” or varieties of influenza might be helpful -before suggesting a classification of symptoms. In former epidemics of -influenza considerable importance was attached to the early -manifestations or first symptoms as characterizing the “form” of -influenza which was in evidence in the individual patient. These were -reported as a “respiratory form,” a “nervous form,” a “gastro-intestinal -form,” and other forms—circulatory, renal, psychic, etc. In the epidemic -of 1889 and 1890 particularly these types were noted, and they have been -described in the subsequent small epidemics, practically characterizing -them as being of one or the other, and frequently as being without any -respiratory symptoms. In the study of our group of cases in the present -epidemic every effort was made to recognize the non-respiratory cases, -but we were unable to find a single case which did not have definite -respiratory symptoms, either early or late, in addition to any other -symptoms present. Only occasionally were nausea, vomiting and diarrhea -or tachycardia, or certain neuroses or psychoses, the leading symptoms. -The respiratory symptoms in some cases seemed to be at the onset -primarily of the lower respiratory system—that is, without the -preliminary coryza. These usually ran a rapidly fatal course, -characterized by marked cyanosis and confusingly irregular chest signs. -We would say, therefore, in so far as our experience goes in this -epidemic, we are not justified in speaking of any particular forms -except the respiratory form, and whenever pronounced manifestations -occurred justifying a characterization of any other form they could more -easily be interpreted as a complication, or the manifestation of a -coincident disease, or of a severe toxæmia. - -The classification of the symptoms, therefore, takes into consideration -largely those symptoms arising from the respiratory system. We are of -the impression that the pathology demonstrated by Dr. Klotz and -described by others justifies the following classification. Clinically -we would recognize two distinct groups of epidemic cases. - -The first includes those _without lung involvement_ having symptoms -arising from the upper respiratory tract, including the trachea and the -larger bronchi. These were practically without any chest signs except -for the rather indefinite signs of an acute bronchitis, and the only -symptoms referable to the respiratory tract were a coryza, soreness of -the throat, hoarseness and a cough of varying degree and character. If -to these symptoms are added those of Leichtenstern just mentioned, one -will have a good description of a so-called simple, uncomplicated -influenza. - -The second includes those _with lung involvement_ and associated with -physical chest signs, in some indefinite and confusing, while in others -definitely conforming with the existing pathology. These symptoms and -chest signs were those associated at one time with what appeared to be -an acute œdema of the lungs. At another time the physical signs were -those of a bronchiolitis (capillary bronchitis), or most frequently of a -broncho-pneumonia, of an isolated type or of a massive type. Finally -there were some forms of lobar pneumonia which at times we were unable -to differentiate from a true lobar (croupous) pneumococcic pneumonia. - - - _Influenza Without Lung Involvement_ - -Of the group without lung involvement nothing further would seem -necessary to be said in addition to what one finds in standard -text-books describing the disease picture of former epidemics. The -incidence of influenza of this type among our group was as follows: Of -153 soldiers 93, or about 60 per cent., had a so-called simple, -uncomplicated influenza, and of the 394 civilians 185, or about 52 per -cent., had no lung involvement. There are a few points in which the -symptoms of the present epidemic seem to be so peculiar that they merit -special consideration. - - - _The Temperature_ - -This can be described as showing a sudden rise to 102–104, at which -point it is maintained for a few days, and subsides by lysis in a few -days more. A typical chart is as follows: - -[Illustration: - - CHART I -] - -Or the temperature might fall one or two degrees for a day or so after -the first rise, and then go up again for one or two more days, and -subside by lysis as is shown in Chart II. - -[Illustration: - - CHART II -] - -This would occur without our being able to find any lung lesion unless -we accept the acute œdema or wet lung as a complication, and this we -were rarely able to recognize by any definite physical signs in the -chest. Cyanosis frequently accompanied this second rise of temperature, -and was later interpreted as being associated with the so-called wet -lung. When the temperature remained up longer than five days it could -safely be concluded that lung involvement must be present. - - - _The Pulse and Respirations_ - -The pulse was invariably slow, or rather out of proportion to the -temperature. Even when the patient seemed very ill the pulse remained -from 84 to 96, and of surprisingly good quality. This was noted also -when some of the more severe pulmonary involvements or some -complications arose. The pulse frequently did not become rapid until -shortly before death. The respirations in an uncomplicated case also -remained about normal. The rate was not accelerated until lung -complications arose, and then a gradually increasing rate was often the -first herald of oncoming danger and a sign of grave prognostic import. -The relation of the pulse phenomena toward the end of a fatal case was -most remarkable. The respiratory rate was accelerated, as has been noted -above, but the pulse rate frequently remained unchanged, being -characteristically slow. In a patient seen in consultation with Dr. -Lester H. Botkin, of Duquesne, Pa., death took place while we were in -the sick room. It was a case of apparently uncomplicated influenza of -seven days’ duration. The respirations were rapid and the pulse was only -96. In the last five minutes of life the heart beats as observed with -the stethoscope never varied, until they suddenly ceased; during the -same time the respiratory efforts were only three agonal ones, the last -being a minute or so before the last heart beat. There were no physical -signs of consolidation at any time recognized in this case, but we feel -that the lung, had we seen it at autopsy, would in all likelihood have -shown the peculiar hemorrhagic and œdematous character so often observed -in the fatal cases. - -There were, of course, marked exceptions to the description of slow -pulse and later rapid respirations observed. In some the pulse rate and -respirations increased, together with or without definite signs of a -grave complication. - - - _Cyanosis_ - -This was recognized early in the epidemic. It was sometimes preceded by -a peculiar flushing of the face, such as accompanies belladonna -poisoning. It might be noticed in the very first days of the attack. The -cyanosis was looked upon as being a very early symptom of lung -involvement. With our later knowledge from autopsies, and especially as -shown by Dr. Klotz, we feel it was surely an accompaniment of, or may -even have preceded, the changes in the lung which have been designated -as œdematous, “wet” or cyanotic. At the earliest appearance of the -cyanosis we were frequently unable to find any change in the physical -signs of the chest. Of course, the indefinite signs of an acute -bronchitis were present, and in some cases an additional “impaired -resonance” was noted over one or both lower lobes, but when this was -definitely present other more definite signs soon followed, and our case -was shifted suddenly from Group I, i. e., without apparent lung -involvement, to Group II, i. e., with definite lung involvement. This -cyanosis was noticed first in the face, and frequently was marked on the -dorsal surface of the hands. It was not unlike the cyanosis which may -sometimes be seen when large doses of certain coal tar derivatives are -taken. In fact, the question arose whether in the epidemic of 1889 and -1890, when the coal tar derivatives were prescribed with such freedom -and with accompanying cyanosis and apparently such deleterious effects, -the cyanosis may not after all have been due more largely to the -infection than to the medication. After that epidemic it was said: -“Influenza has slain its thousands, but the coal tar products have slain -their tens of thousands.” There was no gross hæmaturia or hæmoglobinuria -present in these cases, although a few red blood cells were seen -microscopically. There was, however, epistaxis, sometimes early in the -disease or later associated with the cyanosis. In a few cases there was -hæmoptysis, which we regard as always arising in cases where the wet or -hemorrhagic lung was present. Cyanosis in disease of the lungs, and -especially in the terminal stage of lobar pneumonia, is a familiar and -common occurrence, but the cyanosis observed in this epidemic seemed -quite different from the ordinary. The points of difference were these: -(a) it came early in the disease; (b) it seemed to be more generally -present when very little lung involvement could be demonstrated -physically, and was just as likely to disappear when more definite chest -signs were demonstrable; (c) it was not associated with embarrassment of -respiration; (d) it had no relation with a demonstrable circulatory -disturbance. The pulse did not become rapid; the quality of the pulse -did not change; _the right heart was not dilated_, as is so frequently -the case in the terminal stage of a lobar pneumonia when cyanosis -appears; (e) and finally there was no associated œdema of the lungs, or -at least that œdema of the lungs which occurs in the later stage of -lobar pneumonia, when the pulse becomes rapid, when there is rapid and -labored respiration, when the right heart dilates, when there is cold -perspiration, and when the signs of impending death are plainly evident. -The cyanosis of influenzal pneumonia seemed to be due to an entirely -different cause or combination of conditions from those present in lobar -or pneumococcic pneumonia. The cyanosis of influenzal pneumonia was, -therefore, most confusing, and became all the more so when it was -recognized that it did not yield to the respiratory and circulatory -stimulants usually employed when cyanosis is present. The inhalation of -oxygen was resorted to rather routinely early in the epidemic. It seemed -to temporarily influence the cyanosis, but the results were not -permanent, and the outcome of the cases did not seem to be different -from those in which oxygen inhalations were not used. - -The blood pressure in those cases in which cyanosis was observed was -invariably low. This seemed to be due to the infection, for in several -private patients not belonging to this group of patients with previously -known high blood pressures the blood pressure was observed as much lower -throughout the course of the infection. - - - _Leucopenia_ - -The peculiar behavior of the white blood corpuscles will be discussed -more fully in another paper of this series. Our remarks will deal more -particularly with the clinical observations and interpretations. The -leucocytes fell below the normal from the very onset of the disease; -they varied very little regardless of great changes in temperature; they -did not always increase, or if they did increase at all it was -comparatively little, even in an extensive invasion of the lungs or in -severe complications. Concerning the leucopenia we have no explanation -to suggest, save that it is a clinical characteristic of the disease. -Our first thought was that the infection came on so suddenly and -profoundly there was no time for a leucocyte reaction. But when we -recall other diseases associated with a leucopenia, notably typhoid -fever, which does not come on with such suddenness, our explanation for -the leucopenia of influenza does not seem to hold. The leucopenia must -be simply a peculiar toxic blood reaction characteristic of the Pfeiffer -bacillus invasion. Such an explanation has long been accepted in the -Eberth bacillus infection. - - - _Asthenia_ - -A condition which was frequently noted by the patient was an -indescribable weakness and prostration which appeared early, sometimes -before any other symptoms were noted or before any elevation of -temperature. The young soldier was in apparent perfect condition when he -arose in the early morning. During the “setting up” exercises he did not -feel so fit, and a few hours later appeared extremely weak. When his -condition was called to the attention of the medical officers he was -found to have a slight elevation of temperature and was sent to his bed. - -In former epidemics, as also in this one, marked prostration was -recognized as coming at the height of the disease and remaining -persistently during convalescence. But it does not seem to be recorded -as among the first symptoms. - - - _Influenza with Lung Involvement_ - -Of the group with lung involvement much may be written from a clinical -standpoint, and much confusion may be brought about. Especially is this -so if one has no definite idea of the pathology present, or if one -enters into a discussion of the character of the infection—a point upon -which there is as yet no unanimity of opinion. From the many reports -which have been put forth from the base hospitals of the various -cantonments, and also from the reports coming from civilian practice, it -is evident that scarcely any two groups of laboratory men or any two -individuals of those separate groups have the same idea as to the -bacteriology and the pathology peculiar to this epidemic. - -As long as there is this confusion and element of doubt in the minds of -those to whom we are accustomed to look, the clinician must necessarily -speak with considerable hesitancy, especially when he attempts to -interpret the physical signs observed. In our own group the observations -of Klotz, Guthrie, Holman and others have given us an interpretation of -our clinical findings which, at present at least, is more or less -satisfactory. We shall definitely keep in mind their observations and -conclusions as we go on with the description of the physical signs of -the chest in cases having lung involvement. - -In the description of this group it will readily be seen that the lower -respiratory tract stood the brunt of the infection. Of the 153 soldiers -under our care, 60, or about 40 per cent., were recognized as having -pneumonia. Of these, 34 had undoubted demonstrable signs, while 26 were -questionable, and yet from the temperature and other symptoms we -concluded there was a pneumonia. Of the 394 civilians, 189, or about 50 -per cent., had pneumonia. Of this group there were again some 28 or 30 -in which the diagnosis was doubtful, according to the ordinary way of -making a diagnosis, but we felt sure from the temperature course that -more than a simple influenza was present. In the description of the -physical findings of the chest in these influenzas with lung involvement -it will be readily seen why the diagnosis must sometimes be in doubt. - -Before referring to the physical signs it might be well to describe the -condition and general appearance of the patient when the lungs became -involved. The patient who had been progressing with an apparently simple -influenza, with no chest signs except those of bronchitis or tracheitis, -occasionally slightly cyanotic, became more cyanotic, the elevation of -temperature continued longer than three to seven days, or if it came to -the normal began to rise again, his respirations gradually increased and -the pain in the chest became well localized. One could safely assume -that the patient had developed a lesion in the chest. This could not -always be localized during the first few hours or on the first day. The -evidence of increased bronchial disturbance was frequently recognized, -and later impairment of resonance and diminished breath sounds -associated with “a few crackles” were noted. This, so far as we can -tell, may have been the only evidence of the stage of œdema or “wet -lung.” After this, as the disease advanced, definitely increased vocal -fremitus and rather definite tubular breathing with greater impairment -of resonance were noticed. These signs were usually observed first at -the apex of the left lower lobe, and from here they extended forward -along the inter-lobar sulcus, or downward along the spinal column. If -the lesion was noticed first on the left side, in a day or two it was -found more or less definitely in the right lower lobe also. It seemed to -occur more frequently first in the body of the right lobe, instead of in -the apex of the lobe as on the left side. In both lobes it might spread -to contiguous areas and form a massive consolidation, or it might be -found in small separate areas, some of which would clear up in a day, -while others would persist. - -The expectoration was frothy, containing either blood or masses of -yellowish, greenish purulent material floating in a watery sanguiolent -or clear fluid, or enmeshed in frothy mucus. The amount of expectoration -in some cases was enormous, but as a rule it was scanty. It was thick -and ropy at times and distinctly annoying to the patient. - -At this stage the physical signs were very much in accord with those of -broncho-pneumonia. In a few hours sometimes, or in a day, the small -areas of consolidation became confluent and massive consolidation was -formed. It appeared as though the whole lobe would in time become solid, -as in a true lobar pneumonia. Or the original areas may apparently have -cleared and other areas involved, became the centers of massive -consolidations. In many cases both lower lobes were thus similarly -affected, and one had the physical signs of a double lobar pneumonia. -However, nearly always a small angle of the lobe remained clear, thus -differing from the entire lobe involvement characteristic of a true -croupous pneumonia. Other signs, such as the absence of vesicular -breathing and presence of the crepitant râle, moist râles of all sizes -to very coarse râles, could be noted. As in certain stages of a complete -consolidation, the lung might be dry; no râles present, but definite -tubular breathing present. This in a day or two, or after a longer time, -might give the signs of resolution. The stage of resolution, however, -was almost invariably prolonged, sometimes extending over weeks. With -these variable lung signs were often mingled the signs of a fibrinous or -serofibrinous pleurisy, which occasionally but remarkably infrequently -went on to effusion or empyæma. - -[Illustration] - -[Illustration] - -[Illustration] - -As stated above, the demonstrable pathology was in the lower lobe, and -more frequently in the left than in the right, only occasionally in the -middle lobe, and never, we might say, in the upper lobes. The very -earliest definite signs were found at the apex of the left lower lobe. - -This observation seems to be entirely contradictory to that of the -pathologist, who found in 65 per cent. of all cases coming to autopsy a -lesion in all the lobes of the lungs (Klotz). The only explanation we -can give which seems at all satisfactory to us is that the pathology in -the upper and middle lobes must not have been sufficient, or must have -been of such a nature that it did not yield the physical signs, i. e., -definite impaired percussion resonance, increased vocal fremitus and -tubular breathing, with varying shades of moist râles—signs upon which -we insisted before we were willing to state definitely that there is a -demonstrable pneumonia present. - -In this description it has been attempted to follow the order of -invasion in a lung which seemed to go through the entire course of the -disease. There were, necessarily, all degrees of the process, some cases -showing few signs and yet being remarkably ill, and others all of the -signs with very little other evidence of serious illness. - -We were continually impressed with the notion that the pathology in the -lung, at least the pathology demonstrable physically, did not tell the -whole story of the case, and that the outcome depended as much or -possibly more upon a general infection or toxæmia of which the -recognized condition in the respiratory system was only a small part. We -were particularly impressed with this in the success or failure -following the application of any therapeutic measures. It was quite a -common remark, therefore, in the wards of the hospital among those -associated in the work that “the patient died too quickly to permit of -the succession of the various stages of pneumonia”; or, in the autopsy -room, that if the patient had lived long enough he would have had -demonstrable, well-recognized pathology of the lung, instead of the -cyanotic, wet, spongy lung which was found. - -The temperature course in the pulmonary cases was characterized by its -irregularities, and by its being entirely out of harmony with the extent -and severity of the lung invasion in so far as it could be interpreted -by the physical signs. The temperature as described in a simple -influenza might not come to the normal in the time of three to seven -days, and might even go higher, with no demonstrable chest signs, but -with every other evidence of lung involvement. Later the temperature -might come down by lysis, which was the usual way, and the chest signs -gradually or suddenly become evident. The temperature might remain -normal throughout the rest of the course, and a lobe or even both lower -lobes of the lungs be as solid as in a true lobar pneumonia. -Occasionally the temperature fell by crisis, but there was no associated -change in the physical signs of the chest. In short, the temperature -seemed to run a course entirely independent of the physical signs in the -chest. In two remarkable cases seen in consultation on two consecutive -days the physicians in charge declared that no signs of consolidation -could be found, though all other evidences of pneumonia were present. In -the 12 hours which had elapsed from the time the last examination was -made the temperature fell by crisis. At the consultation, to the -surprise of the family physicians, we found both lower lobes -consolidated, it having occurred apparently with the crisis. Both -patients were healthy-looking, robust, young men, and both recovered -with delayed resolution. In the convalescence of such cases, if the -patient got up too soon or if any other indiscretion took place, a -relighting of the lung occurred. From the above description it can be -readily seen that a diagnosis of the conditions in the chest in -influenzal pneumonia was frequently impossible, because one had to -abandon all his previous ideas of pneumonia, in so far as onset, crisis, -blood picture, sputum, temperature, respiratory and circulatory -phenomena, physical signs and prognosis were concerned. - -Assistance from the laboratory was meager, especially in the early days -of the epidemic. This was due largely to the inability to get laboratory -workers in sufficient numbers to follow the work through, but more -largely to the fact that we were unable to interpret the unusual -laboratory results which were available. When we were once fully aware -of the difficulties in diagnosis which confronted us, we utilized every -practical means at our disposal. Among these was an examination of the -chest with the X-ray. On account of lack of facilities and of help, it -was impossible to make routine X-ray examinations of the chest in all -cases. Besides, it was difficult to interpret the X-ray findings, on -account of the unusual character of the lesions. Also, many of the -patients were so desperately ill one hesitated to disturb them. We hear -that other clinics had similar experiences, and that very little -substantial help came from the X-ray, except in cases with -complications. Several attempts were made to determine the kind of -shadow, if any, the “cyanotic, œdematous, wet” lung would make, but no -satisfactory observations have been forthcoming. From our own -observations and from the discussions of other observers, it would seem -to us that the stereoscopic examination of these chests is the only -possible way of getting satisfactory plate readings in these cases where -the pathology seems so lawless in its extent and peculiar in its -distribution. This method of examination, however, demands facilities -convenient at the bedside and perfect co-operation of the -patient—difficult conditions to meet under the circumstances. In the -acute cases, when the desire to make a diagnosis not only of the -presence but of the extent of the disease was keen, X-ray examination -was largely impractical. In cases of delayed resolution, or in cases -with complications with prolonged convalescence, X-ray examinations were -extremely helpful. - - - _Diagnosis of Influenzal Pneumonia_ - -In the consideration of any disease the well-trodden path of a -painstaking history, a thorough physical examination, and reliable -laboratory investigation, together with an intelligent interpretation, -will usually lead to a definite diagnosis. In certain diseases, as is -well known, the stress must be placed about equally on all of these -factors, while in others one or other factor predominates. In influenzal -pneumonia, until more is known of the etiology (bacteriology) and of the -pathological changes and of the physiological disturbances, the -controlling factor in the diagnosis (we feel embarrassed to admit) must -be the history. This is true not only of the diagnosis of influenza with -or without pulmonary involvement, but is also true of the diagnosis of -the various complications, and will be found to be particularly true in -the recognition of the bizarre sequelæ, which no doubt in the succeeding -months or years will be attributed to or will follow in the train of -influenza. - -With the knowledge that there is a prevailing epidemic of influenza and -that the manifestations are largely in the respiratory tract, any -pulmonary disturbance will necessarily make one suspicious of the -presence or the oncoming of an influenzal pneumonia in the patient under -consideration. The history of the onset, as of simple influenza, is the -greatest factor. This with a continued temperature, cough, cyanosis, -slow pulse, continued asthenia, or even an unusual leucopenia, may have -a greater weight in determining the diagnosis of lung involvement than -will the apparently definite or, as it may happen, the confusing chest -signs. To differentiate from ordinary bronchitis, broncho-pneumonia and -catarrhal pneumonia, one need only refer additionally to the severity -and persistency of the disease when it is of the influenzal type, as -compared with the mildness of the ordinary type. To differentiate it -from croupous pneumonia, one need only compare the confusing symptom -picture of the influenzal pneumonia with the definite, clear picture of -ordinary pneumonia; or the confusing kaleidoscopic chest signs of the -one with the definite, clear-cut signs of the other. The laboratory thus -far has been the smallest factor in making the diagnosis, in that sputum -examinations, blood examinations, blood cultures and urine examinations -are mostly negative in their results, or at least the findings are not -specific. We do not, however, mean to indicate that these tests are not -of the greatest value. The leucopenia is the one outstanding feature -which seems to have separated this infection from other acute lung -infections, excepting miliary tuberculosis. The differentiation of -influenzal pneumonia from an acute tuberculous process in the lung may -be difficult, especially if there is no reliable history available. -However, the fact that pulmonary tuberculosis usually begins at the -apices of the lungs and influenzal pneumonia at the bases or at the -apices of the lower lobes is quite helpful. Of course, the examination -of the sputum for tubercle bacilli will be a deciding factor. - -The differentiation between influenzal pneumonia and diseases of the -pleura is one which practically rarely needs to be made, for there seem -to be very few cases of influenzal infection of the lungs in which the -pleura is not also involved to a greater or lesser extent. - - - _Complications_ - -In considering the complications of influenza one again comes up -squarely against the question: What is influenza and what is the -specific micro-organism responsible for it? If the Pfeiffer bacillus is -the specific cause, what pathology can be attributed to it? It has been -an almost universal observation that the lesions in the lungs and pleura -which characterized the group of cases with lung involvement rarely -yielded a pure culture of the Pfeiffer bacillus, and that secondly in a -large percentage of cases the Pfeiffer bacillus apparently was absent, -and that other micro-organisms, such as the pneumococcus, streptococcus, -micro-organisms commonly found in the pneumonic processes, were present -and predominated. The question arises, therefore, may not all the -influenzas with lung involvement be _complications_ of influenza? It is -our feeling that Pfeiffer bacillus is present throughout the respiratory -tract in all cases, and while it may of itself produce a lesion like a -broncho-pneumonia or a lobar pneumonia, it chiefly prepares the soil for -other germs which may happen to be present, and which are more commonly -found in the pneumonias. We, therefore, look upon the lesion commonly -found in the lung as being a part of rather than a complication of -influenza, and look upon lesions elsewhere, due to the influenzal or -other micro-organisms, as a definite complication. - -There is no doubt that the most frequent complication of influenza, -especially in the present epidemic, is in connection with the pleural -membranes. When one recalls that pneumonia rarely occurs without there -being also a pleuritis, and also when one recognizes that in an -influenzal infection of the lungs the specific micro-organism, together -with any other micro-organism which may happen to be present, seems to -run riot, apparently abandoning its usual mode of invasion, it can be -readily understood why this complication is so frequent and so varied. -The pleurisy was usually of the fibrinous type, and rarely was -accompanied with demonstrable fluid. Of the 153 soldiers in only 3 was -fluid detected in the chest, and of the 394 civilians only 10 showed -fluid. In many more cases fluid was suspected, but X-ray examinations -and free needling of the chest showed that we had misinterpreted the -physical signs. - -After our experience in the epidemic of pneumonia in the spring of 1918, -when the disease was also so prevalent in the cantonments, we of course -expected to see many cases of empyæma and lung abscess in the present -epidemic. In this we were agreeably disappointed. Only one case of -empyæma and only one case with abscess of the lung were found up to the -time of collecting our data and the compiling of our statistics. Both of -these were among the civilians. From our experience since the compiling -of our statistics, we are inclined to believe that this low incidence of -empyæma may not altogether represent the real state of affairs, as we -have since received in the hospital several cases of empyæma, as well as -of abscess of the lung, which seemed to have followed an influenzal -infection which had occurred three or four months previously. One of -these cases was a particularly remarkable one, in that the patient had -already been admitted to the hospital twice since his initial attack of -influenza in October for suspected pleurisy with effusion. We were -unable to find any fluid with the needle, though we felt certain of -having demonstrated it a number of times physically and with the X-ray. -About eight weeks after the second admission, however, pus was found -after several needlings in the left chest, axillary space, apparently -along the inter-lobar sulcus. This case was a good example of many we -have seen in which a pneumonia, or possibly, as we see it now, a -pleurisy, or even a localized empyæma, seemed to confine itself about -the sulcus or fissure between the upper and lower lobes of the lung. -Frequently the process began posteriorly, apparently at the apex of the -lower lobe, and traveled forward and downward across the axillary space -until it appeared in the anterior part of the chest. In most cases we -interpreted our signs as those of a consolidated lung, and scarcely knew -whether the consolidation was in the upper part of the lower lobe or in -the lower part of the upper, or in both. In some cases we suspected a -localized empyæma or an abscess in the sulcus, but in none did we find -pus after exploring with the needle until this recent case occurred. The -passage of the needle in this case, which was done several times before -pus was found, always gave the impression that it was going through -dense fibrous tissue for some distance before the abscess was finally -found. From this experience, and from the extensive and irregular -invasion of the pleura which we have seen demonstrated at autopsies, -there can be no doubt that the clinical history of the complications of -influenza in this epidemic is not a closed chapter. - -In six patients there was a purulent inflammation of the pharynx, larynx -and trachea. It was extensive and produced profound general symptoms, -dyspnœa and profuse purulent expectoration. The lungs were clear, but -the patient seemed for a time in danger of death. The condition was -considered a grave complication. There was only one case of acute -sinusitis, one case of antrum disease, and only four cases of middle ear -infection were recognized. This is in marked contrast to other epidemics -which have occurred to our knowledge in the past fifteen years or more, -and which have been spoken of as influenza or “grippe.” Disease of the -tonsils, middle ear disease, mastoid disease and sinus disease occurred -with great frequency in those sporadic epidemics. This again seems to -show that the deep respiratory tract was more generally and more -severely affected in this epidemic than the upper respiratory tract. - -With the exception of the pleura, the serous membranes were remarkably -free from infection. Only one case of acute endocarditis, three cases of -meningitis (all pneumococcic), none of pericarditis, peritonitis or -arthritis were recognized among the 547 cases of influenza. - -The kidneys did not seem to be involved in the infection. Albumen was -present in the urine, as might be expected in febrile conditions, but no -evidence of acute clinical nephritis, such as suppression of urine, -general œdema or uræmia, was recognized. The condition of the urine in -this epidemic will be described more in detail in another paper of this -series. - -A peculiar pathological process in the muscles was brought to our -attention by Dr. Klotz, who demonstrated a myositis or hyaline -degeneration of the lower end of the recti abdominalis. This lesion is -carefully described in the pathological section. After our attention had -been called to this lesion we recognized several cases clinically having -the same condition. One was in the right sterno-cleido-mastoid muscle -and another was in the left ilio-psoas muscle. This last patient while -he was convalescing developed a severe pain in the left hip, extending -upward into the lumbar region and downward into the thigh. His decubitus -was like that of one suffering with psoas abscess. Every test available -was made to confirm this diagnosis, but all the findings were negative. -The patient rested in the hospital, in bed, for some time, gradually -improved, and eventually made a complete recovery. - -In several cases we also detected an osteitis, especially of the bodies -of the vertebræ. One was of the cervical vertebræ and the other of the -dorsal. The first died after intense suffering. An autopsy was not -obtained. The other had a plaster cast applied as in Pott’s disease, and -improved sufficiently to leave the hospital in comfort. One hesitates -under the circumstances to attribute these bone lesions definitely to -the same infecting micro-organism which was responsible for the epidemic -of influenza, as it might easily have happened that a coincident -quiescent tuberculous lesion was present and relighted during the -epidemic. However, in one case from the service of Dr. J. O. Wallace the -possibility of the bone lesions being due to the Pfeiffer bacillus was -demonstrated. This was a child of 16 months with an epiphysitis of the -upper end of the tibia. The inflamed area was incised and pus was found. -A smear at the time showed the B. influenzæ, which was grown in pure -culture. - -A most interesting complication noted in a few of our cases was a -transient glycosuria. The first case brought to our attention was a -middle-aged female, who complained of failure of vision. Upon making an -ophthalmoscopic examination a papillitis of a mild type was noticed. -This led to a careful study of the urine, and sugar was found in a small -amount for a short period of three days, although the glycosuria readily -disappeared by cutting down the carbohydrate intake, the vision came -back to normal more slowly. In fact, it was almost one month before the -symptoms and signs of the retinal change had entirely disappeared. It is -interesting in this connection to recall similar cases referred to in -Allbutt’s System of Medicine, vol. vi, on influenza, following the -epidemic of 1890 in England. Other transient glycosurias showed no -visual changes. We do not consider these to be true cases of diabetes -mellitus. In all a transient hyperglycæmia was also noted. - - - _Pregnancy_ - -A condition which can scarcely be considered as a complication of -influenza, but which, however, was a large factor in increasing the -mortality among women, was pregnancy. Among the cases included in this -study were five pregnant women, who came to the hospital and were -referred to the medical service. As soon as a complication relative to -the existing pregnancy arose they were referred to the Obstetrical -Department. On account of the great amount of work in caring for the -influenzal patients, and on account of the scarcity of physicians and -nurses, we were unable to follow these cases closely enough to give any -such definite data as we wish. Three miscarried or went into premature -labor. Happily only one of them died. The two which did not miscarry -recovered and left the hospital well. - -We very soon recognized in consultation with the obstetricians that the -pregnant woman was in a really dangerous condition if she contracted -influenza. She was likely to have a termination of her pregnancy in the -height of the infection, no matter how recent or how remote pregnancy -had taken place. If pregnancy did not terminate, the chances of recovery -were less than those of the non-pregnant woman; if it did terminate, the -chances for recovery were still less. To the pregnant woman with -pneumonia very little hope of recovery could be offered. I am indebted -to Dr. Paul Titus, of the Obstetrical Department of the School of -Medicine, University of Pittsburgh, for a report which includes the -cases seen by himself and his assistant, Dr. J. M. Jamison, during this -epidemic. Dr. Titus was kind enough to include in his report certain -conclusions which merit consideration. The report is as follows: “A -series of 50 cases, at all stages of gestation. Interruption of -pregnancy occurred in 21, or 42 per cent., of the cases; 29, or 58 per -cent., in which pregnancy was uninterrupted. Mortality of pregnant women -developing epidemic influenza is higher than that of ordinary -individuals, even though their pregnancy is undisturbed, since 14 of the -29 in whom pregnancy was not interrupted died, an incidence of 48–2/10 -per cent. If a pregnant woman miscarries or falls into labor, the -mortality increases to 80–9/10 per cent. (17 of the 21 in whom pregnancy -was interrupted died). The period of gestation has less influence on the -outcome than the interruption itself. Of 10 at term, 3 lived and 7 died -after delivery. - -“Two main features of this condition as a complication of pregnancy are: -First, pregnant women developing epidemic influenza are liable to an -interruption of their pregnancy (42 per cent. aborted, miscarried or -fell into labor); second, the prognosis, which is already grave on -account of the existence of pregnancy, becomes more grave if -interruption of pregnancy occurs. - -“The cause of the frequency of interruption of pregnancy is probably a -combination of factors: (1) The theory of Brown-Sequard that a lowering -of the carbon-dioxid content of the blood causes strong uterine -contractions sufficient to induce labor. (2) The toxæmia causes the -death of the fœtus, particularly if not mature, when it acts as a -foreign body and is extruded (10 premature fœtuses were born dead, while -1 was born alive, although 9 out of 10 at full term were born alive and -survived). - -“The cause of the frequency of death following interruption of pregnancy -is also due in all probability to a combination of factors: (1) Shock -incident to labor. (2) Increase from muscular labor of carbon-dioxid in -blood already overloaded by the deficiency of the diseased respiratory -organs. (3) Sudden lowering of intra-abdominal pressure by the delivery. -(4) Lowering of blood pressure by the hemorrhage of the delivery. (5) -Strain of labor on an already impaired myocardium.” - -If one had been told a year ago that an epidemic could occur which would -result in the death of 60 per cent. of all pregnant women affected, it -would have been thought too unlikely to warrant any consideration. -Though the effect upon pregnancy of the acute infectious diseases forms -an important chapter in the pathology of pregnancy, it seems that the -profession, and in this the obstetrician is no exception, has never -realized how pernicious and tragic the results of an influenzal epidemic -can be in a community. From the experience in previous epidemics we -cannot but feel that the infection in the present epidemic was unusually -fatal. Whitridge Williams (“Text-book of Obstetrics”) speaks of the -interruption of pregnancy as having occurred in 6 out of 7 cases with -one observer, and in 16 out of 21 in another, while a third has found it -only twice in 41 cases. However, none of these writers speaks of having -had a death. - - - _Sequelæ_ - -In referring to some of the associated conditions of influenza one -scarcely knows whether to consider them as complications or sequelæ. The -pathological process certainly had its origin from the influenzal -attack, but at times apparently assumed an inactive stage. The patient -is usually free from any specific influenzal symptoms, but retains for a -long time other symptoms referable to various organs, or he may have -been normal for a shorter or a longer period and then suddenly develop -symptoms apparently independent of the previous infection. It may be -well to consider all such conditions which followed the febrile attack, -whether immediately or more remotely, as sequelæ, and I shall therefore -speak of them as such. - -The first and probably the most interesting and confusing are the -conditions found in the lungs following influenza. A chronic bronchitis, -an old bronchiectasis, or a previous tuberculous lesion in whatsoever -stage, may present acute symptoms and signs which are difficult to -interpret. The question always arises in the individual case—is this a -process due to the recent influenzal attack, or was it there before the -attack? Is it of streptococcic, pneumococcic, or tuberculous origin? The -history of previous diseases of the lungs may help to arrive at a -diagnosis. The history of the severity of the influenzal attack is of -very little help, because the apparently mildest attack may be followed -by the most profound changes in the lungs, and the gravest attack with a -history of definite lung infection may leave the lungs without a trace -of the previous pathology. The physical examination is helpful, of -course, in determining whether the lesion is at the apices or at the -bases, and from this a reasonably safe inference may be drawn as to -whether it is from a previous tuberculous lesion or a recent influenzal -infection. The Roentgenologist depends almost entirely upon this -localization. If the linear striæ are only at the apex, it is probably -tuberculous; but if they are only at the base, or also at the base, it -is likely to be an influenzal lung. In fact, the Roentgenologist with -his present information is ready to admit that it is most difficult to -speak definitely of the lungs in these cases. The possibility of -confusing the post-influenzal lung with a tuberculous lesion is not -peculiar to this epidemic. After the epidemic of 1889 and 1890 the same -condition was observed by clinicians. Dr. Roland G. Curtin, of -Philadelphia, in 1892 and 1893 conducted a series of clinics at the -Philadelphia Hospital, in which he spoke of the “non-bacillary form of -phthisis,” and showed case after case which he said might be diagnosed -as pulmonary tuberculosis, but because of the recent epidemic and the -absence of the tubercle bacillus he diagnosed them as post-influenzal -lung. - -In the present stage of our knowledge, many of these post-influenzal -lungs will not be diagnosed properly until sufficient time is given for -either the lung to clear up or the tubercle bacillus to appear in the -sputum. We would emphasize the importance at the present time of finding -the tubercle bacillus in all suspicious lung lesions before giving a -positive opinion as to the tuberculous nature, even though the physical -signs are very definite. - -Another group of sequelæ is that due to thyroid disturbance, or -disturbance of the endocrin system in general. Since the epidemic a -number of patients have been seen who noticed an enlargement of a -previously normal thyroid gland or greater enlargement of a previously -hypertrophied gland. In the same way the symptoms of hyperthyroidism -appeared, new in some or a recrudescence in others. - -In some of these there was a disturbance of carbohydrate metabolism, as -shown by an occasional glycosuria and an increase in the blood sugar, or -by a possible disturbance of the suprarenals, as brought out by the -administration of adrenalin hypodermatically (Goetsch test). In the -application of this test in post-influenzal patients it appeared that -the whole endocrin system was in a state of imbalance. - -It appears to us not at all improbable that the so-called psychoneuroses -of which fatigue, nervousness, irritability and tachycardia play such an -important part might also be explained in the same way. These constitute -a group of sequelæ which were frequently recognized after previous -epidemics, and which are again coming to the foreground. - -We are of the opinion, on account of the apparent absence of any -specific pathology of the gastro-intestinal tract and its appendages -during the attack of influenza, that the sequelæ referred to the -digestive system are largely due to exacerbations of previous -physiological disturbances or pathological processes. The patient with a -previous peptic ulcer has a recurrence of his ulcer. The patient with an -infection of the biliary tract has an acute exacerbation, or may have an -attack of biliary colic. In fact, there seem to have been many more -cases of this kind since the epidemic than before, and most of the -patients date the time of the onset from a period soon after recovering -from influenza. - -Very few, if any, patients in our experience have exhibited sequelæ due -to disease of the cardio-vascular or genito-urinary systems. It may be -that these will appear later when the more remote effects of an acute -infection are recorded. - -A very commonplace sequel, but of more or less interest, is the tendency -to furunculosis. Our attention was particularly called to the associated -hyperglycæmia. The blood sugar readings varied from 0.2 to 0.41. There -was no glycosuria, acetone or diacetic acid. We have no explanation to -offer for this, although one might dilate readily on many attractive -theories. The hyperglycæmia, one may add, was readily reduced by a -lowered carbohydrate intake, which also had a curative action on the -furunculosis. - -Finally we would mention the peculiar epidemic which has been observed -apparently over the world, encephalitis lethargica. We do not for a -moment put ourselves on record as regarding this disease as a -post-influenzal affair, but no one will deny that it has a peculiar time -relation to the epidemic; and further, that its distribution is -apparently identical. Its bacteriology seems to be unknown. Its local -pathology in the mid-brain is not peculiar or at variance with -encephalitis produced by known organisms. We have seen five cases; three -of whom had had undoubted influenza, while the other two were entirely -free from even the slightest suggestion of any type of illness previous -to the attack. All of these cases recovered. It has been stated that -following the 1890 epidemic a clinical condition was observed in Europe -which bears a close resemblance to what has been termed at the present -time encephalitis lethargica. - - - _Prognosis and Mortality of Influenza_ - -In giving a prognosis of influenza one has to take into consideration -the peculiar manifestations of the disease, especially the possible and -sudden changes which are liable to take place in the lungs. The points -which lead one to feel that the outlook is grave occur in about the -following order, which is also about the order of the severity of the -symptoms. First, _cyanosis_. This usually appeared quite early and was -considered a forerunner of definite lung infection. It may have been a -symptom only of the “wet lung,” to which reference has been made, but it -was usually followed with definitely recognized pathology in the chest, -and it immediately made the outlook unfavorable. Second, _continuation -of elevated temperature_. If the temperature fell to normal in three or -four days, the outlook was, of course, good; but if it went up again, or -if the temperature did not fall in that time, the chances were that -there was a lung involvement, even though the chest signs were negative -or only those of an acute bronchitis. Strange to say, however, when -definite chest signs were once recognized, the height of the temperature -or the continuation of fever was not so important a prognostic factor. -Third, _increase in pulse rate_. The pulse, as was noted before, was -unusually slow, even though the patient seemed desperately ill; when, -however, it began to increase in rate the condition was usually very -grave. Fourth, _the extent of lung involvement_. This was of very little -prognostic value. Both lower lobes might be solid, and yet if there was -no cyanosis and the pulse and respirations were satisfactory, the -outlook was rather good. On the other hand, there might be the slightest -involvement of the lung, and if the pulse were rapid and cyanosis -present the outlook was grave. Fifth, _depression and stupor_, or loss -of so-called “morale.” If the patient remained clear in his mind, bright -and hopeful, no difference how extensive the involvement or how grave -the symptoms, the prospect of recovery was better. This is, of course, -not peculiar to influenza, but it seemed particularly striking during -the epidemic. Sixth, _a gradually rising rate in respiration_, which -often was not more than two per minute per day, if progressive, even in -the absence of other untoward signs, conveyed a serious prognosis. - -Our mortality among the civilians in comparison with the soldiers was -exceedingly high. The first cases seen by us were among the soldier -patients sent to the hospital. These were as fine a lot of healthy young -men as one can well imagine. They came to the hospital comparatively -early in the infection. After the first week it appeared as though our -experience would be entirely different from those in other localities, -for we had very few deaths. In another week our mortality began to rise, -but never as high as among the civilians, as will be seen by the -following figures. - -Of the 153 soldiers 87 were without lung involvement, and of these none -died; 66 had lung involvement, and of these 16 died. Mortality among the -153 was 10 per cent. Of the 394 civilians 157 were without lung -involvement, and of these 1 died; 237 had lung involvement, or some -other complication, and of these 93 died. Mortality among the 394 was -23.6 per cent. - -It will be seen that the mortality in the civilians was more than twice -as high as in the soldiers. It has already been mentioned that the -soldiers were ordered to the hospital promptly. The civilian patients, -on the other hand, were later in coming to the hospital, some of them -appearing when they had already developed serious complications. Another -factor in determining the mortality were the ages of the patients. The -soldiers ranged from 18 to 34 years, with an average of 20 years. The -civilians ranged from 6 months to 73 years, with an average of 30 years. -Generally speaking, the greater the age the higher was the mortality. - -A third factor which should be considered in determining the actual -mortality is the result of later complications and sequelæ. The figures -as given are those of 547 patients, 110 of whom had died in the Mercy -Hospital and 437 of whom had been discharged therefrom between September -22 and November 30, 1918, the length of the quarantine. Those who were -discharged had been up and about for a week or 10 days before leaving -the hospital. From our experience with post-influenzal patients admitted -to the Mercy Hospital since November 30, we are of the opinion that some -of the patients discharged before November 30 as recovered may have -later developed sequelæ which might have proved fatal. No follow-up -system has been pursued as yet which enables us to speak definitely and -statistically of the present condition of those discharged. - -This compilation does not readily lend itself to drawing any more -specific conclusions, but we cannot desist from expressing our opinion -that in the clinical study of this recent epidemic we find very little -that may not have been observed by clinicians in previous epidemics. - - - - - THE URINE AND BLOOD IN EPIDEMIC INFLUENZA - - By PETER I. ZEEDICK, M. D. - - -Epidemic influenza, unlike other acute infectious processes as -diphtheria and scarlet fever, seemingly attacks the kidney in a rather -mild manner. This statement refers only to the uncomplicated cases, as -other bacterial or toxic agents do play a part in the nephritides -occurring so often with the pneumonias or other complications -following influenza. It is, however, true that in many simple epidemic -cases there is evidence of a transient mild nephritis, or possibly, -more correctly stated, a nephrosis. Some writers observed albuminuria -in 80 per cent. of the cases, while the incidence in other reports -varies from 4 to 66 per cent. It is not always stated with reference -to these figures that the patients clinically were free from the -common complication—pneumonia. The findings of various observers -differ greatly, but they all agree that acute nephritis as a serious -sequel is somewhat rare. - -In the literature of the past epidemics general acknowledgment has been -accorded to the presence of albumin in the urine during the acute stage -of the disease. Many times this has received no further notice or -comment than “febrile albuminuria.” The association of occasional -hyaline and granular casts has also been mentioned. One is impressed -with the fact that the older observers laid but little emphasis on the -urinary findings. It also seems to be true that nephritis as a clinical -entity is not prone to follow the epidemics. In general, our conclusions -from the last epidemic are about the same. - -The data for this paper was obtained from examination of 994 specimens -of urine from 750 patients; of this number 517 specimens were examined -at the Magee Hospital, where members of the S. A. T. C., all young men, -were treated, and 447 specimens from the Mercy Hospital, where, in -addition to the S. A. T. C., we had men, women and children. On account -of the large amount of material and work on hand, as a rule only one -specimen of urine was examined from each patient, but where -complications were suspected repeated daily examinations were made. We -have grouped our results in tables, so that the various points may be -more readily followed. - -Table I shows the urinary findings of uncomplicated influenza cases -admitted to the wards of the Mercy Hospital. None of these cases -developed pneumonia and, after running the usual course, recovered. We -would call attention to the fact that 25 per cent. showed albuminuria. -The amount of albumin was never excessive, and very often was little -more than a faint trace. On the other hand, we have had a few patients -where a previous kidney lesion was known to be present, and naturally in -these cases a heavy cloud of albumin was met with. The albuminuria was -almost always a transient affair, lasting only during the acute part of -the illness, and would rightly come under the class of febrile -albuminuria. We regard it as being more the evidence of nephrosis than a -nephritis. As a rule, the time for the appearance of albumin was after -the fever had been present for at least two or three days. One rarely -met with it in the short attacks of influenza where the temperature came -to normal in less than 72 hours. A certain time factor appeared to be -necessary in order for the nephrosis to develop. Another point of -interest is the presence of red and white blood cells seen relatively -frequently during the early days of the illness. One wonders if this -finding is analogous to the bleeding from the nose and lung so often met -with at the onset of the disease. The red blood cells were seen -microscopically, and only very rarely did we encounter a smoky urine. - - - TABLE I - - URINE ANALYSIS IN CASES OF UNCOMPLICATED INFLUENZA AT THE MERCY HOSPITAL - - ───────┬─────────┬───────────────────────────────┬──────┬──────┬────── - Day of │Total No.│ │ │ │ - Disease│ of │ SPECIFIC GRAVITY │ Alb. │R.B.C.│Casts - │Specimens│ │ │ │ - ───────┼─────────┼───────┬───────┬───────┬───────┼──────┼──────┼────── - │ │1001–10│1011–20│1021–30│1031–40│ │ │ - ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼────── - 2│ 118│ 8│ 31│ 61│ 18│ 29│ 17│ 8 - 3│ 97│ 8│ 15│ 62│ 12│ 23│ 10│ 11 - 4│ 51│ 9│ 22│ 17│ 3│ 11│ 7│ - 5│ 24│ 4│ 2│ 14│ 4│ 5│ 3│ 4 - 6│ 11│ │ │ 8│ 3│ 4│ │ - 7│ 25│ │ 10│ 14│ 1│ 8│ │ - 8│ 12│ │ 2│ 8│ 2│ 6│ │ 3 - 9│ 4│ │ 2│ 1│ 1│ 2│ │ - 18│ 2│ │ 1│ 1│ │ │ │ - ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼────── - Totals │ 344│ 29│ 95│ 186│ 44│ 88│ 37│ 26 - ───────┴─────────┴───────┴───────┴───────┴───────┴──────┴──────┴────── - - - TABLE II - - URINE ANALYSIS IN CASES OF UNCOMPLICATED INFLUENZA AT THE MAGEE HOSPITAL - - ───────┬─────────┬───────────────────────────────┬──────┬──────┬────── - Day of │Total No.│ │ │ │ - Disease│ of │ SPECIFIC GRAVITY │ Alb. │R.B.C.│Casts - │Specimens│ │ │ │ - ───────┼─────────┼───────┬───────┬───────┬───────┼──────┼──────┼────── - │ │1001–10│1011–20│1021–30│1031–40│ │ │ - ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼────── - 1│ 101│ 6│ 22│ 49│ 24│ 5│ │ 3 - 2│ 127│ 1│ 17│ 75│ 34│ 13│ │ 3 - 3│ 82│ 3│ 13│ 55│ 11│ 13│ 1│ 4 - 4│ 36│ 1│ 14│ 18│ 3│ 4│ │ 2 - 5│ 40│ 2│ 9│ 24│ 5│ 6│ 1│ 2 - 6│ 23│ 1│ 5│ 15│ 2│ 7│ 1│ 3 - 7│ 5│ │ 1│ 4│ │ 3│ │ 2 - 8│ 5│ 1│ │ 4│ │ │ │ - 9│ 2│ 1│ │ 1│ │ │ │ - 10│ 10│ 1│ 3│ 5│ 1│ 2│ │ 1 - 11│ 3│ │ │ 3│ │ 2│ │ 1 - 12│ 3│ │ 1│ 2│ │ 2│ 1│ - 13│ 1│ │ 1│ 3│ │ │ │ - 14│ 1│ │ │ 1│ │ │ │ - 15│ 5│ │ 1│ 4│ │ │ │ - ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼────── - Totals │ 447│ 17│ 87│ 263│ 80│ 57│ 4│ 21 - ───────┴─────────┴───────┴───────┴───────┴───────┴──────┴──────┴────── - -The results shown in Table II illustrate the urinary findings at the -Magee Hospital, and, as in the previous table, include cases of -influenza which did not develop pneumonia. The specimens examined were -obtained from young, healthy men, between the ages of 20 and 32, and -showed albumin in 13 per cent. of the cases. This age factor probably -accounts for the lower incidence of albuminuria for this group. - - - TABLE III - - URINE ANALYSIS IN CASES OF PNEUMONIA (INFLUENZAL) AT THE MERCY HOSPITAL - - ───────┬─────────┬───────────────────────────────┬──────┬──────┬────── - Day of │Total No.│ │ │ │ - Disease│ of │ SPECIFIC GRAVITY │ Alb. │R.B.C.│Casts - │Specimens│ │ │ │ - ───────┼─────────┼───────┬───────┬───────┬───────┼──────┼──────┼────── - │ │1001–10│1011–20│1021–30│1031–40│ │ │ - ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼────── - 1│ 47│ 4│ 14│ 25│ 2│ 36│ 7│ 6 - 2│ 22│ 1│ 8│ 9│ 4│ 19│ 1│ 4 - 3│ 9│ 2│ 3│ 3│ 1│ 7│ 1│ - 4│ 6│ 1│ 3│ 2│ │ 4│ 1│ - 5│ 6│ 1│ │ 5│ │ 5│ │ 1 - 6│ 16│ 2│ 7│ 7│ │ 13│ 2│ 7 - 7│ 9│ │ 5│ 3│ 1│ 8│ │ - 8│ 3│ │ 1│ 2│ │ 3│ │ - 9│ 3│ │ 2│ │ │ 2│ │ - 10│ 1│ │ │ │ │ 1│ │ - 11│ │ │ │ │ │ │ │ - 12│ 3│ │ 2│ 1│ │ 2│ │ - 13│ 4│ │ 1│ 3│ │ 3│ │ 1 - 14│ 2│ │ │ 2│ │ 2│ │ - 15│ │ │ │ │ │ │ │ - 16│ │ │ │ │ │ │ │ - 17│ │ │ │ │ │ │ │ - 18│ 1│ │ │ 1│ │ 1│ │ - 19│ │ │ │ │ │ │ │ - 20│ 1│ │ 1│ │ │ │ │ - ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼────── - Totals │ 133│ 11│ 47│ 63│ 8│ 106│ 13│ 19 - ───────┴─────────┴───────┴───────┴───────┴───────┴──────┴──────┴────── - -Table III includes the urinary findings of patients diagnosed as -influenzal pneumonia. In this table the term “Day of Disease” indicates -the day on which the physical signs of pneumonia could be demonstrated, -and not the day on which the patient was taken ill with influenza. The -incidence of albuminuria—79 per cent.—is very high, while the presence -of casts and red blood cells is low. These results are really what one -would expect. As we have noticed in the late stages of uncomplicated -influenza a greater tendency for urinary changes to become apparent, one -would, therefore, most likely find considerable urinary disturbance in -the pneumonia immediately following the epidemic disease. Pneumococcic -pneumonia is prone to be accompanied by an albuminuria. So when we have -both influenzal and pneumococcic etiological factors involved, it is but -natural to have most of the patients showing signs of kidney -disturbance. The amount of albumin present, although generally greater -than in uncomplicated influenza, was not excessive. At times there was -little more than a trace. We noted the relative scarcity of casts—a -condition which differs greatly from our past experience in the ordinary -lobar pneumococcic pneumonia. On the transient nature of this kidney -involvement we have considerable positive evidence, but there is no -question that the time required for the urine to return to normal is -longer after pneumonia than uncomplicated influenza. We have observed -but one or two cases which afterward returned to us presenting clinical -signs of acute nephritis. In fact, in going over our hospital records of -the winter and spring we noted that an unusually small number of acute -nephritics have been admitted. This would seem to be evidence that, as -has been noted in the past, the kidney is not a vulnerable organ in this -epidemic disease. - - - TABLE IV - - URINE ANALYSIS IN CASES OF PNEUMONIA (INFLUENZAL) AT THE MAGEE HOSPITAL - - ───────┬─────────┬───────────────────────────────┬──────┬──────┬────── - Day of │Total No.│ │ │ │ - Disease│ of │ SPECIFIC GRAVITY │ Alb. │R.B.C.│Casts - │Specimens│ │ │ │ - ───────┼─────────┼───────┬───────┬───────┬───────┼──────┼──────┼────── - │ │1001–10│1011–20│1021–30│1031–40│ │ │ - ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼────── - 1│ 3│ │ │ 2│ 1│ 1│ │ 1 - 2│ 12│ │ 1│ 10│ 1│ 8│ │ 6 - 3│ 4│ │ │ 4│ │ 1│ 1│ 1 - 4│ 9│ 1│ 2│ 4│ 2│ 6│ │ 6 - 5│ 8│ │ 4│ 4│ │ 6│ │ 5 - 6│ 8│ │ 5│ 3│ │ 7│ 2│ 6 - 7│ 4│ │ 2│ 2│ │ 3│ │ 2 - 8│ 10│ │ 2│ 8│ │ 5│ 2│ 5 - 9│ 4│ │ 2│ 2│ │ 4│ 3│ 4 - 10│ 6│ │ 1│ 5│ │ 6│ 3│ 5 - 11│ 1│ │ 1│ │ │ 1│ │ 1 - 12│ 1│ │ 1│ │ │ 1│ │ - 13│ │ │ │ │ │ │ │ - 14│ │ │ │ │ │ │ │ - 15│ 2│ │ 2│ │ │ 1│ │ 1 - ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼────── - Totals │ 70│ 1│ 20│ 45│ 4│ 49│ 11│ 40 - ───────┴─────────┴───────┴───────┴───────┴───────┴──────┴──────┴────── - -Table IV includes specimens obtained at the Magee Hospital from patients -diagnosed as pneumonia. The results among these young students were very -similar to those of the previous chart, where all ages were included. -However, casts and red blood cells were more regularly noted. - -From the four tables, we are able to note one or two common facts. In -acute uncomplicated influenza albuminuria occurred 57 times in 447 -specimens, or 13 per cent., at the Magee Hospital. Here we dealt -entirely with the young adult. At the Mercy Hospital 88 positive results -of albumin in 344 specimens, or 26 per cent., from patients of all types -were recorded. The common total would be 781 specimens examined, and -141, or 17 per cent., showing albumin. - -With the advent of pneumonia the incidence of albuminuria was increased. -At the Magee Hospital it was seen 49 times in 70 examinations, or 70 per -cent.; while at the Mercy Hospital 106 positive results were found in -133 specimens examined, a percentage of 79. The combined figures, -therefore, would show 155 out of 203, or 76 per cent. - -The incidence of albuminuria for the epidemic in all its phases would -be, from our figures, 400 in 994 specimens, or 40 per cent. - -Red blood cells were present in 5 per cent. of the influenza cases, and -in 11 per cent. of the pneumonias. This was always a microscopic -observation, save in the case of a slightly smoky urine. Even -microscopically the red cells were not numerous. We noted them at times -quite early in the disease in some of the severe cases which presented -epistaxis and hematemesis. Possibly one might consider the early -presence of red blood cells in the urine as a condition analogous to -those just mentioned, although we never saw anything suggesting free -hemorrhage from the kidney. It is probably better to regard the red -cells as a manifestation of an acute nephrosis of toxic origin. - -Casts were found in 35 per cent. of the cases showing albuminuria. We -are inclined to feel that this observation is somewhat low, but at the -same time we have noted that in uncomplicated influenza one frequently -sees albumin without casts. We were also impressed with the fact that -casts were not as prominent a feature in the influenzal pneumonias as -they are in frank lobar pneumonia of essentially pneumococcic origin. - -During the course of routine examinations several transient glycosurias -were seen. Their transient character was the outstanding feature. The -quantity of sugar was very moderate—our figures were never above 1 per -cent.—and the daily amount of urine was always within normal limits. -Acetone and diacetic acid were absent. A few observations on the blood -sugar showed a rise (.2 to .25), which readily came to normal with -treatment. Clinically these cases were not classed as diabetes mellitus, -but rather as a nervous complication of influenza, involving in some way -the carbohydrate metabolism, probably through the central nervous -system. One case of special interest, which is mentioned elsewhere, was -the association of glycosuria with almost total blindness from a very -intense optic œdema. Sugar (1 per cent.) was present on the day of -admission, while only a trace was noted on the two following days, and -from then on the urine was free from sugar. How many days the sugar had -been present before admission to the hospital we cannot say, but we -could trace the failure of vision back to almost the day of its onset, -which was three weeks previous to our first examination. The eye -symptoms were the only complaints. The patient had had a moderately -sharp attack of influenza a little over two weeks before the first sign -of failure of vision had appeared. We may add that the vision returned -slowly to normal several weeks after admission. The urine and blood -sugar were normal, on a general diet, over a period of one month while -in the hospital. Unfortunately, we have had no further record of this -patient regarding the urine, but her vision still remains normal. Cases -of this type were observed in England after the 1890 epidemic, and are -referred to in Allbutt’s “System of Medicine,” vol. i, on influenza. Our -other glycosuria cases did not present changes in the fundus of the eye. -The glycosuria and glycæmia were transient, and we feel that they do not -represent diabetes mellitus. Most of the patients of this class had long -since recovered from an attack of influenza, and came to the hospital -usually for treatment of various nervous conditions, which at times -simulated neuritis, or otherwise one saw manifestations of general -nervousness, not unlike hyperthyroidism. In all probability, we were -dealing with a hyperglycæmia associated with a hyperactive thyroid -gland. So, after all, the glycosuria, even though rare, is not -bewildering. Symptoms and signs of toxic goitre in direct relation to -the epidemic we claim to have seen, and one is justified, temporarily at -least, in having the thyroid gland father our transient glycosuria. - -In relation to the positive sugar findings, we have had numerous -negative examples of almost equal interest. Furunculosis is a very -common sequel of the epidemic. It is well known that in furunculosis -there is a hyperglycæmia, but no glycosuria and no acetone or diacetic -acid in the urine. All our blood sugar readings were above the normal, -and at times unusually high. They varied from .2 to .41. This last -unusually high amount was in a young physician with recurrent -furunculosis following influenza. There was no glycosuria at any time. -Elimination of carbohydrates not only brought the blood sugar to normal -limits in the course of a week, but also assisted in the cure of the -furunculosis, but in a longer time. In all of this group we saw no -incidence of polyuria or glycosuria. - - - _Hematology_ - -There is very little evidence, as shown in the literature, that special -study on the blood during past influenzal epidemics has been made. A few -references to alterations in the count of cells have been reported for -the last epidemic (1890), but they are, as a rule, very brief -statements. Cabot notes a normal leucocyte count in two-thirds of the -cases, and a moderate increase in the rest. Several observers call -attention to the leucopenia during the height of the disease, with a -subsequent rise after the temperature has fallen to normal. According to -Rieder and Herman (American Journal of Medical Science, 1893, cv. 696), -the leucocytes were not increased in simple influenza, and only very -slightly in the pneumonia following this disease. Herman also noticed a -decline in the leucocytes in pneumonia as a fatal ending ensued. This -finding was one of the few recorded for the 1890 epidemic. Emerson -(Emerson Clinic Diagnosis, 1911, 558) found in influenza almost one-half -of the cases showing more than 10,000 leucocytes, some even reaching -25,000. He further notes that early in the disease the count may be low, -3,000 to 5,000, but it usually rose sharply, to fall again when the -temperature comes to normal. He lays stress on obtaining a leucocyte -curve for each case in order to get a true picture of what changes -occur. The past epidemic has brought out many observations on this -subject. They vary somewhat, as is to be expected, but a common factor -seems to be more or less basic—namely, a leucopenia or a normal count is -the most significant single blood picture we have of uncomplicated -influenza. Further, a leucocytosis is fairly generally, and we believe -correctly, interpreted as evidence of a secondary bacterial invasion in -this particular epidemic, and usually of the respiratory system. The -leucopenia is as much a part of the clinical picture of influenza as it -is of typhoid fever. Leucocytosis always means secondary invasion by -other organisms. - -During the recent epidemic the clinical laboratory department of the -School of Medicine, University of Pittsburgh, has made 747 blood counts -on influenza cases. In most of the cases blood counts were made as a -routine, while repeated counts were done only on selected patients. - -The following table indicates the leucocyte count for our series, -comprising the epidemic in all of its phases. There are a few general -points which appear striking that we may refer to at this time, and -leave until later the discussion of the minor details. One-third of the -counts, including, as they do, many cases of pneumonia, showed a -leucopenia, while 70 per cent. of the total number fell under 10,000. -This last group contains more pneumonias and other complications than -simple influenza. But 5 per cent. of the cases counted showed more than -20,000. All of these undoubtedly had pneumonia or some other -complication. Comparing this finding with our experience in the past -before the epidemic with the pneumococcic lobar pneumonia, one sees at -once that, as far as this type of clinical observation is concerned, the -two pneumonias are totally different. The writer remembers but one case -of lobar pneumonia which showed a persistent white count falling below -10,000. Certainly in this community lobar pneumonia and low leucocyte -counts were unusual combinations until the present epidemic. Further, -the evident depression of leucocytosis even where there was an actual -increase is indicated by 95 per cent. of our counts being below 20,000. -This leads us to state that the pneumococcus, although present in -practically all of our pneumonias, produced in only a small percentage -of the bloods we examined its characteristic increase. The toxic factor -of this influenzal epidemic certainly causes a marked change in the -white cells of the blood. - - - TABLE V - - MERCY HOSPITAL │ MAGEE HOSPITAL - ───────────┬──────┬──────┬──────┬─────┬─────┼──────┬─────┬─────┬───── - │ │ │ │ │ │Influ.│ │ │ - Leucocyte │ │Influ.│Influ.│ │ │Influ.│ │ │ - Count. │Influ.│ Pn. │Compl.│Total│ % │ Pn. │ % │Total│ % - │ │ │ │ │ │Influ.│ │ │ - │ │ │ │ │ │Compl.│ │ │ - ───────────┼──────┼──────┼──────┼─────┼─────┼──────┼─────┼─────┼───── - 2000 or│ │ 2│ │ 2│ 38│ 1│ 28│ 3│ 32 - less│ │ │ │ │ │ │ │ │ - 2000–3000│ 3│ 3│ 1│ 7│ │ 13│ │ 20│ - 3000–4000│ 7│ 12│ 4│ 23│ │ 34│ │ 57│ - 4000–5000│ 14│ 13│ 9│ 36│ │ 41│ │ 77│ - 5000–6000│ 17│ 16│ 6│ 39│ │ 42│ │ 81│ - │ │ │ │ │ │ │ │ │ - 6000–7000│ 15│ 13│ 6│ 34│ 40│ 59│ 37│ 93│ 38 - 7000–8000│ 7│ 8│ 5│ 20│ │ 36│ │ 56│ - 8000–9000│ 8│ 14│ 8│ 30│ │ 37│ │ 67│ - 9000–10000│ 15│ 9│ 8│ 32│ │ 39│ │ 71│ - │ │ │ │ │ │ │ │ │ - 10000–12000│ 4│ 12│ 9│ 25│ 20│ 44│ 27│ 69│ 25 - 12000–14000│ 1│ 1│ 8│ 10│ │ 28│ │ 38│ - 14000–16000│ 5│ 3│ 2│ 10│ │ 22│ │ 33│ - 16000–18000│ 3│ 2│ 2│ 7│ │ 16│ │ 23│ - 18000–20000│ 2│ 2│ 2│ 6│ │ 15│ │ 21│ - │ │ │ │ │ │ │ │ │ - 20000–22000│ │ 1│ 1│ 2│ 2│ 4│ 5│ 6│ 3 - 22000–24000│ │ │ 1│ 1│ │ 8│ │ 9│ - 24000–26000│ │ │ 1│ 1│ │ 4│ │ 5│ - 26000–28000│ │ │ │ │ │ 2│ │ 2│ - 28000–30000│ │ │ 1│ 1│ │ 3│ │ 4│ - │ │ │ │ │ │ │ │ │ - 30000–32000│ │ │ │ │ │ 3│ 3│ 3│ 2 - 32000–34000│ │ │ │ │ │ 3│ │ 3│ - 34000–36000│ │ │ │ │ │ 3│ │ 3│ - 36000–38000│ │ │ │ │ │ │ │ │ - 38000–40000│ │ │ │ │ │ 1│ │ 1│ - 40000–42000│ │ │ │ │ │ 2│ │ 2│ - │ │ │ │ ———│ │ ———│ │ ———│ - │ │ │ │ 287│ │ 460│ │ 747│ - ───────────┴──────┴──────┴──────┴─────┴─────┴──────┴─────┴─────┴───── - -The blood picture in uncomplicated influenza is a normal one for the red -cells and the hæmoglobin, but the white cells are characteristically -altered. We have made many observations on the red blood cells, and from -all aspects the picture appears to be normal. Similarly, there is -nothing significant about the hæmoglobin estimations. Where we have -slight alteration in the red count and in the hæmoglobin it is probably -safer not to attribute the change to the epidemic. We have no records -showing a secondary anæmia due to the initial epistaxis. - -A leucopenia or a normal count is what one should see in most of the -uncomplicated influenzal cases. We are almost ready to say that any -estimation above normal limits means secondary bacterial invasion. The -count may remain low throughout the illness, rising to the normal -rapidly as the temperature falls. We do not regard a leucocytosis at the -end of an epidemic case as part of the blood picture. Our experience is -that with convalescence the normal count returns and remains within -normal bounds. Very often hidden sinus infection is responsible for some -of the post-influenzal leucocytoses. The leucopenia may vary from a -slightly subnormal count to a point well below 2,000. Most of the simple -epidemic cases showed some degree of leucopenia. As far as we have been -able to estimate, we are led to believe that one should not lay any -special stress on the grade of leucopenia as being of prognostic -significance in uncomplicated influenza. Many of the mildest clinical -types showed very low counts, and _vice versa_. There is, however, a -prognostic relation to be noted with reference to a falling white count -in the pneumonia, but this we shall mention again later. The onset of -the leucopenia corresponds to the onset of the disease. It was present -with the earliest cases we examined, and remained fairly stationary, -although we have records of its fluctuating slightly one way or the -other. But one must remember in this regard the personal error in blood -counting, and also particularly the error of the apparatus. For careful -work only those counting chambers and pipettes should be used that have -a Bureau of Standards certificate. The duration of the leucopenia was -fairly close to the duration of the disease. - -How many cases of influenza of several days’ illness having about 12,000 -leucocytes, a few sticky râles in the chest, but no signs of definite -consolidation, have been observed by the clinicians? These cases recover -without further change, and the diagnosis is handed in as influenza -without a complication being mentioned. In collecting the blood reports -from this group the 12,000 cells accordingly must be considered as -having occurred in a simple influenza. We hold that this is not a case -of uncomplicated epidemic disease. There is undoubted evidence, as is -acknowledged by the clinician, of a bronchiolitis; and how many lungs -showing a bronchiolitis at autopsy fail to have a broncho-pneumonia? -True it may not be demonstrable by our physical examination. This is -often the origin of many high counts in what apparently is considered -uncomplicated influenza. - -The blood picture of the pneumonia following the epidemic was more or -less constant, although at the same time the features of the count may -be quite different. One could roughly divide the results into three -groups: (1) leucocytosis, (2) leucopenia, (3) intermediate or normal. -Some pneumonias could be followed during their course through all of -these classes. Before discussing the white count we can briefly dismiss -the other phases of the blood examination by stating that the red blood -cells and hæmoglobin presented nothing by the usual examinations which -was of special significance, or in any way characteristic. - -As an example of the group showing a leucocytosis let us follow a -patient through an acute influenzal attack, followed by a pneumonia with -a subsequent recovery. An initial leucopenia, gradually or suddenly -changing into a very moderate leucocytosis (10,000–15,000), was noted at -the onset of the pneumonia. During the course of the complication the -number of cells in the majority of cases increased, but rarely advanced -beyond 20,000. With lysis or crisis the count dropped toward normal, and -by the time the lung signs had disappeared the white cells were at the -usual number, or very slightly increased. The point which seemed to us -to be of importance was that, even although we had a leucocytosis, it -was nothing like the count that one would expect for a lobar pneumonia. -Of course, there were a few high counts, but looking at the group as a -whole they were relatively low. There are a number of variations to this -form of blood picture which we might briefly consider. We have observed -secondary rises in the leucocyte count concurrent with a new lung -involvement. This type was the one so prone to develop into a condition -of non-resolution, fibrosis and ultimate death, with a continuous -moderately high leucocytosis to the end. Another variation which we -learned to fear was the fall of leucocytes to normal or subnormal after -a primary rise, when the clinical course of the case in no way indicated -a crisis or lysis pending. Seemingly, the longer the primary -leucocytosis had been present the more serious was the subsequent -leucopenia. We regard this form of secondary leucopenia, if one may use -such a term, as a prognostic sign of some value. As in lobar pneumonia, -a high leucocyte count has been, as a rule, a favorable feature. - -The second group, or those showing a leucopenia throughout their course, -was by no means an unusual thing. This is a cardinal point—in fact, one -of the most striking clinical features of the epidemic. The leucopenia -here does not have the prognostic value that it seems to have in the -group just referred to previously. We have observed cases go through a -pneumonia with 4,000–5,000 white cells in a relatively easy manner. -When, however, the leucocytes fall to 3,000 or under, one may be -reasonably sure that the outcome is doubtful, even with the general -condition of the patient at the time favorable. In the pneumonias of -this group which died the leucocytes have always fallen to about 2,000 -cells. We have a number of observations taken from one-half to four -hours before death showing counts in the immediate neighborhood of -2,000, but never below this number. Where recovery has taken place the -cells go forward to the normal, more or less keeping pace with the -general clinical picture. - -Of group three there is not much to say, except that on one hand it -tends toward a leucocytosis, and on the other to a leucopenia. This -group comprises a considerable number of the pneumonias. We are not in a -position to say anything regarding the relative mortality of this group. -The development of a leucopenia from these cases after a period of some -stability in the leucocytic curve is of bad prognostic import. Not -infrequently we have noticed rather wild abrupt rises to 20,000 in the -leucocytes toward the late half of the disease. This curve was nearly -always sustained until the end, which, as a rule, was recovery. - -We do not need to consider at any length the effect on the leucocyte -count of complications not of lung origin. Acute sinuses in head, otitis -media and meningitis always produced a variable moderate leucocytosis. -The change was not so marked in meningitis, as our cases were all -preceded by a pneumonia which had independently invoked a slight -leucocytic response. As a complication of the pneumonia we have noted an -abrupt rise following an acute pleuritis with effusion, and similarly -after the onset of an empyema. These complications seemed to be able to -induce a leucocytosis with more certainty and ease than the more serious -pneumonic condition. Possibly, as they occurred toward the end of the -infection, the toxic factor of the epidemic influenza was more or less -spent, and the secondary invader had a freer hand to act in its normal -way. - -Differential counts were made in 194 cases, including influenza, -influenzal pneumonia and influenzal complications. We have taken the -average percentage of each type of cell for the groups, which are purely -numerical divisions based on the leucocytic count. No differentiation is -made for the various clinical divisions of the epidemic in the following -table: - - LEUCOCYTES 2,000–8,000. - P. E. L.M. S.M. Trans. - Total counts 86 66% 1% 13% 17% 3% - - LEUCOCYTES 8,000–10,000. - P. E. L.M. S.M. Trans. - Total counts 33 69% 1% 11% 16% 3% - - LEUCOCYTES 10,000–20,000. - P. E. L.M. S.M. Trans. - Total counts 45 76% 2% 10% 19% 3% - - LEUCOCYTES 20,000–30,000. - P. E. L.M. S.M. Trans. - Total counts 17 79% 2% 8% 7% 4% - - LEUCOCYTES 30,000–40,000. - P. E. L.M. S.M. Trans. - Total counts 13 85% 1% 5% 6% 3% - -The differential count in general indicates an increase in the -polymorphonuclear leucocytes as the total leucocytic number increases. -This is really what one would expect. There also seems to be an increase -of the large mononuclear cells, with a slight diminution in the small -mononuclear elements, particularly in the count below 10,000. Abnormal -cells were encountered very seldom. One can hardly say that the epidemic -has a characteristic differential blood picture, except, perhaps, that -an increase of the large mononuclears is present in the low counts. -This, however, may hold true for any leucopenia. - - - _Conclusions_ - -1. Epidemic influenza is often accompanied by a transient slight -albuminuria with a few red blood cells and casts. Acute nephritis as a -clinical entity does not appear to be other than a rare sequel. - -2. Epidemic influenza tends to produce a leucopenia. - -3. A leucocytosis in influenza, as a rule, indicates a secondary -infection. - -4. The pneumonia following influenza shows, as a rule, but a very -moderate leucocytosis, while, on the other hand, the presence of a -leucopenia is by no means infrequent. - -We are greatly indebted to Miss R. Thompson, Messrs. Mock, Frost, -Marshall and Scott for their assistance in this work at the Magee -Hospital. - - - - - THE TREATMENT OF INFLUENZA - - By W. W. G. MACLACHLAN, M. D. - - -One may frankly say there is no specific treatment for influenza. -Possibly we are in error in introducing the discussion, particularly on -treatment with such a definite and unsatisfactory conclusion. The same -statement has been made after all the previous pandemics, and one -wonders whether a like remark is going to apply to the next similar -scourge. The past two or three months should bring to the medical -profession a certain humility which should stimulate a keener sense of -research, especially as we now have at our disposal highly organized -laboratories where unsolved problems can be viewed from almost any -angle. Yet we are really, save here and there, putting our forces -together in the study of the disease. It is obvious that a fleeting -epidemic makes a most difficult subject for study, especially during a -time when there is a paucity of physicians. May we not hope, however, -that some researches on the disease may be forthcoming, so that we may -safely feel that at least preventive or protective measures will be -possible? - -There is no one who is able to say that this or that drug has not been -thoroughly tried. The alkalies, salicylates, antipyretics, quinine and -the sedatives have all been freely used in the last as well as the -present epidemic. Each group of drugs has its following, although it -appears to be a general rule in this epidemic to use the antipyretics -(coal tar products) as little as possible. From the distant past we have -numerous records of treatment. Willis (1658) emphasized the value of -sweating and the use of diaphoretics, but at the same time he states -that in mild cases the cure is left to nature; Sydenham (1675) claimed -considerable value in fresh air. He also paid more attention to -restricting the diet, and was not favorable to the use of anodynes. One -certainly obtains the impression from the records of past epidemics that -many of the general principles in treatment were similar to what are now -in vogue. Medicinal remedies, of course, varied greatly, but to -enumerate them would be merely giving a résumé of the progress of -therapeutics. Sufficient is it to say that influenza has certainly, -since the earliest days, given therapeutists an ample opportunity to -test their wares. - -The outstanding respiratory complication, pneumonia, has added a very -undesirable phase to the disease. In fact, the greater part of the -mortality was due to this serious sequela. Some interesting points have -been brought out in serum and blood therapy for this type of pneumonia. -The use of whole blood or serum from convalescent patients in cases of -pneumonia opens up a new and not unlikely fruitful means of treatment. -The method of treatment possibly may be applicable as an emergency -measure in other diseases, as has been shown in the case of scarlet -fever and poliomyelitis. We also have the anti-pneumococcic sera -available for therapeutic use. The drugs and the general treatment of -the pneumonia are virtually the same for the last two epidemics. - -The protean manifestations of the 1890 epidemic, with its unusual -nervous sequelæ, have not been seen to any extent, as far as we yet -know. In fact, the present epidemic appears to be relatively free from -complications other than those occurring in the lung during the acute -course of the disease. Hence, in all likelihood, there will be less of -the nervous after effects to be treated. It is, however, too early to -hope that the nervous system is going to escape. - -In another part of this volume the vaccine therapy is discussed in -detail, so that we shall not repeat what has been brought out in that -article. We would, however, emphasize the value of honest and accurate -clinical reports of the use of vaccines, in order to establish their -present status in epidemic influenza. Overestimation and commercialism -are very likely to ruin a method of treatment, even when it may be of -value in a certain phase of the disease. If we do not carefully weigh -the pros and cons of the vaccine treatment in this epidemic from a -purely scientific and coldly neutral attitude, we are simply doing the -public and ourselves an injustice. - -The treatment of influenza as the disease presented itself to us in this -community will be considered under three divisions—acute influenza, -pneumonia, and other complications. - - - _Acute Influenza_ - -There is one important thing to be done in the treatment of influenza, -whether the infection be mild or severe. Have the patient go to bed as -soon as possible. In most of the acute attacks the individual went to -bed of his own accord; but there were, unfortunately, too many instances -where the patient refused to surrender, trying, as we say, to fight the -attack. Some appeared to be able to accomplish this feat. But how many -of our cases of fatal pneumonia can be clearly linked up with this group -of the mild or subacute preliminary course? No matter how light the -attack may appear to be, the patient should be told of the necessity of -remaining in bed until the pulse, respiration and temperature have -returned to the normal and remained normal for at least five days. At -the onset a hot bath, with care to avoid chilling, followed by a drink -of hot lemonade and a Dover’s powder, gave considerable relief to the -patient. - -The value of good nursing cannot be overestimated. The nurse must see -that the patient is always well covered and kept warm, not even -permitting him to rise in bed to reach for a drink; also the regulation -of the temperature of the room should be carefully watched. The main -point is to have plenty of fresh air. We have noticed that the patient -appeared more comfortable if the air was slightly warmed. Water should -be given at regular intervals. Under no consideration should an acute -influenza case be allowed to get up to go to the toilet. - -At the onset, and while the febrile attack is still present, there is -little desire for food—but one does not need to worry about the question -of nourishment in such an acute illness. Milk, cream, cocoa, gruels and -fruit juices may be given at first, and as the fever subsides the diet -increased. We have found that the appetite returned to normal very -readily. In view of the urinary findings indicating a slight transient -nephritis, meat broths are to be avoided until the convalescent stage is -reached. We have been very guarded in recommending cold sponging in -acute influenza. As a rule, it was not necessary. The icebag to the head -is often of great value in the intense headache, which is so frequent. -It is our opinion that in the treatment of uncomplicated influenza what -has just been mentioned constitutes the important part. Most physicians -would agree with this. However, when we advance to drug therapy, we come -into the personal realm of likes and dislikes of drugs and methods of -usage. - -We do not intend in any way to give our views in a dogmatic manner, nor -to touch upon all of the remedies that have been advanced. At the onset -of the disease a moderate calomel purge, followed by a saline, was given -in all cases. We were practically free from the so-called intestinal -type of influenza which was seen in some other communities, consequently -we did not hesitate to use calomel. Castor oil or magnesium sulphate was -given afterward, as was found necessary. Abdominal distention was rarely -seen, and when it occurred a plain soapsuds enema with turpentine was -administered. - -Quinine sulphate (gr. iii-v, three times a day) combined with -phenyl-salicylate (gr. v) was a routine measure. We often noticed -deafness after a very few doses of quinine. It was then discontinued. -Acetyl-salicylic acid (gr. v, three to six times a day) seemed to have a -palliative effect on the severe headaches, although during the height of -the disease the general muscular aching did not appear to be relieved by -its use. It was not used routinely. These drugs possibly made the -patients more comfortable, but we were very skeptical as to their -influence on the general infection. The raising of the leucocyte count -by quinine in influenza appears very unlikely. The use of alkaline salts -has been a general procedure, particularly as we are now on the alkaline -wave of therapeutics. Sodium bicarbonate was added to the drinking water -of all patients (two drams to the quart). We gave this salt for its -diuretic effect. In a few cases more active diuresis by the alkalines -was readily and easily produced by the use of “imperial drink” three or -four times a day. We felt that good kidney elimination was of -considerable importance. - -The use of tartrates and citrates, as in “imperial drink” in a condition -where we know some kidney impairment is present, is possibly flying in -the face of danger—especially in view of the fact that these salts are -so available in the production of experimental nephritis. But we have -only to see their application in the human in mercury bichloride -poisoning, where an intense nephrosis usually develops, to fully realize -that these salts may be given without danger to the kidney. We do not -suggest that the kidney lesions of influenza and mercury bichloride -poisoning are the same. We are merely bringing out this point of analogy -in support of their use in certain desirable cases. - -The respiratory symptoms gave us more concern than any other phase of -the uncomplicated case. The irritating, distressing, non-productive -cough suggested both a sedative and expectorant. Ammonium chloride (gr. -iii-v, t. i. d.) was the usual expectorant. It seemed to increase in -value with the more chronic type of case. It is our impression with -those acute hacking coughs that the sedatives produced more gratifying -results. Elixir terpin hydrate with heroin, codeine and occasionally -morphine were preferred. When good results were noted sedatives were -given liberally. Steam inhalations combined with tr. benzoin co., -followed by spraying the throat with medicated liquid petroleum, gave -some relief. The tendency to œdema, however, as we saw it in the cases -complicated by pneumonia made us hesitate to use inhalations. Possibly -the fear was groundless. Morphine (grs. ⅙) was given for sleeplessness, -and it was repeated if necessary. - -Cardiac stimulants were rarely needed. The tincture of digitalis was the -choice, but in the uncomplicated cases was very seldom used. - -At the beginning of the epidemic we prescribed whisky in almost every -case. Our idea was that it would have a sedative action. At the present -time we are very doubtful of its value. Toward the end of the epidemic -we used it very moderately. The results obtained possibly depended for -the most part upon the type of patient. Some of the soldiers asked to -have it discontinued, not from any moral point of view, while others -wished more frequent doses. The elderly patients seemed to appreciate -this remedial agent to a fuller extent. - - - _Pneumonia_ - -The pneumonia following the original infection was, from the standpoint -of physical diagnosis, often difficult of diagnosis in its early stages. -The infection commencing as an influenza would at times pass -imperceptibly into pneumonia, and obviously the points brought out in -the previous paragraphs on treatment were applied until the diagnosis of -pneumonia had been established. Some new factors were peculiar to the -pneumonia and demanded further changes in the handling of the cases. - -We would again emphasize the value of careful nursing to conserve the -patients’ strength. They should be kept warm, well covered, with plenty -of fresh air. Water should be given regularly and abundantly. The diet -should be light, one depending a good deal upon the severity of the -case. We believe it is safer to limit the diet to fluids while the -infection is still pronounced, but as soon as the crisis has passed one -may increase the diet freely and fairly rapidly. - -Regular elimination from the bowel should be helped by the use of castor -oil every other day, the dosage made to comply with the patient. We -noticed much less abdominal distention in this form of pneumonia than -one is accustomed to see in the ordinary lobar pneumonia. If distention -were present, plain soap enemas with turpentine gave very satisfactory -results. Turpentine stupes also are of considerable value. Rest at night -is needed. When a hypnotic was necessary we gave morphine (gr. ⅙), and -repeated if the desired results were not obtained. - -The day is coming when we are going to isolate our pneumonia cases. This -was almost an impossibility during the stress of the past epidemic, but -we know that temporary and fairly satisfactory methods can be applied. -Many hospitals provided for a type of isolation. In a pneumonia ward -sheets stretched between the beds keep the fine spray which a heavy -cough always produces from spreading over the next two or three beds. -This method is simple and can be easily carried out. We feel almost -certain of having seen convalescent influenza cases develop pneumonia -from the adjacent pneumonia patients. As much as is physically possible, -the uncomplicated influenza and the pneumonia cases should be separated. -Further, it is to be kept in mind that reinfection by another group of -pneumococcus is quite possible, even in a ward containing only pneumonia -patients. - -We did not observe any special effect of quinine, salol, salicylates -after the pneumonia had developed and, therefore, these drugs were -discontinued. Digitalis in the form of the tincture was at first made a -routine measure, but toward the middle of the epidemic we stopped this -routine usage and gave it only as it appeared to be indicated. Our -impression was that the heart was not involved as it is in ordinary -pneumonia. A slow, full pulse, as was so often the rule, did not seem to -require digitalis. For more rapid action of the drug one of the -hypodermic digitalis preparations or strophanthin was given. - -Caffein sodium benzoate or salicylate seemed to be of considerable value -given hypodermically every two or three hours, the last dose at 4 P. M. -Its action as a respiratory stimulant and also as a diuretic was what we -desired to obtain. The drug was used fairly early in the pneumonia, and -although it was never prescribed routinely we gave it frequently. - -Atropine was indicated whenever signs of œdema were evident. Its action -was not always successful, but in certain severe cases we believe that -large repeated doses of atropine saved a few lives. One-fiftieth (1/50 -gr.) grain hypodermically, repeated every hour for several doses, was -usually well borne. We noticed twice in each of two cases after using -small doses (1/100 every four hours) a peculiar rapid cyanosis not -associated with dyspnœa develop. This reaction remained, however, for -only a short time, about 15 to 20 minutes, but it was rather alarming -while it lasted. - -The drug therapy is not very satisfactory in lobar pneumonia, and it is -less so in the form of pneumonia which follows influenza. There is -practically nothing essentially new in the drug and general treatment of -this serious complication over what was shown in 1890, or even in the -earlier epidemics, save that our nursing and hygienic measures are -undoubtedly better. - -The addition of an immune serum (anti-pneumococcus serum No. 1) to the -treatment of pneumonia is a milestone in the history of the handling of -this disease, but we must keep in mind that the pneumonia of the past -epidemic was not the usual pneumococcic lobar pneumonia. That the -pneumococcus was present in a great many cases is shown in another -article of this series, but we also know that the B. influenzæ was -present in many, and that it played an active part in the disease is -evidenced by the constant low blood count or actual leucopenia. A -leucopenia in true lobar pneumonia is most unusual in the United States. -The rarity of Type I pneumococcus was noteworthy. We were practically -unable to get any anti-pneumococcic serum which was known to be of value -at the time of the epidemic, so naturally could not apply this method of -treatment as was desired. About half a dozen 50 cc. bottles were in -possession of the army medical officers here, but they unfortunately -could get no further supply after this was used. We would have liked -very much to have combined the anti-pneumococcic serum in Type I cases -with the citrated convalescent blood, as was used by us during the -epidemic. The anti-pneumococcic chicken serum of Kyes should also be -considered. This serum has had but a very localized trial, but from -competent observers who have given it to a considerable extent in some -of the army camps we are led to believe that it has a very definite -value. Major Lawrence Litchfield informed the writer that he had -observed excellent results with Kyes chicken serum during the past -epidemic in the treatment of pneumonia. This serum was not available for -our use. It is to be hoped that further experience with Kyes serum will -be favorable, because from the practical standpoint in the treatment of -pneumonia it has many commendable features. Again, we desire to point -out that the use of anti-pneumococcus sera in influenzal pneumonia may -not be a fair test of their true value. - -Very early in the epidemic we realized that the pneumonia was of unusual -severity and most difficult to treat satisfactorily. We were at once -impressed by our helplessness, particularly in those patients showing -cyanosis. Nothing we did seemed to vary the course of the pneumonia -after this sign was evident. - -Our work in the epidemic began about October 10 on receiving a large -batch of soldiers, about 100, from the Student Army Training Corps of -the University of Pittsburgh. At the end of the first week several -points were impressed on our mind. Firstly, in the severe cases of -pneumonia; and in the early part of the epidemic most of the pneumonia -was severe, the mortality was excessive, much higher than we have been -accustomed to experience in Pittsburgh, where, as a rule, our hospital -ward pneumonia is a very severe infection. Secondly, the wide variation -in the severity of the epidemic as presented in the student soldiers -coming from identical surroundings and conditions, the mildness on the -one hand and the malignant character of the influenza on the other, was -a very striking feature. This led to our adopting a form of treatment -which was quite successful. - -We worked purely on the hypothesis that those individuals recovering -from a mild or moderate influenza infection developed a higher grade of -immunity than those in whom the disease was more severe or fatal, and -this immunity could be transferred to another. This, of course, was -merely inference. If the mild cases did present a higher immunity, one -would naturally think that immune bodies would be present in the blood, -and that in transfusion from cases which had recovered one might have a -measure of therapeutic value for this epidemic. Recently Spooner, Scott -and Heath and others have demonstrated specific agglutins in the serum -of patients convalescing from the epidemic. On October 17 we gave whole -citrated blood from a convalescent case of uncomplicated influenza to an -influenzal pneumonia patient. The result in this case was strikingly -good, and for the following five or six weeks this method was frequently -used. We decided to give the whole blood instead of the serum, as we -were able to treat the cases more readily and rapidly in this way. Our -method of transfusion was, fortunately, very simple. - -We had treated but a few cases when the report of McGuire and Redden -appeared. These observers working in the Naval Hospital at Chelsea, -Mass., presented very excellent results in the use of immune serum from -convalescent influenza cases in the treatment of pneumonia. They -reported 30 recoveries out of 37 cases, with 1 death, and 6 cases still -under treatment at the time of their report. This form of treatment -began at Chelsea on September 28, 1919. In Texas, on October 15, Brown -and Sweet gave two cases of influenzal pneumonia citrated blood from -convalescent influenza patients. Their two cases recovered. Our -published results, although not showing such excellent figures as from -the Chelsea observers, agree very well with their work. - -Since that time a number of confirmatory reports have been brought -forward. Ross and Hund have shown that this method has been of value in -their hands, and recently a further statement from McGuire and Redden -tends to confirm their first views as to the value of immune serum from -convalescent patients. Their last report giving a mortality of 6 in 151 -cases of pneumonia cannot be other than positive proof of the value of -this method of treatment. - -As the technical side of the work has been given in several articles, we -hardly think it necessary to again review it in detail. A few phases -should, however, be recalled. It would seem that either serum or the -whole citrated blood may be used. Solis-Cohen and his group of workers -believe that whole blood has stronger bactericidal properties than -defibrinated blood or the plasma. But yet one cannot complain, even on a -theoretical basis, against the results obtained with serum by McGuire -and Redden. The use of whole blood increases the detail of the -procedure, in that the agglutination reactions must be estimated. -Unfavorable results in this regard also naturally cut down the supply of -available donors. In a military hospital a dearth of donors does not -arise, but in civilian practice the problem is very different. In our -work we never gave more than 100 cc. of whole blood; usually the amount -varied between 50 cc. and 75 cc. On account of the small amount we felt -that isoagglutination would not be a serious factor, and in more than -200 injections we failed to see any evidence of ill results from this -source. Giving up to 500 cc., as was done by Ross and Hund, is probably -a different affair, and accurate agglutination tests are essential. We -feel that if the case is treated sufficiently early in the disease as -much good can be shown to occur after 50 cc. as after 100 cc. of blood. -We do believe, however, that the pooling of sera, where one is able to -carry out this method, as it means a liberal supply of donors, is really -the method of choice. Syphilis must be ruled out, both clinically and -serologically. - -As we emphasized previously, the problem presented in the army hospital -and in civilian practice is a little different. We have had some -experience with both sides. Fortunately, the greater part of our work -was with the Student Army Training Corps, where army conditions were -more or less carried out. There was never any difficulty in getting -donors. In fact, the idea of giving blood appealed to these young -fellows. In civilian life it is, in our experience, a more difficult -problem. The usual personnel of the public ward has always its fair -percentage of positive Wassermann reactors, and the type of individual -is quite different from the young soldier. For a relative or friend we -could easily get a donor, but this group would cover only a small -percentage of the cases one wished to treat. The technique of giving -blood can be reduced to a very simple procedure, and by no means should -be regarded as a difficult surgical undertaking. Combining the receiving -apparatus of Ross and Hund (J. A. M. A., 72, 1919, p. 642) with the -syringe method for giving the blood which we suggested in our previous -article makes an ideal arrangement. - -The results depend upon the time of treatment. The earlier the pneumonia -is recognized the better are the chances of recovery. It is our belief -that the majority of influenza cases which kept a fairly high -temperature for more than four days had a lung lesion, even if we could -not make out definite consolidation. As the convalescent influenza serum -may have value only for the influenza infection, it would, therefore, -appear but logical that a late pneumonia which almost always has other -organisms present would not react as favorably. We have seen very few of -the deeply cyanotic type recover even with serum. The essential rule is -to treat them before this stage develops. - -We have observed little or no change in the leucocyte count, even after -successful treatment, and taking our group as a whole we are rather -surprised at this result. Other observers have noticed a marked increase -in the leucocytes as the case reacted favorably to the injections. We -agree with McGuire and Redden that the patients with counts below -10,000, as a rule, show the best results. This possibly indicates that -the influenza infection is predominating, and that the usual secondary -invaders (pneumococcus and streptococcus) are at this time playing but a -little part. Hence the value of early treatment is apparent. - -From the published results of different workers and our own experience, -we feel that influenza immune serum or whole citrated blood given early -in the pneumonia is of undoubted value—in fact, almost specific. If the -epidemic reappears next year, unless some other better method is -forthcoming, we would advise its more general use, and would suggest the -collection of pooled serum as early as possible in the epidemic. - -At the end of this article there is appended a series of our ward record -charts of patients who developed pneumonia following the influenza. -These charts are shown to indicate the results of giving immune -convalescent citrated blood in pneumonia. The ones presented are from -some of the group which recovered. We have, of course, the charts from -the fatal cases, but as they do not bring out any special point, save -that there was little or no change after treatment, we are omitting -them. It is not our idea, however, to give the impression that we have -had nothing but success with this method of treatment. It might be well -to emphasize some of the salient points which are brought out. - -(1) The regularity of the drop in temperature after the injection is -almost generally demonstrated. - -(2) The occasional chill following the injection seemed to have no -untoward results. - -(3) The leucocytes show, as a rule, little or no variation after -transfusion. Our work agrees with McGuire and Redden’s statement that -the cases with a leucocyte count under 10,000 give the best results with -immune serum. - -(4) The time of injection in many of the cases was by no means ideal, in -that the disease was advanced; and again in many the injection should -have been repeated sooner. This, however, is no fault of ours. - -(5) One injection of 50 cc. of citrated blood from a good donor, if -given early enough, may be all that is necessary. Several charts bear -out this statement. - -(6) The day of disease is dated from the onset of the influenza. The -demonstrable signs of pneumonia correspond roughly to the initial rise -in temperature following the influenza. The day of disease of the -pneumonia is not indicated on the chart, as this information we have -obtained from the daily notes. - - - _Complications_ - -The epidemic was well spent before we observed many complications, save -those referable to the lung. Later various forms of sequelæ have been -appearing. One must guard, however, against the danger of attributing -all of our ills to the past epidemic. We are not going to give in detail -the treatment of these various conditions, nor even mention all of the -many complications. The main points, however, we desire to emphasize. - -We have previously considered pneumonia, which is the principal -complication with simple influenza, and the two are closely allied. As -an end result of the pneumonia, non-resolution and fibrosis of the lung -are of first importance. We cannot say very much on the treatment of -this condition. The duration varied from a few to several weeks, and -recovery was infrequent. Our treatment aimed at supplying as much -nourishment as was possible to give, with, in addition, good nursing. -The treatment otherwise was purely of a general hygienic type. Tepid -sponging appeared to give considerable relief from the profuse sweating -these patients so often had. Drugs were of value only for some local -effect. We wonder if carefully handled vaccine therapy at the onset of -such a complication might not prove of some value. The autogenous would -be the one of choice. - -Empyema was not found to be as prevalent as one would imagine. With so -much non-resolution of lung following the pneumonia we were surprised to -see so little empyema. All delayed resolutions we explored with the -needle, so we feel that the condition, if present, would have been -recognized. The treatment of empyema need not be given any special -emphasis. It is, as of old, a surgical affair. One or two new points in -the technique have been brought out in the way of drainage, but possibly -they have not been sufficiently tried to lay any stress upon them at -present. Dakin’s solution in certain chronic cases appeared of value. -Our empyema cases did well. - -Pleurisy with effusion was observed a number of times, although it has -been our experience to find a very few large effusions. Pleural puncture -often gave negative results, even when the signs did appear to indicate -the condition. We aspirated the fluid when present. The end results were -always good. In only one case did we have to repeat the aspiration for -reaccumulation of fluid. - -Chronic bronchitis, accompanied at times with considerable dyspnœa, has -been seen on several occasions. There is very likely associated with -this condition some fibrosis of lung, and probably some organization of -small bronchioles themselves. Expectoration has been variable, profuse -or scanty, mucoid or purulent. We consider rest in bed, with as full a -diet as possible to build up the general condition of the patient, the -best form of treatment. These cases had little or no temperature, and -consequently at first absolute rest was not considered necessary, but we -now regard it as the essential part of the treatment. Atropine and -heroin are of value at certain times. We confess to have seen very -little benefit from the expectorants. We are rather surprised that this -sequela is not of more frequent occurrence. - -Phlebitis, in our series usually of the formal vein, occurred about as -often as it does in typhoid fever. The end result, however, is much -better than in typhoid. We have seen only one case where “the milk leg” -has resulted. Rest and elevation of the limb were all that we required. -In the acute stage, if pain was present, a light, carefully applied -icebag was added. It is important to rest the limb for at least two or -three weeks, and to caution the patient against remaining on the feet -too long for some weeks after recovery. - -We saw a great deal of acute sinus infection, often occurring even while -the attack of influenza was present, but, as a rule, this complication -followed the attack. At times several weeks intervened. The ethmoidal -sinuses are most susceptible, but a considerable number of acute frontal -sinus infections were noted, the latter often immediately following or -occurring during the acute period of the influenza attack. The majority -of these infections appeared transient, and disappeared with a little -local treatment. In fact, in frontal sinusitis cold applications seemed -to be all that was necessary. With some of the more chronic infections -nose and throat surgery has been followed by relief of symptoms. Acute -suppurative otitis media, considering the number of influenza patients, -was not common. Ear drum puncture was done if necessary. We saw one case -of acute mastoiditis develop. The mastoid process was opened and -drained. - -Acute suppurative meningitis, following or associated with pneumonia, -appeared on three occasions. The pneumococcus was cultured from the -spinal fluid in all cases. Anti-pneumococcus sera intraspinally (Type I -or the Kyes serum) should be given. The Type I serum is of value in a -similar group infection. We have had no experience with this method, but -some recoveries from pneumococcus meningitis have been reported after -the early use of serum given into the spinal canal. - -Following the 1890 epidemic cases complaining of blindness or partial -loss of vision, with optic œdema or neuritis and a glycosuria, were -occasionally observed. We have seen one of this type, and several -transient glycosurias without eye signs or symptoms. The glycosuria may -be of nervous origin. Our method of treatment was one of elimination and -rest. The gastro-intestinal tract was emptied with calomel, and -afterward a morning saline was given for a few days. Hot packs were -administered, one a day for about two weeks. The patient was instructed -to drink as much water as possible, and we eliminated sugar, bread and -the 20 per cent. vegetables from the diet. The glycosuria lasted for -three days, while the vision, although beginning to improve at once -after treatment, took five weeks to return to normal. The patient was -kept in bed for three weeks. How long the glycosuria had been present -before admission to the hospital we do not know. The transient -glycosuria group without the eye manifestations required very little -treatment. They also showed a transient hyperglycemia. A carbohydrate -free diet very rapidly cleared up these cases. After a time we decided -to watch the course of this group on a non-restricted diet, even with -sugar, and we found that they all returned to normal (blood and urine), -in a few days clearly indicating their transient nature. We do not -regard this process as a diabetes mellitus. We do not give the hot -packs, although free elimination by bowel was attained in all. These -cases were recognized only through routine urine examination. - -Furunculosis with a high blood sugar, in one case 0.41, without -glycosuria was a very interesting complication. We saw a great deal of -furunculosis, always with the increased blood sugar from 0.2 to 0.3, but -never with glycosuria. Reducing the carbohydrates, or even a fast day -with good intestinal elimination, had excellent results. - -Neuritis and general debility have often been associated with nasal or -tonsilar infection, which when surgically corrected led to the -disappearance of symptoms and improvement of health. - -Finally, we wish to refer to an isolated case of acute osteomyelitis -which was incised, and from the purulent fluid present in the bone B. -influenzæ was grown in pure culture. This is a very unusual -complication, and is of particular interest on account of the positive -bacteriological finding. The patient made an uneventful recovery. - - McGuire and Redden Jour. A. M. A., 1918; lxxi, p. 1311. - McGuire and Redden Jour. A. M. A., 1919; lxxii, p. 709. - Brown and Sweet Jour. A. M. A., 1918; lxxi, p. 1565. - Ross and Hund Jour. A. M. A., 1919; lxxii, p. 640. - Spooner, Scott and Jour. A. M. A., 1919; lxxii, p. 155. - Heath - Maclachlan and Fetter Jour. A. M. A., 1918; lxxi, p. 2053. - Heist and Cohen Jour. Immunol., 1918; iii, p. 261. - Kyes Jour. Med. Res., 1918; xxxviii, p. 495. - -[Illustration] - - - - - THE PREVENTION OF EPIDEMIC INFLUENZA WITH SPECIAL REFERENCE TO VACCINE - PROPHYLAXIS - - By SAMUEL R. HAYTHORN, M. D. - - - INTRODUCTION - -In developing practical measures for the prevention or control of -influenza epidemics, preventive medicine faces one of the most difficult -problems of modern times. By means of quarantine, protective vaccination -and instructions in personal hygiene many of the diseases which formerly -ravaged the world have been brought under control. At first glance it -would seem to be a simple matter to apply the principles which we have -found successful against these diseases to influenza and let it go at -that, but in the recent epidemic many of the formerly successful -measures were tried and found to be either inefficient, inapplicable, or -at least of doubtful value. - -During the pandemic there was little time to think collectedly, and no -time to analyze procedures, and even now it is far from easy to -determine what things were done wisely and what things were of no -practical value. There exists the greatest difference of opinion as to -what measures should again be used when the need arises, and what ones -should be discarded. For instance, there are confirmed exponents of -prophylactic vaccines, and equally able men who are convinced of their -uselessness; enthusiastic advocates of the face mask, and almost as many -objectors; those who would close schools, churches, theatres, etc., and -those who claim that such measures serve only to prolong the epidemic. -One naval officer is said to have stated that he had accumulated figures -either to prove or to disprove the usefulness of any preventive measure -yet recommended. There is, in short, a chaos of opinions with followers -who vary from the one extreme of believing there is “virtue in all -things” to those of the other extreme who state that every susceptible -person develops the disease in the degree of his susceptibility, -regardless of any and all preventive measures used. While there remain -so many points on which definite, concrete knowledge is lacking, and so -much controversy over the relative value of various measures, this paper -can do little more than state the facts and discuss their bearing on -prevention as impartially as possible. - -Great progress has been made in controlling contagious diseases in -recent years—a fact which can be easily verified by anyone who will -compare the sick reports of the Great World War with those of any war -previous to the beginning of the present century. The diseases which -have been most easily controlled have been those against which -prophylactic vaccines or prophylactic sera have been developed. -Smallpox, dysentery and typhoid fever have lent themselves readily to -control by protective vaccination, while reliable temporary immunity can -be afforded by the administration of sera for protection against -diphtheria and tetanus. These are by no means all, but are probably the -most striking illustrations; and with such examples before us, the -greatest hope for the prevention of influenza apparently lies in the -development of a prophylactic vaccine against it. - - - _History of Prophylactic Vaccination in General_ - -The name vaccine came from “vacca,” or cow, and was originally applied -by Jenner (1796) to the virus taken from cowpox pustules for -prophylactic inoculation against smallpox. It has come to be loosely -applied to all forms of preventive inoculations except sera. We have, -therefore, a variety of vaccines which differ in their nature and method -of preparation. Some are produced by growing the virus in insusceptible -animals, some are composed of attenuated viruses, and most common of all -are the bacterial vaccines, sometimes called “bacterins,” which are -prepared from killed cultures of bacteria. Sera are used in prophylaxis, -as well as treatment, and are made by bleeding and separating off the -serum from animals which have been immunized against the cause of the -disease in question. Sera and vaccines are wholly different products, -and the distinction should be made in discussing them, although there is -a common tendency, particularly among lay writers, to use the words -interchangeably. Smallpox is the classical example of a disease which -can be completely controlled by universal vaccination. The parasite -causing smallpox has never been certainly demonstrated, but over a -century ago Jenner showed that cowpox, a localized, non-fatal disease, -protected against smallpox. Modern methods have proven that a cow -inoculated with smallpox virus develops cowpox, and that thereafter the -virus loses its power to produce smallpox when it is returned to man. -Instead, it causes a local pustule, and confers immunity to smallpox -over a considerable length of time. Rabies is another example in which -the exact cause of the disease is still in doubt, and in which a -protective vaccine has proven of great value. Rabies vaccine was -developed by Pasteur, and is prepared by drying the spinal cords of -rabbits that have been killed by a highly virulent rabies virus. -Typhoid, dysentery, pneumonia and several other diseases of known -etiology have been more or less controlled by the use of vaccines made -from their respective bacterial causes. These vaccines are of the -“killed bacteria” type of vaccines, and credit for their application to -human disease belongs to Sir Almroth Wright (1896). The preparation of -bacterial vaccines is very simple. Bacteria which are known to cause a -certain disease are isolated in pure culture, grown on artificial media, -killed either by chemicals or heat, standardized either by counting, or -drying and weighing, and suspended in salt solution for subcutaneous -injection. Salt suspension vaccines are usually given in three or four -increasing doses, about one week apart. Le Moignic and Pinoy (58) first -elaborated a lipovaccine for triple typhoid vaccination, which was used -extensively in France during the war. Whitmore, Fennel and Peterson have -recently also advised the drying of killed bacteria and the suspension -of them in oil. This method makes it possible to give a single massive -dose of bacteria which is sufficiently large to completely immunize the -individual against the disease, and which prolongs the immunizing period -by allowing slow absorption over a period of several weeks. These -vaccines are called lipovaccines, have been adopted in the United States -Army as the standard typhoid vaccine, and promise in time to supersede -the salt suspensions entirely from a commercial standpoint. Many other -modifications in the preparation of bacterial vaccines have been -advised, notably the class known as sensitized vaccines. These are -prepared by incubating bacterial vaccines for a time with the serum -taken from animals already immunized against them. The serum apparently -absorbs many of the toxic substances, and permits the injection of more -efficient doses. Besredka advised the use of living cultures which had -been incubated with immune sera, on the basis that vaccines so prepared -were very active and non-toxic. The sensitizing treatment, however, does -not stop the growing powers of the bacteria, and vaccines of the -Besredka type are generally considered dangerous and so are little used. -Sensitized killed bacterial vaccines, on the other hand, are quite -popular. - -When a sufficiently large dose of vaccine is given to an individual -there is usually a transient rise in temperature for from 12 to 48 -hours; the local focus of injection becomes sore and inflamed, and a -white count often shows an actual increase in the number of -polymorphonuclear leucocytes in the general circulation. A series of -doses are usually given. If after a few days blood is withdrawn from the -patient and immuniological tests made, it will generally be found that -the patient’s leucocytes take up bacteria, and particularly the type of -bacteria of which the vaccine was composed, more readily and in greater -numbers than the leucocytes of the ordinary individual. Wright and -Douglas (52) and Neufeld and Rimpau (53) have shown that this effect of -increased phagocytosis is brought about by the vaccine through the -production of substances which act specifically on the bacteria and -render them more susceptible to inclusion within the white cells. These -substances belong to the group of antibodies, and are known as -“opsonins” or “bacteriotropins,” and are specific for any given -bacteria. Moreover, the serum of the patient will, as a rule, be found -to have developed the faculty of agglutinating and bacteriolysing -suspensions of the specific organism injected and of fixing complement -in the presence of an antigen prepared from that organism. In animal -work it has been possible to go still farther, for it can be shown that -the resistance of the animal can be raised until it is no longer -possible to kill it with the same dose which is found to be fatal for -the unimmunized animals. Not only has animal work made it possible to -determine the protective powers of vaccines, but it has also served to -show the specific nature of the protective power and the relative extent -to which “group” or “crossed” protection can be conferred by vaccinating -with closely allied organisms—as, for instance, paratyphoid bacilli in -typhoid fever. The non-toxic nature of vaccines is also determined by -animal experiment before such preparations are injected into humans. - -The most successful prophylactic bacterial vaccine which has been -developed so far is that for typhoid fever. A comparison of the -occurrence of typhoid fever in the United States Army before and since -the use of anti-typhoid vaccine is all that need be cited to convince -one of its value. At the time of the Spanish War there was no -vaccination against typhoid fever, and there were 20,738 cases, with -1,580 deaths, among 107,973 men who remained in the camps in the United -States during the war (54). - -During the summer of 1911, the maneuver division of the United States -Army, having 12,801 men, all of whom had been vaccinated against typhoid -fever, were stationed at San Antonio, Texas. Two cases of typhoid fever -developed among them, and neither case died. Among the civilian -population of the city, living under usual conditions during the same -time, there were 49 cases of typhoid fever, with 19 deaths. Since 1912, -typhoid vaccination has been compulsory in the United States Army, and -the largest epidemic of typhoid fever which I have found reported so far -during the late war was that at Camp Greene (55), Charlotte, N. C., -where 18 cases developed. Only 12 of these men had received the complete -series of immunizing doses. For a complete discussion of the value of -typhoid vaccine the interested reader is referred to Gay’s Monograph -(56) on typhoid fever. - - - _Prophylactic Vaccination Against Influenza_ - -The hope of finding an early solution to the vaccine problem in -influenza appeared to be in the development of a prophylactic “bacterial -vaccine” similar to that which proved so efficient for typhoid. In his -discussion of the vaccine problem in pneumonia, Fennel pointed out that, -theoretically, any disease of microbic origin in which spontaneous -recovery is at all possible should yield to specific prophylactic -measures. The difficulty, however, of preparing a bacterial vaccine for -influenza comparable to that for typhoid fever is that the unquestioned -cause of influenza has yet to be determined. The probable cause of -influenza is the Pfeiffer bacillus, but its relationship has not been -proven beyond question. On the other hand, the innocence has likewise -not been proven, as Dr. Holman in his article of this series has ably -shown. It is not my intention to go deeply into the question of -etiology, but simply to bring out a few points which _a priori_ seemed -to indicate that the reasonable solution of vaccine prophylaxis was in -the preparation of a pure Pfeiffer bacillus suspension. - -The experiments in man lead to very surprising results. Rosenau, Keegan, -Goldberger and Lake, at Gallops Island, Boston, Mass., (1) inoculated -volunteers with pure culture of B. Pfeiffer, with secretions of the -upper air passages and with blood from typical cases of influenza. -Sixteen men, of whom 13 were supposedly non-immune, had Pfeiffer bacilli -installed into their nasal passages, and none of them developed the -disease. Secretions filtered and unfiltered also gave negative results. -Contact with well-developed early cases also failed. McCoy and Richey -(1a) conducted similar experiments in San Francisco, with negative -results. The men of the latter group had been vaccinated with a mixed -streptococcic vaccine, which may have played some part. Had the -experiments with the Pfeiffer bacillus been negative and the other -experiments positive, they would have shown that the bacillus of -Pfeiffer was not the cause of influenza; but since all attempts were -negative, it merely brought out the fact that there had been a change, -due probably to some immune factor, which seemed to have acted alike on -the Pfeiffer bacillus and all other types of virus present, and to have -made them all innocuous. These experiments still leave the cause of -influenza in question. - -Those who are opposed to the Pfeiffer bacillus being the cause of -influenza in its epidemic form base their position on the points that -the common finding of the bacillus might be accounted for on the grounds -of its being a secondary rather than a primary invader; that while it is -not so common at ordinary times, it does occur with other organisms in -whooping cough and sometimes in chronic diseases of the air passages, -and that the rules of Koch have not been complied with in that the -organism has not been found in every case of the disease; that where it -has been grown in pure culture and inoculated into man and animals, it -has either produced no disease, or the lesions which followed have not -been typical of epidemic influenza. On the side of those who believe -that the Pfeiffer bacillus is the chief cause, or, at any rate, that it -is partly responsible for epidemic influenza, are the facts of its -fairly constant presence in the purulent bronchial secretion of patients -suffering from epidemic influenza; its relatively uncommon occurrence at -other times; its known pathogenicity in occasional cases of meningitis, -and in the inflammation of the bony sinuses of the head and face; the -relative immunity of nearly all common laboratory animals and the fact -that the attempts to transfer epidemic influenza from man to man failed -not only when Pfeiffer bacilli were used, but also when direct contact -and direct coughing by the patient into the face of the volunteer were -tried. The argument that many cantonment laboratories failed to find the -organisms loses weight when we find that the percentage of positives -increased where the material examined was removed directly from the -lungs at autopsy, where special cultural methods were in use and where -the laboratory personnel was large enough to devote a sufficient amount -of time to each individual culture. All of these points indicate that -the organism was overlooked in a great many instances. In our laboratory -we found the examination of sputa very unsatisfactory because of the -great amount of contamination, and because the bacillus seemed to lose -its ability to grow after a relatively short time in the sputum in -vitro. Moreover, I am convinced that the bacillus changes its morphology -to such an extent under varying conditions as to make it impossible of -identification when present among other organisms in sputum smears. The -failure of animal inoculations is also not conclusive evidence against -the Pfeiffer organism, because guinea pigs, rats and mice have a natural -immunity for them. Rabbits are only slightly susceptible, and then only -to intravenous injections. The mixture of the Pfeiffer bacillus with any -one of several other pathogenic organisms will increase the -pathogenicity of both. Monkeys inoculated intracranially develop a -typical Pfeiffer bacillus meningitis. - -Whatever the ultimate outcome of the investigations as to the parasitic -cause of epidemic influenza, the Pfeiffer bacillus was the generally -accepted cause at the beginning of the 1918 epidemic, though it was at -once realized that most of the deaths were due to complicating -pneumonias and to secondary infections with other organisms. Under the -circumstances, one of two courses was open: (a) the acceptance of the -Pfeiffer bacillus as the presumptive cause of influenza and the -preparation of a specific prophylactic vaccine against infections with -that organism; or (b) the use of a mixed bacterial vaccine containing -the common and most deadly secondary infecting organisms, designed to -increase the patient’s general resistance by decreasing his -susceptibility to the allied, collateral and secondary infecting agents. -Attempts were made along both lines, with more or less unsatisfactory -results. - - - _The Attempt to Develop a Specific Prophylactic Vaccine by the Use of - Pure Pfeiffer Strains_ - -By a specific prophylactic vaccine for any given disease, we mean a -material which when inoculated into an individual will actively protect -that individual against the given disease. In infectious diseases, the -immunizing material is usually of microparasitic origin (in contrast to -desensitizing substances used in pollen diseases and those due to -unusual sensitiveness to foreign proteins), and is specific only for the -disease caused by the microparasite from which the material was -prepared. With the knowledge in hand during the epidemic, the logical -plan seemed to be to prepare a pure Pfeiffer bacillus vaccine, the -object of which was to eliminate primary infection with that organism -and thus prevent the secondary invaders from obtaining a fertile soil. - -While specific Pfeiffer bacillus vaccines had been tried in treatment, -the field was a comparatively new one so far as prevention was -concerned. Many of the biological products companies had so-called -influenza vaccines on the market for treatment purposes, and many of -these contained Pfeiffer bacilli. A few preparations of pure strains of -the bacilli were also available, but I was unable to find any records of -their use for prophylaxis. Lacy (2) reported two cases of sinusitis -treated with autogenous vaccines made from pure Pfeiffer strains—one -patient improved rapidly and the other showed no change. Investigation -of several of the other references on influenza vaccines showed that -mixed vaccines had been used in each instance. The work of Flexner and -Wolstein (3, 4 and 5) indicated that active immunizing substances could -be prepared from the Pfeiffer bacillus, although they worked with serum -instead of vaccines. They prepared an anti-influenza-meningitis serum by -immunizing goats and horses. These sera cured monkeys of experimentally -produced influenzal meningitis. The sera showed agglutinins and -bacteriotropins for Pfeiffer bacilli, as well as positive fixation tests -in dilutions of 1 in 100, but they contained no lysins. The serum was -offered for intradural use in treating influenzal meningitis, but was -found to have no value when used in human cases. - -The first references which we have found on the use of pure Pfeiffer -bacillus vaccines for the prevention of epidemic influenza were those of -Leary (6), (7), and of Rosenau (8). Shortly after the appearance of the -first influenza cases in Boston, Leary used a vaccine prepared from -several strains of Pfeiffer bacilli both for the treatment of influenza -and for its prevention. The vaccine for the latter purpose was given to -medical students and nurses, and the first results were apparently very -encouraging. Continued use has not been convincing. Barnes (9) reported -an attempt to protect the employees and patients of an institution near -Woonsocket. On October 9 a case of influenza developed in the female -ward, and was followed five days later by another. On October 22 the -disease appeared in the male ward, and the same day 172 employees and -patients were given their first inoculation with Leary’s vaccine. Doses -of 400, 800 and 1,200 million bacilli were given at 24–hour intervals. -All persons who had developed influenza before the three doses had been -completed were excluded from the computation of the disease incidence, -which was found to be 20 per cent. both among vaccinated and -unvaccinated individuals. The mortality rate was 16 per cent. for the 25 -cases among the vaccinated, and 15.8 per cent. among 57 unvaccinated -patients. The result failed to show any protective qualities for the -vaccine. - -The best controlled vaccine experiment in which Leary’s vaccine was used -was that reported by Hinton and Kane (10), and was carried out at the -Monson State Hospital for epileptics. The hospital had a population of -979 inmates, ranging from 4 years of age to senility; of these 461 were -vaccinated and 518 were not. Vaccination was begun on October 6, and -three doses of 400, 800 and 1,200 million were given at 24–hour -intervals. The first case of influenza developed a few hours after -vaccination was completed, but there were no more cases before October -12, when five cases developed. The table shows the result of the work, -and that the vaccine failed to protect. - - Population. No. of % of No. of % of - Cases. Cases. Deaths. Deaths. - Vaccinated 461 163 35.4% 28 17.1% - Unvaccinated 518 178 32.4% 24 13.4% - -Attempts to protect by the use of Leary’s influenza vaccine were made in -11 other Massachusetts institutions, but the results cannot be used to -compare the incidence and mortality rates between the vaccinated and -unvaccinated, because the epidemic was either on the wane, or at least -well advanced when the vaccinations were begun. The reports are of great -interest in showing the large number of vaccinations which failed to -protect. - -In the Taunton State Hospital about 800 were vaccinated, and among them -there were 81 cases of influenza and 17 deaths from pneumonia, even -though the epidemic was on the wane when vaccinations were begun. - -In the Gardner State Colony 834 were vaccinated after the peak of the -epidemic had passed. This number included all but 15 of the inmates who -had not contracted influenza up to that time. Out of this group, 62 -vaccinated individuals developed the disease. - -At the Massachusetts School for Feeble-Minded 457 inmates were selected -for vaccination and controls. Of the 234 vaccinated, 56 developed -influenza. Of the 223 unvaccinated, 185 developed influenza, with 16 -pneumonias and 12 deaths. The vaccinated group, however, were a more -vigorous group of individuals to begin with, and represented a higher -mental grade than the unvaccinated group, so that the evidence was -considered of questionable value. - -At the Wrentham State School the influenza epidemic was well under way -before vaccinations were begun, and hence the susceptible individuals -were in a large part either affected or infected with the disease. Of -1,198 unvaccinated persons, 758 developed influenza, giving a morbidity -rate of 63 per cent. Of 128 vaccinated, 13 developed influenza and 1 -died. Physicians in this institution believe that the vaccinated were -not as ill as the unvaccinated patients. - -In the Medfield State Hospital, having a total population of 1,940,421 -cases of influenza, with 63 deaths, had occurred before vaccinations -were begun. Of the remaining unattacked inmates 902 were vaccinated. -After the completion of vaccination one new case appeared among the -unvaccinated, and there were none among the vaccinated. - -At the North Hampton State Hospital there were 9 cases of influenza, 4 -of whom died, among 444 unvaccinated individuals, and 9 cases, with 1 -death, among 563 vaccinated patients. - -Among 506 patients vaccinated at the Westborough State Hospital there -developed 15 cases of influenza, 2 of which terminated fatally. Of the -415 unvaccinated controls, 25 developed influenza and there were no -deaths. At the time vaccinations were completed only 13 had developed -influenza. - -In the Worcester State Hospital vaccination was carried out after the -epidemic had entirely subsided. - -At the Bridgewater State Hospital no vaccines were used, but the -morbidity rate was 29.9 per cent., as contrasted with 32.9 per cent. -among the unvaccinated at Monson. - -At the Danvers State Hospital the population of 853 adults was divided -into three sections. One section was vaccinated with the Leary vaccine, -one section with an unheated influenza vaccine prepared by Dr. Rosenau -at the Chelsea Naval Hospital, and one section held as controls. The -epidemic had, however, reached its height before vaccination was begun, -and no information as to the relative value of the vaccines could be -determined. - -In Hinton’s (11) report the analysis covered the studies on about 6,000 -vaccinated individuals, which represented slightly less than half of the -population of 12 Massachusetts State institutions. Hinton’s conclusions -were as follows: “The heated suspension of influenza bacilli used as a -prophylactic vaccine did not prevent influenza, lessen its severity nor -its complications, and, as far as could be ascertained, resulted in no -harm.” - -About the same time that Leary was working on his vaccine, Rosenau -prepared an unheated suspension of Pfeiffer bacilli, isolated from cases -of influenza of the existing epidemic, which he used at the Chelsea -Naval Hospital and in an experiment at the Pelham Bay Naval Training -Station. The writer is indebted to Surgeon-General of the Navy W. C. -Braisted for the data from which this report was compiled—the report of -the Sanitary Officer of the station not having been completed at the -time the information was furnished. The vaccine experiment was made in -the isolation regiment, which had remained practically free of -influenza. Inoculations were begun on September 30, when 638 men were -given the first dose of vaccine, 833 men being held as controls. On -October 4 the second dose was given to 589 men, and vaccination was -completed on October 8, when 565 men were inoculated. This group -comprised the total number who received three inoculations. On October -14 practically all of these men were transferred, so that it was very -difficult to get a complete record. Those cases which developed -influenza prior to October 10 have been omitted by the writer, both from -the control and vaccinated groups, because it is unfair to consider the -incidence of influenza among controls which developed prior to the time -the inoculations were completed in the vaccinated group. Between October -10 and October 24 there were 27 cases of influenza which developed among -the vaccinated, and 30 among the controls, giving a morbidity rate of -3.6 per cent. among the 833 controls, as compared to 4.7 per cent. among -the 565 vaccinated men. Emphasis is laid on the fact that these -morbidity rates were calculated for both groups on the number of cases -that appeared after vaccination had been completed. The result failed to -show protective qualities in the vaccine. - -Influenza vaccines for prophylaxis were also prepared in great -quantities by the New York City Board of Health, and were made under the -direction of W. H. Parke. No reports on the value of their vaccines have -as yet appeared, and the writer has been unsuccessful in obtaining any -data on the matter. The Parke vaccine was made in the following way: A -large number of strains of Pfeiffer bacilli were isolated from cases of -influenza during the epidemic. These were grown on a veal infusion agar -containing 1 per cent. peptone, 0.5 per cent. of sodium chloride, 5 per -cent. chemically pure glycerin, and the reaction of which was made -neutral to phenolthalein in the cold. The agar was melted, and from 3 -per cent. to 5 per cent. of citrated horse blood was added to it at a -temperature above 95° C. The media was then slanted and cooled in 6 × 1 -inch test tubes. Most of the vaccines contained about 17 different -strains of Pfeiffer bacilli. The strains were inoculated separately on a -series of slants, and at the end of 24 hours the cultures were washed -off with sterile water and the washings from each series were placed in -a separate bottle. Smears were then made to determine whether or not -gram positive organisms were present, and as soon as each bottle was -found to be free from contamination the contents were pipetted off into -a 1,000 c.c. flask, and the dilution with sterile salt solution -containing 0.25 per cent. phenol made. All of the strains were mixed -together in the large flask. A sample was then removed for -standardization by Wright’s method, and the flask was submerged for one -hour in water at 53° C. Transplants for sterility were made and watched -for 48 hours. The vaccine was then diluted so that each cubic centimeter -contained 1,000,000,000 Pfeiffer bacilli. Prophylactic vaccination was -carried out by giving ½ c.c., 1 c.c. and 1½ c.c. doses at seven-day -intervals. - - - _Author’s Vaccine_ - -At the request of the Department of Public Health of the city of -Pittsburgh, the writer undertook to prepare Parke’s vaccine in large -quantities. The vaccine was to be prepared under the direction of a -committee consisting of Drs. Oskar Klotz, W. L. Holman, E. W. Willetts, -George L. Hoffman and the writer, and the vaccine was to be turned over -to the City Health authorities for distribution in the community. The -work was carried out at the Singer Memorial Laboratory, and was begun -the same day that the committee was appointed. Thirteen strains of -Pfeiffer bacilli were used. Holman contributed six strains, isolated at -autopsies done by Klotz at the Magee Hospital. Other fresh cultures were -furnished by Willetts; Wiese, of the City Laboratory, and by the Singer -Laboratory. The media used was that recommended by the New York Board of -Health, save that sheep’s blood was used instead of horse blood because -of convenience. The same technique was employed, with the exception that -a modification of the Hopkins method of standardization was used instead -of the Wright method. This was done because Pfeiffer bacilli are -extremely small, tend to form unbreakable clumps and tangles, and so -increase the difficulties of making satisfactory counts, either by means -of the Wright method or with the Helber-Glynn counting chamber, that the -methods are independable. Opalescent standards permit of such enormous -variations that it was decided to use the Hopkins method, or a slight -modification which we found so satisfactory that we will give our method -here in detail. - - - _Method of Standardization_ - -When the sample was removed for standardization it contained not only a -thick suspension of Pfeiffer bacilli, but also bits of agar and -blood-stained debris. It was necessary to rid the suspension of the -gross contamination, and this was done at first by filtering it through -sterile glass wool filters, and later by centrifuging it at slow speed -for about 10 minutes. The suspension then contained little but the -Pfeiffer bacilli, and was placed in the Hopkins tube and centrifuged for -½ hour on the sixth contact of the rheostat. This gave the per cent. of -Pfeiffer bacilli in the suspension, and the necessary dilutions to make -1,000,000,000 per cubic centimeter were readily determined. The Hopkins -tube consists of a centrifuge tube, with a capillary tube sealed on at -the smaller end. The centrifuge tube is graduated in 10 c.c., 5 c.c. and -1 c.c. amounts, and the capillary portion is graduated in 0.01, 0.02, -0.03, 0.04 and 0.05 c.c. amounts. To standardize the vaccine, 10 c.c. of -the sample was centrifuged in the tube and the amount of sediment read -on the capillary scale. If the amount of bacilli fell between the -graduations, an additional amount of sample was added, so that the -sediment reached one of the graduated lines, the exact amount of sample -added being noted. The percentage of the suspension could thus be -determined by dividing the number of c.c. of sample used into the amount -of the sediment obtained, and the number of bacteria calculated -according to Hopkins table. The table available to us did not list the -Pfeiffer bacillus, but according to it a 1 per cent. suspension of -staphylococcus contains 10 billion organisms to the cubic centimeter, -and we estimated that Pfeiffer bacilli were about half the size of -staphylococci. This assumption was borne out by a number of Wright’s -method counts on standardized suspension of bacilli. We, therefore, -calculated that a 1 per cent. suspension of Pfeiffer bacilli should -contain about 20 million organisms. Then, if 10 c.c. contain 0.02 c.c. -of bacterial sediment, the per cent. was calculated by taking 0.02/10 = -0.2 per cent., the strength of the suspension. If 1 per cent. contains -20 billion, then 0.2 per cent. contains 4 billion per c.c. In order to -get a 100 million per c.c. suspension, it would be necessary to dilute -the original suspension 40 times. - -Every method of standardization is more or less inaccurate, but the -above described method gave a fairly uniform product. Drying and -weighing is claimed by many to be more accurate, but even with this -procedure a fair amount of non-bacterial sediment is present in the -material to be weighed. - -After the vaccine was completed, cultures were made from the final -dilutions and were watched for 48 hours. Mice and guinea pigs were -injected with the first samples to make certain that the material was -non-toxic. Two laboratory employees also volunteered and received full -doses before the first batch of vaccine was released. The first five -litres were turned over to the Red Cross on October 31, one week from -the day the work was begun. In three more days the laboratory reached a -capacity of 10 litres a day, and on the fifth day the order was received -to discontinue preparation of the vaccine. - -Relatively little of our vaccine was given out, and in the rush it was -not possible to determine which physicians had been given our vaccine -and which had received commercial mixed products, so there is no data on -its protective powers. - -As soon as we found that there was no call for prophylactic vaccines, we -planned some animal experiments; but inasmuch as we were unable to get -our cultures of Pfeiffer bacilli virulent enough to kill mice or guinea -pigs, the minimum lethal dose could not be determined, and without it it -was impossible to determine the protective value of the vaccine. Mr. -Purwin, in our laboratory, injected a 25–gram mouse intravenously with 2 -c.c. of a milk thick suspension of Pfeiffer bacilli without killing the -animal. He was successful in getting a small needle into the tail vein -and in slowly injecting the whole amount. The mouse was sick for about -36 hours, but entirely recovered. Guinea pigs were insusceptible to very -large doses. Had we succeeded by means of a vaccine in completely -immunizing a man against Pfeiffer bacilli, we still would have been -uncertain that he was immune to influenza in its “epidemic” form. - -The absence of virulence in our laboratory strains may not mean that the -cultures were non-virulent when first isolated, but it suggests the -uselessness of attempting to make active vaccines from strains kept on -artificial media for months or years, such as those commonly offered for -sale by commercial houses. - -The loss of virulence in strains that have been isolated for some time -is interesting in the light of Parker’s (12) work upon toxine production -by Pfeiffer bacilli. She found that toxic filtrates appeared in infusion -broth cultures in from 6 to 8 hours, and that 2 c.c. of a 20–hour -filtrate would kill a medium-sized rabbit in from 1 to 3 hours. It was -also found that the poison deteriorated so rapidly that, in order to -determine its toxicity, the tests had to be made on the same day that -the filtrate was obtained. Parker succeeded in making an anti-serum -against the poison, which appeared to be antitoxic for it both in vitro -and in vivo. This work is interesting, and may be a step toward the -development of a practical prophylactic serum. - - - _Conclusion_ - -From the above data, it is apparent that there is very little to -indicate that an immunity to epidemic influenza is conferred by the use -of a prophylactic vaccine composed of inert Pfeiffer bacilli alone. If a -desirable vaccine is to be obtained through the use of these organisms, -there must be radical changes in the mode of preparation of the vaccine -or in the size of the doses given. - - - _The Attempt to Protect Against Epidemic Influenza by the Use of Mixed - Vaccines_ - -For some years commercial houses have been carrying mixed vaccines for -the treatment of colds, which they called influenza vaccines. These -preparations were made up usually of six or more different varieties of -bacteria, and all of them were of similar composition. There was more or -less variation in the doses, both as far as the total number of bacteria -and the relative number of the different types were concerned. A typical -example of a so-called “mixed influenza vaccine” may be given about as -follows: - - B. Influenza (Pfeiffer) 25 to 400 million per c.c. - M. Catarrhalis 25 to 400 million per c.c. - B. Friedlander 25 to 400 million per c.c. - Pneumococci 25 to 400 million per c.c. - Streptococci 25 to 400 million per c.c. - Staph. Albus-Aureus 50 to 800 million per c.c. - ——— ———— - Totals 175 to 2800 million per c.c. - -These vaccines were recommended in the various catalogues for use either -alone or together with other vaccines in the prophylaxis and treatment -of common colds, and in acute and chronic diseases of the respiratory -tract. As a matter of fact, they had been used very little in -prophylaxis, and had failed to show very much value in treatment. In -discussing these vaccines from the standpoint of treatment, R. M. Pearce -(13) had the following to say: “A mixed vaccine for common ‘colds’ -containing several organisms (staphylococcus, streptococcus, -pneumococcus, micrococcus catarrhalis group, bacillus of Friedlander -group, diphtheroid group, bacillus influenza) is one of the most recent -bacterial ‘shotgun’ mixtures, which takes the chance of one lucky -bull’s-eye in seven shots.” “No one can claim a scientific or even a -common-sense basis for the treatment of a cold by such a mixture.” -Catarrhal mixed vaccines of a similar kind were refused acceptance by -the committee on “New and Non-efficial Remedies” of the American Medical -Association, in June, 1918 (14), on the grounds that insufficient -evidence of their therapeutic value had been furnished by their -manufacturers. - -While the above illustrates the status of “mixed vaccine” for -therapeutic purposes, it is a well-recognized fact that it is possible -to produce an immunity for most of the bacteria composing such vaccines, -if killed cultures of the various strains are injected in sufficiently -large doses. Again referring to Pearce’s article, we find the statement: -“Prophylactic vaccination rests on a sound, scientific basis of -experimental studies and clinical observation.” - -The attempt to protect against epidemic influenza by the use of mixed -vaccines was based largely on the following points. The medical -profession was confronted by a rapidly approaching deadly epidemic, -against which ordinary measures of control had failed. The epidemic was -supposed to be due to a primary infection with Pfeiffer’s bacillus, but -all of the fatal cases were found to have profound secondary or -symbiotic infections, with one or more of the strains contained in the -“mixed vaccines.” It was known that mixed bacterial proteins, even -though they were not actually specific, possessed certain qualities of -producing reactions unfavorable to infections in general, which were -characterized by a temporary rise in temperature, by an increase in the -number of leucocytes, and by a more or less demonstrable amount of -active immunity against each one of the contained bacterial toxins. The -artificial production of a leucocytosis was especially desirable, -because a characteristic of epidemic influenza was the failure of -leucocytosis on the part of the infected individual. In other words, -mixed vaccines were used because they were the only available substances -which offered the hope of creating a reaction against the secondary -invaders which were so commonly the cause of death in influenza. - -Since Pittsburgh’s experience with prophylactic vaccination had chiefly -to do with the use of commercially prepared mixed vaccines, a brief -history of the local experience with them may be of interest. - -About the time that the first cases of influenza were being reported -from the Pittsburgh district, articles on preventive vaccines as used in -Boston and at some of the camps began to appear in the daily papers, -shortly after which came the announcement that the Carnegie Steel -Company was offering free vaccination to their employees and to the -families of their employees. Dr. W. O. Sherman, chief surgeon for the -company, advocated the use of the vaccine because he hoped to increase -the immunity to secondary infection and to produce an active -leucocytosis in the vaccinated individuals, and at the same time to -allay panic among the employees at a time when an interruption of -manufacturing and mining pursuits might be disastrous to the entire -country; and he did it with the assurance that if the vaccine did no -good, it would at least do no harm. He took steps to arrange for the -collection of data by which he hoped to determine whether or not the -vaccine as used by their company did any good. His report has not yet -appeared. Other large corporations at once instituted prophylactic -vaccinations with commercial “mixed vaccines.” - -In contrast to the altogether laudable efforts of these companies to -protect their employees, a complete history of the vaccine episode in -this community necessitates the recounting of a very different phase in -the matter. When it became known that corporations were vaccinating -their employees, people in general naturally began to investigate. -Physicians’ offices were besieged by persons who either demanded -vaccination at once or wanted to know whether or not there was “anything -in it.” Conscientious physicians in their turn called up the offices of -the medical societies, the various laboratories, and telegraphed -everywhere trying to get some definite data before recommending the -vaccine to their patients. It was impossible to answer the question -definitely, because it was a new procedure and purely in the -experimental stage. On the whole, the medical profession handled the -situation in a competent and dignified manner, for the great majority -gave vaccines only after a full explanation to the effect that its value -was in doubt, or else refused to give it altogether. There were some, -however, who were not conscientious, and the unscrupulous practitioner -seldom had a better chance to impose upon the public. The demand for -vaccine soon exceeded the supply, and it is claimed that there were -doctors who gave any type of vaccine they could obtain without regard to -its bacterial make-up or intended purpose. Anti-diphtheritic serum was -given in many instances, and it is said that even normal salt was used. -Statements to the effect that exorbitant sums were being charged and -that guarantees of prevention were being made resulted in the Red Cross -Society undertaking the distribution of the vaccine. To protect itself, -the Medical Society issued the following notice in the weekly bulletin -for October 26, 1918: - - The Society wishes it understood that at present there is no vaccine, - serum or inoculation which will secure anyone against influenza. It is - desirable that everyone should avoid hysteria and consider only the - reports which are officially given out by the Health Department, since - of late various methods of prophylaxis and treatment have found their - way into the daily newspapers, and these may prove harmful rather than - do good. - -Almost simultaneously the daily papers published the report of -Surgeon-General Blue, of the United States Bureau of Public Health, -which expressed practically the same opinion. It was not the intention -of either of these articles to criticise the practice of vaccination, -but merely to warn the public against profiteering and fraudulent -guarantees. They had the unexpected effect, however, of causing people -to completely lose faith in prophylactic vaccines, and in many instances -to become actually antagonistic to them. It was during this period that -the preparation of vaccines from pure influenza strains was undertaken, -under supervision of the County Society and for distribution through the -Department of Public Health. Two days after the first supply of this -vaccine was ready the Red Cross authorities telephoned that there was no -further call for vaccine. The man in charge of the distribution stated -concretely that “the bottom had dropped out of the vaccine business.” A -few days later the Department of Health issued an order to stop the -preparation of the vaccine. - -Many pharmacies, having small supplies of vaccines, realized the great -call for it and the difficulty of obtaining a new supply, and were also -guilty of commercialism. Certain of the large biological product -companies were no exception. One house issued a hand-bill, printed in -red on a yellow background, which stated: “Epidemic influenza is due to -the influenza bacillus. The present epidemic of influenza has a tendency -to develop pneumonia. The use of our influenza bacillus vaccine No. —— -will abort the influenza and avoid pneumonia and other sequelæ. When -pneumonia has developed, it can be reduced to less than one-third the -mortality and duration usual with other methods of treatment,” etc. -Practically all of the above statements are still unproven, and probably -will never be shown to be true. Such a bulletin undoubtedly lays this -firm of vaccine manufacturers open to prosecution under the law -protecting against false and fraudulent advertising. Several fairly -well-authenticated incidents occurred in which the representatives of -vaccine houses offered factory managers and others share and share alike -in the profits, if the brand of vaccine made by them was used. It is on -such happenings as the above that the writer advocates legal measures, -allowing Boards of Health to control the advertising of remedies and -distribution of biological products during epidemics. - -How much Pittsburgh will learn from the experience with vaccines will -depend on the numerous analyses of data which were acquired during the -epidemic. - - - _Data on the Prophylactic Value of Mixed Vaccines_ - -Proof of the prophylactic value of mixed vaccines for epidemic influenza -depends entirely upon the results of its practical application to human -subjects in times when the disease is prevalent. Animal determinations -are out of the question, because it has not been possible to produce the -epidemic form of influenza experimentally. If all people were equally -susceptible and were equally exposed, it would be a simple matter to -compare the number of vaccinated persons who developed the disease with -the number of unvaccinated persons who contracted it; but since many -thousands were vaccinated and some of them contracted the disease in -spite of it, and a greater number of persons who were not vaccinated -entirely escaped, the analysis is extremely difficult. - -The time element is a big factor. In instances where vaccination was -completed in a community before the epidemic appeared there, the figures -are worth more than those in which vaccination was undertaken after the -epidemic had become established. This is true, because the most -susceptible persons in a community developed the disease as soon as they -were exposed, the less susceptible ones were not attacked until later, -and the insusceptible ones escaped altogether. Whenever vaccination is -begun during an epidemic, the persons vaccinated for prophylactic -purposes are necessarily chosen from those who have not yet developed an -attack. The later in the epidemic that vaccination is begun, the greater -will be the number of persons selected for vaccination from among those -more or less naturally immune. Then, if the total number of cases among -the vaccinated is compared with the total number of cases among the -unvaccinated, the apparent value of the vaccine is increased; but the -estimation is not a fair one, because the vaccinated group is -unavoidably selected from among relatively immune persons, while the -controls include all of the very susceptible people who were suffering -from the disease at the time vaccination was begun. Where vaccination is -begun after the epidemic is advanced, the only figures worth while are -those obtained by a day-by-day or a week-by-week comparison between the -number of cases developing among controls and the number of cases -appearing among those vaccinated, and by beginning that comparison at a -time subsequent to the day on which the prophylactic inoculations were -completed. - -Aside from the interpretation of the results there is possibly a more -serious reason for objecting to the beginning of vaccination during an -epidemic. This lies in the danger of producing a temporary negative -phase in the patient, which makes him somewhat more susceptible to -natural infection for a few hours immediately following each -administration. - -McCoy (15) outlined the requirements necessary for an ideal vaccine -experiment as follows: 1. The community should be as large as possible, -and should number at least 10,000 persons. 2. The conditions under which -they live should be as nearly equal as possible. 3. The turnover, or -rather the change in population, should be as small as possible. 4. The -social service should be efficient and reliable, so that it can be -definitely ascertained when anyone becomes sick and what the disease is -from which he is suffering. 5. Fifty per cent. should be vaccinated -before the epidemic arrives, and the other 50 per cent. should be held -as controls. - -No examples were found which came up to the above requirements, but -there were some instances in which vaccination was completed before the -epidemic appeared, and some in which we were able to get a week-by-week -comparison between vaccinated and unvaccinated groups. Most of the data -which has been reported shows that vaccination was begun about the last -of the second or the first of the third week of the epidemic, and in -some instances not until after the peak was passed. Add to this the fact -that the vaccine was given in from three to four doses, at from three to -seven day intervals—a course which required in the neighborhood of two -weeks for completion—and it is obvious that the full protective powers -of the vaccine were not acquired by the individual until the worst of -the epidemic was over and the number of cases were rapidly subsiding. - -In order to get the best understanding from these experiments, the data -will be presented in three series: I. Those instances in which -vaccination was completed before the epidemic appeared. II. Those -instances in which it is possible to compare the relative occurrence of -influenza in both the vaccinated and unvaccinated groups after -vaccination was completed. III. Those instances in which vaccination was -begun after the epidemic appeared and in which comparisons of total -figures only are available. - - -_Series I. Those Instances in Which Vaccination Was Completed Before the - Epidemic Appeared_ - -1. The only instance in the Pittsburgh community in which vaccination -was completed before the epidemic appeared is that reported from the -Dixmont Hospital, Dixmont, Pa., and furnished me through the courtesy of -Dr. Hutchinson (16). The institution had a population of about 1,000 -patients and 300 employees. Prophylactic vaccination was begun on -October 20, and was completed about November 6. Each c.c. of the vaccine -used contained 200,000,000 each of B. Pfeiffer, Micrococcus Catarrhalis, -B. Friedlander, Pneumococci, Streptococci and Staphylococci, both Aureus -and Albus. Four doses were given of 4 minims, 8 minims, 12 minims and 16 -minims, respectively. Inoculations were carried out at four-day -intervals. Owing to the isolation of the institution from the general -community, the first case did not appear until two weeks later—namely, -on November 20. The results are shown by the table. - - Population. No. of % of No. of % of - Cases. Cases. Deaths. Deaths. - Vaccinated 600 44 7.3% 0 0% - Unvaccinated 700 69 9.8% 9 1.2% - -None of the vaccinated patients developed pneumonia, though there were -15 cases among the unvaccinated. - -This experiment shows a slight percentage in favor of vaccination, and -indicates that there was some decrease in the severity of the secondary -infections. - -2. The experiment reported by McCoy, Murray and Teeter (17) showed quite -opposite results from the above, and was an excellent example of a small -though completely controlled test. In an asylum for the insane in San -Francisco all of the patients under 41 years of age were divided into -two groups—one group was kept as controls and the other was given a -vaccine furnished by F. O. Tonney, of the Chicago Health Department. The -vaccine contained 500,000,000 each of B. Influenza, Pneumococcus I, II -and III, 1,500,000,000 Pneumococcus IV, 1,000,000,000 Streptococcus -Hæmolyticus and 500,000,000 Staphylococci. Doses of 0.5 c.c., 1 c.c. and -1½ c.c., which were given at 48–hour intervals. Inoculation was -completed on November 15, and the first case of influenza appeared on -November 26. The table shows the result. - - Vaccinated. Not Vaccinated. - Persons in group 390 390 - Cases of influenza 119 103 - Cases of pneumonia 23 17 - Number of deaths 10 7 - -3. The report of Minaker and Irvine (18) included several groups of men, -the first two of which apparently belonged in our first series. They -used a vaccine, each c.c. of which contained 5,000,000,000 B. Pfeiffer, -3,000,000,000 each of Pneumococcus I and II, 1,000,000,000 Pneumococcus -III, 100,000,000 Streptococcus Hæmolyticus. In all, they vaccinated -11,179 persons. - -(a) Their first group numbered 4,950 persons in quarantine at the Naval -Training Station. The quarantine was maintained for 24 days, and no -influenza appeared during that time. Three thousand five hundred and -fourteen of them were released at a time when there were still 200 to -300 cases of influenza being reported daily in San Francisco. Out of the -3,514 men, 15 had influenza, and there were no deaths. - -(b) At the Mare Island Navy Yards 1,950 marines were released -immediately after completion of the inoculation. They were turned into -Valejo and San Francisco, where influenza was at its height. Only 35 -cases, with 1 death, occurred, and these developed shortly after the men -were released in San Francisco. This group was controlled with an -unvaccinated group of 8,232 persons who remained at Mare Island, and -1,296 cases of influenza, with 65 deaths, occurred among the controls. - -(c) At San Pedro 3,100 were vaccinated, and of these 53 had influenza, -and there were no deaths. The occurrence among these was compared with -the prevalence of the disease in Los Angeles, but this part of the -report leaves much to be desired in the way of the relative dates, etc. - -(d) The fourth group, consisting of 1,080 civilians, developed 14 cases, -with no deaths. However, vaccination of this group was not completed -until 21 days after the pandemic had appeared in the community. -Minaker’s and Irvine’s analyses show a favorable percentage for -vaccination in the first two groups, but their groups three and four -were not sufficiently well controlled to be of much help. - -4. In a report which appeared during October, 1918, Eyer and Lowe (29) -published the results of prophylactic inoculation of 1,000 New Zealand -troops with a mixed catarrhal vaccine. They controlled their experiments -with 19,000 New Zealand troops who were not inoculated. A comparison of -the incidence of acute respiratory disease and influenza during the -primary wave of the epidemic as it appeared during June and July, gave -two cases among the vaccinated troops and an average of 43.2 cases per -thousand among the controls. - -Later they reported (58) the results of much larger experiments as -carried out at 17 different camps and hospitals. The vaccine which they -used was a typical “mixed” vaccine, save that the authors emphasized the -advantage of using strains not more than three generations removed from -the body. At some of the camps their reports were unfavorable, but upon -the whole their results, as summarized below, were most encouraging. In -most instances inoculations were completed just prior to the arrival of -the autumn epidemic. - -Out of a total average strength of 21,759, approximately 16,104 men -received full prophylactic vaccination, and approximately 5,700 were -uninoculated, or had received only 1 dose; 3,366 cases of influenza -developed—15 per cent.; 1.3 per cent. occurred among the vaccinated, -while 4.1 per cent. developed in the uninoculated; 8 per cent. of the -severe cases among the protected died, as compared to 23 per cent. among -the uninoculated. The death rate for all infected cases was 0.26 per -cent. among the inoculated and 2.2 per cent. among the uninoculated. - -NOTANDA.—All of the above reports, comprising the “Series I” -experiments, indicate that mixed vaccines reduced the number of severe -illnesses and lowered the death rate to some extent. - - - _Series II. Those Instances in Which It Is Possible to Compare the - Relative Occurrence in Both Vaccinated and Unvaccinated Groups After - Vaccination Was Completed_ - -1. The report on prophylactic vaccination at the Hospital for the Insane -at Retreat, Pa., was very kindly furnished by Dr. Charles B. Maberry -(20). When the epidemic approached, the institution was placed in -quarantine and remained free from influenza until October 28, when two -cases appeared in nurses who had broken quarantine. Influenza spread in -the male ward, but the female wards were kept free during the whole of -the epidemic. There were 370 male patients, but 60 were in the infirmary -and were not included in the calculation. Out of 310 patients, 210 -received vaccines. Ordinary commercial mixed vaccine was used, and -vaccination was begun two days after influenza appeared. During the -first week there were 40 cases of influenza, 6 of which occurred among -those who had received a single dose of the vaccine. After the first -week there were 38 cases of influenza, with 10 pneumonias and 5 deaths, -among the unvaccinated, giving a morbidity rate of 38 per cent. and a -mortality rate of 5 per cent. In the vaccinated group there were no -cases after vaccination was completed. Maberry states further that in -ward III the only cases which appeared subsequent to vaccination were in -six patients who refused preventive inoculations. This appears to be the -most favorable of any of the reports. - -2. Nurses on duty in hospitals everywhere suffered greatly from -influenza, and those of Pittsburgh were no exception. Some of the -hospitals vaccinated the nurses during the epidemic and some did not, -and it was hoped that by getting a week-by-week comparison of the number -of cases among vaccinated and non-vaccinated nurses some reliable data -would be obtained. A circular letter sent to all of the hospitals in the -community contained a blank asking for the number of nurses, date of -appearance of the epidemic, use of vaccine, dates of inoculations, and -for a week-by-week occurrence of influenza in each group. Only 7 -hospitals complied with the request, and of them only 5 sent complete -data. Complete reports were received from the Allegheny General, -Columbia, Presbyterian, South Side and St. Francis Hospitals. Of a total -of 336 nurses in these 5 institutions, 38 developed influenza in the -first week, 48 in the second, 39 in the third, 43 in the fourth, and 45 -subsequent to the fourth week, making a total of 213—a morbidity of 63 -per cent. The Mercy and St. Margaret’s Hospitals reported the total -number of nurses and the occurrence of influenza among them, and adding -in their reports there were 521 nurses on duty in 7 hospitals, with 257 -cases of influenza, giving a morbidity rate of 50 per cent.; 28 cases of -pneumonia and 11 deaths, giving a 2 per cent. mortality rate. The total -figures from hospitals where vaccines were used are against vaccination, -due partly to the fact that vaccination was started late. In these -hospitals the morbidity was 66 per cent. and the death rate 3 per cent. -In the hospitals where vaccines were not used the morbidity rate was 20 -per cent. and the death rate 1.2 per cent. No dependable data was -obtained, but the report from the South Side Hospital was interesting. -Of 60 nurses on duty, 36 had influenza and 2 died. Of this number 19 -were stricken the first week. Three days after the first cases were -admitted to the hospital vaccination was begun, and was given to most of -the nurses still on duty. Of those taking vaccines 20 developed -influenza and 1 died during the period of immunization, but after the -inoculations were completed there were no more cases in either group. - -During the epidemic it was said that benefit was derived from the use of -vaccines on nurses at the West Penn Hospital, but the writer was unable -to obtain a report from this institution. The collected data on nurses -was useless, though it is interesting, in that it shows the possibility -of making figures prove almost anything you want them to prove. - - - _Series III. Those Instances in Which Vaccination Was Begun After the - Epidemic Appeared, and in Which Comparisons of Total Figures Only Are - Available_ - -Undoubtedly the largest attempt at prophylaxis against epidemic -influenza through the use of “mixed vaccines” was that made under the -direction of Dr. W. O. Sherman for the Carnegie Steel and H. C. Frick -Coke Companies. The results which Dr. Sherman hoped to attain when he -planned using the vaccine and collecting the data have already been -given. Commercial mixed vaccines similar to those described under the -“Series I” experiment were used, and four doses, three days apart, were -given. Inoculations were begun on October 20, 1918, and were completed -during the first week of November. Vaccine was administered to the -employees and their families without charge. Later cards were given to -all employees, and they were made to fill them out and return them. On -the cards were blanks calling for the name, age, sex, color, number of -inoculations, whether or not the employee himself or any member of his -family had had influenza, and how many days the sick individuals had -been in bed. Each mill and mine was then supplied with a set of blank -forms providing for a complete statistical record of the number of -inoculations and the total incidence of influenza, pneumonia and death. -From the reports of the respective mills and mines the total figures -given in the charts were compiled. - -Difficulties were encountered in every part of the work. The vaccine -demand was so great that the products of three different firms were -used. So many doctors were in service that most of the vaccine had to be -given by carefully coached nurses. The bulletins of the United States -Bureau of Public Health and of the Allegheny County Medical Society, -with their warnings about influenza vaccines being only in the -experimental stage, appeared just at the time the work was begun and -caused a great many to refuse to complete vaccination after one or two -doses had been given. So few medical men were left that it was -impossible to have them see all cases and so determine the nature of -many of the illnesses which were occurring. It was assumed, therefore, -that any employee who had fever and was sick for a period of three days -had influenza, and that any who were confined to bed for seven days or -more had pneumonia. The figures of the central offices were made up from -the reports of 14 steel mills, 1 cement factory, 4 warehouses and 57 -mining districts. The accuracy of data depended on the careful work of a -great many local statistical workers, which made individual variations -hard to control. The greatest difficulty of all, however, lay in finding -a common basis for comparisons of the incidence of influenza, pneumonia -and death in the vaccinated and non-vaccinated groups, since the data on -the former group included the occurrence only after the peak of the -epidemic had been passed, and that of the latter group included the -occurrence for the entire epidemic. - -The total figures are given in the three charts. - - - CHART I. - - CARNEGIE STEEL COMPANY. - - All Works Except Homestead, City Mills, Columbus, Lucy and Isabella. - - STATISTICAL REPORT ON INOCULATION AGAINST INFLUENZA. - - 1. Number of employees who had influenza 5,728 18% - - 2. Number of employees who did not have influenza 24,956 - —————— - Total number of employees 30,684 - - 3. Total number of persons - inoculated One inoculation 2,983 - Two inoculations 3,675 - Three inoculations 4,626 - Four inoculations 10,053 - —————— - Total 21,337 - - 4. Cases influenza developed - after No inoculations 2,133 23% - One inoculation 745 25% - Two inoculations 776 21% - Three inoculations 794 17% - Four inoculations 1,280 12% - —————— - Total 5,728 - - 5. Cases influenza pneumonia - developed after No inoculations 804 37% - One inoculation 356 48% - Two inoculations 403 52% - Three inoculations 321 40% - Four inoculations 459 36% - —————— - Total 2,343 - - 6. Deaths from influenza and “flu - Pneumonia” after No inoculations 104 4.7% - One inoculation 32 4.3% - Two inoculations 33 4.2% - Three inoculations 21 2.6% - Four inoculations 33 2.5% - —————— - Total 223 3.9% - - - CHART II. - - H. C. FRICK COKE COMPANY. - - STATISTICAL REPORT ON INOCULATION AGAINST INFLUENZA. - - 1. Number of employees who had influenza 5,248 31.4% - - 2. Number of employees who did not have influenza 11,464 - —————— - Total number of employees 16,712 - - 3. Total number of persons - inoculated No inoculations 3,122 - One inoculation 2,483 - Two inoculations 2,548 - Three inoculations 3,550 - Four inoculations 5,009 - —————— - Total 13,590 - - 4. Cases influenza developed 47.9% - after No inoculations 1,495 of (3 - One inoculation 634 25.5% - Two inoculations 770 30.2% - Three inoculations 1,078 30.4% - Four inoculations 1,271 25.0% - —————— - Total 5,248 - - 5. Cases influenza pneumonia 6.3% - developed after No inoculations 94 of (4 - One inoculation 33 5.2% - Two inoculations 42 5.4% - Three inoculations 69 6.4% - Four inoculations 85 6.7% - —————— - 6.1% - Total 323 of (4 total - - 6. Deaths from influenza and “flu 2.0% - No inoculations 30 of (4 - One inoculation 13 2.0% - Two inoculations 21 2.9% - Three inoculations 16 1.5% - Four inoculations 37 2.9% - —————— - 2.2% - Total 117 of (4 - - - CHART III. - - BESSEMER & LAKE ERIE RAILROAD. - - STATISTICAL REPORT ON INOCULATION AGAINST INFLUENZA. - - 1. Number of employees who had influenza 1,275 24% - - 2. Number of employees who did not have influenza 3,986 - —————— - Total number of employees 5,261 - - 3. Total number of persons - inoculated No inoculations 3,091 - One inoculation 232 - Two inoculations 249 - Three inoculations 479 - Four inoculations 1,210 - —————— - Total 2,170 - - 4. Cases influenza developed - after No inoculations 705 55% - One inoculation 111 48% - Two inoculations 91 36% - Three inoculations 129 27% - Four inoculations 239 19% - —————— - Total 1,275 - - 5. Cases influenza pneumonia 40% - developed after No inoculations 283 of (4 - One inoculation 75 67% - Two inoculations 59 64% - Three inoculations 51 42% - Four inoculations 69 28% - —————— - Total 537 - - 6. Deaths from influenza and “flu 5.6% - Pneumonia” after No inoculations 40 of (4 - One inoculation 5 4.5% - Two inoculations 0 - Three inoculations 0 - Four inoculations 3 4.3% - —————— - Total 48 - -Charts I and III show a decrease in the incidence of influenza in direct -proportion to the number of inoculations given. This finding would have -been very important had vaccination been completed before the epidemic -appeared. There is, however, no convincing evidence in either of these -charts that the vaccine cut down the relative number of pneumonias, or -decreased the death rate to any appreciable extent. Chart I also shows -the interesting fact that influenza occurred slightly more often among -those who had one inoculation than among those who were not vaccinated -at all. - -Chart II would indicate that influenza occurred much less frequently in -the vaccinated than in the control group, but a closer analysis brings -out the contradictory finding that influenza occurred at the same rate -in the group of 634 persons who had only 1 dose that it did in the group -of 1,271 who completed the course. - -The reports from the separate communities were so conflicting that to -attempt to analyze them leads only to confusion. - -No reports of harmful effects from the use of the vaccine were received, -and several physicians who attended sick employees say that, even though -the figures do not show it, they feel certain that the vaccinated -persons in general were not as sick as those who were not vaccinated. - -On account of the conditions under which the vaccinations were done and -the reports compiled, Dr. Sherman has not felt justified in making a -report, fearing that erroneous conclusions might be drawn from the data. -We are greatly indebted to him for the use of his reports, without which -our account of the influenza epidemic in Pittsburgh would have been very -incomplete. - -2. Another large steel corporation who used vaccine but asked that their -names be withheld furnished the following report. During the epidemic -the company offered free vaccination to its 27,000 employees and their -families. Commercial mixed vaccines were used, three injections given, -and vaccination begun on October 19, which was about the time of the -peak of the epidemic in Pittsburgh. The results include a record of all -employees who lost over six days between October 1 and November 30. - - ───────────────────────────────┬────────────┬───────────┬─────────── - EMPLOYEES │ MORBIDITY │ PNEUMONIA │ MORTALITY - ───────────────────────────────┼──────┬─────┼─────┬─────┼─────┬───── - │ No. │ % │ No. │ % │ No. │ % - ───────────────────────────────┼──────┼─────┼─────┼─────┼─────┼───── - Received only one dose 3,895│ 511│13.13│ 31│ 0.8│ 28│ 0.72 - Received only two doses 3,329│ 414│12.44│ 40│ 1.2│ 19│ 0.57 - Received all three doses 9,897│ 468│ 4.75│ 46│ 0.46│ 32│ 0.32 - ───────────────────────────────┼──────┼─────┼─────┼─────┼─────┼───── - Total of above 17,119│ 1393│ 8.14│ 117│ 0.68│ 79│ 0.46 - Received no doses 10,036│ 1522│15.17│ 154│ 1.53│ 106│ 1.06 - ───────────────────────────────┼──────┼─────┼─────┼─────┼─────┼───── - Total for both groups 27,155│ 2915│11.66│ 271│ 1.10│ 185│ 0.76 - ───────────────────────────────┴──────┴─────┴─────┴─────┴─────┴───── - -Before satisfactory conclusions can be drawn from these figures it is -necessary to know how many of the 10,036 persons became sick before -vaccination, and whether or not the rate of decrease in this group was -not similar to that shown by the number of patients who developed -influenza during the intervals between their doses of vaccine. The -relatively high percentage of cases following the first and second doses -are capable of explanation on one, or perhaps on all, of the three -following grounds: (a) the general subsidence of the epidemic, which -showed a rapid decrease by the time the third dose was given; (b) the -increased protection afforded by the three doses of vaccine, and (c) the -broken resistance of the patient following sudden sensitization by the -vaccine. - -3. Rosenow (21) prepared a mixed vaccine by growing the various bacteria -in glucose broth, for from 18 hours to 36 hours, centrifuging and -suspending the sediment in salt solution and making up the vaccine on a -percentage basis. - - - FORMULA OF VACCINE - - Pneumococci, Types I (10 per cent.), II (14 per cent.) and - III (6 per cent.) 30 per cent. - Pneumococci Group IV and the allied - green-producingdiplostreptococci described 30 per cent. - Hemolytic Streptococci 20 per cent. - Staphylococcus Aureus 10 per cent. - Influenza bacillus 10 per cent. - -Most of the vaccine was distributed within a radius of 200 miles of -Rochester, Minn., but samples were furnished to physicians all over the -country, who agreed to return statistics on its use. No evidence was -found that this vaccine caused a temporary break in the resistance of -the user. Out of a total of 20,972 persons vaccinated, 14.6 cases of -influenza, 1.8 cases of pneumonia, with 1.8 mortality, occurred per -thousand in the six weeks following vaccination. As controls, he took -“such persons in institutions, colleges, factories and communities where -vaccine was used, and included only those reports which contained -accurate data as to the incidence and mortality among them.” Among -61,753 such controls he found 229 cases of influenza, 15.7 cases of -pneumonia and 3.4 deaths per thousand. He concluded from his results -that “it appears possible to afford a definite degree of immunity by -prophylactic inoculations to persons against the more serious -respiratory infections during the present epidemic.” It is quite -difficult to agree with Rosenow in his interpretation of the figures as -presented by him, inasmuch as he made no allowance for the stage of the -epidemic at which vaccination was carried out, either among the -vaccinated or the non-vaccinated. Such a comparison would be well nigh -impossible where the vaccine was sent in varying quantities to such a -large number of places. - -4. League Island Report (22). Vaccines were used as a preventive in 50 -persons, most of whom were hospital apprentices and in the wards 12 to -15 hours a day. Other precautions were used, such as masks, but not a -single case developed in the group. The vaccine was used as a curative -agent in 50 uncomplicated cases; none of the patients injected early -developed pneumonia. - -5. Puget Sound Navy Yards Report (23). The vaccine used at this station -was made from hæmolytic streptococci, no other organisms being used; -4,212 men were vaccinated, and not one died from influenza. Among 111 -Philippinos isolated and vaccinated there occurred only 2 cases. Among -361 marines vaccinated early there occurred 2 cases. Among 62 marines at -the ammunition depot who were vaccinated early there occurred 3 cases, -only 1 of which occurred after completion of vaccination. Among 662 -bluejackets at Seattle Training Camp only 10 men developed the disease. -Among 83 at the aviation corps there were 32 cases—31 of them developed -the disease within a few hours after the first injection. There were no -deaths in any of the above groups. The period of observation was closed -on October 21, and so few cases of influenza appeared subsequent to that -date that it seemed that the epidemic was practically over at the time -the data was obtained. - -6. Kitano (24) used a vaccine for prophylaxis containing 0.2 m.g. of -Pfeiffer bacilli per c.c. on 10,300 persons with encouraging results. He -used vaccine for treatment on 87 patients, without any deaths. In the -same group were 270 cases treated in the usual way, with 23 per cent. -mortality. The vaccine lessened the severity, shortened the period of -illness, and lowered the mortality. - -7. Wynn (25) used mixed vaccines in the treatment of influenza, and -believed they aborted the disease if given early. - -8. Norman White (26) states that vaccination in India would be -impractical, because the disease is so brief and severe that it would be -over before innumerable doctors could complete inoculations. - -9. Whitingham and Sims (27) reported the use of a mixed vaccine in an -institution where 156 were inoculated and 149 were not. The case -incidence was 5 per cent. among the vaccinated and 12 per cent. among -the controls. No statement of the stage of the epidemic at which -vaccination was done is mentioned in the report. - -10. Cadham (28) reported on inoculations in a military hospital and in -the civilian population near Winnipeg. Of 282 vaccinated soldiers -admitted to the hospital, 17 had pneumonia and 5 died. Of 238 not -vaccinated, 41 had pneumonia and 17 died. Among 24,184 civilians given -two doses, 9.7 per cent. had influenza and 0.5 per cent. had pneumonia -and 0.09 per cent. died. Among 85,941 controls, 24.8 per cent. had -influenza, 2.2 per cent. pneumonia and 0.66 per cent. died. Cadham -states that most of the inoculations were made early in the epidemic, -but no accurate statistics were kept on the point. - -11. A conference was held at the British War Office on October 14, 1918 -(30), to discuss prophylactic vaccination and vaccines for treatment of -influenza. Elaborate plans regarding dosage and gathering of statistics -were made. - -NOTANDA.—For reasons already given, the reports in Series III fail to -give very reliable data on which to base a knowledge of the value of -preventive vaccination against epidemic influenza. - - -_The Attempt to Prevent Pneumonia as a Complication of Influenza Through - the Use of Lipovaccine_ - -Whitmore, Fennel and Peterson (31) developed a method of preparing an -oily suspension of killed bacteria which they called “lipovaccine.” The -method was used at first in making typhoid and dysentery vaccines. The -advantages of lipovaccines (32) over salt suspensions are: the -prevention of autolysis of the bacteria, thus increasing the length of -time during which the vaccine remains active; the slow absorption of the -dose, allowing the patient to continue to absorb immunity-producing -substances over a period of days or weeks; the administration of a -single massive dose, which does away with the three doses necessary when -salt suspensions are used; and perhaps, also, the direct reduction in -the toxicity of the dose by the lipoid material. - -Based upon the classification of pneumococci by Dochez and Gillespie -(33) in this country, and by Lister (34), (35), (36) in South Africa, -and upon the latter’s successful use of anti-pneumonia vaccine on the -Rand, an anti-pneumonia lipovaccine was prepared at the Army Medical -School which contained approximately 10,000,000,000 each of types I, II -and III pneumococci. The vaccine was made by growing the pneumococci in -dextrose broth, centrifuging them out of the broth with a sharpless milk -centrifuge, drying the sediment at 55° C., weighing it out so that each -cubic centimeter of the finished vaccine contains 0.83 m.g. of each -type, and making a suspension of them in olive oil. More recently -cotton-seed oil has been used. - -The result of the use of a salt suspension pneumococcus vaccine at Camp -Upton was published by Cecil and Austin (37). A study of the -agglutination and protective power of the serum of 42 persons vaccinated -against pneumococcus types I, II and III demonstrated that a definite -immune response could be secured to types I and II but not to type III. -Twelve thousand five hundred and nineteen men were vaccinated at the -camp, and most of the men received three or four inoculations at -intervals of from five to seven days. The men were under observation for -ten weeks, and during that time no cases of pneumonia of the three fixed -types occurred among those who had received two or more injections. In a -control of approximately 20,000 men there were 26 cases of pneumonia of -types I, II and III. The incidence of pneumococcus type IV pneumonia was -less among the vaccinated than among the unvaccinated groups. There -were, however, 17 cases of pneumonia among the vaccinated men, compared -to 173 cases of pneumonia among the controls. The annual pneumonia death -rate for vaccinated groups in the army was 0.83 per one thousand, and -for unvaccinated groups was 12.8. - -Fennell reported the use of pneumo-lipovaccine in Washington during the -influenza epidemic, but the number of cases cited by him were too small -to permit of definite conclusions. His results appeared favorable. - -Cecil and Vaughan (37a) reported on the results of vaccination with -pneumo-lipovaccine at Camp Wheeler; 13,460 men, comprising 80 per cent. -of the camp, were inoculated. Most of these men were under observation -for 2 or 3 months after vaccination, and there occurred among them 32 -cases of pneumococcus types I, II and III pneumonia. In one-fifth of the -camp which was not vaccinated there occurred 43 cases of pneumonia. They -observed that influenza caused a marked reduction in the resistance to -pneumonia among vaccinated as well as non-vaccinated men. Of 155 cases -of pneumonia of all types, which developed one week or more after -vaccination, 133 were secondary to influenza. The death rate among -vaccinated men one week or more after vaccination was 12.2 per cent., -whereas the death rate for 327 cases of all types of pneumonia which -occurred among unvaccinated groups was 22.3 per cent. The death rate for -primary pneumonia among vaccinated groups was 11.9 per cent., and among -unvaccinated 31.8 per cent. It was found that protective bodies do not -begin to appear in the serum after lipovaccines are given until the -eighth day after the injection. Twenty-four cases of pneumonia occurred -in the first week after vaccination. In their conclusions Cecil and -Vaughan state that there was no evidence whatever that pneumococcus -vaccine predisposed the individual, even temporarily, toward either -pneumococcus or streptococcus pneumonia. Most of the reactions after -vaccination were mild, but one disagreeable feature was that in a -certain percentage there persisted a small fluctuating mass at the site -of the injection. Lacy saw a number of these cysts aspirated, and the -contents were found to be a sterile, oily fluid, with many leucocytes -present. In one instance the primary reaction disappeared within a few -days after vaccination, but recurred after four months and persisted for -several weeks. - -NOTANDA.—The army lipovaccine apparently offers a certain definite -amount of protection against pneumonia, which was the most dangerous -complication of influenza. The protective substances do not appear in -the serum until eight days have elapsed after the vaccination, and while -no definite evidence has appeared to show that there is a temporary -increase in susceptibility immediately after vaccination, the best -results would undoubtedly be obtained where the dose is given something -more than eight days before the appearance of the epidemic. The -indications are that the vaccine will not protect against influenza, but -that the complication of pneumonia is less likely to occur in the -vaccinated than in the unvaccinated individual. - - - _Summary_ - -Records of attempts to confer immunity to influenza by the use of -vaccines have been separated into related groups and studied. Those -where pure Pfeiffer strains were used have been considered in one group. -Those where mixed vaccines were used have been analyzed in three -sub-groups or series, depending on the relation between the times of -vaccination and of the advent of the epidemic, upon whether or not a -week-by-week comparison of the occurrence of influenza among vaccinated -and unvaccinated groups was made, and upon whether or not statistics for -total comparison alone were available. The third group included the -reports of the use of army pneumo-lipovaccines for the prevention of the -secondary pneumonia complications of influenza. - - - _Conclusions_ - -From our statistics we conclude that: - -1. There is as yet no evidence that vaccines composed purely of strains -of Pfeiffer bacilli will confer immunity to epidemic influenza. - -2. The only data which can be used as a basis for estimating the value -of mixed vaccines as a preventive for epidemic influenza must be -obtained from experiments in which vaccination was either completed -before the epidemic appeared, or in which week-by-week comparisons -between the number of cases occurring in the vaccinated and unvaccinated -groups can be made. - -3. Data obtained from experiments conducted under the above -qualifications is inconclusive, but presents little evidence of the -value of mixed vaccines in protecting against influenza. There is, -however, an indication that mixed vaccines used prior to the arrival of -the epidemic will lessen the number and the severity of secondary -pneumonias, and will probably lower the death rate to a small degree. - -4. The army pneumo-lipovaccine apparently offers some protection against -primary infections with types I, II and III pneumococci, and a somewhat -lesser amount of protection against secondary pneumococcic infections -with these strains following influenza. - -5. While it is impossible to say that the large number of influenza -cases developing almost immediately after vaccination would not have -occurred anyway, it is at least suggestive that a temporary break occurs -in the resistance after the inoculation, and that unusual care should be -taken by persons who have been recently vaccinated, particularly when -they are in the midst of an epidemic disease. - - - PART II. GENERAL PROPHYLACTIC MEASURES - -One of the most remarkable things about the 1918 pandemic was the great -rapidity with which it spread to all parts of the world. From the report -of the first cases which landed in Boston until the epidemic arrived in -San Francisco the time consumed was less than two months, and the peaks -of the two epidemics were just about one month apart. Apparently no part -of the world escaped. Asia, Europe, Africa, North and South America, and -some of the remote islands of the Pacific, all reported large epidemics, -with high mortality and great suffering. The deplorable failure of -precautionary measures in controlling the spread, or at least in -limiting the disease, may be offset in a measure by the unusual -conditions under which almost everybody had been living. Vast numbers -from all over the world were gathered together because of the war. -Thousands of men were housed together in army camps or in training -cantonments. Other thousands were doing relief work or engaged in the -manufacture of munitions. Most of those at home were doing double duty, -and were on a severe nervous strain. Everyone everywhere was working to -the limit and was consequently fatigued. The necessities of war had cut -down the amounts of food generally, and sugar and fat rations -particularly. Traffic, both between nations and at home, had never been -so great nor accommodations so insufficient. So that it is likely that -all of these and many more changes in the daily routine of individuals -led to a condition of lowered resistance, and at the same time increased -their chances of exposure. One point, at least, stands out prominently, -and that is that “influenza as it occurred clinically during the first -great wave was different from those cases which appeared later.” This -was seen in the acuteness of the onset, in the severity of symptoms, and -in the high mortality rate. Therefore, any measure which afforded -protection, if only for the time being, is worthy of retrial. - -In view of the fact that recurrences have followed closely in the wake -of all former influenza epidemics, and with the hope of stimulating -concerted investigation of preventive measures, the American Public -Health Association (57), at its meeting in Chicago in December, 1918, -appointed a committee to outline “a provisional working formula, based -on the facts and opinions brought out at the meeting.” A summary of the -opinions as taken from the report of the committee is given here. They -reported that the disease was probably due to some micro-organism or -virus as not yet identified; that while it was known as “influenza,” it -was not known to be identical with the disease generally known under -that name; that there was no known laboratory method of differentiating -it from ordinary colds, bronchitis, etc.; that there was no known -laboratory method of determining when a patient ceased to be infective; -and that the deaths from influenza were due to secondary pneumonia -resulting from an invasion by one or more forms of streptococci, or by -one or more forms of pneumococci, or by the so-called influenza bacillus -or bacillus of Pfeiffer. Because of the clear and concise manner in -which this report brings out the opinions held, at the time, by a -majority of the medical profession a portion of the report is given here -_verbatim_. - -“Evidence seems conclusive that the infective micro-organisms or virus -of influenza is given off from the noses and mouths of infected persons. -It seems equally conclusive that it is taken in through the mouth or -nose of the person who contracts the disease, and in no other way except -as a bare possibility through the eyes by way of the conjunctivæ or tear -ducts. - -“If it be admitted that influenza is spread solely through discharges -from the nose and throats of infected persons, finding their way into -the noses and throats of other persons susceptible to the disease, then, -no matter what the causative organism or virus may ultimately be -determined to be, preventive action logically follows the principles -named below, and, therefore, it is not necessary to wait for the -discovery of the specific micro-organism or virus before taking such -action. - -“1. Break the channels of communication by which the infective agent -passes from one person to another. - -“2. Render persons exposed to infection immune, or at least more -resistant, by the use of vaccines. - -“3. Increase the natural resistance of persons exposed to the disease by -augmented healthfulness.” - -The ways and means of carrying out these principles are many and varied, -and it is merely the intention of this paper to put together a sort of -digest of some of the more important arguments for and against some of -the seemingly more important measures proposed. - - - _Methods Proposed for Breaking the Channels of Communication_ - -(a) Rigid quarantine for all persons suffering from the disease and all -contacts. During the epidemic quarantine was advocated by many people. -It was pointed out that the disease spread most rapidly in camps, in -ships, and in quarters generally where large numbers of persons were -closely associated; that it was quite as contagious and more rapidly -fatal than most diseases which are regularly quarantined; that while it -was admitted that there is no laboratory method to make certain the -diagnosis, and no method of telling how long convalescents are capable -of transmitting the disease, as there is, for instance, in diphtheria, -still there is no question of the value of the arbitrary quarantine used -in measles, scarlet fever and smallpox, all of which are diseases in -which the parasitic causes are not known. Further, the opinion was -expressed that complete isolation and quarantine would not only protect -the community from influenza, but that it would also in a measure -protect the patient from contact with numerous outside strains of -pneumococci and streptococci, and so lessen secondary infection and -reduce the general mortality. - -There are many reasons why quarantine is not applicable in epidemic -influenza. Most important of all is probably the inability to make -certain the diagnosis, especially during the early stages in light -cases. This would work detrimentally in several ways. Really ill -patients would delay calling a physician until late, for fear of -unnecessary quarantine. Many needless and unjust quarantines would -result when the diagnosis was uncertain and the physician anxious to -carry out quarantine measures efficiently. Many patients would have -contacts running about and infecting their neighborhoods while a delayed -diagnosis was being made. Influenza was so contagious during the -epidemic that it would have necessitated general quarantine not only of -all infected persons but also of all contacts to have obtained any -favorable results, and since nearly everyone was either a patient or a -contact, all lines of business would literally have been paralyzed by -the procedure. If it is true that the infected person is most dangerous -to others before he has developed symptoms himself, he is a carrier -impossible of detection and control. Points in favor of the hypothesis -that infected persons spread the disease before they develop symptoms -are found in the following facts. As the disease passed from community -to community officials became alert for the appearance of the first -case. In army barracks and in large institutions it was often possible -to determine the first case at its development. The case was, in many -instances, removed at once and isolated, but I have seen no instance in -which such a measure was successful in curbing the disease. As -subsequent cases appeared they were likewise immediately removed, but -the cases continued to spread just the same. Bloomfield (38) cited the -incident of a student who spent a few hours visiting his sister in a -part of the country where there had been no influenza. He appeared well -at the time, but six hours after his return to school he developed -influenza. Two days after the contact the sister came down with the -disease. On the other hand, he told of a student who did not contract -the disease, though he slept for two nights in the same bed with his -roommate, who had returned to school with a well-developed case of -influenza. The unsuccessful attempts to transmit influenza in the -experiments of Rosenau (37), McCoy (37a) and others already cited would -indicate that the cases from whom the material was taken were no longer -infectious, although some of them had been showing symptoms for only -about 12 hours. Bloomfield observed that the general use of face masks -in the wards did not alter the course of the epidemic, and stated that -if face masks are protective, infection from early unisolated cases must -be assumed. - -Provided influenza is generally transmitted during the period of -incubation, a theory which seems consistent with the facts, rigid -quarantine for epidemic influenza is impracticable and probably useless. - - - _Partial Isolation by Means of the Cubicle System_ - -The so-called cubicle system consists in the dividing of rooms, or more -particularly of wards, into small compartments by means of suspending -sheets from wires so that each bed is separated from its neighbor. Capps -(39) reported favorably on the method as used at Camp Grant, where -sheets or halves of tents were suspended from wires or from the mosquito -netting frames which were a part of the standard beds. Doctors, nurses -and attendants were forced to wear masks in the wards, and patients were -not allowed out of the cubicles without them. In discussing this paper -Thayer emphasized the value of screening, masking and the wearing of -gowns, and also recommended thorough washing of the hands between the -examination of each two patients; and Emerson called attention to the -fact that the first demonstration of the cubicle system as an adequate -means of preventing acute respiratory diseases was made at the Pasteur -Institute of Paris, where it had been in operation for 10 years. The -latter stated that the system had been used in various hospitals in -America and was essential for the care of diphtheria, measles and -scarlet fever. He further indicated that if the technique of personal -cleanliness of nurses, doctors and attendants could be perfected, it was -probable that the height of the cubicle partition could be reduced to -that of a “red string.” The method certainly seems worthy of -consideration and trial, particularly in large general hospitals and -public institutions. - - - _The Use of the Face Mask_ - -The question of the value of wearing a gauze mask over the mouth and -nostrils during an influenza epidemic is still an open one. Masks, -however, have been found useful in protecting against some other -diseases of respiratory origin. In December, 1917, Weaver (40) reported -favorably on the use of gauze masks in the Durand Hospital of Infectious -Diseases. The masks were used by nurses in attendance upon patients with -contagious diseases, and also by patients who were convalescing from -diphtheria, meningitis or pneumonia and who were in the same wards with -those having other respiratory diseases. In a later article Weaver (41) -stated that by the use of masks they had been able to reduce the -percentage of diphtheria carriers among their nurses in the diphtheria -wards to 5.2 per cent., as compared to the average of 23.25 per cent. -during the 20 months immediately preceding their adoption of their use. -He recommended the general use of masks for physicians when in contact -with all types of respiratory diseases. In March, 1918, Capps (39a) -reported encouraging results in the control of infections through the -masking of all patients at Camp Grant. During the epidemic the wearing -of masks became quite general, and was very popular in many sections. - -Several sets of laboratory experiments have been carried out recently to -determine whether the masks are of practical value or not. The -experiments have generally consisted in spraying cultures of living -bacteria over sterile bacterial plates which were protected by one or -more layers of gauze. A number of variations were made in the manner in -which this was done: (a) the distance between the nozzle of the spray -and the mask was varied, and the distance between the plate and the mask -kept constant; (b) the distance between the plate and the mask varied, -and the distance between the nozzle and the mask kept constant; (c) the -use of masks both over the nozzle of the spray and over the plate being -kept constant, and the distance between the two masks varied. In a -somewhat different set of experiments the mask was placed over the mouth -of a person, who was told to talk or cough over an agar plate, and the -bacterial plate being held at various measured distances from the face. -By counting the number of colonies which developed upon the plates it -was possible to get fairly reliable data as to the efficiency with which -the bacteria were intercepted by the gauze. Weaver (42) found that if -enough gauze was used, it would filter out all of the bacteria passing -from the spray in the direction of the plate. The efficiency of the mask -being in direct proportion to the fineness of the mesh and the number of -layers employed. Doust and Lyon (43) made a series of experiments to -determine the distance through which droplets are carried when expelled -under different circumstances. They found that in ordinary speech -infected material is projected for about four feet, and that during -coughing the material is carried about ten feet. They demonstrated that -masks of medium meshed gauze, two to ten layers thick, worn by the -person coughing did not prevent the passage of infectious material into -the air, but that a three-layer buttercloth mask was much more -efficient. Haller and Colwell (44) used three distinct sets of -experiments—one with the mask over the mouth of the patient, one with -the mask over the plate, and the third with masks over both—and -concluded that a five-layer mask made up of 24 × 20 mesh protected the -plate in the second series of experiments. They suggested marking one -side of the mask, so that it would always be worn with the same side -out. Leete (45), in England, by a similar series of experiments -concluded that a dry mask of six to eight layers of butter muslin worn -by a contact would protect him against droplet-carried infections. -Dannenberg (46) suggested making the gauze mask over a copper screen -wire frame to give it shape and keep it away from the mouth, thus -keeping it relatively dry. All observers agree that masks while dry are -more efficient than they are after they have become moist. - -The efficiency of the mask has also been widely discussed from the -clinical standpoint. Mink (47) in discussing their use at the Great -Lakes Training Station said that he had no objection to the mask as it -is “intended to be worn,” but that as it “was worn” by the medical corps -men at the station 8 per cent. of those who used the mask developed -influenza, as compared to 7.75 per cent. of those who did not; 30 per -cent. of the dental officers at the station developed the disease in -spite of the fact that they were all accustomed to wear masks during -their work. In discussing the mask Vaughan (48) said: “With reference to -the mask, I am strongly of the opinion that we have overestimated its -value. * * * When I went to Camp Devens they were not using the mask. I -called the doctors together and told them its use was not compulsory, -but I said: ‘Every doctor who took care of cases of pneumonic plague and -did not wear a mask died from it, and every man who cared for pneumonic -plague cases and didn’t wear a mask did contract it.’” They were then -allowed to choose for themselves. It has been pointed out that the -epidemic dropped off at once in San Francisco with the universal -compulsory use of the mask on the street, but it is also said that the -epidemic in Los Angeles, which ran a course parallel to that in San -Francisco and in which masks were only indiscriminately used, began to -drop off simultaneously. While it is difficult to get at the facts, it -seems that, provided epidemic influenza is carried through the air or by -means of droplets, the universal use of masks should decrease the number -of exposures. The claim has been made that masks merely tend to prolong -the epidemic, and that susceptible persons develop the disease after the -epidemic proper has passed. If the mask will protect the susceptible -individual until the virulence of the disease has decreased, it will -better that individual’s chances for recovery, and so is worth the -trouble. - - - _General Closing Orders_ - -In most large cities orders were issued closing churches and theatres -and prohibiting public gatherings of all kinds. In New York these places -of public gathering were not closed, and it has been pointed out, as an -argument against closing orders in the future, that the death rate there -was less than in Boston, Philadelphia, Pittsburgh, etc. Copeland (49), -of the New York Board of Health, stated that the unventilated picture -shows were closed, but that the theatres were used as places of public -instruction. New York’s relatively low death rate was difficult of -explanation, but it is very certain that it had nothing to do with the -fact that closing orders were not in vogue. If it were possible to -obtain the figures, it would be interesting, indeed, to compare the -death rate from influenza among New York’s theatre-attending public -during the epidemic with the death rate of the community in general. - -Generally speaking, any unnecessary public gatherings are inadvisable -during any epidemic. While our exact knowledge of the mode of -transmission of influenza is incomplete, it is unquestionably a contact -disease. People who have been exposed and who have not yet contracted -the disease are known to have transmitted it to a third person. A -certain number of people from infected homes will attend public -gatherings as long as they are able, for it is impossible to get -together any large group of persons all of whom are going to play fair. -It is true that these meeting places may be used in a measure to allay -panic and to instruct the public in health measures, but there are many -efficient and far less dangerous methods of accomplishing the same -results. Vaughan in discussing assemblies in large halls mentioned that -in a hall at Camp Forest, which held 9,000 people, the individuals had a -space of about 16 inches laterally between their noses. He pointed out -that if many of them were talking, coughing or sneezing, the air -contamination would soon become so great that it could make little -difference whether there was a roof over the building or not. He -emphasized the fact that it is just as possible to crowd men in the open -as it is indoors. Ventilation is undoubtedly an important factor, but it -cannot correct overcrowding. As far as the educational value of the -public gatherings was concerned, it may be observed that regular -attendants of theatres and moving-picture houses during the year of 1918 -had become quite accustomed to appeals regarding all sorts of public -movements from speakers who appeared between the acts, or pictures, but -that the closing of these places threw a wholesome scare into them which -made them pay far closer attention to prophylactic measures than almost -anything that could have happened. “Object-lessons are always superior -to didactic teaching.” In Chicago a new argument for the closing of -theatres was advanced. It was said that with no place to go many people -retired earlier and obtained more than their accustomed amount of rest. -It was believed that this aided in increasing their natural resistance. -The argument that the closing of these places served only to delay the -epidemic is an argument in favor of the measure, because the virulence -of the disease decreased rapidly as the epidemic progressed. - - - _The Closing of Schools_ - -Boards of Health generally were opposed to the closing of the public -schools. This position gave rise to innumerable clashes with anxious -parents. The health authorities took the position that children were -relatively insusceptible to influenza; that while they were quiet in a -well-ventilated schoolroom they were little exposed; that those who -coughed or sneezed could be examined at once, and that daily school -inspection would lead to early discoveries of all cases, so that doctors -and nurses could take immediate steps to treat the patients and to -protect the families from which they came. Copeland advocated the -continuance of the schools in New York, and based his position on the -fact that out of 1,000,000 children in New York City 700,000 came from -tenement homes. He believed these children were far better off in -school, where they received daily medical attention, than upon the -streets or in unhygienic homes. - -In Pittsburgh the school children were quizzed as to the number of sick -at home, and this gave valuable information on the stage of the -epidemic. They were sent home with printed warnings against sneezing, -coughing and spitting, and were thus used as a means of instructing -their parents. The Pittsburgh schools were kept open until the sickness -of a number of teachers and the withdrawal of many scholars made it -advisable to close. - -Three very potent arguments have been brought forward in favor of -closing the schools: (1) As long as the schools are open children from -infected homes are forced into contact with children from uninfected -homes, and we are at present unaware of the extent to which the disease -may be carried by a third person. (2) Children in as yet uninfected -homes which are comfortable and hygienic are far better off than they -are in school, and can hardly be considered in the same class with -children from unclean tenements. (3) If the period of greatest contagion -is before symptoms develop, inspection, while valuable for the -institution of treatment, cannot hope to aid in curbing the epidemic. It -is evident that different measures must be employed in applying closing -orders to crowded cities, moderately large towns and rural districts. -The difficulty lies in determining the best means for serving each -community. - - - _The Closing of Public Dance Halls_ - -Public dances should undoubtedly be prohibited during epidemics. They -not only present all the bad features of other public gatherings, but -during the dancing people are brought in very close contact and often -breathe directly into each other’s faces. In addition, air currents are -stirred up and a certain amount of dust is raised. During the exercise -the dancers breathe more rapidly and deeply, thus inhaling unusually -large amounts of dust, droplets and contaminated air. Another feature is -found in the “resistance-breaking” element of alternate overheating and -rapid cooling of the body. - - - _Regulation of Public Eating and Drinking Places_ - -Public eating places are a necessity and cannot be closed. People should -be cautioned against using them as places of amusement and of -congregation during epidemics. Boards of Health should feel it just as -much their duty to see to the sterilization of dishes and eating -utensils as they do to the enforcing of any other public health -functions, and they should also insist on the daily inspection of the -employees of such establishments. The beer saloon question may be passed -over for the present, but the soda-water fountain as conducted during -the 1918 epidemic was undoubtedly a great menace. Ice cream, syrupy -mixtures, etc., of various kinds are readily contaminated by pathogenic -organisms which may serve as secondary infectors, if in no other -capacity. The syrups, moreover, adhere to the spoons and glasses, which -are rarely thoroughly washed and are practically never sterilized -between customers. The use of paper dishes and glasses is probably a -step in the right direction, but the spoons should be thoroughly washed -and sterilized. The fact that soda-water employees are not always -selected for high-grade intelligence, and are generally left largely to -their own hygienic procedures, makes the chances of transferring -infections at these places enormous. If soda fountains are allowed to -continue business at all during the epidemics, it should be only under -the very strictest supervision by Boards of Health. The scalding of all -utensils should be enforced by law. - -People generally should be cautioned to use exceptional cleanliness in -the preparation of all foods in the home. In discussing the recent -epidemic Lynch and Cummings (50) stated that “the mess-kit wash water -proved the major route of transmission from sick to well in the army.” -Vaughan said: “I am pretty certain, not convinced, that hand-to-mouth -infection is of more importance than droplet infection.” - - - _Regulation of Traffic_ - -Business must be conducted in epidemic as well as in normal time, and -employees must go to and from their places of occupation. In cities -where the distance from the residence to the business districts is -great, street cars and other public conveyances must be used. Their use -undoubtedly increases the number of contacts and leads to a wider -distribution of the disease, but, like eating in public restaurants, it -is a chance which many have to take. Few places offer better -opportunities for exposure than street cars—where people of all grades -of intelligence, representing all states of health and degrees of -cleanliness and uncleanliness, are crowded closely together, breathe -into each other’s faces, and handle the same straps and supports. - -In Pittsburgh the cars have a seating capacity for from 30 to 50 -persons, but during the morning and evening hours they are crowded to -capacity, and are commonly seen to carry more than 100 passengers at a -time. Here, too, the unkempt, indifferent foreign element is -conspicuous, and these people are known to disregard all hygienic -teachings. A few days after the appearance of the epidemic the street -cars were placarded with warnings against coughing, spitting and -sneezing. The cards instructed people who became ill to go home, to go -to bed and to remain there until they were well. Later a second order -appeared which gave notice that all windows in street cars were to be -kept raised six inches and that no heat was to be allowed in the car. -The order was intended to improve ventilation, and, for a wonder, it was -enforced. During the first few days the weather was fine, warm and -clear, and the draught caused by the open windows brought no discomfort; -but later the weather became cold and several days of drizzling rain set -in. The cars with open windows became very uncomfortable, but the -streetcar employees insisted upon obeying the order to the letter. No -judgment was exercised by them, and the windows were kept open night and -day, cold or warm, crowded or empty, in fair and rainy weather alike, -and no heat was allowed to be turned on. Many people preferred standing -to exposing their backs and necks to the cold draughts, and it is more -than likely that such use of open windows did far more harm than good. -As above quoted, Vaughan pointed out that crowding is just as dangerous -out of doors as indoors, and it is certain that crowding in cold, -draughty cars is dangerous, both from the close contact and because of -the added danger of lowering bodily resistance. - -In an attempt to decrease the crowding on public conveyances the -so-called “stagger-hour” system was adopted in New York. Under this -arrangement manufacturers and business houses changed their working -hours in such a way that the morning and evening travel was spread out -and the average number of people carried per hour was proportionately -decreased. - -Looking backward over the methods used to decrease the spread through -the use of public conveyances, it seems that the following procedures -have the best claims for retrial: (1) Placarding the cars. This appeared -to reduce the amount of coughing and sneezing, even in face of the fact -that the cars were unusually draughty and chilly. (2) The adoption of -the “stagger-hour” system where the practice is feasible. (3) The -instruction of the people to use the street cars as little as possible. - - - _Enforcement of Anti-Spitting Ordinances_ - -All street cars and trains carry anti-spitting notices either to the -effect that spitting will be prohibited on penalty and fine and -imprisonment, or giving stated amounts of the fine. Yet spitting is -constantly indulged in in these places and one rarely sees or hears of -the enforcement of the law. If the ordinance was worth making a law, it -is certainly worth enforcing, and yet there is probably no law so -flagrantly broken. Ordinary police officers pay no attention to the -enforcement of the spitting ordinance and have been known to refuse to -even reprimand spitters. The incident of a sanitary officer wearing a -uniform and a cap, indicating to the public his official position, who -was seen sitting in the smoking car in a local suburban train and -spitting profusely on the floor has been recounted on very reliable -authority. Another incident is known in which a street car conductor was -asked by one passenger to stop another who was expectorating abundant -mucoid sputum upon the floor. The conductor replied that he had orders -not to notice such things. It is no wonder that people are indifferent -to such impotent measures. Whether it is possible to convey epidemic -influenza or not by means of sputum, it is certain that tuberculosis is -spread in this way, and that influenza predisposes to tuberculosis and -causes old healed tuberculous foci to become active. People should be -made to understand that they may have tuberculosis without knowing it -themselves, and that by spitting it may be transmitted to other persons. -Spitting by persons aware that they have tuberculosis is criminal -negligence and such persons should undoubtedly be prosecuted. If a -person knows that he has tuberculosis and deliberately spreads about the -infection so that other persons contract the disease and die from it, he -is directly responsible for the deaths. It would be hard to imagine -trying to control manslaughter committed in any other way by merely -putting up signs in conspicuous places forbidding the act. The average -boy acquires the spitting habit between the ages of 8 and 12 years, and -in many instances carries it to the grave. The one possible way of -stopping spitting seems to lie in teaching the dangers of it to -children, beginning in the kindergarten and emphasizing it throughout -the child’s education. It is possible that in this way spitting may -become obsolete in two or more generations. - - - _Increasing Natural Resistance by Augmented Healthfulness_ - -If there is any way of increasing the natural resistance against -epidemic influenza, it is a most desirable goal toward which to work, -but it must first be determined along what lines the effort is to be -directed. It was not the aged, the unconditioned nor the physically -unfit who suffered most from influenza, but was rather the best trained, -most healthful and most robust young persons we had. Those in the army -had been selected because of their physical fitness and they had further -received excellent physical training in the various camps and -cantonments. It would not be possible to bring any large percentage of -the general public up to such a stage of “augmented healthfulness” as -healthfulness is generally understood. It has been said that men in the -military camps were more commonly infected because they were more -active, went about more and were, therefore, more frequently exposed. In -one particular this statement is true, for men marching rapidly and -exercising violently breathe more deeply and at a faster rate than they -do under ordinary conditions, so that they naturally draw greater -quantities of air into their lungs. It was an obvious fact that those -persons given to sedentary lives were less often affected than the -active and vigorous. Practically speaking, it would seem that during -influenza epidemics people should be instructed to take more than the -usual amount of sleep and rest, to indulge only in mild exercises, to -eat good, wholesome food, to wear warm clothing, to seek mental and -physical relaxation at home, and, above all, to avoid crowds and public -gatherings. - -In some instances the constant use of oils in the nose and throat was -advised, the theory being that the oil served the double purpose of -preserving the healthy condition of the mucous membranes by lessening -crusting, crevicing and drying, and of mechanically protecting from -infection by the presence of the layer of oil. Many of the different -liquid paraffins, both medicated and in the natural state, were used. It -is probably advisable to apply such oils either with a swab or from a -medicine dropper, rather than to attempt to spray them, since in the -latter method there is some danger of blowing infectious material down -into the trachea and larynx. - -It is hardly necessary to point out the importance of augmented -cleanliness of the mouth, teeth and throat by means of mild antiseptic -washes and tooth-cleansing materials during an epidemic. - - - GENERAL MEASURES - - - _Public Health Administration_ - -Unless one had had a wide experience in the administrative side of -public health matters, it would be useless for him to try to discuss the -details of handling any sort of an epidemic, and even then local -conditions vary so much in different cities and States that each -administrator’s experience must differ greatly. The difficulty with -reports of epidemics by public health officials is usually found in the -fact that the reports are impersonal compilations and convey no idea to -the reader, or rather to the student (for no mere reader is attracted to -them), of what situations were faced, of what difficulties were in the -way, of how the conditions were met, or what the administrator after due -reflection would advise doing next time under similar circumstances. In -the face of inexperience the writer ventures the following suggestions -for improvement, though no originality is claimed for the ideas. - -The administrative powers should be centralized in one individual, or in -an executive officer acting for a competent board of advisers, who -should be endowed with the powers to carry out the measures which seem -best suited to meet the situation at hand, and who should be beyond the -pale of political interference and in position to prevent political -fiascos, built more or less directly on health regulations. - -The United States Public Health Service should work toward standardizing -health laws and penalties for all States. - -Thorough enforcement of ordinances requiring the reporting of all cases -and all deaths as now demanded by public health rulings should be -insisted upon. These reports are so important to a knowledge of the -progress of the epidemic that the section on preventive medicine of the -American Medical Association (51) has just advised the consideration of -eliminating from membership in the Association any physician who -willfully fails or refuses to comply with the regulations requiring the -reporting of communicable diseases. Additional information can be -obtained by daily canvasses of the schools, when open, of the large -industries, and of the daily admissions to hospitals. Data on the daily -facilities for the handling of additional cases in hospitals should be -on file in the office of the administrator of health. - -Printed instructions giving in detail the proper procedures for -isolation of the patient and the protection of the family should be -supplied to physicians for distribution at the first visit to suspected -cases. - - - _Desirable Laws_ - -Some specific laws governing the following points would be of great -advantage during the progress of an epidemic: (a) A law providing for -the commandeering by boards of health of vaccines, sera or other -substances for which a sudden unusual demand may occur, and for the -distribution of such substances by the authorities to the public at the -prices ordinarily asked. (b) A law permitting the exclusion from the -daily papers by boards of health of advertisements containing obviously -false and fraudulent statements relative to the epidemic. (c) A law -permitting the health authorities to go into public eating places and -demand proper sterilization of dishes and eating utensils with the -alternative of closing the establishment. (d) A set of laws making the -penalties sufficient to prevent violations of the regulations. - - - _Education of the Public_ - -From the beginning to the end of an epidemic the health authorities, -aided by the medical profession, should take the public wholly into -their confidence. At the first news of the approach of the disease a -general bulletin should be issued giving all of the main facts that are -available. This was done in a way by the American Public Health Service, -but the bulletin reached only a small fraction of the people, and -although parts of it appeared later in the daily papers, it was pretty -generally missed. The papers should be used freely and the space paid -for when necessary, so that the news of the epidemic is featured -emphatically. The establishment of a question and answer department or a -bureau of information would take care of a great deal in the way of -denying misinformation. The public should be encouraged to report -helpful facts of all kinds, but with the understanding that no rumors -would be published without investigation and confirmation. In this way -it would be possible to prevent articles advising harmful and useless -remedies from reaching the press, and aid in suppressing some of the -“Sure Cures,” so many of which appeared to abuse the confidence of the -unwary during the 1918 epidemic. Several such cures have been most -interestingly discussed in a recent bulletin of the United States Public -Health Service. The bulletin divides the “Sure Cures” into three -different classes, as follows: “First comes the individual who has a -specific remedy, the formula of which he will sell for a price * * *; -next comes the person with a pseudo-scientific treatment, e. g., -isotonic sea water, ‘orzono therapy,’ ‘harmonic vibrations.’ * * * Still -another type, who gives freely of his advice that humanity may be spared -from pestilence.” Among the latter are found advice for placing sulphur -in the shoes, wearing of amulets, inhaling of alcohol, chloroform, etc., -as well as numerous religious and mental science treatments, etc. A -frank statement of facts and a discussion of the ridiculous side of many -of these claims would undoubtedly benefit the entire public. The -placarding of the cars and the warnings posted in conspicuous places no -doubt helped greatly, and this method undoubtedly should be continued. -As long as theatres are allowed to remain open, speakers may be used to -advantage to emphasize important points. The County Medical Societies -should be asked to appoint committees for supplying information or for -seeing that the information given to the public is authoritative. In -large cities committees may be organized among hospital superintendents, -so that the heartiest co-operation between health authorities and -hospitals will be available. The ever-ready aid of the Red Cross and of -every other auxiliary body should be employed to the fullest extent to -allay apprehension and relieve suffering. - - - _Summary_ - -The exact knowledge of the mode of transmission of epidemic influenza is -still wanting, but it is known to be spread by contact. Attention should -be directed toward every practical means of decreasing the number and -intimacy of contacts. Publicity campaigns and other educational measures -should be pushed strongly. Health Departments should adopt a policy of -preparedness during inter-epidemic times, should make every effort to -centralize and standardize their work, and should take steps to obtain -sufficient legal backing, so that upon the appearance of the epidemic -they can take the lead, speak with authority and enforce their -ordinances and measures. The physician’s duty is to inform himself on -the value of the various measures, and if he is at odds with the public -health methods, he should settle them between epidemics, so that when he -is called upon to carry out public health orders he can do it to the -letter and without criticism. Laymen should learn that quiet living -without violent exercise, the keeping of good hours, the avoidance of -public gatherings and of unnecessary exposure is the best policy to -pursue during influenza epidemics. They should strictly obey the orders -of those who have specialized in the control of epidemics, and all -business men must stand ready to help in every possible way and to make -their business interests subservient to the public good. - - - BIBLIOGRAPHY - - 1. Rosenau, Keegan, Public Health Report, 1919; xxxiv, No. 2, - Goldberger and Lake p. 33. - 1a. McCoy and Richey Public Health Report, 1919; xxxiv, No. 2, - p. 34. - 2. Lacy Jour. Lab. and Clin. Med., 1918; iv, p. 55. - 3. Wollstein Jour. Exper. Med., 1911; xiv, p. 73. - 4. Flexner Jour. Amer. Med. Assoc., 1913; lxi, p. - 1872. - 5. Park and Williams Bacteriology, 1914 Edition; p. 437. - 6. Leary Jour. Amer. Med. Assoc., 1918; lxxi, p. - 2098. - 7. Leary Amer. Jour. Public Health, 1918; viii, p. - 755. - 8. Rosenau Preliminary report furnished through - Surgeon-General of the Navy W. C. - Braisted. - 9. Barnes Jour. Amer. Med. Assoc., 1918; lxxi, p. - 1849. - 10. Hinton and Kane The Commonwealth Mass. State Dept. Health, - 1918; vi, Nos. 1 and 2, p. 28. - 11. Hinton and Kane Hinton’s Report. - 12. Parker Jour. Amer. Med. Assoc., 1919; lxxii, p. - 476. - 13. Pearce Jour. Amer. Med. Assoc., 1913; lxi, p. - 2115. - 14. Committee on New and - Non-Official Jour. Amer. Med. Assoc., 1918; lxx, p. - Remedies 1967. - 15. McCoy Personal Communication. - 16. Hutchinson Dixmont Hospital Report. - 17. McCoy, Murray and Jour. Amer. Med. Assoc., 1918; lxxi, p. - Teeter 1997. - 18. Minaker and Irvine Jour. Amer. Med. Assoc., 1919; lxxii, p. - 847. - 19. Sherman Report. - 20. Maberry Report from Hospital for Insane, Retreat, - Pa. - 21. Rosenow Jour. Amer. Med. Assoc., 1919; lxxii, p. - 31. - 22. Beaver, Boles and Case Jour. Amer. Med. Assoc., 1919; lxxii, p. - 265. - 23. Ely, Lloyd, Hitchcock - and Nickson Jour. Amer. Med. Assoc., 1919; lxxii, p. 24 - 24. Kitano Jour. Amer. Med. Assoc., 1919; lxxii, p. - 1575. - 25. Wynn Pract. London, 1919; cii, p. 77. - 26. Norman White Lancet., 1919; i, p. 707. - 27. Whitingham and Sims Lancet., 1918; ii, p. 865. - 28. Cadham Lancet., 1919; ii, p. 885. - 29. Eyre and Lowe Lancet., 1918; ii, p. 485. - 30. Conference British War - Office - 31. Whitmore, Fennel and Jour. Amer. Med. Assoc., 1918; lxx, p. 427; - Peterson also p. 902. - 32. Fennel Jour. Amer. Med. Assoc., 1918; lxxi, p. - 2115. - 33. Dochez and Gillespie Jour. Amer. Med. Assoc., 1913; lxi, p. 727. - 34. Lister Publications of the South African Institute - for Medical Research, No. 2, 1913. - 35. Lister Publications of the South African Institute - for Medical Research, No. 8, 1916. - 36. Lister Publications of the South African Institute - for Medical Research, No. 10, 1917. - 37. Cecil and Austin Jour. Exper. Med., 1918; xxviii, p. 19. - 37a. Cecil and Vaughan Jour. Exper. Med., 1919; xxix, p. 457. - 38. Bloomfield Johns Hopkins Bull., 1919; xxx, p. 1. - 39. Capps War Med., Vol. ii, p. 371. - 39a. Capps Jour. Amer. Med. Assoc., 1918; lxx, p. 910. - 40. Weaver Jour. Amer. Med. Assoc., 1918; lxx, p. 76. - 41. Weaver Jour. Amer. Med. Assoc., 1918; lxxi, p. - 1405. - 42. Weaver Jour. Infect. Dis., 1919; xxiv, p. 218. - 43. Doust and Lyon Jour. Amer. Med. Assoc., 1918; lxxi, p. - 1216. - 44. Haller and Colwell Jour. Amer. Med. Assoc., 1918; lxxi, p. - 1213. - 45. Leete Lancet., 1919; i, p. 392. - 46. Dannenberg Jour. Amer. Med. Assoc., 1918; lxx, p. 99. - 47. Mink Jour. Amer. Med. Assoc. 1918; lxxi, p. - 2175. - 48. Vaughan Jour. Amer. Med. Assoc., 1918; lxxi, p. - 2100. - 49. Copeland Jour. Amer. Med. Assoc., 1918; lxxi, p. - 2173. - 50. Lynch and Cummings Jour. Amer. Med. Assoc., 1918; lxxi, p. - 2174. - 51. Amer. Med. Association Public Health Report, 1919; xxxiv, p. 1413. - 52. Le Moignie and Pinoy Compt. rendu. Soc. Biol., 1916; lxxix, pp. - 201 and 352. - 52a. Wright and Douglas Proc. Royal Soc. Med., 1904; lxxiii, p. - 128, and lxxiv, p. 147. - 53. Neufeld and Rimpau Zeitschr. f. Hyg., 1905; li, p. 283. - 54. Rosenau Prevent. Med. and Hyg., 1918. - 55. Brown, Palfrey and Jour. Amer. Med. Assoc., 1919; lxxii, p. - Hart 463. - 56. Gay Typhoid fever. (Published by Macmillan Co., - 1918.) - 57. Eyre and Low Lancet. I, April 5, 1919; p. 557. - - - - - PHYSIOLOGICAL AND PHYSIOLOGICAL CHEMICAL OBSERVATIONS IN EPIDEMIC - INFLUENZA - - By C. C. GUTHRIE, PH. D., M. D. - - -The material consisted of cases in the acute stage of epidemic influenza -with and without clinical pulmonary involvement (alveolar); of -convalescents, and of normal individuals without influenzal history. - -It was hoped that it would be possible to follow selected cases over -considerable time periods, observation to compromise coordinated -clinical as well as laboratory data, but the exigencies of the situation -rendered this impossible. Unfortunately, this limits the value of the -studies. But since similar observations were made on cases ranging from -normal to the gravest severity—in fact, preceding death but a few hours -in some instances—and from the nature of the findings, certain -conclusions are clearly warranted. - -It is regrettable that the data on certain points is not more extensive, -and particularly that other methods of observation were not employed. As -an example of the latter, measurements and analyses of expired air may -be given, as this was planned from the beginning and unsuccessful -efforts made to provide the required apparatus. In view, however, of the -circumstances of the investigation, it is felt that the studies made -are, on the whole, reasonably comprehensive and complete. And it is only -fair here to acknowledge that this was rendered possible by the cordial -and practical support of the Medical School, the military authorities, -the director of the laboratories, clinical colleagues, particularly Dr. -W. W. G. Maclachlan, and last, but not of less importance, of the -members of the department who made the studies. - -In presenting the results, it is deemed most expedient and practical to -omit extensive tabulations and to summarize the data under each subject. - -From the report it will be obvious that certain studies were in -preliminary stages at the termination of the investigation. This was due -in certain instances to the lateness of their undertaking, or time -consumed in providing essential equipment and methods; or to -disappearance of suitable cases due to waning of the epidemic. - - - RESULTS - - - _Circulation_ - -For the most part, cases showing marked clinical symptoms were studied. -The pulse in severe cases frequently was weak and rapid but regular. In -some cases it was less rapid than the clinical state would seem to -indicate. - -_Arterial Blood Pressure_ was low; systolic pressure in severe cases -ranging downward from 95, and diastolic down to 40 or under. In patients -in early stages of convalescence the pressure showed a marked advance -toward normal levels. Arterial blood pressure seemed a reliable general -index of the condition of the patient. - -_Venous Blood Pressure._—The observations included patients who a few -hours later expired. The Von Recklinghausen method was used. No marked -abnormality was observed, so other methods of observation were deemed -superfluous. - - - _Respiration_ - -In severe cases, frequently it was rapid and of shallow character; but, -like the pulse, often it was less rapid than the clinical state would -seem to indicate. - -_Cyanosis_ of dark hue and marked degree was prevalent in the earlier -severe cases, and in some cases appeared entirely out of proportion to -the state of circulation and respiration and to the post-mortem findings -as reported by Dr. Klotz. - - - _Blood_ - -Hemorrhage being not uncommon, the blood was tested for coagulability, -but in this respect no marked departure from the normal range was noted. - -_Coagulation._—Coagulation time was observed by stirring blood in a test -tube with a wire and noting the time of the appearance of fibrin and by -means of a Biffi-Brooks coagulimeter. The extreme ranges observed were -from 2½ to 5½ minutes. The average by defibrination was 3 minutes and 36 -seconds, and by the Biffi-Brooks method 4 minutes and 38 seconds. - -_Red Corpuscles._—Osmotic resistance. A number of bloods were examined -by observing their resistance to osmotic laking by exposure to a series -of hypotonic sodium chloride solutions. Though some differences were -observed, from the evidence obtained, it is not permissible to conclude -that such variations were constant or of a significant magnitude. - -_Color_ on exposure to air. It was early observed that venous blood from -cyanotic patients was very slow to take on arterial hue on exposure to -air. - -_Plasma Bicarbonate._—The plasma bicarbonate was determined in seven -cases by Miss Waddell by the method of Van Slyke and Cullen. In all -except one of these the results were within the normal range as given by -Van Slyke. Three were in the lower normal range, being 54.1, 55.1 and -60.5 respectively, expressed in terms of cubic centimeters of CO_{2} -reduced to 0°, 760 mm. Hg. pressure, bound as bicarbonate by 100 c.cm. -of plasma. Three were in the median range, being 64, 65.5 and 71 c.cm. -In one case the bicarbonate CO_{2} was reduced to 46.6 c.cm. - -There seemed to be no constant relation between the apparent severity of -the clinical condition of the patient and the bicarbonate reading. In -the one case in which this was found to be reduced below Van Slyke’s -lower normal limit the blood was taken only a few hours before death. - -_Hemoglobin Per Cent._—As determined by the Sahli hemoglobinometer (by -Miss Lee) and as estimated by the total oxygen capacity (Van Slyke -method) (by Dr. Rohde and Mrs. Macklin), the hemoglobin content ranged -within normal levels. - -_Relative Volume of Corpuscles._—A limited number of hematokrit tests on -severe cases gave results in normal levels. - -_Spectroscopic Studies._—Sera obtained from 20 post-mortem bloods were -examined spectroscopically. In eight an absorption band in the red was -observed. In some instances such a band was observed in blood obtained -shortly after death and before coagulation had occurred, while other -similar bloods, as well as bloods obtained at longer intervals after -death, exhibited no such band. A similar band was observed in one case -from blood obtained from a patient about 12 hours before death from -pneumonia following influenza. Medication was not a causative factor. To -ammonium sulphide the band in the red reacted as methemoglobin and the -position (as estimated by Dr. Menten) corresponded with methemoglobin. -Oxyhemoglobin bands in such bloods occupied normal positions as -determined by Dr. Menten. On diluting such bloods with water no -abnormality in character or position bands was observed, save in one -instance (No. 778 below). This does not, however, disprove the -possibility of such abnormality in the hemoglobin within the cells, for -moderate dilution only of serum rendered the band in the red invisible, -presumably by dilution. - - Detailed examination of the absorption bands was made with a direct - reading wave-length Hilger Spectroscope (which was calibrated by - line spectra derived from salts added to an alcohol flame) by Dr. - Menten. This spectroscope had an accuracy of about two Angstroms. In - all, seven post-mortem bloods were examined, viz. autopsy numbers - 756, 761, 763, 773, 778, 784, and 787. In five of these, sufficient - serum was obtained to make readings. All gave the two characteristic - oxyhemoglobin bands in the blue-green with centers of the bands at λ - 758μμ λ and 542μμ. The second oxyhemoglobin band varied slightly in - width in the different samples. In addition to the two oxyhemoglobin - bands in each of four of the above sera, viz: Nos. 756, 763, 767 and - 787, an absorption band in the red was found with the center of the - band as follows: Number 756 at λ 627μμ, number 761 at λ 634μμ, - number 763 at λ 625μμ, and number 787 at λ 634μμ. These bands varied - considerably in intensity and could only be identified when the two - oxyhemoglobin bands were merged and appeared as one broad band. As - controls for the position of the oxyhemoglobin bands two normal - bands were examined, which showed two bands with centers also at λ - 758μμ and λ 543μμ. For comparison of the methemoglobin bands of the - above post-mortem bloods, a sample of this hemoglobin compound was - made by adding potassium ferricyanide to normal blood until the - solution became brownish in color. The center of this methemoglobin - band was found at λ 634μμ. In blood from autopsies number 773 and - number 778 sufficient serum could not be obtained to make a reading. - To each of these bloods distilled water was added. The laked blood - of 778 gave a methemoglobin band with the center at λ 632μμ on - examination 24 hours after autopsy. Similar treatment of corpuscles - five days subsequently gave no indication of the presence of any - methemoglobin spectroscopically. - - From the serum and from the laked corpuscles of number 784 no trace - of methemoglobin was found when the blood was examined a few hours - after removal at autopsy. - -_Oxygen Capacity._—The total oxygen capacity was determined by the Van -Slyke method (by Dr. Rohde and Mrs. Macklin). At this stage the more -pronounced type of influenza had subsided, but in early convalescence -the capacity was within normal ranges. - -Other studies using different technique gave concordant results, but -there were indications that oxygen was more slowly absorbed than -normally. - -_Oxygen Content of Venous Blood_ measured by the Van Slyke method (by -Dr. Rohde and Mrs. Macklin) on the same bloods examined for total oxygen -capacity seemed to indicate a mild deficiency as compared to normal -bloods. - -_Gases, Kinds, Quantity and Rate Yielded to Vacuum._—In general it may -be said that quantitative differences observed are not considered -fundamental, but that the studies indicate abnormal slowness in oxygen -absorption. - -_Gases, Quantity and Rate of Absorption on Exposure to Air After -Extraction by Pump._—The results emphasize slowness of oxygen absorption -as compared to normal blood. - - The material to be examined was exhausted for three minutes in the - receiver of the Van Slyke apparatus. One c.cm. was then transferred, - with as little exposure to air as possible, to a small empty bottle, - which was then closed and placed in communication with a calibrated, - horizontal tube, containing a segment of alcohol, which served the - dual purpose of a seal and an air volume change indicator. (See Fig. - 1.) The apparatus was made in duplicate and mounted on a common - base, so that simultaneous readings on different samples could be - made. After establishing the zero position of the alcohol segment, - the base on which the bottles were mounted was vigorously shaken in - a uniform manner. Ten seconds after the period of shaking, the - volume readings were taken. Successive periods of shaking and - reading were conducted at 30-second intervals, until the test was - completed. Actual volume changes were then calculated, tabulated and - plotted. - - The greater confidence is placed on the results obtained by - observing the color of the blood, as described below; but since then - the method has been checked up and the results indicate that the - findings were of sufficient accuracy to warrant their inclusion in - this report.[1] - -Footnote 1: - - Studies along this line are being made with improved apparatus, the - results of which, together with the description of the apparatus, will - be published elsewhere. (See Am. Gr. Physiol., 1920, li, 195.) - -[Illustration: FIG. 1.] - -_Effect of Addition of Serum on Behavior on Exposure to Air._—The -persistence of venous hue of blood exposed to air was noted above. It -was observed that the addition of serum from the same blood -conspicuously shortened the time required for such blood to acquire an -arterial hue. The addition of normal serum was more effective in this -respect than pathological serum. Measurements of the rate of absorption -of such blood after the addition of serum indicated acceleration of -oxygen absorption. From this it would seem that the oxygen transmitting -capacity of the serum was diminished. - -_Effect of Addition of Dry Sodium Bicarbonate on Behavior on Exposure to -Air._—The addition of a small quantity of dry sodium bicarbonate to a -blood refractory to arterialization on exposure to air enormously -accelerated the process, as judged by the color. To what extent the -change in color may have been due to causes other than oxygen absorption -was not determined. - - - _Comment_ - -The most significant positive findings were evidence of deficiency of -serum oxygen transmitting capacity or rate, and the detection in serum -of an absorption band in the red corresponding to methemoglobin. The -presence of the abnormal substance giving rise to the absorption band is -considered of special interest as indicating abnormal chemical -conditions in the blood, rather than material change in hemoglobin -oxygen capacity. - - - - -THE BACTERIOLOGY OF EPIDEMIC INFLUENZA WITH A DISCUSSION OF B. INFLUENZÆ - AS THE CAUSE OF THIS AND OTHER INFECTIVE PROCESSES - - By W. L. HOLMAN, B. A., M. D. - - - _Introduction_ - -In a study of the bacteriology of a respiratory disease such as -influenza, the technical difficulties encountered are very great and -must be overcome before we can draw useful conclusions from the results -obtained or attempt to determine the etiological factors. The important -methods of attacking such a problem include: (1) the study of stained -smears and cultures from the various available materials, along with the -demonstration of the bacteria in the lesions found in the disease by a -study of sections; (2) tests with the various materials to determine the -presence of the causative agent, which includes experiments on man and -animals and is more inclusive than the mere study of the bacteria -isolated; (3) immunological studies of man suffering from the disease, -or of man and animals treated with the materials from the disease; (4) -pathological, clinical and epidemiological studies linked with the -above. - -Many of the difficulties and sources of error in these methods are -manifest to all, but certain points may be indicated as more important -in the phases of the work on which I am to report. - - - _General Methods of Investigation_ - -Stained smears from the material available. The choice of the material -is of first importance. Sputum to be of any real value must be obtained -from the deeper portions of the respiratory tract, should be as free as -possible from the secretions of the buccal cavity, and should be washed -in saline before it is used. These are considered among the first -requirements in the study of lung infections by the pneumococci and are -equally important in influenza. Swabs from the nasopharynx should be -obtained with the same precautions as are demanded in meningococcal -work. The other available material—such as blood, lung puncture fluid, -pleural fluid and spinal fluid—must be collected with the greatest care. - -The staining methods should, naturally, include those which will bring -out the various types of bacteria, and must include the Gram method, -using dilute alcoholic fuchsin (1-20) as the counterstain. The varying -morphology of the B. influenzæ and its frequent minute size make it -difficult to detect. It is not the only Gram negative small bacillus -seen in smears from the throat, but when it occurs in the typical -schools, or where there are numerous bacilli to be seen, its -characteristics are quite definite. I have recently isolated an anærobic -Gram negative bacillus from a series of swabs from the buccal cavity -which suggests in many ways the morphology of the B. influenzæ, which -will indicate one of the many difficulties to be met with in the study -of stained smears. They are, nevertheless, of great use as a control on -cultures, and most helpful in the study of the material from sources -other than the respiratory tract. - -Cultures of the bacteria from the various materials. Here we have the -greatest difficulty of all. The medium chosen determines the bacteria -which will appear to predominate, and there is no single medium that -will answer all purposes. Streptococci will appear to be in excess when -serum broth is used, as I have previously shown; pneumococci with -Avery’s pneumococcus medium; and staphylococci, the Gram negative cocci, -and the diphtheria group with Loeffler’s serum. Ordinary blood agar is -perhaps the best general medium for direct and secondary plating. There -have been many special media devised for growing the B. influenzæ, but -the one I have used most and found particularly helpful is heated blood -agar made after the general method of Voges. - -The extremely tiny colony of B. influenzæ on ordinary blood agar makes -it particularly difficult to detect, and one is apt to get the wrong -impression of its numbers from the macroscopic appearance of the plate. -In attempts at isolation there must be a liberal use of media in picking -colonies, as many suspicious ones will turn out to be immature growths -of B. xerosis, M. pharyngis (or M. catarrhalis), streptococci, or more -rarely pneumococci and other organisms. Replating from such picks is -frequently necessary, and further plates, from the original culture on -heated blood agar, must often be made before the B. influenzæ can be -isolated. The care required in all stages of the isolation of this -organism, the unstinted use of media for plating and for picks, the -number of stained smears to be studied, and the further transfers -necessary to verify results, all these limit the amount of material -which can be studied with any degree of accuracy. If further the -streptococci, the pneumococci, the Gram negative cocci, the capsulated -Gram negative bacilli and many others are to receive any attention, it -can readily be appreciated that a few cases carefully studied are of far -more value than a large number hurriedly examined in an uncertain -routine. - -The pathological study of the same cases on which I have done the -bacteriology will be found in Dr. Klotz’s paper in these communications, -and I will merely refer to some of the bacterial findings in the -sections of the lungs and bronchi. The more inclusive methods which have -been used in attempts to determine the etiological factor in influenza -we have been unable to attempt, but I will refer later in this paper to -the findings of the investigations of others. Immunological studies have -been limited to a few investigations on the presence of agglutinins, -complement binding substance, skin reactions and the amount of -complement present in the sera of certain patients. The epidemiological -and clinical studies are reported by Drs. Johnston and Lichty in this -series of reports. - - - _Material Studied_ - -The material used in the study I am reporting included swabs from the -large bronchi and fluid from the lungs and pleural cavities of 32 -autopsies, as well as blood cultures from 22 patients and swabs from the -nasopharynx of 31 individuals. Fifteen sera were tested for fixation of -complement with an antigen made from several strains of B. influenzæ. -Fourteen other sera were tested for agglutinins. Complement content was -determined in the sera of 25 patients. Skin tests after the Von Pirquet -method were done on 14 convalescents, and carefully stained -nasopharyngeal smears without cultures were studied from 48 patients. - -The chief attention was given to the study of the autopsy material and -we concentrated on the isolation of B. influenzæ. At the same time we -did not neglect the other bacteria making up the flora of the bronchi, -lungs and pleural cavity in these cases. The various types were isolated -and most of them fully identified. - - - _Technique_ - -Direct smears were made on sterile slides of all material studied and -stained by Gram’s method. The counterstain was always alcoholic fuchsin -diluted 1-20 in distilled water. Direct cultures were made on a human -blood agar plate containing 5 per cent. blood, which was further smeared -just before use with defibrinated blood. This latter procedure was later -discarded, as it did not appear to assist to any marked extent the -growth of B. influenzæ. Blood broth containing a few drops of -defibrinated blood and blood agar slants smeared with blood were also -used. Heated blood agar (2-3 c.cm. of defibrinated human blood added to -100 c.cm. of ordinary agar at a temperature of from 90 to 100° C., or as -the agar comes from the sterilizer) was used in the last nine cases to -replace the blood agar slant in the direct cultures and as the medium of -choice for transfers of the B. influenzæ. - -I prefer the ordinary blood agar plate to the heated blood plate because -the former gives readings which are very helpful in distinguishing -colonies of various types. B. influenzæ appears as clear, tiny, -pinpoint, inert colonies. B. xerosis or the pseudodiphtheria group gives -more opaque but often rather similar colonies. Gram negative cocci as M. -pharyngis siccus have dry, raised, soon becoming wrinkled, inert -colonies, varying greatly in size; M. catarrhalis, more moist, inert -colonies. The cocci of the streptococcus viridans group appear as very -small colonies with greening, or are not infrequently inert, while thin, -flattened colonies with central thickening may sometimes be noted. Those -of the streptococcus hemolyticus group occur as small, frequently -nipple-like colonies with clear, wide zones of hemolysis; pneumococci as -moderately small, moist, dewdrop-like colonies with center collapsing -early and with greening; streptococcus or pneumococcus mucosus as -larger, watery, sticky colonies with greening and frequently an early -clearing near the colonies. - - - TABLE I. - - BACTERIOLOGY OF THIRTY-TWO AUTOPSIES FROM INFLUENZA CASES. - - ───────┬─────┬───────────┬─────┬──────────────────┬───────────────────── - AUTOPSY│DATE.│ DAY OF │HOURS│ DIRECT │ B. INFLUENZÆ - NUMBER.│ │ DISEASE. │P.M. │ SMEAR—GRAM’S │ - │ │ │ │ METHOD. │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┬─────┬─────── - │ │ │ │ │BRONCH.│LUNG.│PLEURAL - │ │ │ │ │ │ │FLUID. - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 741│ 1918│ 3│ 16│G +staph. Few │ 0 │ + │ 0 - │ Oct.│ │ │ pneumo-like. Few│ │ │ - │ 9│ │ │ chains of elong.│ │ │ - │ │ │ │ cocci. │ │ │ - │ │ │ │ │ │ │ - │ │ │ │ │ │ │ - │ │ │ │ │ │ │ - │ │ │ │ │ │ │ - │ │ │ │ │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 743│ 11│ 5│ 8│Br. G—bac. from │ + │ 0 │ – - │ │ │ │ coccoid to short│ │ │ - │ │ │ │ threads. Mostly │ │ │ - │ │ │ │ scattered. Some │ │ │ - │ │ │ │ phagocyted. │ │ │ - │ │ │ │ Fewer G +cooci │ │ │ - │ │ │ │ in short chains.│ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 744│ 11│ 7│ 11│Br. G—bac. │ + │ – │ 0 - │ │ │ │ moderately stout│ │ │ - │ │ │ │ about in small │ │ │ - │ │ │ │ groups and │ │ │ - │ │ │ │ scattered. │ │ │ - │ │ │ │ G+diploc │ │ │ - │ │ │ │ (pneumo) also G—│ │ │ - │ │ │ │ threads. Phago. │ │ │ - │ │ │ │ of both in a few│ │ │ - │ │ │ │ cells. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 745│ 12│ 10│ 6│Br. G +—large │ + │ 0 │ –– - │ │ │ │ bac., strept. │ │ │ - │ │ │ │ short, G—B, few,│ │ │ - │ │ │ │ very short, no │ │ │ - │ │ │ │ threads. │ │ │ - │ │ │ │ │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 746│ 12│ 5│ ½│Br. G—B very │ + │ – │ 0 - │ │ │ │ short, no │ │ │ - │ │ │ │ threads. │ │ │ - │ │ │ │ Irregularly │ │ │ - │ │ │ │ scattered. More │ │ │ - │ │ │ │ seen in left │ │ │ - │ │ │ │ bronchus. A few │ │ │ - │ │ │ │ cells │ │ │ - │ │ │ │ phagocyted. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 747│ 13│ 6│ 3│Br. G+diploc, │ + │ – │ – - │ │ │ │ fairly numerous.│ │ │ - │ │ │ │ G—B tiny, as │ │ │ - │ │ │ │ diplos and in │ │ │ - │ │ │ │ long threads │ │ │ - │ │ │ │ scattered or in │ │ │ - │ │ │ │ small groups. │ │ │ - │ │ │ │ Pleural fluid │ │ │ - │ │ │ │ and lung no │ │ │ - │ │ │ │ bacteria seen. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 748│ 13│ 4│ 4│Br. nothing like │ – │ + │ 0 - │ │ │ │ B. I. seen. G+ │ │ │ - │ │ │ │ small elong. │ │ │ - │ │ │ │ diplo. Numerous │ │ │ - │ │ │ │ G + diploc. in │ │ │ - │ │ │ │ lung. │ │ │ - │ │ │ │ Comparatively │ │ │ - │ │ │ │ few Q-B, very │ │ │ - │ │ │ │ short. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 749│ 14│ 4│ 15│Br. G+large pneumo│ – │ – │ 0 - │ │ │ │ like, many │ │ │ - │ │ │ │ G+large bacilli,│ │ │ - │ │ │ │ single and in │ │ │ - │ │ │ │ pairs. Few G—B │ │ │ - │ │ │ │ very tiny and │ │ │ - │ │ │ │ widely │ │ │ - │ │ │ │ scattered; lung,│ │ │ - │ │ │ │ heavy mixture as│ │ │ - │ │ │ │ in bronchi. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 750│ 14│ 9│ 6│Br. G+B large like│ – │ – │ 0 - │ │ │ │ B. welchii, │ │ │ - │ │ │ │ G—rather stout │ │ │ - │ │ │ │ coccoid forms, │ │ │ - │ │ │ │ G+C in pairs and│ │ │ - │ │ │ │ short chains. │ │ │ - │ │ │ │ Tiny G—coccoid │ │ │ - │ │ │ │ forms like B. I.│ │ │ - │ │ │ │ Lung G+ │ │ │ - │ │ │ │ pneumo-like and │ │ │ - │ │ │ │ caps, chains; no│ │ │ - │ │ │ │ B. I. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 751│ 14│ 7│ 6│Br. G +cocci large│ – │ – │ + - │ │ │ │ elong.? caps, │ │ │ - │ │ │ │ also G +C in │ │ │ - │ │ │ │ flat pairs. │ │ │ - │ │ │ │ G—coccoid forms.│ │ │ - │ │ │ │ Lung, numerous │ │ │ - │ │ │ │ bacteria. │ │ │ - │ │ │ │ G+strept. with │ │ │ - │ │ │ │ flattened cocci.│ │ │ - │ │ │ │ Some G-short │ │ │ - │ │ │ │ forms? │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 752│ 15│ 13│ 15│Br. G+pneumo-like.│ – │ + │ 0 - │ │ │ │ G+B smaller than│ │ │ - │ │ │ │ B. welchii, │ │ │ - │ │ │ │ occasionally │ │ │ - │ │ │ │ tiny G │ │ │ - │ │ │ │ -diplobacillus. │ │ │ - │ │ │ │ Lung, G+chains │ │ │ - │ │ │ │ of cocci Gram │ │ │ - │ │ │ │ weak. Few G—tiny│ │ │ - │ │ │ │ bacilli │ │ │ - │ │ │ │ scattered or in │ │ │ - │ │ │ │ groups. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 756│ 16│ 8│ 18│Br. numerous G+B. │ – │ 0 │ – - │ │ │ │ B welchii like. │ │ │ - │ │ │ │ G—B large and │ │ │ - │ │ │ │ few tiny. │ │ │ - │ │ │ │ G+round diploc. │ │ │ - │ │ │ │ Pl. fluid almost│ │ │ - │ │ │ │ pure │ │ │ - │ │ │ │ pneumo-like, few│ │ │ - │ │ │ │ G-forms probably│ │ │ - │ │ │ │ the same. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 757│ 16│ 6│ 14│Br. G—B tiny, to │ + │ + │ 0 - │ │ │ │ medium. G—like │ │ │ - │ │ │ │ M. catarrhalis. │ │ │ - │ │ │ │ G+cocci, pairs │ │ │ - │ │ │ │ and chains. Few │ │ │ - │ │ │ │ B. W. like. │ │ │ - │ │ │ │ Lung, many G—B │ │ │ - │ │ │ │ like B. I. Some │ │ │ - │ │ │ │ cells filled, │ │ │ - │ │ │ │ also G—cocci. M.│ │ │ - │ │ │ │ catarrhalis like│ │ │ - │ │ │ │ and rare B. │ │ │ - │ │ │ │ welchii like. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 758│ 16│ 14│ 16│Br. pneumo-like in│ + │ ? │ 0 - │ │ │ │ excess. G—B from│ │ │ - │ │ │ │ tiny to forms │ │ │ - │ │ │ │ stouter than B. │ │ │ - │ │ │ │ I. Few strept. │ │ │ - │ │ │ │ rare M. │ │ │ - │ │ │ │ catarrhalis. │ │ │ - │ │ │ │ Lung, │ │ │ - │ │ │ │ pneumo-like. │ │ │ - │ │ │ │ Phago. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 761│ 17│ 7│ 19│Br. pneumo-like. │ + │ – │ 0 - │ │ │ │ B. I. like │ │ │ - │ │ │ │ common, M. │ │ │ - │ │ │ │ catarrhalis │ │ │ - │ │ │ │ like. Both B.I. │ │ │ - │ │ │ │ and M. │ │ │ - │ │ │ │ catarrhalis │ │ │ - │ │ │ │ phagocyted. B.I.│ │ │ - │ │ │ │ single or in │ │ │ - │ │ │ │ threads. Some │ │ │ - │ │ │ │ typical groups. │ │ │ - │ │ │ │ Lung, pneumo, │ │ │ - │ │ │ │ caps, rare, M. │ │ │ - │ │ │ │ catarrhalis │ │ │ - │ │ │ │ like. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 762│ 17│ 10│ 12│Br. numerous B.l. │ + │ + │ + - │ │ │ │ like typical, │ │ │ - │ │ │ │ also many │ │ │ - │ │ │ │ pneumo. and M. │ │ │ - │ │ │ │ catarrh. Lung │ │ │ - │ │ │ │ same. M. │ │ │ - │ │ │ │ catarrh. │ │ │ - │ │ │ │ phagocyted. B.I.│ │ │ - │ │ │ │ smear, many │ │ │ - │ │ │ │ phagocyted, many│ │ │ - │ │ │ │ pneumo. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 763│ 17│ 11│ 13│Lung, pneumo-like,│ 0 │ – │ – - │ │ │ │ slight │ │ │ - │ │ │ │ phagocytosis. │ │ │ - │ │ │ │ Pl. fl., pneumo │ │ │ - │ │ │ │ and few strept.,│ │ │ - │ │ │ │ slight │ │ │ - │ │ │ │ phagocytosis. │ │ │ - │ │ │ │ │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 764│ 17│ 9│ 6│Br. B.I. smear. │ + │ 0 │ 0 - │ │ │ │ Cells crowded. │ │ │ - │ │ │ │ Pneumo-like │ │ │ - │ │ │ │ fewer, │ │ │ - │ │ │ │ occasional │ │ │ - │ │ │ │ G—stouter │ │ │ - │ │ │ │ thread. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 765│ 17│ 9│ 16│Br. pneumo. B.I. │ + │ + │ 0 - │ │ │ │ few scattered. │ │ │ - │ │ │ │ G+flattened │ │ │ - │ │ │ │ diploc. Phago. │ │ │ - │ │ │ │ of B.I. and │ │ │ - │ │ │ │ pneumo. Lung, │ │ │ - │ │ │ │ pneumo-like, │ │ │ - │ │ │ │ rare strept. │ │ │ - │ │ │ │ very │ │ │ - │ │ │ │ questionable G—B│ │ │ - │ │ │ │ free and in │ │ │ - │ │ │ │ cells. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 767│ 18│ 10│ 14│Br. rather round │ – │ – │ 0 - │ │ │ │ pneumo-like with│ │ │ - │ │ │ │ caps. B.I. few. │ │ │ - │ │ │ │ Scattered, also │ │ │ - │ │ │ │ in cells. Lung, │ │ │ - │ │ │ │ few bacteria. │ │ │ - │ │ │ │ G+strep. often │ │ │ - │ │ │ │ phagocyted. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 770│ 19│ 11│ 9│Br. crowded with │ + │ + │ – - │ │ │ │ B.I. like. Few │ │ │ - │ │ │ │ G+cocci and │ │ │ - │ │ │ │ fewer M. │ │ │ - │ │ │ │ catarrh. like. │ │ │ - │ │ │ │ Pl. fluid │ │ │ - │ │ │ │ G+flattened │ │ │ - │ │ │ │ pairs, pus │ │ │ - │ │ │ │ cells, │ │ │ - │ │ │ │ phagocyted. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 773│ 21│ 20│ 3│Br. few bacteria │ – │ – │ – - │ │Recurrence.│ │ G+and │ │ │ - │ │ │ │ G—pneumo-like. │ │ │ - │ │ │ │ Rare G+—thread. │ │ │ - │ │ │ │ Lung, pneumo and│ │ │ - │ │ │ │ rare strept. Pl.│ │ │ - │ │ │ │ fluid, │ │ │ - │ │ │ │ pneumo-oat │ │ │ - │ │ │ │ shapes, etc. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 778│ 24│ 23│ 17│Br. B.I. smear. │ + │ + │ – - │ │ │ │ Fewer large │ │ │ - │ │ │ │ pneumo. Lung, G │ │ │ - │ │ │ │ + small diploc. │ │ │ - │ │ │ │ Few B.I. like. │ │ │ - │ │ │ │ Pl. fluid, few │ │ │ - │ │ │ │ cells, no │ │ │ - │ │ │ │ bacteria. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 781│ 26│ 5│ 4│Br. crowded with │ – │ + │ – - │ │ │ │ staph. like. │ │ │ - │ │ │ │ Fewer G—B, │ │ │ - │ │ │ │ larger than │ │ │ - │ │ │ │ B.I., few M. │ │ │ - │ │ │ │ catarrhalis │ │ │ - │ │ │ │ like. Lung G+ │ │ │ - │ │ │ │ small staph. │ │ │ - │ │ │ │ like, caps, │ │ │ - │ │ │ │ cocci in pairs │ │ │ - │ │ │ │ and chains. Few │ │ │ - │ │ │ │ tiny G—B. Pl. │ │ │ - │ │ │ │ fluid │ │ │ - │ │ │ │ pneumo-like and │ │ │ - │ │ │ │ elong. cocci in │ │ │ - │ │ │ │ chains │ │ │ - │ │ │ │ capsulated. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 782│ 26│ 8│ 3│Br. numerous B.I. │ + │ – │ 0 - │ │ │ │ like scattered, │ │ │ - │ │ │ │ some phagocyted.│ │ │ - │ │ │ │ Fewer G+ flat │ │ │ - │ │ │ │ pairs with │ │ │ - │ │ │ │ capsule. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 783│ 26│ 8│ 1│Br. G+small caps, │ + │ – │ 0 - │ │ │ │ pneumo-like. │ │ │ - │ │ │ │ Lung poor smear,│ │ │ - │ │ │ │ occasional │ │ │ - │ │ │ │ pneumo-like. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 784│ 28│ 8│ 6│Br. capsulated │ + │ + │ 0 - │ │ │ │ pneumo-like, few│ │ │ - │ │ │ │ strep. Lung, │ │ │ - │ │ │ │ chiefly │ │ │ - │ │ │ │ pneumo-like. few│ │ │ - │ │ │ │ G—B like B.I., │ │ │ - │ │ │ │ also │ │ │ - │ │ │ │ G—pneumo-like. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 786│ 29│ 4│ 2│Br. G+cocci in │ + │ – │ 0 - │ │ │ │ round pairs and │ │ │ - │ │ │ │ rather flat │ │ │ - │ │ │ │ chains, │ │ │ - │ │ │ │ suggested caps. │ │ │ - │ │ │ │ Tiny G—B very │ │ │ - │ │ │ │ rare. Lung │ │ │ - │ │ │ │ streptococci │ │ │ - │ │ │ │ flattened, often│ │ │ - │ │ │ │ phagocyted. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 787│ 29│ 8│ 2│Br. numerous │ + │ + │ 0 - │ │ │ │ pneumo-like, │ │ │ - │ │ │ │ bacillary forms.│ │ │ - │ │ │ │ A rare │ │ │ - │ │ │ │ suspicious B.I. │ │ │ - │ │ │ │ like, some of │ │ │ - │ │ │ │ these in cells. │ │ │ - │ │ │ │ Lung, caps, │ │ │ - │ │ │ │ elongated │ │ │ - │ │ │ │ diplos, and │ │ │ - │ │ │ │ chains of elong.│ │ │ - │ │ │ │ cocci. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 791│ Nov.│ 6│ 6│Br. few bacteria. │ + │ + │ – - │ 1│ │ │ G+pneumo-like │ │ │ - │ │ │ │ round, G—B and │ │ │ - │ │ │ │ threads, size │ │ │ - │ │ │ │ varies, like │ │ │ - │ │ │ │ B.I. Lung, G + │ │ │ - │ │ │ │ caps, pneumo. │ │ │ - │ │ │ │ G+Large B. few │ │ │ - │ │ │ │ suspicious │ │ │ - │ │ │ │ G—coccoid forms.│ │ │ - │ │ │ │ Pl. fl. caps, │ │ │ - │ │ │ │ pneumo and caps,│ │ │ - │ │ │ │ elong. chains. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 792│ 2│ 6│ 3│Br. caps, │ + │ + │ – - │ │ │ │ pneumo-like bac.│ │ │ - │ │ │ │ forms and │ │ │ - │ │ │ │ chains. G-caps, │ │ │ - │ │ │ │ pneumo-like. Few│ │ │ - │ │ │ │ G—B. │ │ │ - │ │ │ │ questionable. │ │ │ - │ │ │ │ Lung. caps, │ │ │ - │ │ │ │ pairs and chains│ │ │ - │ │ │ │ of elong. cocci,│ │ │ - │ │ │ │ in cells. Pl. │ │ │ - │ │ │ │ fluid, numerous │ │ │ - │ │ │ │ caps, chains of │ │ │ - │ │ │ │ diploc. │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - 793│ 4│ 10│ 3/2│Br. M. catarrh. │ – │ – │ – - │ │ │ │ and G+cocci, few│ │ │ - │ │ │ │ bacteria, few │ │ │ - │ │ │ │ G—B. Ear, │ │ │ - │ │ │ │ G+cocci. │ │ │ - │ │ │ │ │ │ │ - ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼─────── - │ │ │ │ Total │ 20 │ 13 │ 2 - │ │ │ │B. influenzæ │ 66½ │ 46 │ 14 - │ │ │ │ found—Percentage│ │ │ - │ │ │ │ │ ——— │ ——— │ ——— - │ │ │ │Total percentage │ │ 78 │% - │ │ │ │ for B. influenzæ│ │ │ - ───────┴─────┴───────────┴─────┴──────────────────┴───────┴─────┴─────── - - ───────┬───────────┬─────────┬─────────┬─────────┬──────────────── - AUTOPSY│PNEUMCOCCI.│ STREPT. │HEMOLYTIC│ S.P.A. │ OTHER COCCI. - NUMBER.│ │MOCOCCI. │ STREPT. │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 741│ │ │ │+ │G+ diploc. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 743│ │Pleural │ │ │Br. G + diploc. - │ │fluid and│ │ │not like pneumo. - │ │seen as │ │ │ - │ │diplos in│ │ │ - │ │direct │ │ │ - │ │smear. │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 744│Lung + │ │ │ │M. tetrag. in - │ │ │ │ │Br. M. pharyng. - │ │ │ │ │in Br. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 745│ │ │Pleural │Pl. │ - │ │ │fluid, │fluid, │ - │ │ │also seen│also seen│ - │ │ │in smear.│in │ - │ │ │ │smears. │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 746│ │ │ │ │Strept. viridans - │ │ │ │ │from bronchus. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 747│ │ │ │Bronchus │Strept. viridans - │ │ │ │and │from bronchi and - │ │ │ │pleural │lung. - │ │ │ │fluid. │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 748│Lung+, not │ │ │ │Strept. viridans - │isolated │ │ │ │from bronchus. - │from │ │ │ │ - │bronchus. │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 749│Bronchus │ │ │Bronchus │ - │Lung? │ │ │and lung.│ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 750│Bronchus? │ │ │ │ - │Lung? │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 751│ │Pleura. │ │ │M. tetragenous - │ │Lung. │ │ │from bronchus. - │ │Bronchus.│ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 752│Bronchus │ │ │ │Strep. viridans - │and lung. │ │ │ │from bronchus - │ │ │ │ │and lungs. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 756│ │ │ │Pleural │Strep. viridans - │ │ │ │fluid. │from bronchus. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 757│Bronchus │ │ │Bronchus │M. tetragenous? - │and lung. │ │ │and lung.│from lung. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 758│Bronchus │ │ │ │M. - │and lung. │ │ │ │catarrhalia-like - │ │ │ │ │from lung. - │ │ │ │ │Strep. viridans - │ │ │ │ │from lung and - │ │ │ │ │bronchus. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 761│Bronchus │ │ │Bronchus │ - │and lung. │ │ │and lung.│ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 762│Pleural │ │ │ │M. catarrh. like - │fluid and │ │ │ │from lung and - │bronchus. │ │ │ │bronchus. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 763│Pleural │ │ │ │ - │fluid. │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 764│Bronchus. │ │ │ │Staph, albus - │ │ │ │ │from bronchus. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 765│ │ │Lung. │ │M. catarrh. from - │ │ │ │ │bronchus and - │ │ │ │ │lung. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 767│Bronchus. │Lung. │ │Bronchus.│ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 770│Bronchus. │ │ │Bronchus,│ - │ │ │ │lung, │ - │ │ │ │pleural │ - │ │ │ │fluid. │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 773│ │ │ │Bronchus.│Strept. viridans - │ │ │ │ │bronchus. - │ │ │ │ │Sarcina albus - │ │ │ │ │lung. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 778│Bronchus │ │ │Lung. │ - │and lung. │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 781│ │Lung and │ │Bronchus │Staph. albus and - │ │pleural │ │and lung │sarcina from - │ │fluid. │ │abscess. │pleural fluid. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 782│ │Bronchus │ │ │ - │ │and lung.│ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 783│Lung. │ │ │Bronchus.│M. catarrh. like - │ │ │ │ │bronchus. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 784│Bronchus │Bronchus │ │ │M. catarrh. like - │and lung. │and lung?│ │ │bronchus. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 786│Bronchus. │ │Bronchus │ │Staph, albus - │ │ │and lung.│ │from bronchus. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 787│ │ │ │Bronchus │ - │ │ │ │and lung.│ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 791│Bronchus │ │ │Bronchus │ - │and pleural│ │ │and lung.│ - │cavity. │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 792│Bronchus, │ │ │ │Staph. albus, - │lung and │ │ │ │lung, strept. - │pleural │ │ │ │viridans lung, - │fluid. │ │ │ │M. catarrh. like - │ │ │ │ │lung and - │ │ │ │ │bronchi. - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - 793│?Throat. │ │Bronchus,│Throat, │Strept. viridans - │ │ │lung, arm│ear and │from throat. - │ │ │vein, │bronchus.│ - │ │ │spleen │ │ - │ │ │ear. │ │ - │ │ │ │ │ - ───────┼───────────┼─────────┼─────────┼─────────┼──────────────── - │20 │6 │4 │16 │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┴───────────┴─────────┴─────────┴─────────┴──────────────── - - ───────┬───────────────┬────────────┬────────────── - AUTOPSY│ OTHER G—B. │ OTHER │ NOTES. - NUMBER.│ │ BACTERIA. │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 741│ │ │Nine plates - │ │ │used to - │ │ │isolate B.I. - │ │ │Sp.a. overgrew - │ │ │all cultures. - │ │ │B.I. seen in - │ │ │blood smear - │ │ │agar in 24 - │ │ │hours. - ───────┼───────────────┼────────────┼────────────── - 743│Br. lux. white │ │Pericard, - │almost coccoid.│ │fluid and - │ │ │liver juice, - │ │ │no growth. - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 744│ │ │Pneumococcus - │ │ │from lung. No - │ │ │attempt after - │ │ │first plate to - │ │ │isolate B.I. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 745│ │ │Swab from - │ │ │ruptured - │ │ │rectus. - │ │ │Sterile. No - │ │ │material from - │ │ │lung. - ───────┼───────────────┼────────────┼────────────── - 746│B. coli from │B. xerosis │The overgrowth - │bronchi and │from │of B. coli in - │lung. │bronchus. │lung material - │ │ │prevented - │ │ │further - │ │ │attempts to - │ │ │isolate B.I. - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 747│ │B. subtilis │Five picks - │ │group from │from blood - │ │pleural │agar plate - │ │fluid. │failed to - │ │ │recover B.I. - │ │ │from lung. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 748│ │ │B.I. not seen - │ │ │nor isolated - │ │ │from the - │ │ │bronchi. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 749│B. coli from │ │The overgrowth - │bronchus and │ │of B. coli - │lung. │ │prevented any - │ │ │further - │ │ │attempts to - │ │ │isolate B.I. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 750│B. coli from │ │B. coli again - │bronchi and │ │present as in - │lungs. │ │No. 749. - │ │ │Direct smear - │ │ │suggests heavy - │ │ │contamination. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 751│ │Spore-bearer│ - │ │with tiny │ - │ │cols, pleur.│ - │ │B. xerosis │ - │ │from bron. │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 752│ │ │B.I. like seen - │ │ │in original - │ │ │culture on - │ │ │blood agar but - │ │ │not isolated - │ │ │from bronchus. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 756│B. coli from │B. xerosis │Compare No. - │bronchus and │from │749 and 750. - │pleural fluid. │bronchus. │Fluid from - │ │ │lung not - │ │ │obtained for - │ │ │culture. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 757│ │B. xerosis │This case 14 - │ │from │hours P. M. - │ │bronchus. │gave B.I. from - │ │ │all the - │ │ │material. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 758│B. coli from │ │The B. coli - │bronchus. │ │did not - │ │ │prevent the - │ │ │isolation of - │ │ │B.I. like seen - │ │ │in original - │ │ │blood agar - │ │ │cultures of - │ │ │lung. - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 761│B. coli from │ │Even after 19 - │bronchus. │ │hours P. M. - │ │ │the B.I. was - │ │ │isolated. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 762│ │B. xerosis │ - │ │from lung. │ - │ │B. subtilis │ - │ │from │ - │ │bronchus. │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 763│ │ │No growth from - │ │ │lung on plate. - │ │ │B.I. like seen - │ │ │in original - │ │ │culture from - │ │ │pleural fluid. - │ │ │No material - │ │ │from bronchus. - ───────┼───────────────┼────────────┼────────────── - 764│ │ │Material only - │ │ │from bronchi. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 765│B. coli from │ │ - │bronchus and │ │ - │lung. │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 767│ │ │Blood culture - │ │ │15/10 gave - │ │ │pure growth of - │ │ │pneumo. - │ │ │mucosus. - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 770│ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 773│ │B. xerosis │No growth from - │ │from │lung except - │ │bronchus. G │sarcina. Only - │ │+ B lux. │2 colonies - │ │white │from pleural - │ │pleura. │fluid on blood - │ │fluid. │agar plates. - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 778│Non-motile, │ │Ten plates and - │non-fermenting,│ │30 picks were - │lux, white from│ │done for the - │bron. │ │isolation of - │ │ │B.I. - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 781│ │ │B.I. like seen - │ │ │from 24 hour - │ │ │Ht. blood agar - │ │ │from bronchi - │ │ │and lung but - │ │ │only isolated - │ │ │from lung on - │ │ │replating. Bl. - │ │ │culture 25/10 - │ │ │sterile. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 782│ │ │No B.I. like - │ │ │on 24-hour Ht. - │ │ │blood agar - │ │ │from lung. - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 783│ │ │No B.I. like - │ │ │on 24-hour Ht. - │ │ │blood agar - │ │ │from lung. - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 784│ │ │Numerous B.I. - │ │ │like on - │ │ │24-hour Ht. - │ │ │blood agar of - │ │ │bronchi and - │ │ │fewer from - │ │ │lung. Isolated - │ │ │by replating. - ───────┼───────────────┼────────────┼────────────── - 786│ │ │Pleural fluid - │ │ │not collected - │ │ │sterilly, - │ │ │Haemol. - │ │ │strept. - │ │ │isolated. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 787│B.M.C. from │ │All the - │bronchi. │ │bacteria - │ │ │isolated were - │ │ │seen in - │ │ │24-hour Ht. - │ │ │blood agar - │ │ │cultures from - │ │ │bronchi and - │ │ │lung. - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 791│ │ │Replated from - │ │ │Ht. blood agar - │ │ │to isolate - │ │ │B.I. from - │ │ │lung. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 792│ │ │B.I. like seen - │ │ │on 24-hour Ht. - │ │ │blood agar - │ │ │from bronchi - │ │ │and lung but - │ │ │not pleural - │ │ │fluid. - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┼───────────────┼────────────┼────────────── - 793│B. coli from │ │B.I. like - │throat. │ │never seen - │ │ │except from - │ │ │throat which - │ │ │may have been - │ │ │B. coli. - ───────┼───────────────┼────────────┼────────────── - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - │ │ │ - ───────┴───────────────┴────────────┴────────────── - - EXPLANATORY NOTE. - - B.I.—B. influenzæ. - - S.P.A.—Staphylococcus pyogenes aureus. - - M. pharyog—Micrococcus pharyngis siccus. - - Br.—Bronchus. - - Phago.—phagocytosis. - - Ht.-Heated blood agar. - - B. W.—B. welchii. - -Staphylococci develop opaque, paint-like colonies of varying size, with -or without hemolysis, and so do other less frequently found bacteria -give more or less distinctive colonies. The heated blood agar does not -show these differences. - -The colonies most liable to be confused with those of B. influenzæ are, -therefore, those of B. xerosis, immature colonies of the Gram negative -cocci and certain colonies of the streptococcus viridans group. -Transfers should always be made to heated blood agar of all colonies -suggestive of B. influenzæ, or when the growth of the B. influenzæ has -only occurred in the more crowded portions of the plate, and it is -difficult to pick pure cultures, attempted pickings should be made to -this medium for further platings. It is frequently necessary to make -further blood agar plates from the original blood agar, blood broth or -heated blood agar cultures after longer incubation periods, depending on -the findings in smears from these media. The heated blood agar is the -best of these to encourage the growth of B. influenzæ. It must, however, -be used at once, or within a very few days of its preparation, and -cannot be kept on hand as a stock medium. I have not found it as useful -for plating because of the difficulty of differentiating colonies. The -phenomenon of the star-like and more luxuriant growth of the colonies of -B. influenzæ about colonies of other bacteria has often been noted, and -will be referred to in a later portion of this report. Here it may be -said that this is at times a marked feature of certain mixtures and must -be recognized in studying the plates. The finding of B. influenzæ in -picks from apparently isolated colonies of other forms is not uncommon, -and is the same type of difficulty which I have discussed in papers on -streptococci. It is important to recall, in connection with cultures -taken from the lungs at autopsy, the experimental work of Norris and -Pappenheimer, who showed that B. prodigiosus put in the mouth -immediately after death could be recovered from the lungs in over 50 per -cent. of the cases studied. - - - _Results of the Author_ - -In Table I are shown my results from the 32 cases which came to autopsy. -The B. influenzæ was isolated from one or more sources in 25, making a -total of 78 per cent. Most of the negative cases probably also had this -organism, but I did not grow it from the material which I used for -culturing. The work of others would indicate that it may have been -present in other regions, such as the sinuses of the head or other -portions of the lung and respiratory tract. The positive results show B. -influenzæ present in 20 out of 30 cases from the bronchi; in 13 of 28 -from the lungs; in 2 of 14 from the pleural cavity; in 9 of 26 from both -bronchi and lung where both were cultured; in 8 of 26 from the bronchi -with the lung negative; in 3 of 26 from the lung with the bronchi -negative; once of 10 from the pleural cavity with both the bronchi and -the lung negative, and once from all three sources. - -The negative results occurred in seven cases. In three of these (749, -750, 756) B. coli overgrew the cultures from the bronchus, in two also -from the lung, and in one, without lung culture, from bronchus and -pleural cavity. The mere presence of B. coli, however, did not preclude -the isolation of B. influenzæ, as is seen in cases 746, 758, 761 and -765. The finding of B. coli would suggest a post-mortem invasion. The -hours after death before the autopsy was done were in these seven cases, -½, 15, 6, 18, 16, 19, 16, respectively. That delay in performing the -autopsy, as emphasized by Spooner, Scott and Heath, adds to the -difficulty is self-evident, but successful isolations of B. influenzæ -have been obtained after even longer periods than in the negative cases -(761). In the fourth negative case (763) the bronchus was not cultured. -A pneumococcus was grown from the pleural cavity and no growth was -obtained from the lung. In the original culture from the pleural cavity -influenza-like forms were seen but could not be isolated. In the fifth -case (767) a blood culture three days before death gave a growth of -pneumococcus mucosus which was also grown from the lung at autopsy. -Direct smear from the bronchus showed very few influenza-like forms. Our -sixth negative finding was in a case of 20 days’ illness, the patient -having had a recurrence (773). Staphylococcus pyogenes aureus, -streptococcus viridans and B. xerosis were grown from the bronchus. Only -a sarcina form grew from the lung, and a further probable air -contamination occurred on the media from the cultures of the pleural -cavity. The B. xerosis colonies were confusing, picked as possible B. -influenzæ, and, before this was discovered, the overgrowth prevented -further attempts to isolate the influenza bacilli. The last unsuccessful -case was one with a general infection of a hemolytic streptococcus from -an acute otitis media. The streptococcus was isolated from the bronchus, -lung, spleen, arm vein and the middle ear at autopsy. - -It will be seen that in these seven negative cases technical -difficulties prevented the isolation of the B. influenzæ, even if it had -been present. I would not, therefore, conclude that the organisms were -necessarily absent, but rather that we have failed either to secure -material from the focus of infection or on account of the other reasons -mentioned. - -It is very evident that a variety of secondary organisms very frequently -overgrow the field and become numerically predominant. In our first case -staphylococcus pyogenes aureus overgrew all the other organisms present -in cultures from the lung material. B. influenzæ was, however, seen in -the original 24-hour blood agar culture. It required 9 blood agar plates -before the organism could be isolated. In another case 10 plates were -used for the isolation. - -The findings of the bacteria in the lung sections are particularly -interesting and instructive. The entire series of cases have not been -completely studied, so I am unable to tabulate the findings. In cases -761 and 762 sections of the lung showed influenza-like bacilli to be -almost pure in the earlier stages of the process, while in areas with -purulent foci pneumococcus-like and other Gram positive cocci were also -numerous. In some cases B. influenzæ-like organisms were to be seen in -overwhelming numbers. In others they were scarce, while in some nothing -resembling B. influenzæ could be found in the sections. Positive -cultures were often independent of whether the influenza-like forms were -to be seen in smears or sections or not, although they were found in the -great majority of the cases. The findings in the direct smears and the -bacteriological results make useful material for comparison. - -Swabs from the nasopharynx were cultured from 31 individuals; nearly all -of these were cases suspected of diphtheria or as carrying the -diphtheria bacillus, and no particular effort was made to isolate the B. -influenzæ. They were seen in the mixed culture occasionally. In the last -eight cases the heated blood agar, ordinary blood agar and Loeffler’s -serum were seeded from the throat swabs. B. influenzæ practically -overgrew all the other bacteria from seven of these cases on the heated -blood agar medium and was isolated without difficulty; all eight showed -M. catarrhalis. The two other media gave little or no evidence of the -presence of B. influenzæ. As I have said above, our attention was -concentrated on the autopsy material. These cultures from the throat -were simply made to demonstrate the usefulness of the heated blood agar. - - - TABLE II - - BACTERIA SEEN IN DIRECT SMEARS FROM NASOPHARYNX - - ════════════╤═════════╤═══════════════╤══════════════════╤═════════════════ - Type of │Number of│ B. │ │ M. - Disease. │Patients.│Influenzæ-Like.│Pneumococcus-Like.│Catarrhalis-Like. - ────────────┼─────────┼───────────────┼──────────────────┼───────────────── - Early │ 24│ 14│ 17│ 6 - Serious │ 13│ 13│ 13│ 9 - Convalescent│ 11│ 8│ 11│ 6 - ────────────┼─────────┼───────────────┼──────────────────┼───────────────── - Total │ 48│ 35│ 41│ 21 - Percentage │ │ │ │ - of │ │ │ │ - positives │ │ 73│ 86│ 43 - ────────────┴─────────┴───────────────┴──────────────────┴───────────────── - - - _Direct Smears from Nasopharyngeal Swabs_ - -It is recognized by most of the modern investigators that little -reliance can be put on the finding of B. influenzæ-like bacilli in -direct smears. The organism is markedly pleomorphic, occurring as -extremely small coccoid forms up to threads of various lengths. -Notwithstanding these morphological variations the organisms are usually -seen as tiny bacilli, and these are considered as the typical form. We -carried out a series of microscopical examinations of carefully made -smears from the throats of patients with influenza. Particular attention -was given to the occurrence of organisms resembling in morphology and -staining B. influenzæ, pneumococci and M. catarrhalis. We have divided -the cases roughly into three types—early, serious, and convalescent. -Table II shows our results. The term B. influenzæ-like was used for the -typical morphological picture so often described. Dr. Frost and Mr. -Scott carried out this portion of our work and their results are -interesting. - -Blood cultures were done on 22 cases. Pneumococcus mucosus was grown -from one patient who three days later came to autopsy (Case 767). In -another case pneumococcus-like organisms were seen in smears from the -dextrose broth flask after 24 hours’ incubation. These, for some unknown -reason, did not grow on blood agar plates. After 48 hours smears made on -blood agar from the original flask gave a growth of B. influenzæ and a -M. catarrhalis-like organism. I consider this result a very -unsatisfactory one, being quite unable to explain the failure to grow -the pneumococci-like forms on transfer. Possibly the acidity developed -might account for it. - - - TABLE III - - AGGLUTINATION TESTS WITH SERA OF CONVALESCENT INFLUENZA PATIENTS - - ═══════════════════════════╤═══════════╤═══════════╤═══════════ - DILUTION OF SERUM │ + │ +– │ – - ───────────────┬───────────┼───────────┼───────────┼─────────── - Convalescents │1-1 │ 3│ 0│ 2 - │1-10 │ 5│ 2│ 7 - │1-40 │ 2│ 3│ 9 - │1-80 │ 0│ 1│ 13 - │1-160 │ 0│ 0│ 14 - ───────────────┼───────────┼───────────┼───────────┼─────────── - Normal Controls│1-10 │ 1│ 2│ 0 - │1-40 │ 0│ 1│ 2 - ───────────────┴───────────┴───────────┴───────────┴─────────── - - The complete agglutination as would be indicated by +++ or ++ was - not seen. - -Agglutination tests were carried out with the sera of 14 convalescents -and 3 normal individuals. A polyvalent emulsion of strains of the -influenza bacillus isolated from our cases was used. The results are -shown in Table III. Tubes were incubated at 37.5° C. The results did not -indicate anything in the nature of a specific reaction. Dr. Frost -carried out this work during the height of the epidemic, but we were -unable to continue it further. A short review of the work of others will -be found near the end of this paper. Miss Thompson and Mr. Mock studied -complement fixation, using the sera of 15 convalescents against an -antigen of B. influenzæ. Their results were negative. The antigen -appeared to be slightly more anti-complementary than were emulsions of -staphylococcus or B. coli. Huntoon also noted this anti-complementary -character of emulsions of B. influenzæ. - -Attempts were made to estimate the amount of complement present in the -fresh blood serum of influenza patients. The technique was to use a 1-4 -dilution of the patient’s serum, adding measured amounts of this to a 1 -per cent. blood emulsion, with 1 unit of amboceptor and determine the -smallest amount necessary to bring about complete hemolysis. This test -was carried out on eight patients ill for only a few days. The average -amount of the dilute serum was 0.181 c.cm. Fifteen patients, -convalescent after a moderate illness, gave an average of 0.276 c.cm. -Two patients seriously ill with temperatures of 104.3° F. and 105° F. -required 0.4 c.cm. to bring about complete hemolysis. We would not like -to draw any very definite conclusions where we are dealing with such -small fractional differences. This lessening of complement has been -noted in other infectious diseases and may be important in the questions -of immunity in influenza. Dr. Frost carried out a number of cutaneous -tests after the method of Von Pirquet, using a polyvalent, weakly -alkaline emulsion of influenza bacilli in 25 per cent. glycerin. Eleven -convalescents were tested and none of them showed any local or general -reaction. The suggestion that these results may indicate an increase in -resistance is discussed in another place. A number of strains of -pneumococci which we had isolated from our autopsy cases were -differentiated by the agglutination method. Type I was found 3 times; -type II, 10 times; type IV, 9 times. Four showed agglutination with both -type I and type II sera. Type IV pneumococcus was isolated in one case -from the right and left bronchus as well as the lung. In another case -the same type pneumococcus was recovered from the lung and pleural -fluid. These results are similar to those found by numerous workers. - - - _The Hemophilic Bacteria_ - -The discovery by Pfeiffer of the hemophilic character of the bacillus -found by him in cases of influenza opened up a new group of -micro-organisms known as the hemophilic bacteria. Davis (1915) has laid -particular stress on the group character of these bacilli, and the more -they are studied the more clear does it become that there are several -distinct members. The B. influenzæ is by far the most important as well -as the most frequently found of the group and is considered as the type -organism. - -All these bacteria require for their growth the presence of some form of -hemoglobin. The actual amount necessary may be very small, and Davis -suggested that it may have a catalytic action. A great deal of work has -been done in attempts to discover just what portions of the hemoglobin -are necessary to bring about this phenomenon. In our discussion on media -for the influenza bacillus we will briefly describe some of the various -hemoglobin preparations that have been used successfully. It must at -this point be emphasized that blood is very useful in many media to -stimulate the growth of a great variety of bacteria, and the transfers -made from such luxuriantly growing cultures may grow very poorly or not -at all on ordinary media, and this might easily lead to erroneous -conclusions on the hemophilic character of the organisms studied. There -are certain bacteria which grow so much better on media containing blood -that such media are sometimes necessary for their isolation, although -after a few transfers they will grow on ordinary media. This is true for -bacillus pertussis, and throughout the literature a good deal of -confusion has arisen in not recognizing this temporary hemophilic -character of certain bacteria. The true hemophilic bacteria do not grow -except in the presence of hemoglobin in some form or other. The problem -becomes almost academic when we consider the small amounts of hemoglobin -that are necessary. Davis has shown that a dilution of 1 in 180,000 is -sufficient, and in the interesting discussion between Cantani and Ghon -and Preyss it was demonstrated that hematin or other hemoglobin product -was necessary in the agar before B. influenzæ would grow in the presence -of other bacteria, and that this hematin could be derived from the blood -in the meat which was used in making the basic infusion. - -_Symbiosis._—The fact that other bacteria can bring to growth the -influenza bacillus on media otherwise unsuited to its needs brings up -the interesting problem of symbiosis, which is one of the most important -characters of the influenza bacillus. Not only do other bacteria make -possible the growth of B. influenzæ on media on which the influenza -bacillus will not grow, but they stimulate a better growth on blood agar -and other more or less favorable media. Grassberger first noted this -stimulating character of other bacteria and described and illustrated -the very large colonies of B. influenzæ which develop in the -neighborhood of colonies of staphylococcus and other bacteria. -Staphylococci killed by heat were found to have a similar effect. -Meunier nicely described this phenomenon by using the term satellites -for the circles of B. influenzæ colonies which develop about the -colonies of other bacteria. A great number of workers have since noted -this characteristic relationship between B. influenzæ and other -bacteria, and occasionally have laid stress on its importance in the -problems of the infections by the influenza bacillus. Allen particularly -emphasized the probable importance of this in discussing the problem of -carriers of B. influenzæ as sources of danger. There seems no doubt that -this symbiotic relationship depends on so altering the hemoglobin -products as to render them more readily available for the influenza -bacillus. This is indicated by the fact that on various media containing -hemoglobin, altered so that it encourages the growth of B. influenzæ, no -such symbiotic stimulation can be demonstrated. This phenomenon is quite -peculiar to this bacillus, distinguishes it from most of the other -members of the group, and should be always determined before an organism -is classed as B. influenzæ. - -_Other Hemophilic Bacteria._—The question of a pseudo-influenza bacillus -was first raised by Pfeiffer and has been studied by many workers after -him. Grassberger, who carefully investigated this problem, worked more -particularly with two strains showing the extreme of variation between -the small characteristic morphology of the B. influenzæ and the thread -forms supposed to be characteristic of the so-called pseudo-influenza -bacillus. The great majority of workers have agreed with him in -concluding that this morphological variation is not sufficient nor -constant enough to justify separating two such groups. Nevertheless many -reports indicate peculiar tendencies of certain strains toward thread -formation. There seems to be suggestive evidence that the organism -described by Cohen in 1909 under the name B. meningitidis -cerebrospinales septicemicus is different from true B. influenzæ. -Although the cultural characters were apparently identical, this -organism was definitely pathogenic for guinea pigs and rabbits. The -involvement of joints in the cases reported by Longo and others would -suggest a greater pathogenic power for these strains. Prasek and Zatelli -reported a similar bacillus from meningitis, and Davis found that his -meningitis strains were more pathogenic for rabbits than were others. -Wollstein has studied this question very carefully and found a marked -difference between the strains from the meninges and those from the -respiratory tract in their pathogenicity for rabbits. The strains with a -tendency to thread formation were usually also those grown from the -meninges, but she concluded from the results of serological tests that -all strains of B. influenzæ are of one race, irrespective of their -origin or virulence. The question is still an open one, as Batten and -others described strains from the meninges which are non-pathogenic, and -Ritchie found his strains from meningitis pathogenic for guinea pigs but -not for rabbits. The irregularity and wide divergence in the results of -blood cultures may have a definite relationship to these differences in -the pathogenicity of strains. - -Other hemophilic bacteria include the bacillus described by Friedberger -under the name of B. hemoglobinophilus canis. This organism is to be -found in the preputial secretion of dogs. It does not show the -phenomenon of symbiosis, and I have found that it grows rather more -freely and is more resistant to drying than is the influenza bacillus. -Krage has confirmed Friedberger’s findings growing this bacillus from 60 -per cent. of his dogs, and believed it a pyogenic organism just as B. -influenzæ may be. - -The hemophilic and hemolytic organisms described by Davis, which he -isolated from pathological urine, were non-symbiotic and non-pathogenic. -Koch has described a similar organism from puerperal infection. Whether -the hemophilic organism described by Thalhimer from the uterus in a case -of puerperal infection, those found by Cohen in urethral discharge in -one case and the pelvic exudate of another, and the findings of Kretz in -pyelitis, Wright in pyelonephrosis and Klieneberger in cystitis cases, -possibly refer to this same bacillus is, of course, uncertain. Pritchett -and Stillman found a somewhat similar bacillus, which they called -Bacillus X, from the mouths of 24 persons. It was hemophilic and -hemolytic, stouter than B. influenzæ and showed long tangled threads in -blood broth. It was non-pathogenic and is probably the same as Davis’ -organism. - -Davis described another hemophilic bacillus from a patient with purulent -foci which was non-hemolytic and non-symbiotic. It was grown from an -abscess of the shoulder joint, the blood and the bronchial secretion of -an infant. Cyanosis was a marked feature of this case. Paranhos -described a hemophilic bacillus from meningitis, which, however, was -Gram positive, and Moon reported an anærobic hemophilic bacillus from an -infection of the ethmoid sinus. The work of Jordan would suggest that -there may be two groups of B. influenzæ based on the indol production. - -_Morphology._—The morphology of B. influenzæ has received more than -usual attention. In what we consider its characteristic form, it is an -extremely small bacillus, usually single but sometimes in pairs, and not -infrequently exhibiting polar staining. In direct smears, where there -are many bacteria present, they are frequently arranged in the schools -so frequently described. The development of thread forms is today -considered quite characteristic for B. influenzæ. The organisms vary -from moderately long bacillary forms to very long twisted or curled -threads suggesting leptothrix. In such cultures chains of tiny bacilli -are also quite often noted. At the other extreme we have exceedingly -tiny coccoid forms, resembling in size the B. bronchisepticus, which, as -Ferry has shown, are small enough to pass through many grades of -filters. - -It is the thread forms, as discussed above, that have received most -attention in relation to the so-called pseudo-influenza bacillus. The -observations of Wollstein, Lacy and many others showed these forms to be -common in meningeal infections and that, as a rule, they are more -pathogenic for animals than other strains. Another interesting and -important observation is that emphasized by Dick and Murray of the -possible confusion of these forms with Gram negative leptothrix. That -this confusion is liable to occur is illustrated by reports such as -Macdonald finding leptothrix in a meningeal infection, now looked upon -as an example of influenzal meningitis, and the probable B. influenzæ -reported by Dick, and, as quoted by Dick and Murray, the finding of a -Gram negative leptothrix as the cause of broncho-pneumonia by Kato. The -2 per cent. leptothrix reported by Nuzum and his co-workers from the -recent epidemic may be still another example. Equally important is the -recognition of the great frequency of this thread development in the -majority of B. influenzæ cultures on ordinary blood agar media, or even -in the water of condensation of fresh blood agar tubes. The delayed -growth of this bacillus on ordinary blood agar would lead to its being -frequently overlooked unless smears are made, and the irregular thread -forms are recognized as being the B. influenzæ. This development of -thread forms was particularly noted in my work before pickings were made -to the Voges heated blood agar, but because I had been forewarned by -discussing these morphological variations with Lacy, I was able to -recognize them as forms of B. influenzæ. Most of my early isolations -showed these predominating, and they were also noticed in cultures sent -from the Public Health Laboratory at Washington. These cultures on -further transfer, however, showed in 24 hours the typical small form on -ordinary blood agar as well as on the Voges medium. On the latter the -development of thread forms was greatly delayed and frequently did not -appear at all, although after long periods other abnormal, swollen and -irregular shapes sometimes developed. - - - _Media in Growth of B. Influenzæ_ - -The discovery of the hemophilic character of B. influenzæ has been -confirmed by a long list of investigators. The agar smeared with pigeon -blood as used by Pfeiffer has not, however, been found fully -satisfactory and many modifications have been made. The fact that -hemoglobin in some form is necessary for the growth of these bacteria -has led to a great deal of study in attempts to discover the chemical -part, or parts, essential for this purpose. Hemoglobin in very small -amount, as shown by Davis and others, is sufficient to make media -suitable for growing B. influenzæ. This fact has led to much confusion, -owing to the difficulty of eliminating all possible sources from which -some form of hemoglobin might enter the media. Kitasato used a glycerin -agar and succeeded in growing the influenza bacillus for 10 transfers. -Pielicke, however, did not consider that Kitasato was actually dealing -with the influenza bacillus, but that he as well as Babes, Bruschettini -and Markel had most probably streptococci in their cultures. Besson held -the same view of Kitasato’s organism. It would further appear from the -illustrations of Klein that he also grew streptococci and not the B. -influenzæ. The first culture of the influenza bacillus was probably -obtained by Bujiwid in February, 1890. He grew on agar smeared with the -spleen pulp of an influenzal patient a tiny bacillus which he was unable -to grow on blood free medium, but he did not appreciate its importance -until Pfeiffer’s article appeared. Teissier in his book on “L’ Influenza -en Russie” mentioned this culture. - -The hemophilic character of these bacteria indicates that they are -rather strict parasites, and despite the researches of Nastjukoff with -various egg media, and Cantani with a number of supposedly -non-hemoglobin additions to the agar, as well as the studies on -symbiosis, with other bacteria, by Cantani, Neisser, Luerssen and many -others, it still remains true that some form of hemoglobin is necessary -for their growth. Fresh blood either incorporated in the medium or -smeared on the surface is not the best medium for these bacteria. -Altered hemoglobin is much more favorable, and a variety of methods have -been devised to bring about those alterations which stimulate the growth -of B. influenzæ. One of the earliest, as well as one of the very best, -of these is the method of Voges, who added blood to melted agar at a -temperature of about 100° C. I have found this medium exceptionally -suited to growing B. influenzæ, and I consider it excellent for the -primary culture from the original material, for pickings from plates and -to obtain a heavy growth of B. influenzæ for any purpose. The medium was -used by Delius and Kolle (1897), Grassberger (1898), who spoke very -highly of it, and Paltauf (1899), who said that the use of this medium -made the demonstration of B. influenzæ possible when only a very few -were present. A great many other workers have used it with success, and -during the recent epidemic it has gradually found its place. Levinthal’s -medium (1918) is practically the same, although he boiled and filtered -the agar after the addition of the blood. The growth of B. influenzæ on -the Voges agar can properly be described as luxuriant, and to anyone -only accustomed to the use of ordinary blood agar it is an agreeable -surprise to see this supposedly delicate bacillus growing so remarkably -well. - -Various other methods have been used to bring about this beneficial -change in hemoglobin. Gioelli (1896) used a medium made up of 1.1 per -cent. hemoglobin and 21.5 per cent. malt extract. This is reddish brown -in color, becomes clear when neutralized with potassium hydrate and -remains so on heating. This added to agar is reported as very favorable -in growing this bacillus. Ghon and Preyss described a medium made up of -meat, peptone, salt and agar prepared in the ordinary way, but not -filtered for at least a week, and then only roughly. This medium is -favorable for symbiotic growths. He further used beef blood heated in a -soda solution and blood heated in water as hemoglobin preparations to be -added to agar. Thalhimer found an amorphous hemoglobin medium to be more -favorable than when a purer hemoglobin was used. W. F. Robertson found a -hemoglobin agar, prepared by allowing sheep’s blood to clot, decanting -off most of the serum, freezing and then thawing what remains and adding -1 c.c. of this to an agar tube at about 60° C., to be very favorable for -the growth of B. influenzæ. Cantani used a blood treated with pepsin and -hydrochloric acid, digested some days in the incubator, filtered and -made weakly alkaline. This mixture was heated for a few minutes, -refiltered and added to the medium. He speaks of it as extraordinarily -good for B. influenzæ. Blood treated with trypsin has been used by -Matthews, Averill, Young and Griffiths, Harris, A. Fleming and others. -Fleming further found that this alteration in hemoglobin can be brought -about in a number of other ways. Blood boiled in agar (suggesting the -Voges agar) and the tubes slanted while hot, blood boiled in water, the -clotted blood precipitated and the clear fluid added to agar, or more -rapidly by adding equal quantities of sulphuric acid to the blood and a -similar amount of potassium hydrate he obtained altered blood suitable -for media. He reported that by any of these methods he could obtain a -medium very stimulating to the growth of B. influenzæ. By the addition -of brilliant green (1 in 500,000) he inhibited the growth of -staphylococcus, streptococcus and pneumococcus. For storing cultures of -B. influenzæ Fleming found a minced meat medium with the addition of -blood to be the best. I have found this medium without the blood to be -an excellent one for keeping a great variety of cultures. Bernstein and -Loewe have reported the use of gentian violet (1 in 5,000) for the same -purpose as the brilliant green used by Fleming. Avery’s oleate blood -agar medium he reported to be largely selective. It checked the growth -of pneumococci and streptococci, but gave luxuriant growths of B. -influenzæ. Pritchett and Stillman have used it with excellent results -recovering B. influenzæ from a very high percentage of the cases -studied. - -The use of symbiotic bacteria has been extensively studied in -investigations of the biology of B. influenzæ, and it has been shown, as -noted elsewhere, that such accessory bacteria will bring to growth B. -influenzæ on media otherwise quite unsuited to its needs. It has been -further found that on various preparations of hematin agar, on which B. -influenzæ refused to grow, such media could be rendered favorable for -their growth by the addition of living or freshly killed cultures of -staphylococcus and many other bacteria. And although the method is well -known, it has not been extensively used for the purposes of isolation. -Many of the workers, however, have pointed out the importance of looking -for growth of the influenza bacillus in the neighborhood of the more -easily grown bacteria which almost always develop in cultures from the -respiratory tract. Grassberger has particularly studied this problem and -has made practical application of the method. Accidental contamination -of plates with air bacteria have made possible, in some instances, the -isolation of B. influenzæ—as, for example, in the finding of Heyrovsky -from a case of empyema of the gall bladder—while other workers have -pointed out the difficulty of demonstrating growth where B. influenzæ is -pure in the material cultured, and the comparative ease and relative -luxuriance of growth where other bacteria are present. To just what this -stimulating effect is due has been much discussed, and it is generally -agreed that the hemoglobin is markedly changed and rendered more -available by the action of these germs. It is to be noted that on a -medium containing blood altered by heating or by the various methods as -described by Fleming the foreign bacteria no longer show any symbiotic -action on B. influenzæ. Grassberger considered the effect of the -bacteria on the blood to be the same as that of heating. Allen laid -particular stress on this symbiotic character. He used a staphylococcus, -either living or killed, in making his cultures and noted the difficulty -of growing B. influenzæ from material in which it occurred pure. W. F. -Robertson made use of these facts of symbiosis for both isolation and -stimulation of growth. He employed alternate drills of M. catarrhalis or -pneumococcus with the B. influenzæ, and Brown and Orcutt used strains of -hemolytic streptococci for the same purpose. The latter authors -considered that the beneficial effect of the streptococci was merely due -to the setting free of the hemoglobin. The fact that similar results are -to be obtained by the use of non-hemolytic bacteria as well as forms -giving green color changes to the blood makes this explanation -untenable. In my own studies I have confirmed the results of several -previous workers. I have found that B. influenzæ is stimulated in its -growth by the presence near it of colonies of staphylococcus pyogenes -aureus and albus, pneumococci, streptococcus viridans and hemolyticus -and other bacteria. The largest colonies of the bacillus I have obtained -were those growing near the periphery of a colony of an air nocardia. I -have also noted that emulsions of a staphylococcus killed by boiling for -five minutes, when added to ordinary blood agar, had a marked -stimulating effect, although no evidence of hemolysis was present. This -effect was practically absent if the emulsion was boiled for 15 minutes, -or after being killed was left at room temperature for several days. -There was no evidence of these stimulating effects by any of these -methods when heated blood agar was used, the colonies on this medium -growing equally large by themselves. Comparative studies of the effect -of different bacteria can be simply carried out as follows: Smear evenly -the surface of an ordinary blood agar plate with an emulsion of B. -influenzæ. Seed this plate at various points with minimal amounts of the -various bacteria. After various periods of incubation the size of the B. -influenzæ colonies about the other bacterial growths can be estimated, -and impression preparations on cover glasses will give very interesting -pictures. - -The growth of B. influenzæ in primary cultures from sputa and similar -sources is to be explained by the probable presence of traces of blood -or altered hemoglobin as well as the symbiotic relationship with other -bacteria. Fichtner used fresh heated sputum (60 to 65° C.) in place of -blood, and Richter a medium made with sterilized pus. Parker, in her -study of a filterable poison produced by the B. influenzæ, found veal -infusion broth with 10 per cent. defibrinated blood heated to 75° C. -until the blood coagulated and settled on standing to be the best for -the purpose. Jordan in his study of indol production by these bacteria -used a meat infusion broth with 5 per cent. sheep’s blood added at 90° -C. or over and filtered through cotton or paper. Wittingham and Sims -noted that in using blood from influenza cases the bacteria frequently -did not grow, more especially B. influenzæ; and Rivers found human blood -poorer than cat or rabbit blood for growing this organism, as did -Minaker and Irvine. It would seem clear from this review of some of the -suggestive work on the methods of growing B. influenzæ that little -attention should be given to the results of many workers, where ordinary -media were used, particularly when the difficulties of isolation were -not appreciated. - - - _B. Influenzæ as a Pathogenic Bacterium_ - -If B. influenzæ is the causative agent in clinical influenza, there is -certainly ample evidence that it is pathogenic to man. The symptoms of -toxemia, which are so manifest in the pandemic disease as well as in the -sporadic cases, would indicate that the etiological agent is markedly -toxicogenic. Animal experiments by Pfeiffer, and a long list of -investigators following him, would seem to show that the majority of -cultures of B. influenzæ do not have any power of establishing -themselves in the animal tissue. Killed cultures showed equally as high -toxic effects as the living, and so it was generally concluded that many -of the general effects in influenzal infections were of a toxic nature. - -There are many exceptions to the above-mentioned failures to produce -infections in animals. Cantani obtained very constant positive results -by subdural injections. He first clearly showed that killed cultures -were markedly toxic and that virulence could be raised very definitely -by animal passage. By injecting brain emulsion with a culture he -obtained a subcutaneous abscess in a rabbit which after eight days still -contained the living organism. Nastjukoff found that animals with a -lowered resistance, or definitely ill from, for example, an artificial -tuberculosis, became infected while others did not. Jacobson showed that -B. influenzæ injected with streptococci caused a definite mixed -infection, and that after six passages the influenza bacillus alone -could produce a fatal infection. Saathoff (1907) confirmed Jacobson’s -findings and found pneumococci equally effective. Davis (1915) also -confirmed the principle established by Jacobson of the symbiotic -relation of other bacteria to infection with B. influenzæ. He used a -culture of a non-virulent staphylococcus pyogenes aureus, and was able -to produce death invariably in guinea pigs after intraperitoneal -injection. From the heart’s blood, as a rule, only the hemophilic -bacillus was recovered. He also found animal passage increased the -virulence, and further that M. catarrhalis and an avirulent -streptococcus had the same effect as the staphylococcus. Slatineanu -(1901) found that he could infect animals with B. influenzæ if the -cultures were injected along with weak solutions of lactic acid, and -that after animal passage by this method the bacillus became more -virulent and would eventually kill by itself. It must not be forgotten -in this connection that strains of B. influenzæ from meningitis cases -are frequently definitely pathogenic for animals. The importance of -considering these various factors in a discussion of infection by this -organism is, of course, very evident. Ecker found his strains pathogenic -for mice after subcutaneous injection, and the bacilli were readily -obtained from the heart’s blood. Spooner and his co-workers from their -results of more than a hundred intraperitoneal injections concluded that -the organism is not pathogenic for mice. - -In all animal experiments it is of the greatest importance that the -bacteria be known which may interfere in the experiments through -spontaneous infection (often liable to be induced by the injection) from -the animal’s own flora, as well as the greater susceptibility of -previously diseased animals (Nastjukoff). It would appear from the -results of Bruschettini and Cornil and Chantemesse in the early days of -the influenza bacillus, and those of Lamb and Brannin in their recent -study, that these authors did not seriously consider the spontaneous -infection of guinea pigs and rabbits with B. bronchisepticus or the -bacillus of rabbit septicæmia, both morphologically, very similar to B. -influenzæ. Rosenow in his experiments with streptococci from cases of -influenza has also apparently failed to realize the importance of the -lung lesions produced by the B. bronchisepticus in guinea pigs as -reported by Theobald Smith, myself and many others. - -Parker has found a filterable poison from the influenza bacillus which -developed rapidly (6 to 8 hours) in a special heated blood broth medium, -deteriorated rapidly even in the cold, and killed rabbits in quantities -of 2 c.c. in from 1 to 3 hours. Rabbits could further be immunized -against this poison, and their sera protected other rabbits against -fatal doses. This is the first time that a true powerful toxine has been -obtained. Couret and Herbert obtained toxine from B. influenzæ in -Avery’s oleate broth. Huntoon and Ross also clearly demonstrated toxine -production by this organism so that it would appear, with this -confirmation, that the B. influenzæ can be definitely classed among the -toxine producers. Toxemia being the most striking clinical -characteristic of influenza, we have in these findings very strong -evidence of the etiological importance of this hemophilic bacillus to -the disease. A very interesting observation was made by Latapie that the -serum of a goat immunized against influenza bacillus is toxic if it is -used shortly after the injection of the microbes, but that this toxicity -is absent three weeks after the last injection. It would appear to me -that the evidence of a filterable virus from the secretions of the -respiratory tract does not eliminate the very probable toxine from such -materials. The production of toxine by this organism probably depends, -as is the case with very many of our toxine formers, on the most -favorable combinations of conditions. That it is not readily formed in -artificial cultures, or that it is very unstable if formed, is evidenced -by the frequent failures of a great many workers. It has been suggested -that different symbiotic conditions in the respiratory tract determine -the amount of toxine produced. Huntoon found a high toxine production in -mixed cultures with streptococci. This, however, does not appear to be -necessary, as there is ample evidence of severe toxemia from pure -infections with B. influenzæ in various parts, such as the accessory -sinuses of the head, the meninges, the lungs and other parts of the -respiratory tract. - -It is not fundamentally necessary that a toxine producing organism be -present in overwhelming numbers before it can be accepted as the cause -of the toxemia. Nor, on the other hand, must we have toxemia every time -the organism is found. The prevalent idea among bacteriologists would -appear to be the reverse of what I have just stated. It would, indeed, -be extremely difficult to make bacteriological diagnoses of a great many -of our diseases, where the etiological factor is well established, if -these conditions were required. We do not do so, for example, in -diphtheria, examinations of stools for typhoid, nor in infections with -the tetanus bacillus. We recognize carrier cases of meningococcus, B. -typhosus, hemolytic streptococci and many others, without detracting -seriously from their importance in definite types of infection. Formerly -the specificity of the different bacteria for definite disease processes -was very rigid, but today we interpret more broadly the finding of -gonococcus in endocarditis, the meningococcus in bacteremia, B. typhosus -in osteomyelitis, streptococci and pneumococci in all manner of -infections and many other bacteriological results. True it is that the -various bacteria show predilections for attacking certain tissues, but -the varying susceptibilities bring about the greatest variations in the -manifestations of these infections. - -The B. influenzæ is not confined to the causation of severe pandemic or -epidemic influenza, but includes in its field purulent bronchitis, -meningitis, sinusitis, conjunctivitis and many other pathological -processes. It further should be recognized as a relatively frequent -cause of complications in measles and other diseases. - - - _Infections of the Respiratory Tract_ - -The disease influenza is primarily an infection of the respiratory -tract. It varies from one of the most acute and fatal diseases we know -of through all grades of severity—from chronic infections lasting over -years to the familiar three or five day fever. This graduation is to be -found more or less marked in all our bacterial infections, but would -seem to be not generally recognized or appreciated as occurring in -infections with the influenza bacillus. That Pfeiffer was dealing with -one phase of the disease when the influenza bacillus was discovered does -not invalidate the results of numerous workers which have been added -since then. - -Probably the greatest confusion in attempts to get a clear picture of -this protean disease has been and is a non-recognition of influenza as a -frequent complication of other diseases, such as measles (Jochmann, -Susswein, Tedesko and very many others). The second cause for this -confusion has been the misinterpretation of the facts demonstrating the -rather frequent occurrence of carriers. During an epidemic the vast -majority of patients show the disease as an upper respiratory infection -of varying degrees of intensity, but which usually subsides after -periods of from three to five days of fever. Along with this we have -other graded manifestations of further involvement of the tract with -laryngitis, bronchitis, bronchiolitis and all degrees of -broncho-pneumonia. To prevent the severe lung involvement prompt -treatment must be carried out, under which rest in bed is by long odds -the most important. This will be discussed in another paper of this -series, and was particularly well demonstrated in the results at the -Naval Hospital as verbally reported to me by D. G. Richey. The -interesting point is that the infection can be controlled, but this does -not indicate the etiological factor as different from that acting in the -more severe cases. - -The epidemiological evidence would seem to show very clearly that the -incubation period is approximately two days, and that a period of six -weeks is the usual limit for the severe wave of the epidemic in -different localities. In my opinion, during this period every exposed -individual in a community has received the influenza bacillus in the -respiratory tract, and that all the susceptible individuals are attacked -and show more or less evidence of the infection. As a consequence of -this general distribution we have great numbers of individuals carrying -the organism, and the aftermath is to be noted in other and later -manifestations of the same infection. - -Sporadic cases of influenza appear during inter-epidemic periods and -more or less healthy carriers are frequent. Scheller’s study in -Königsberg showed, if we can rely on his figures, that the carriers were -very numerous during an epidemic year (winter 1906-1907), being 24 to 33 -per cent.; that as the epidemic became less widespread (winter -1907-1908) it fell to 10 to 13 per cent.; as it was disappearing (summer -1908) he found only 1.5 to 3.3 per cent.; while when the epidemic was -completely over (winter 1908-1909) there were no carriers of B. -influenzæ found. These results are taken from studies of sputa and -throat smears of 138, 218, 155 and 185 cases, respectively, for the -periods mentioned. The monumental work of Tedesko, who reported the -results of 1,479 cultures, covering 11 years (1896-1906), would indicate -that B. influenzæ is continually present in the population. However, in -carefully analyzing his results, it is very clear that in the great -majority of his cases it was of definite etiological significance. -Lobular pneumonia, acute, purulent and chronic bronchitis, and most -frequently clinical influenza, are the prominent diagnoses in all his -tables. He was able to grow B. influenzæ repeatedly from individual -patients for many months. - -Lord in similar studies (1902, 1905, 1908) brought out somewhat similar -facts. He laid particular stress on the cases of chronic bronchitis with -numerous B. influenzæ in the sputum and a probable confusion of these -with pulmonary tuberculosis. He was able to follow a number of his -patients for several years. B. influenzæ was grown in culture from the -sputum of one of these in 1902; in November, 1903; in February, 1904, -and in February, 1905. In other cases the organism was shown to be -present by culture practically continuously for months and even years. -Lord, with Scott and Nye, in a recently published article (1919) -reviewed his former results and showed a relatively high incidence of B. -influenzæ in the respiratory tract of apparently healthy people. Davis -studied 534 cases, further indicating the prevalence of this organism in -the community. - -The B. influenzæ has been recovered from the respiratory tract during -the clinically pure influenza, from the sputum and lung in influenzal -pneumonia, and from the purulent sputum in all grades of bronchitis. -These should all be looked upon as true infections by the influenza -bacillus, the varying manifestations merely differing with the -resistance of the individual. In the epidemic in the fall of 1918 -pneumonia was the outstanding feature. Preceding this in the English -publications we have reports of outbreaks of purulent bronchitis. -Macdonald and his co-workers, finding the B. influenzæ frequently -present, considered the condition as one indication of a virulent -infection by this organism. Hammond, Rolland and Shore reported similar -cases, and Abrahams and his co-workers looked upon the cases of purulent -bronchitis as occupying a position, without any definite line of -demarcation, between those with definite broncho-pneumonia on the one -side and those with simple bronchial catarrh on the other. H. E. -Robertson emphasized the serious nature of influenzal purulent -bronchitis and the almost epidemic character and rather high mortality -of the outbreak in the winter and spring of 1917-1918. There were also -numerous mild outbreaks of influenza before the overwhelming culmination -of the last three months of 1918, as reported by Orticoni and many -others and noted by Johnston in this series of papers. Greenwood in an -epidemiological study emphasized the point, previously made evident by -Parsons for the pandemic of 1889-1892, that the mass attack is preceded -by numbers of individual cases. In this country it was noted during the -winter of 1917-1918 and the following spring that the B. influenzæ was -rather frequently found in the respiratory infection in our army camps -(Soper, Cole and MacCallum and others). - -It is well recognized that when the actual epidemic struck there were -comparatively few bacteriologists familiar with the B. influenzæ. The -real difficulties of isolation, the more favorable media, the facts of -symbiosis, the importance of carriers, the varying manifestations of the -infection and many of the other vitally important points, although more -or less fully reported in the literature, were nevertheless practically -unknown. It was my own experience, and that of many others. This must be -seriously considered in analyzing many of the reports on bacteriological -findings throughout the period of the severe wave and even after. - - - _Results of Others During the Recent Pandemic_ - -It will be impossible to review the numerous reports on the recent -epidemic that have appeared. Many of these can be discounted, as far as -the finding of B. influenzæ is concerned, for the reasons mentioned -above. The often quoted report of Little, Garofalo and Williams, who did -not even use a hemoglobin medium, will serve as an example. Little -attention should be given to others where the large numbers of cases -precluded the requisite time and media necessary for such a difficult -problem. Friedlander and his co-workers in their report from Camp -Sherman made no mention of the number of sputa, throat swabs or -autopsies which they examined bacteriologically. The incidence of -influenza showed a total of 10,979 cases, 2,001 of pulmonary œdema or -pneumonia and 842 deaths. They recorded one culture from the sputum with -pneumococcus predominating which gave two colonies of B. influenzæ, and -this bacillus was grown from the lung exudate at one autopsy. Their -conclusions that “B. influenzæ (Pfeiffer) has not been demonstrated as -the causative organism” is certainly true from their results, but that -“the frequency of its detection has not exceeded the frequency of its -existence under normal conditions” can hardly be considered as -established, if we accept the many results mentioned above as indicating -its presence during inter-epidemic times, unless they mean by normal -conditions practically complete freedom from this organism. - -The prevalence of B. influenzæ in various sections of this country may -be indicated by the following reports chosen from many available ones. -Keegan, from the First Naval District Hospital, found B. influenzæ 19 -times from 23 in cultures grown from the lungs. In 6 cases these -cultures were pure. Medalia reported from Camp McArthur the following. -Out of 2,279 sputa of influenza suspects, 76.8 per cent. showed “B. -influenzæ” in smears, and 445 sputa from cases of broncho-pneumonia -showed it in 54 per cent. It was found in culture in only 10.6 per cent. -of these last cases. He considered sputum smears of practical diagnostic -help. He further grew B. influenzæ twice from the blood during life, -once with a pneumococcus and once alone. Necropsy cultures gave B. -influenzæ in 2 of 3 cultures from the brain, 19 of 34 from the heart, 19 -of 36 from the spleen, 54 of 65 from both lungs, 50 of 62 from the right -pleura and 47 of 62 from the left pleura. The percentage of positive -results ranged from 53 in the spleen to 83 in the lungs. Nuzum and his -associates only found B. influenzæ in 4 of 100 cases from the bronchial -secretions, but it is interesting to note that he grew it in practically -pure culture from both lungs of one case at autopsy. Synnott and Clark -in Camp Dix found streptococci and pneumococci predominating, and, -although making no particular effort to study the B. influenzæ or -determine its frequency, they found it in the majority of cases when it -was looked for. Blanton and Irons reported as follows from Camp Custer. -From cultures of the nose and throat of 357 examined before the epidemic -struck, B. influenzæ was found in 5.1 per cent.; in 366 throat cultures -of influenza cases without physical signs of pneumonia the same organism -was grown in 44, or 8 per cent.; sputa typed for pneumococci 740 times -from influenza cases with pneumonia gave isolations of B. influenzæ 38 -times, or 5 per cent.—8 times alone, but here it should be remarked that -these latter isolations were only attempted after the organism was -suspected from the morphological picture of the smears; from 280 -autopsies B. influenzæ was recovered 8 times from the lung and 3 times -from the heart’s blood. This report covered the period from the outbreak -of the epidemic, October 5 (or as given by Soper, September 30) to -October 22, at the outside a period of 22 days. During this time 366 -throat cultures, 510 blood cultures, 740 sputa typed for pneumococci, -280 autopsies with cultures from both lung and heart’s blood, made a -total of primary cultures of well over 2,000. The technical difficulties -would make it almost impossible to handle such a mass of material and -get reliable results for the incidence of B. influenzæ. - -Brem, Bolling and Casper in Camp Fremont found B. influenzæ in 259 from -537 selected cases in swabs from the nasopharynx. It was also noted in a -fair number of other examinations. Opie and his co-workers found B. -influenzæ to be very frequent at Camp Pike. Spooner, Scott and Heath -isolated B. influenzæ at Camp Devens from the sputa of 104 cases, from -nasopharyngeal swabs in 11 out of 18 attempts and from the pleural fluid -8 times out of 45, twice pure. From 37 autopsies they found B. influenzæ -in 23 and in pure culture in at least 1 lobe of the lung in 16. From 82 -blood cultures at autopsy B. influenzæ was recovered twice. Nichols and -Stimmel studied lung punctures during life and grew the B. influenzæ -from 7 out of 10 attempts, 5 times in pure culture. Stone and Swift at -Fort Riley found B. influenzæ in 18.7 per cent. of 928 sputa and in 5.2 -per cent. of 77 sputa from fatal cases. He recovered it from autopsy -material; 21 times from 51 lungs, once alone; twice from 26 pleural -fluids; twice from 30 heart bloods; 19 times from the sinuses of 40, and -9 times from the ear and mastoid of 17 cases. - -Lamb and Brannin at Camp Cody examined 80 typical cases early in the -epidemic. They found B. influenzæ predominated in 46 per cent. being -present with pneumococci on 41 per cent. of the plates. They also grew -the influenza bacillus from a fair number of other cases. - -Wollstein and Goldbloom in the Babies Hospital of the City of New York -found the B. influenzæ in 13 of 17 sputa during life and in both lungs -of all 18 autopsies as well as in the heart’s blood of one. Kotz found -it in half of his 30 cases. Pritchett and Stillman grew the influenza -bacillus from 41 of 49 cases of influenza, from 40 of 43 cases of -influenza with broncho-pneumonia, from all of six other -broncho-pneumonia cases and from 11 of 20 cases of lobar pneumonia, -making a total of 98 positive findings from 118 or 82 per cent. They -further found 25 positives from 54 convalescent and 74 from 177 normal -sputa. Wolbach found this organism in pure culture in one or more lobes -of the lungs of 9 from 23 cultured cases. It was demonstrated in 23 of -28 either by culture or in section. - -Similar results are to be found in reports from Great Britain. Martin -noted a great increase in the numbers present as the sputum became more -purulent. Hicks and Gray found B. influenzæ by culture in 75 per cent. -of their cases. They were seen in direct smears in only 70 per cent. -Gotch and Wittingham considered M. catarrhalis to be the etiological -factor as it was found in all of their 50 cases. B. influenzæ was grown -in 8 per cent., although B. influenzæ-like bacilli, were seen in 62 per -cent. of their smears. Averill, Young and Griffiths studied the sputum -from 41 cases and found B. influenzæ in 32. It is interesting that -Macdonald and Lyth determined the incubation period to be 41 hours as a -minimum in their own experience and that from the posterior nares of one -of them B. influenzæ was obtained. - -Schofield and Cynn found the B. influenzæ in Korea. Kraus in Brazil -found it in the sputum in 62 per cent. of his cases of influenza. It was -also found in the organs of 27 who had died, being in pure culture in -five. It has further been found in France, Italy and practically all -parts of the world where investigations have been made. The German -literature is at present only available in the report of the British -Medical Research Committee which is written in a more or less popular -manner with a rather strong tendency against the importance of B. -influenzæ. Dietrich, Simmonds, Bergmann and others, however, found B. -influenzæ rather frequently. Such quotations as “Uhlenhuth, a diehard of -bacteriologic orthodoxy, has clearly shown signs of uneasiness” and “one -empyema and one throat swab yielded the looked for growth” will indicate -why this review is of little use. It is certainly necessary to “look -for” the B. influenzæ to get results of any worth. - -Secondary, ancillary or symbiotic bacteria are of cardinal importance in -these infections. It has been considered by some writers as -characteristic for the influenza bacillus to be followed so frequently -with such a variety of secondary invaders. Sahli looked upon the complex -of B. influenzæ, pneumococcus and streptococcus as the true etiological -cause of influenza. Abrahams and his associates discussed the symbiotic -effect of the B. influenzæ in raising the virulence of pneumococci -previously present in the patient and many other investigators lay -stress on these symbiotic relationships. - -Pneumococci appear to be the commonest of these secondary -micro-organisms judging from the various published reports, but the fact -must not be overlooked that, particularly in America, the typing of -pneumococci has drawn a disproportionate attention to this group. -Hemolytic streptococci have received much attention (Ely and his -co-workers and several others). M. catarrhalis (Gotch and Wittingham and -several of the British writers), members of the B. mucosus capsulatus -group (Nichols and Stimmel, Rucker and Wenner), staphylococcus aureus -(Patrick), various ill-defined streptococci (Rosenow and several British -writers), capsulated cocci apparently different from pneumococci, B. -pestislike forms and many others have been given more or less attention, -often as clearly recognized secondary infections, but not infrequently -as of primary significance. - -B. influenzæ, however, is the organism most regularly found in this -pandemic where carefully looked for, and the evidence of its lowering -the general resistance to bacterial invasion is very strong. The -experiments of Ghedini and Fedeli showing the effect of the toxine on -muscular tone and those of Ghedini and Breccia who found a similar -effect on blood vessels are worthy of note. - -The fact that the flora differs so widely in various regions is what one -might expect and many investigators have emphasized the significance of -this. Bacteria in the mouth and throat are readily transmitted from -individual to individual and under the conditions in the training camps -and our modern life, the development of local flora is not surprising. -That it is of very great importance is recognized by all and it is often -a determining factor in the severity of the infection. Nevertheless, -influenza in this pandemic has been almost equally severe whatever the -secondary organism may have been. - -I have discussed in another place the suggestion of the stimulating -effect of various bacteria on the growth and toxine production of B. -influenzæ. Huntoon showed the effect of hemolytic streptococci in -cultures to be helpful in toxine production. An important point, -however, is that no one bacterium has been shown to be exclusive in thus -affecting the growth on media of the influenza bacillus, and in the -animal experiments in raising the invasive and pathogenic power of this -organism the same appears to be true. The infection in influenza, in the -vast majority of cases, rapidly becomes a mixed one. The secondary -organisms at times completely dominating the field, at least as far as -numbers go, most frequently invade the blood stream and it would appear -often play the important role in many of the secondary conditions. - - - _Chronic Infections_ - -B. influenzæ is a frequent finding in the sputum of patients with -chronic bronchitis, pulmonary tuberculosis and other chronic conditions -in the respiratory tract. Boggs recovered this bacillus from two cases -of bronchiectasis, Richards and Gurd had a similar case and Tedesko -reported several. The literature is filled with references to the -finding of B. influenzæ in cases of chronic bronchitis. Those reported -by Lord, Madison and Tedesko quoted above will serve as examples. The -frequent positive cultures in cases of pulmonary tuberculosis so often -referred to in reviews of the literature and the significance of these -findings, as pointed out by Scheller, are important as bearing on the -much debated subject of the effect of influenza on this disease. These -types of chronic infection by the influenza bacillus should be more -generally recognized as they undoubtedly will become more numerous -following this last epidemic if we can judge from the experience of the -past. - - - _Infections of the Pleura_ - -The recovery of B. influenzæ from the pleural cavity is not uncommon as -is shown in the above review. The findings of MacCallum, Cole and others -during the spring of 1918 are particularly interesting. Beall in 1906 -reported a case of empyema with large quantities of green pus in which -B. influenzæ was found in pure culture. - - - _Sinuses of the Head_ - -Infection of the accessory sinuses of the head has long been recognized -as occurring in influenza. Frankel found B. influenzæ in 4 from 40 -infected antra. Lindenthal, who was particularly interested in the -question of sporadic influenza, found the bacillus in one or more of the -head sinuses in six of eight carefully studied cases. He considered that -the B. influenzæ remained in these areas during inter-epidemic times and -from hence caused the sporadic outbreaks of influenza. Howard and -Ingersoll reviewed the literature up to 1898 and grew B. influenzæ from -one of three acute antral diseases. They did not find it, however, in 12 -chronic cases. Clemens believed the influenza bacillus to be present in -the sinuses rather frequently in cases where it was overgrown or -difficult to culture from the lower respiratory secretions. Moszkowski -grew it in one case from the pus of the antrum. Tedesko recorded several -positive results and many others are reported in the literature. - -The two cases reported by Lacy (1918), the findings during the present -epidemic by Stone and Swift of B. influenzæ in 13 of 28 sphenoidal and 6 -of 12 ethmoidal sinuses cultured at necropsy, those by Spooner, Scott -and Heath, of B. influenzæ in four frontal sinuses and in eight -sphenoidal, and the recovery by Wolbach of B. influenzæ in cultures from -the sinuses in certain cases where the lung cultures were negative, -emphasize the importance and frequency of the infection by this organism -in these cavities. Keegan, who laid particular stress on lung punctures -and autopsy examinations, pointed out that in throat cultures the -probability that the influenza focus is often not in the pharynx but in -some recess of the nasal cavity. - -H. E. Robertson in the spring of 1918 reported the infection of the -sinuses in seven cases of tracheo-bronchitis with patches of -broncho-pneumonia and the growth of B. influenzæ from sphenoid, ethmoid -or frontal sinuses of all these cases. He also found this organism in -the sphenoid of six cases dying with various diseases as well as in two -accident cases with death under 24 hours. The importance of these -results was laid stress on by the author, not only on account of the -probable toxic absorption and the general menace of spread, but, more -particularly, because such individuals, acting as carriers, could -furnish foci for the spread of epidemics. - - - _Eye and Ear_ - -Infections of the eye by the influenza bacillus are quite common. This -subject is fully discussed by Axenfeld (text-book, “The Bacteriology of -the Eye”). Giani and Picchi found it in the eye in 66 per cent. of -influenza cases, in 90 per cent. of epidemic conjunctivitis, and in the -normal eye of 5.8 per cent. Wynekoop, in 1903, reported having found -this organism in cases of conjunctivitis in 1899. Guiral, in the recent -epidemic, found influenza bacillus constantly present in the secretions -in cases of what seemed to be Week’s conjunctivitis. Ulceration of the -cornea was rather common. One such case is mentioned in which there was -no pain in the eyes, but general symptoms of influenza. The middle ear -is also sometimes infected. Between the report of Kossel in 1893 and -that of Stone and Swift in 1918, who found the middle ear and mastoid to -contain B. influenzæ in 8 of 17 cases, there have been many references -in the literature to this complication by the influenza bacillus. The -evidence indicates, however, that in the middle ear, as in the pleural -cavity, the secondary bacteria are far more often the important ones. - - - _Meninges_ - -Influenzal meningitis seems to stand by itself as a manifestation of the -pathogenic effects of B. influenzæ. The literature is too voluminous to -review in this place, but the evidence would seem to point to a more -invasive and pathogenic type of this organism, if not to a separate -member of the group. - - - _Invasion of the Blood Stream_ - -The evidence in clinical influenza would suggest at times a bacteremia -in addition to the severe toxemia, which is such a constant feature of -the disease. Simultaneously with the discovery of B. influenzæ, Canon -reported finding bacilli of similar morphology in blood smears, but was -unable to grow them, and it would appear at least doubtful that he was -dealing with the influenza bacillus. Meunier is probably the first who -grew this organism from the blood. He recovered it from 8 blood cultures -out of 10 in cases of broncho-pneumonia following measles, and in one -other case of broncho-pneumonia. A very full discussion of this question -is to be found in Canon’s book on “The Bacteriology of the Blood in -Infectious Diseases.” Of particular interest are the results of Ghedini, -who made a careful study of 28 influenza patients. B. influenzæ was -grown from the blood in 18 of these at the height of the fever, while in -the 10 negative cases the disease was milder or the blood was taken only -after the temperature had fallen. The amount of blood used was 20-30 -c.c., and it was cultured in lecithin broth. In practically all of his -cases several cultures were taken, and in a number of the positive cases -negative results were obtained both before and after the acme of the -fever. He also grew the bacillus from 8 of 14 spleen punctures of these -patients. Madison (1910) reported the recovery of this bacillus from the -blood of a patient with a primary broncho-pneumonia who recovered. This -author also used about 30 c.c. of blood. Thursfield, in 1910, also -reported two cases of B. influenzæ bacteremia in which the organisms -were recovered at the height of the temperature. One had influenza, the -other phlebitis, and both recovered. Tedesko and several others have -found it in the heart’s blood in many cases, more especially in -broncho-pneumonia after measles. - -During the present epidemic the positive cultures of this bacillus from -the blood have been rather infrequent. J. S. Fleming had 2; 2 are quoted -in the report of the Influenza Committee of the Advisory Board to the D. -G. M. S. (Peters and Cookson); Medalia had 2 during life and 19 of 34 at -autopsy; Orticoni, Barbie and Leclerc in 5 of 10 blood cultures in one -series, and 7 of 19 in another; Stone and Swift 2 at autopsy; McKeekin, -in Australia, influenza-like bacilli in 4; Blanton and Irons three times -in the heart’s blood, one of these pure; Spooner, Scott and Heath twice -in the heart’s blood at autopsy, and Wollstein and Goldbloom from the -heart’s blood in one child. In the majority of these findings the -bacillus was not found in pure culture. Abrahams and his associates -found the B. influenzæ along with a pneumococcus and M. catarrhalis from -the heart’s blood in one case. In our positive blood culture there was -evidence of the same mixture being present. - -Before drawing sweeping conclusions against the invasion of the blood by -B. influenzæ it must be remembered that the quantity of blood used has -been generally only about 10 c.c., and often much less, the difficulty -of observing growth if the culture is pure has been largely overlooked, -the use of more favorable media than blood agar and the possible -inhibitory action of influenzal blood, as suggested by Wittingham and -Sims, Rivers and others, has not been considered, and further that -sufficient care has not been exercised to obtain blood at the most -favorable period in the disease. It may be recalled that the problem is -quite similar to that of demonstrating the organisms in the blood in -patients with streptococcus viridans bacteremia. - -All the available evidence, however, points to the invasion of the blood -in influenzal infections as being a very fleeting one. Unless this is -true, it would be surprising in the many hundreds of blood cultures -which have been taken in the concentrated study of patients during the -recent pandemic, if more successful cultures had not been obtained. -General infections with localization of B. influenzæ in different parts -of the body are here of interest—such as that reported by Slawyk and -others. Whether the strains causing meningitis, and which apparently -more frequently invade the blood, are really different members of the -hemophilic group or only forms with a higher invasive power is still, I -believe, an open question. - - - _Endocarditis_ - -In endocarditis the B. influenzæ is probably, after streptococci, the -organism most frequently isolated from the blood. Rosenthal from heart’s -blood at autopsy, Schlangenhaufer, Jehle two cases, Horder (1907) six -cases, and who believed he was the first to isolate B. influenzæ from -the blood, Tedesko in a number at autopsy, Spat, F. J. Smith, Saathoff, -Libman four cases, Sacquepee, McPhedran, Mann, Rainaford and Warren -three cultures from two patients, and a number of others all bear -witness to its frequency. - -Other organs of the body are sometimes found to contain B. influenzæ. -Adrian, Schultes, Basile and Tedesko have all recovered this organism -from the diseased appendix. Several years ago a bacillus, considered, to -be B. influenzæ, was grown from the pus of an appendix abscess in our -laboratories. Wright found it in pyelonephrosis. Klieneberger found -influenza-like bacilli in cases of cystitis. Menko reported the bacillus -from orchitis, and Cohn found numerous influenza-like bacilli in the -discharge from urethritis. Meunier found it in pure culture in a case of -osteoperiostitis. Huyghe, Besancon and Griffon recovered it from -infected joints, as did Pacchioni in a general infection. Weil found it -in the pus about the hip joint one month after an attack of influenza. -This short review serves to illustrate that the influenza bacillus, -although generally limited to infections in the respiratory tract, is, -nevertheless, capable of infecting other parts. - - - _Immunity—Phagocytosis_ - -Phagocytosis of the B. influenzæ has been very frequently noted in the -study of sputum smears. It has been observed, moreover, that this -phenomenon occurs most frequently when the patient is on the road to -recovery (Pfeiffer, Martin, and others), and it may indicate an -important reaction on the part of the body to this organism. Tunnicliff -in a recent report, however, did not find the opsonic index to be raised -above the normal in her patients, and Tunnicliff and Davis had -difficulty with a spontaneous phagocytosis of this bacillus. This -difficulty was to a large extent absent in her later study. - - - _Agglutination_ - -Agglutination tests have been used by many investigators in attempts to -determine a specific reaction in the sera of persons suffering from -influenza. Such reactions develop, as we know, against secondary -infecting bacteria, so that unqualified conclusions cannot be drawn that -agglutinins in the sera of patients against B. influenzæ indicate the -etiological importance of this organism. Vagedes using a dilution of -1-50 found 8 positives among 27 patients tested. Lord found the test -most inconstant. Ghedini obtained useful results by using serum in -dilutions 1-20 to 1-30, and had 17 positives from 28 influenza cases. He -found agglutinins present three to four days after the height of the -infection, and noted that the sera became practically normal after three -to four weeks. Fichtner, although he obtained agglutination with sera of -influenza patients in high dilutions (1-100 and 1-750), found his -controls were often agglutinated, and consequently drew no conclusions. -Wollstein (1906) did a series of agglutination tests, using various -strains of B. influenzæ. The sera of patients she found very -unsatisfactory, but by immunizing rabbits with this organism she -obtained sera with titres up to 1 in 400. She could find no differences -among the various strains studied. Somewhat similar results were -obtained by her in 1915 working with strains from the meninges and the -respiratory tract. Odaira carried out a rather extensive series of -tests, using immunized rabbit sera and a special method of making his -bacterial emulsions. He was able to distinguish B. influenzæ from both -B. pertussis and the so-called Cohen’s bacillus of meningitis. -Friedberger’s dog bacillus, however, could not be differentiated from B. -influenzæ by this means. A. Fleming during the recent epidemic had good -results with the sera of 21 patients. He incubated at 50° C. for two -hours. He also used sera of immunized rabbits and got marked -agglutination against the homologous strain, but varying results with -other strains. He noted some strains agglutinated readily, while others -did not. Eyre and Lowe noted an increase in agglutinins in the sera of -people vaccinated against the influenza bacillus. Couret and Herbert -could distinguish two types and a possible third among their strains. -Park and his co-workers found numerous types by means of agglutination. -Absorption of agglutinins was found helpful by these last two workers. -There are so many factors capable of altering the sensitiveness of -bacteria to agglutination, as in the well-known experiments of Neufeld, -that we must recognize that much work is still to be done before we can -properly interpret the results of these agglutination tests. - - - _Binding of Complement_ - -Complement fixation tests were carried out by Odaira but his results -were much less satisfactory than those he obtained by means of -agglutination. Rapaport made an extensive study of this test, using the -sera of patients in various stages of convalescence. Three hundred and -fifteen convalescents showed 54.5 per cent. positive while 300 controls -only gave 9.5 per cent. positive results. Most of the positive cases -were in patients three to five days after their illness, but the -reaction was found in convalescents after from 1 to 45 days. Sera from -acutely ill patients at times showed negative or slightly positive -reactions but these same sera after keeping for some days and retesting -often gave strongly positive results. This would appear to be a -promising field for investigation. - - - _Anaphylaxis_ - -Hypersensitiveness was noted by W. F. Robertson in chronic infections -with B. influenzæ. Wollacott in a letter to the British Medical Journal -suggested that the severity of the recent outbreak of influenza may -possibly be due to the development of a state of anaphylaxis. There -would seem to be at least some evidence in favor of such a view in the -fact that the severe outbreak was preceded by epidemics of a milder form -of influenza and that the influenza bacillus was probably widely spread -during this time. Greenwood, as quoted above, noted that primary cases -always precede the mass attack. Of course, the term anaphylaxis has been -used to explain almost everything. Nevertheless, the theory is -interesting. The skin tests which we did for hypersensitiveness were, as -I have noted above, negative but there is a possibility that the failure -of the reaction may indicate a higher resistance or even an antitoxin, -now that the bacillus can be classed as a toxicogenic one. -Anti-influenza sera have been produced by a few investigators (Latapie, -Wollstein) but have not found any practical application during this -pandemic. Vaccination is discussed elsewhere in these studies. - - - _Experiments on the Human_ - -There has never been in the history of medicine so many experiments on -human beings as have been carried out in the attempts to discover the -etiological factor in the recent pandemic of influenza. Davis has called -attention to a successful human inoculation with pure cultures of B. -influenzæ which he performed in 1906. During the present investigation -at least 200 men have volunteered as experimental subjects, and the -results of many different methods of attempting to transmit the disease, -have been disappointing and inconclusive. I will not attempt to review -the reports at present available, as a great deal of the work done has -not yet appeared in print. The important point is that the results do -not affect the various views held as to the causative agent in pandemic -influenza nor the massive evidence for transmission of the disease under -natural epidemic conditions. - -It is my opinion, as expressed above, that practically all of the -population are rapidly infected during such a pandemic as we have had. -The resistant have escaped, and it would appear to be very difficult to -break down this resistance. The human experiment carried out by -Pettenkofer on himself and his assistant with vibrion choleræ is an -example, but we have numerous others demonstrating the same kind of -phenomena in most of our diseases of established bacterial origin. In -diphtheria we have an explanation in the varying antitoxic content of -the sera, but we really know very little of what are the actual factors -in preventing or determining infection among exposed individuals in the -natural history of most diseases. The reports of Leonard Hill and Gregor -are well worth reading in this connection, as well as the editorial in -the same number of the British Medical Journal. We are not in a position -to be very dogmatic on the causes of epidemics. The mere presence of the -bacteria or any other living virus is not in itself sufficient to -explain the phenomenon, and one of the chief objects of this paper is to -indicate from the collected facts, that in the words of Flexner, “the -case against the influenza bacillus is not proved.” - - - _Conclusions_ - -1. B. influenzæ is one of a group of hemophilic bacteria and there are -probably strains of this organism which may be differentiated which will -lead to further subdivisions of the group. - -2. B. influenzæ as we understand it today, is distinguished by its -morphological and staining characters; its requiring hemoglobin in some -form for its development; its showing symbiotic reactions with other -bacteria which stimulate its growth; the production of a toxine and its -usual low pathogenicity for animals. - -3. The media found most favorable for its growth are those containing -blood with the hemoglobin content altered in certain ways, (1) by -heating, (2) the addition of various chemicals, (3) by the action of -other bacteria or their products. The heated blood agar I have found to -be a most efficient and readily prepared medium. - -4. Since B. influenzæ is so difficult to isolate, it is necessary to be -very cautious in interpreting results unless the greatest effort has -been made to demonstrate the presence of this organism. - -5. B. influenzæ should be considered, from the evidence at hand, as the -bacterial causative agent in epidemic influenza, and it should be -recognized that secondary infections following the primary attack by -this organism are both frequent and important. This view I believe the -logical one, unless much more convincing evidence than we have today may -demonstrate another more probable living virus as the cause. - -6. B. influenzæ is a frequent etiological factor in purulent and chronic -bronchitis, broncho-pneumonia and other acute and chronic respiratory -infections, in meningitis, endocarditis, sinusitis, conjunctivitis and -other conditions, as well as in complications of many other diseases. - -7. There are many carriers of the bacillus among our population, both in -apparently normal individuals and in those suffering from chronic -infections of bronchi, sinuses or other parts. - -8. The problem of what constitutes resistance or susceptibility to this -infection are as far from solution as they are in most other respiratory -diseases, and the attempts to explain the reasons for epidemics have -been as futile as they are for meningitis and many other respiratory -epidemics. - -9. It would not appear that the immunological reaction against this -infection has been discovered, but the possibility of its being of an -antitoxic nature opens an interesting field for investigation. - - - BIBLIOGRAPHY - - Abrahams, Hallows and - French Lancet., 1919; i, p. 1. - Abrahams, Hallows, Eyre - and French Lancet., 1917; ii, p. 377. - Abstract of Foreign - Literature on - Influenza Jour. A. M. A., 1918; lxxi, p. 1573. - Adrian Quoted by Tedesko, q. v. - Allen Lancet., 1910; i, p. 1263. - Averill, Young and - Griffiths British Med. Jour., 1918; ii, p. 111. - Avery Jour. A. M. A., 1918; lxxi, p. 2050. - Babes Deutsch. Med. Wochen., 1892; xviii, p. 113. - Batten Lancet., 1910; i, p. 16. - Basile Baumgarten Jahresb., 1907; xxiii., p. 284. - Beall Jour. A. M. A., 1906; xlvi, p. 1442. - Bernstein and Loewe Jour. Infect. Dis., 1919; xxiv, p. 78. - Besancon and Griffon Quoted by Scheller, q. v. - Besson Text-book, translated by Hutchens, 1913. - Blanton and Irons Jour. A. M. 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We shall largely confine our -attention to the observations which came directly under our supervision, -and in as much as this investigation was continued during the epidemic -as it swept over this district, the intensive study was limited to a -time period of about five weeks. During this period much material was -collected, which since then, has taken us a considerable time to -analyze. We have thought it more valuable to restrict our discussion to -this material in that it illustrates the pathological lesions as they -occurred during the acute stage of the disease. We have not entered upon -a discussion of the sequelæ or the chronic lesions which are not -uncommonly found following in the wake of an acute epidemic nor do we -deal with the lesions arising in cases of sporadic influenza, such as -are always with us. As is so well illustrated in the literature, there -is probably no disease which has so many late complications and sequelæ -as influenza. The investigations upon the protean lesions have been -fully reported in numerous papers during the intervals between -epidemics. A comprehensive bibliography upon influenza will be found at -the end of the extensive report by Leichtenstern (1905). There is very -much less accurate information available upon the actual lesions present -during the acute disease when present in epidemic or pandemic form, than -upon the many clinical complications in various systems and organs. In -fact, our knowledge of the pathology of influenza lies more largely in -the field of associated lesions such as the late events in the bronchi, -the sinuses of the head, abscesses, meningitis and other conditions, -rather to be viewed as complications than as portions of the disease. -There are relatively few thorough pathological analyses of the influenza -lesions as they are found in the acute epidemic disease. - -A fair literature has already appeared upon epidemic influenza from the -many countries and regions over which the present pandemic (1918) has -swept. These reports by various authors are offered from different -viewpoints, some investigators being impressed with certain features -which they bring into marked prominence in their reports. It thus -happens that up to the present there is a decided lack of uniformity in -the opinions expressed upon different phases of the subject. The nature -of the pathology of the past epidemic has given rise to many expressions -of opinion as well as dogmatic statements, which are found to differ -from those of others. It seems to us that this apparent confusion arises -partly through the somewhat different characteristics of the disease as -it has made its appearance in different centers. We hear it repeatedly -stated that the types found in different military camps and urban -communities were quite unlike those of other regions. It is evident that -such differences in the clinical course actually did exist and that the -epidemic though having a common foundation upon which the disease -process was built differed in what might be looked upon as symbiotic -complications during the early and acute stages. Differences in the -nature of the findings in various communities also probably lay in the -fact that the bacterial flora associated with the causative agent of -influenza was quite different in different regions. We mention this here -so that a full appreciation will be obtained for the differences in the -pathological characters of the disease as they are found in one region -or another. We appreciate, of course, that if the concomitant bacterial -flora associated with the underlying cause of influenza, differs in -different regions, so, too, will the bodily reactions differ within -certain degrees. We are becoming more familiar with different types of -bacteria, and the resulting inflammatory reaction which is often unique -or at least particular, and that not uncommonly the nature of the -inflammatory process suggests the type of bacterium involved. This -argument, of course, must not be driven too far, for we well know that -the same micro-organisms under different conditions can cause types of -inflammatory reactions wholly divergent. - -In as much as our observations are confined to a particular group of -cases and the study of these was undertaken during the five weeks of the -acute epidemic, these results are not to be compared with the collected -statistics on influenza as they shall be made over a period beginning -with the onset of the epidemic and ending with the last vestiges -remaining after months or it may be years of time. Our observations are -to be considered only in the light of the events taking place during the -height of an epidemic wave. In as much as influenza presents itself -during an epidemic in different forms, we shall again mainly limit the -report upon our investigations of those cases having respiratory -lesions. Our acute observations were made upon the tissues of those who -had died of this disease. It is impossible, or nearly so, to fully study -the tissues of those with lesser lesions and who recover. Hence, if we -divide the influenza cases into those (1) without pulmonary lesions and -(2) those with pulmonary lesions, we must state that all of our cases -coming to autopsy fall in the second group. It is true that one of these -having pulmonary lesions was not brought to his fatal termination by -them but by a septicæmia arising in the middle ear. He had distinct -lesions in his lungs. In other words, our autopsy material represents -epidemic influenza in which the lung was definitely involved in an -inflammatory state. In all but one of these the pulmonary lesion was the -cause of death. - -No doubt, if opportunity had presented itself to follow a large epidemic -through months of its progress, during which late complications in -various portions of the body would make their appearance, our analysis -would give a different picture and the pulmonary factor for the fatal -termination would not be in such prominence. - -Of the first group, those cases of epidemic influenza not showing -pulmonary lesions, we will have very little to say, in as much as the -pathological investigations of them is impossible, or nearly so, during -the height of the disease. - -Such cases apparently do not die at this period. I am willing to admit -that individuals without pulmonary involvement may succumb, but I -question whether their death has been due to the result of the -influenzal lesions, be it in nose, pharynx, larynx or trachea, or be it -in the intestine, but rather that the fatal termination occurred later -in the course of this complex disease, when distant vital organs became -involved or incapacitated in a toxemia or secondary bacterial invasion. -We must clearly distinguish these cases from the clear-cut ones of -epidemic influenza, looking upon the new circumstances as complications -aside from the original disease. Such, for example, is the case we have -mentioned where a fatal streptococcus bacteriæmia followed in the wake -of an otitis media. In our experience we have not had a fatal case of -the acute epidemic disease in which the lung was not involved. - -In types of epidemic disease such as we have just had, where the -epidemic wave has passed over in a period of four or five weeks, there -is always much to be regretted which has been left undone. We tried as -far as possible to gain all the information available at the time of -collecting our materials and of laying aside such of the work which -could be accomplished at a subsequent date. The materials were collected -from divergent sources in the cadaver, and the more perishable -substances were analyzed immediately. During the period of the epidemic -32 autopsies were performed and as much use as possible was made of each -for a thorough comprehension of the lesions. - - - _Materials_ - -During the period of our work 639 patients were admitted to the hospital -suffering from clinical influenza. The cases varied in type from the -very mild to the extremely ill. The majority of the cases were of the -type of “three-day fever.” Clinically 81 cases developed pneumonia, and -of these, 35 died. It would, of course, be impossible to say how many -other individuals had a pulmonary involvement which could not be -recognized clinically. In fact, some of the cases which did come to -autopsy were only recognized as having a pulmonary involvement when the -lungs were examined outside of the body. The physicians freely admitted -that the physical signs were quite unusual and unlike those of the -ordinary forms of pneumonia. In fact, except for the fact that we were -living in the midst of an epidemic of respiratory infections, there was -nothing to make the clinician suspect that many of these cases had a -pulmonary involvement. Obviously, when the recognized signs of different -types of pneumonia made their appearance, the clinician did not fail to -make proper interpretation of the lung involvement. This, as we shall -discuss later, is an event superadded to a lung condition which -pathologically must be recognized as pneumonia (inflammation) and which -differs so decidedly from what we know of as croupous or lobar -pneumonia, as well as ordinary broncho-pneumonia that it would be -incorrect to include them under this heading, although the distribution -of the lesion may have lobar, bronchial or lobular characters. - - - TABLE I - - ════════════════════════════════════════════════════════════════════ - DATE 1918 PATIENTS PATIENTS CASES IN DEATHS - ADMITTED DISCHARGED HOSPITAL - ──────────────────────────────────────────────────────────────────── - October 5 65 0 65 0 - 〃 6 23 0 88 0 - 〃 7 61 0 149 0 - 〃 8 77 0 225 1 - 〃 9 42 1 266 0 - 〃 10 35 1 300 0 - 〃 11 9 0 307 2 - 〃 12 2 16 290 3 - 〃 13 10 0 298 2 - 〃 14 1 18 278 3 - 〃 15 4 13 266 3 - 〃 16 9 23 248 4 - 〃 17 10 19 235 4 - 〃 18 16 34 217 0 - 〃 19 38 29 225 1 - 〃 20 27 0 252 0 - 〃 21 37 43 245 1 - 〃 22 33 7 270 0 - 〃 23 14 20 263 2 - 〃 24 20 17 266 0 - 〃 25 27 21 272 0 - 〃 26 10 29 250 0 - 〃 27 18 3 265 1 - 〃 28 10 31 243 3 - 〃 29 6 16 231 0 - 〃 30 11 27 215 1 - 〃 31 2 15 202 2 - November 1 2 18 185 0 - 〃 2 4 18 170 1 - 〃 3 5 1 174 0 - 〃 4 2 19 156 1 - 〃 5 5 0 161 0 - 〃 6 4 16 149 0 - ——— —— - Admissions. 639 35 - ──────────────────────────────────────────────────────────────────── - -The individuals admitted to this hospital were obtained from the two -military camps at the University of Pittsburgh and the Carnegie School -of Technology. All of them were enrolled in the army service and ranged -from the ages of 18 to 30. They were vigorous individuals, who had -passed their physical examinations for the army. The epidemic made its -appearance in these camps on October 2, rapidly ascending from a report -of two ill on October 2, four on October 3, eight on October 4, to 65 on -October 5. On October 11 there were 307 cases in the hospital. - -Of these cases 35 died, the day of death being indicated in the -following table. - - - TABLE II - - ═══════════════════════════════════════════════╤═══════════════════════ - DAY OF DISEASE ON WHICH DEATH OCCURRED │ NUMBER OF CASES - ───────────────────────────────────────────────┼─────────────────────── - Third │ 1 - Fourth │ 3 - Fifth │ 4 - Sixth │ 4 - Seventh │ 4 - Eighth │ 5 - Ninth │ 3 - Tenth │ 4 - Eleventh │ 3 - Thirteenth │ 1 - Fourteenth │ 1 - Twentieth │ 1 - Twenty-third │ 1 - ───────────────────────────────────────────────┴─────────────────────── - -The time as indicated in the above table has no relation to the length -of time that the patients were ill of pneumonia, but refer to the period -of illness from the beginning of the influenza. The duration of the -pneumonia is indicated in another table. - -Of the 35 fatal cases 32 came to autopsy. Facilities were available to -do the work very satisfactorily, in that the hospital was well provided -with a modern post-mortem room and its accessories. The notes on the -autopsies were taken immediately and fully, and the materials for -subsequent study were collected in different types of preserving fluid. -Portions of tissue were collected from all of the organs for -microscopical study, while fluids from the chest, lungs, bronchi and -heart were obtained for bacteriological investigations and for some -chemical analyses. - -Added to the above material we also had the opportunity of reviewing and -studying the lesions of 18 autopsies performed by Dr. J. W. McMeans. -These cases were very similar to our own series, in that they were cases -of epidemic influenza amongst soldiers who were being cared for at the -St. Francis Hospital. The disease processes were quite alike in the two -series, and the analyses made by Dr. McMeans are comparable in our own -and serve as a means of checking our results obtained in another -institution. The similarity of the lesions in the lungs and other organs -serve to indicate that what is reported in this paper is an index of the -nature of the lesions of epidemic influenza as it occurred in the -Pittsburgh district. In a few instances the autopsies performed by Dr. -McMeans revealed more advanced pulmonary lesions with abscess and -gangrene than were noted in the cases autopsied at the Military -Hospital. The process, however, in the two series of autopsies was -identical. - - - _General External Features_ - -There were no external characteristics of the bodies which were -autopsied by us which were constant. Some features were more commonly -present than others. Of these the cyanosis of the face, head, neck and -shoulders, and in a few instances of the upper extremities, attracted -our attention more than any other. This cyanosis was present in over -one-half of the number of cases, and it was confined almost always to -the upper part of the body. The face, ears and neck were always more -affected than other parts. This cyanosis bore no relation to the length -of time after death when the body was viewed, as we found that when it -was present during life it maintained its prominent appearance for a -long time after death. - -The cyanosis differed from the bright hue or flush as it is at times -observed in ordinary pneumonia, the color in these instances being of a -dark purple, or better a purplish blue. The lips and ears showed the -most intense color. The cyanosis was not associated with any evidence of -œdema. The capillaries of the tissues were filled with blood which was -of a very dark character. Cyanosis could also be seen in the finger tips -about the nails. This was more marked in the upper extremities than in -the lower. The skin of the body rarely showed any cyanosis, these -tissues being quite pale, or at times showing a slightly yellowish -tinge. In one instance the cyanosis of the head and neck was accompanied -by a slight purplish rash upon the upper portion of the chest. This rash -was of a petechial kind, there being slight hemorrhage into the tissues. -The lesion, however, was not of the blotchy purpuric type which has been -observed by others during this and past epidemics (Cole). This single -case is the only one where we had evidence of superficial hemorrhages -into the skin. - - - TABLE III - - │CYANOSIS│ │ NO - │ │ │CYANOSIS - ═════╪════════╪═══════════════════════════════════════════════╪════════ - NO.│DEGREE │DISTRIBUTION │ - ─────┼────────┼───────────────────────────────────────────────┼──────── - 741│+ │Chest and upper extremities │ 747 - 743│+ + │Face, neck and ears │ 748 - 744│+ + + │Head and neck (upper portion of chest and │ - │ │ thighs mottled and purple) │ 749 - 745│+ + │Head and neck and upper extremities │ 751 - 746│+ + │Ears, neck and shoulders │ 752 - 750│+ + │Face, ears and neck │ 764 - 756│+ + │Neck, jaw, shoulders and upper extremities │ 765 - 757│+ │Face, neck, shoulders, arms and chest │ 778 - 758│+ + + │Face, ears, neck and upper chest │ 782 - 761│+ │Face, ears, neck and upper chest │ 784 - 762│+ │Ears, neck and chest │ 786 - 763│+ │Head and neck │ 793 - 767│+ │Face, ears and neck │ - 773│+ + │Neck, ears and cheeks, extending moderately to │ - │ │ upper chest. Hemorrhage into conjunctiva │ - 781│+ + │Eyes, lips, ears and neck │ - 783│+ + │Face, lips, neck and fingers │ - 787│+ + + │Ears, neck and shoulders │ - 791│+ + │Ears, neck and upper chest │ - 792│+ + │Ears and back of neck │ - ─────┼────────┼───────────────────────────────────────────────┼──────── - 19│ │+ Blotchy or slight │ - │ │ 6 │ 12 or - or│ │++ Moderate │ - │ │ 10 │ 38.6% - 61.4%│ │+++ Well marked │ - │ │ 3 │ - ─────┼────────┼───────────────────────────────────────────────┼──────── - 770│ │Fine petechial rash over upper chest. │ - ─────┴────────┴───────────────────────────────────────────────┴──────── - -Occasionally we met with small hemorrhages lying in the upper layers of -the subcutaneous tissue. These lesions were small and could not be seen -from the external surface. Nevertheless, some of them seemed to have -occurred in direct contact with the deep cutis and surrounded portions -of the deep skin appendages. From an examination of our cases there was -no reason at the time of autopsy to lay any particular stress upon the -occurrence of these hemorrhages. Subsequently, it has come to mind, and -since learning of the unusual frequency of boils and deep pustules -making their appearance as post-influenzal sequelæ, that these minute -lesions may have a bearing upon the localization of infection in the -skin tissues. We must appreciate, of course, that other factors of a -constitutional nature probably render the individual more susceptible to -the invasion of the staphylococcus, and that such factors are -all-important in allowing this organism to gain a foothold. Whether the -decreased sugar-tolerance with hyperglycemia, which has been observed in -the late stages of influenza, bears a relation to the increased -susceptibility, as appears to be the case in diabetes mellitus, is an -interesting point for further investigation. Other constitutional states -are also undoubtedly involved in the increased susceptibility to the -infection which the patient suffers. Elsewhere (Dr. Holman) it is shown -that the natural complement content is considerably depressed during the -height of the influenza. With such factors present and with the -available infecting micro-organisms, it is possible that the minute deep -skin hemorrhages bear a relation to the immediate localization of the -infection. - -In two instances slight hemorrhages were observed into the conjunctival -tissues. In each case they were unilateral and occupied the tissues -contiguous to the inner canthus. In one case there was well-marked -icterus with yellow coloration of the scleræ and skin. In this case the -icterus was associated with degenerative changes in the liver, there -being no recognizable obstruction to the bile passages. The icterus had -come on quite acutely and without any special clinical manifestations. -In the epidemic of 1890 jaundice was present in a considerable number of -cases (Medical Record, 1890, xxxvii, 473). Cole made similar -observations in the epidemic of influenza amongst the Canadian soldiers. -Œdema of the skin was not met with in any of our cases. This point is -worthy of comment, inasmuch as some authors have been impressed with the -serious damage taking place in the kidney and the resulting incapacity -of these organs. Although, as we shall point out later, the kidney -tissues in these cases showed a decided toxic degeneration, there was no -evidence that a glomerular damage of serious degree ever occurred. The -urinary excretion, as is pointed out in a report by Dr. Zeedick, varies -considerably with the intensity of the disease. It is unusual to find -derangement of kidney function to a degree to reflect seriously upon the -general bodily state. At least this has been our experience in the -present epidemic. Even where subsequently we were able to demonstrate a -considerable tubular degeneration in the cortex of the kidney the change -in the kidney function was not of sufficient magnitude to lead to a -water-retention to be recognized in an anasarca. I wish to distinguish -clearly at this point the difference in finding an œdema in certain -involved tissue structures in various parts of the body and arising -through an inflammatory reaction due to the presence of peculiar focal -irritation, as compared with the accumulation of fluid in many and -irregular situations as it occurs through retention and faulty excretion -by the kidneys. Various organs as we have found—as, for instance, the -lung, heart and liver—showed a condition of œdema which was not to be -reconciled with an inadequate circulation because of a cardiac or renal -incompetency. These œdemas, which we will discuss later, are local and -are the result of damaging influences inducted in and upon the tissues -where they are found. - - - _Muscle_ - -In all of our cases we have been struck with the excellent physique of -the individuals succumbing to this epidemic. All were youths in the best -of health, of good muscular build and strong bony frame-work. -Post-mortem rigidity set in fairly rapidly after death. Where this -rigidity had “set” for six or more hours it required much force to -change the position of the muscles. The voluntary muscles of the thorax -and abdomen were always carefully observed, and in a number of instances -the muscles of the thigh were also examined. It was not possible -routinely to dissect the muscles of the extremities, so that we are -unable to give an accurate account of the occurrence of degenerations in -these structures. We have, however, observed the reactions taking place -in the pectorals, psoas and muscles of the abdominal parietes. Changes -were observed with greatest frequency in the recti of the abdomen. -Degeneration occurred in these muscles in 14 instances, while the same -tissues suffered rupture, in part or completely with hemorrhage, in six -instances. It was not uncommon to find marked degeneration in the lower -segment of the rectus muscle on one side, while degeneration and -hemorrhage had occurred in its fellow on the opposite side. In four -cases rupture of the entire belly of the muscle had taken place, so that -a considerable space had occurred between the broken ends and a large -clot of blood filled the intervening space. This degeneration, which was -seen only in the voluntary muscles, was quite interesting and in its -milder degrees was rather difficult to detect. All gradations of loss of -muscle color were seen. In some instances the muscle simply seemed to -have lost its meaty lustre, while again in the more severe instances the -muscle color had changed from the bright red to an insipid yellow or -clay color. The most marked degeneration occurred in the midportions, -while the ends of the muscle masses at the points of attachment were -less involved. Complete rupture of the rectus always occurred in the -lowermost segment, a short distance above the insertion into the pubic -bone. At times the distribution of the degeneration within the muscle -was quite patchy, and irregular islands of yellow about 2 cm. in -diameter were splashed through the muscle masses, which in themselves -were paler than normal. Where the muscle degeneration was advanced the -tissue was soft and at times even buttery. It resembled the character of -the degeneration observed in typhoid fever, although I have no -recollection amongst many enteric cases of having seen the degeneration -of the muscle occur so acutely. Recklinghausen claimed that these -hemorrhages were most unusual in influenza. This is contrary to our -findings. - -Degenerations of a similar kind as those of the abdominal recti were -found in both pectorals. In the chest region, however, the degeneration -was less frequent and less severe. We observed it only twice, and in -neither instance had the degeneration led to a rupture and hemorrhage of -the muscle bundles. Kuskow observed a single case of degeneration and -hemorrhage of the pectoral muscles. In the psoas muscle we observed -degeneration on two occasions, in one of which the lesion was associated -with a partial separation of the muscle fibers and hemorrhages into its -substance. In one case clinically, but not coming to autopsy, a lesion, -which from its character we presume to have been a degeneration, -occurred in the sterno-mastoid, being accompanied by hemorrhage and the -development of a firm clot the size of a hazel nut. In the subsequent -history of this case the lesion passed through an aseptic process of -organization with contracture so that the patient has recently been -developing a “wryneck.” Kohts in 1890 reported the finding of muscle -degeneration and abscesses in the arm. The condition arose as a late -complication of influenza. - -From our experience at the autopsy table in observing the relative -frequency with which muscle degeneration occurs in the severe cases of -epidemic influenza, we feel convinced that numerous cases which recover -pass undiagnosed of this condition. Furthermore we have evidence, as -illustrated in a case observed by Dr. McMeans, wherein a lesion which -occurred in the gluteal muscles was followed by a localizing infection -at this site that these muscle degenerations and hemorrhages may have -serious consequences. There are a number of instances in which -post-influenzal complications of the nature of deep-seated abscesses of -the extremities, thorax, and abdomen may have their explanation for the -localization in a primary muscle damage accompanied by hemorrhage and -followed by an infection of variable type. Cole also comments upon the -development of abscess in the deep muscles where degeneration had taken -place. In illustrating some of our findings to Dr. J. Anderson he -immediately recognized such a condition in the pectoral muscles of a -patient in which he was unable to arrive at a conclusion of the -pathological events which had taken place. It is one of the noteworthy -features in this disease that the voluntary muscles of certain regions -are apt to suffer severe damage, while the heart and the various -unstriped muscular tissues are little if at all affected by a similar -process. It would be interesting to know whether the lack of response -and the delayed functional recovery on the part of the muscles of the -extremities in so many patients who have suffered influenza is the -result of the damaging influence of a peculiar intoxication present in -this disease. One of the features in influenza is the prostration of the -patient, and with it there is definite muscular weakness. We have been -prone to lay the responsibility of this state entirely at the door of -the nervous tissues. Here, however, we are able to offer evidence that -quite aside from the lesions arising in the nervous tissue, there is -definite muscle damage which, as we shall again discuss when describing -the microscopic features, incapacitates even to the point of complete -destruction the muscle elements in various fields of the body. Before, -however, being able to state that the muscular weakness of the -extremities is the result of such damage by toxins it is necessary to -obtain more definite information regarding the frequency with which -these degenerations occur in the limbs. In our own material we are -unable to discuss the matter with adequate figures. We are, however, -impressed with the changes observed in the muscles which were available -to us. Naturally, too, a certain number of muscle degenerations have -escaped our detection because of our unfamiliarity with the mildest -grades. In fact, we have already discovered in our microscopic studies -that certain cases, which in the macroscopic had escaped us, showed -well-marked lesions under the microscope. - - - TABLE IV - - MUSCLE DEGENERATION - - ABDOMINAL RECTI │ PECTORAL │ PSOAS - ═══════════════╤═══════════════════════╪═══════════════╪═══════════════ - TOXIC │HEMORRHAGE INTO RECTUS │ TOXIC │ TOXIC - DEGENERATION │ │ DEGENERATION │ DEGENERATION - ───────────────┼───────────────────────┼───────────────┼─────────────── - 745 on 10th day│745 both on 10th day │756 on 8th day│756 on 8th day - 749 on 4th │752 both on 13th │770 on 11th │792 on 6th - 752 on 13th │756 both on 8th │ │ - 756 on 8th │764 both on 9th │ │ - 757 on 6th │765 both on 9th │ │ - 762 on 10th │778 both on 23d │ │ - 763 on 11th │————————————————— │ │ - 764 on 9th │ RUPTURE OF │ │ - 765 on 9th │ RECTUS │ │ - 767 on 10th │ │ │ - 770 on 11th │745 right on 10th day │ │ - 778 on 23d │756 both on 8th day │ │ - 783 on 8th │778 right on 23d day │ │ - 791 on 6th │ │ │ - ───────────────┴───────────────────────┴───────────────┴─────────────── - -We have convinced ourselves that the marked hemorrhage taking place in -the muscle tissue follows upon a primary degeneration of this tissue and -its spontaneous rupture. The amount of hemorrhage is in proportion to -the degeneration and fracture of the muscle elements. The hemorrhage -does not precede the muscular change, nor does it have any antecedent -relation to the actual tearing of the muscle fibers. - -A much better appreciation of the muscle degeneration was obtained in -the _microscopic_ studies of these tissues. The various gradations of -tissue change could be followed, which was not possible in the naked-eye -examinations. Some points respecting this degeneration were quite -noteworthy. Firstly, the process of degeneration in its early stages and -advancing through the acute destructive periods was not accompanied by -any inflammatory reaction. Evidence of inflammatory exudate was obtained -only when the degeneration had proceeded to a degree permitting of -rupture with hemorrhage, or in the late stages when the areas of marked -muscle dissolution were undergoing repair. We have no evidence to -indicate that bacteria were present during the beginning of the -degenerative process. Bacteria could not be demonstrated in section. The -appearance of the tissue suggested a purely toxic process which was -selective in its action, picking out voluntary striped muscle tissue and -attacking certain muscle groups in preference to others. It was also -interesting to observe in the early stages of the degeneration that -individual fibers lying amidst healthy and unchanged muscle elements -would show degeneration in many of its stages. This appearance was often -unique, particularly when in the early stages of the process the -involved fiber would still retain its normal position and shape though -markedly altered in its staining and chemical qualities. - -The degeneration as observed in these cases showed many of the -characters like that of waxy degeneration seen in typhoid fever. Similar -appearances to these have also been described in connection with the -toxic degenerations which occur in the vicinity of infections by the gas -bacillus. In fact, all the stages observed in the one can be seen in the -other. They differ, however, only in the degree to which final -destruction takes place and in the speed with which the degeneration is -accomplished. The character of the degeneration is well studied in -sections stained with hematoxylin and eosin, eosin-methylene blue, and -best of all in the phosphotungstic acid hematoxylin. By the latter -method one is able to follow clearly the grade of degeneration as it -effects the muscle striations. On the other hand, the peculiar waxy -appearance of the early degenerating fibers is best seen in sections -stained with eosin or fuchsin, where the striated muscle fibers are -found to be changed to a more intensely staining red body of homogeneous -character and devoid of all evidence of their original internal -architecture. These bland waxy fibers were often of the size and shape -like the normal. On the other hand, the fibers are also not uncommonly -swollen, stretching the sarcolemma to almost the bursting point. -Following this primary bland degeneration the fiber takes on irregular -shapes, becoming constricted and collapsed at irregular intervals, so -that islands of the waxy contents lie within the sarcolemma, being -separated from each other by constricted areas in which the original -myoplasm has undergone decomposition and sometimes complete absorption. -This irregular destruction of the muscle contents often has a granular -stage in which the original muscle substance has become disintegrated. -The sarcolemma follows the condition within it, stretching when the -fiber is swollen and shrinking, or even becoming collapsed when the -inner substance is becoming liquified and absorbed. The sarcolemma does -not suffer the degenerative changes of the inner fiber, nor can one -observe nuclear changes in this sheath which are significant. - -When first studying this process of degeneration it appeared to us that -the earliest change was a loss of the transverse striations and the -subsequent disappearance of the longitudinal fibrillæ. We have -subsequently found that this is incorrect and that the changes observed -in the markings of the fibers were not constant. At times the muscle -substance would progress through stages of degeneration up to the point -of disintegration and dissolution while the transverse striæ were still -discernible in the altered fiber. The one constant change that we have -observed in the degenerating fibers was the early loss of staining -qualities as obtained by the phosphotungstic acid hematoxylin. In such -preparations the earliest effect of the intoxication upon the muscle -fiber was a change in reaction to this stain. Sometimes within a given -fiber small irregular and poorly staining blotches could be observed, -while the remaining portion of the fiber was normal in its appearance. -Later these poorly staining areas became larger, occupying the entire -width of the fiber and being distributed at irregular intervals in its -length. Finally the characteristic staining quality was entirely lost, -although in the poorly colored cell transverse striations were still -discernible and a true waxy stage had not yet taken place. - -At times the waxy degeneration advanced into the stage of disintegration -by an irregular destruction within the fiber. When this occurred the -fragments of waxy substance took on curious coiled and grotesque shapes, -while a granular destruction was taking place in their periphery. -Neither inflammation, œdema nor a vascular reaction could be determined -in these tissues of mild or severe change. The reaction as is indicated -in the table occurred quite acutely and was not accompanied by fatty -products commonly seen in the slower forms of degeneration. - -Gradually the debris of the degenerated fibers is absorbed and the -sarcolemma shrinks and collapses upon itself. During this stage a -reaction occurs in the sarcolemma with nuclear proliferation. At times -the last vestiges of the muscle fiber are seen to be surrounded by a -crown of nuclei and cells reminding one of the appearance of the -degenerating nerve cells in the Gasserian ganglion in hydrophobia. The -involved area becomes active in appearance, showing proliferation of -fibroblasts and the appearance of occasional lymphocytes and plasma -cells. Scar tissue continues to develop in proportion to the amount of -damage done. In areas where hemorrhage had taken place the amount of -scar tissue is exaggerated, owing to a process of organization which is -taking place quite apart from the muscle degeneration. Thus not a few -scars scattered through the voluntary striped muscles are the final -outcome of this toxic degeneration occurring in epidemic influenza. Some -of these lesions may account for the indefinite pains and symptoms of -which the patient complains for so many months after his acute illness. -I refer particularly to lesions occurring in the psoas and muscles of -the back as possible explanations for the partial invaliding of some -individuals. - -In a certain number of cases of acute influenza the patients complain of -severe abdominal pain, in the absence of any localizing symptoms or -evidence of intestinal derangement. Such was the case with a number of -the above cases coming to autopsy, and the sole evidence we could offer -was muscle degeneration with or without massive hemorrhage. The -abdominal pains complained of were more of the nature of dull aches with -occasional exacerbations and shooting or lancinating “stitches.” Rarely -was the patient able to define the position of the pain, not being able -to state whether it was within the abdomen or in the parietes. Most -frequently they claimed it was internal. We have on no occasion -demonstrated an intra-abdominal lesion which could account for such -pains. None of our cases was of the type of “intestinal influenza.” We -are, therefore, led to the conclusion that the muscle degenerations of -the various degrees, from the slight with few muscle elements involved -to the severe with rupture and hemorrhage, account for a proportion of -the clinical symptoms of (muscle) pains and aches as well as weakness. -We cannot claim that coughing was a necessary factor in inducing rupture -of the abdominal recti. In some of the cases with rupture severe -coughing had not been observed during the illness. - - - _Upper Respiratory Tract_ - -The pathological changes found in the nose, pharynx and larynx were of -relatively slight importance and most variable in their severity and -incidence. The majority of individuals had few clinical manifestations -of disease in these parts. Some, however, complained of dryness of the -pharynx with slight feeling of fullness. An examination of these parts -revealed some congestion, varying from a red injected mucosa to a bluish -cyanosis. In the nose the reaction was rarely as acute as is seen in -infectious coryza, but even where relatively little change was to be -seen in the tissues hemorrhage from the erectile tissue was not uncommon -during the acute stages. No particular lesion was to be found associated -with nose bleed. There was an unusual absence of excessive secretion -from nose and pharynx in the majority of cases. One was also struck with -the infrequency with which the larynx was involved. A certain number of -individuals complained of hoarseness, and in them injection of the vocal -cords with some swelling was found. In many others, however, even where -an intense infectious process was present in the lower respiratory tract -the larynx was almost without change. It was from the level below the -larynx that the acute reaction in the respiratory system was found. - -In all of our cases the trachea showed definite inflammatory reaction. -Of the 32 cases there were 26 having an acute tracheitis, 5 with an -acute mucopurulent inflammation and 1 with a reaction in the subacute -stage. In the majority of the cases with acute tracheitis there was a -thin layer of exudate lying upon the mucosal surface. At times the -trachea was filled with a frothy serous fluid, the greater part of which -had its origin in the lung. Nevertheless, as we shall point out later, -we did obtain microscopical evidence indicating that during the early -acute stage of the tracheitis a considerable serous exudate escapes from -its mucosa. This serous inflammatory reaction is an important one for -all of the mucosal structures upon which the virus of influenza obtains -a footing. This we have found true for the trachea, bronchi and alveoli -of the lungs. In some cases the exudate was grey and lay in close -contact with the injected tissues. At first sight this grey exudate -suggested necrosis, but it was readily wiped from the underlying -structure. Some leucocytes and cell debris with many bacteria made up -the content of this grey exudate. - -The macroscopic appearance of the trachea was that of an intensely -injected structure which had largely lost its normal lustre. The naked -eye could distinguish that anatomical change had occurred in the surface -tissue of the trachea and that there was unusual evidence of intensely -injected vessels lying in the submucosa. In only one instance was there -an appearance of a true necrotic membrane lying upon the surface of this -intensely inflamed layer. This apparent membrane was found to consist of -a wide patch of desquamated epithelial cells which was lying as a -delicate necrotic plate upon the surface. This thin layer was devoid of -a meshwork of fibrin threads as usually accompanies a true false -membrane of other sources. - -The early intense inflammatory reaction of the surface membrane of the -trachea was characteristic, and in our experience was never exceeded in -intensity by other infections. A desquamation of the lining membrane was -also a common finding. Naturally this intense reaction so commonly found -in the trachea extended without interruption into the main bronchi and -their divisions. The finding of this continuous surface inflammation is -good evidence of the mode of spread of the infectious process along -these membranes, beginning in the upper portions and by direct -continuity involving more and more of the respiratory tubes toward the -lung. - -The varying grades in the intensity of the inflammatory reaction upon -the inner surface of the trachea was well illustrated in the microscopic -sections. Even with the different degrees of the reaction there was a -fairly constant character to the inflammation. In this way the response -was found to differ from that commonly observed in ordinary infections -of the respiratory tract. The first striking feature is the marked -response of the vascular channels, both blood and lymphatic. The vessels -lying in the submucosa were found intensely engorged so that their walls -were stretched to the point of bursting. In fact, not a few vessels were -seen whose walls, probably under the stress of intoxication and -dilatation, had given way leading to a flooding of the neighboring -tissue with their contents. Where such vessels lay close underneath the -surface the hemorrhage escaped into the lumen of the trachea. -Accompanying this early vascular response there was found a marked -serous exudate leading to a stretching of the submucosal tissues by -distention of the interstitial spaces. This reaction resembled an acute -inflammatory œdema and occupied the area between the mucosa and the -inner border of the cartilage rings. Beyond this region no response was -found. Thus in the earliest stages, and where the mucosa was still -intact, the main reaction was of the nature of an intense serous -inflammation with congestion of the blood vessels and frequent -interstitial hemorrhages. - -Shortly following the development of the serous exudate in the -submucosal tissues, the epithelial lining is found to suffer from the -reaction. The serous exudate does not remain confined to the -interstitial tissues, but is poured out through the mucosa into the -trachea. It would appear that the amount of this clear exudate may -become greater than can be dealt with by the mucosa, with the result -that an accumulation of this serous fluid takes place between this -epithelial layer and its basement membrane. We have repeatedly seen -considerable stretches of the mucosa lifted from the basement membrane -and shed in large plaques into the lumen. These mucosal cells at the -time of their desquamation retain fairly well their morphological -characters, and do not show evidence of necrosis prior to their removal. -Disintegration of these cells naturally occurs while lying in the -secretion of the trachea, and a variable cellular mass in stages of -disintegration may often be found both in smears and sections. When the -epithelial cells are lifted in wide plates, a type of bleb develops -which is easily broken and then disintegrates. - -The desquamation of the lining membrane is a fairly constant occurrence -in the cases coming to autopsy. In the majority of those which we have -examined the greater portion of the trachea was completely denuded, save -for small islands lying in the recesses near the mouths of the mucous -ducts. In one case this lesion was accompanied by a process of -ulceration, due in all probability to the invasion by other -micro-organisms. The denuded tracheal surface usually shows a further -inflammatory reaction in which a cellular exudate then makes its -appearance. This reaction is mainly one in which lymphocytes and plasma -cells infiltrate the spaces previously occupied by the serous fluid. The -reaction is limited to the submucosa and does not extend into the -tissues beyond the cartilages. We have found only occasional -polymorphonuclear leucocytes lying close below the surface. During this -period, however, varying grades of degeneration may occupy the upper -layers. The basement membrane particularly seems to suffer by losing its -characteristic outline and staining qualities. This membrane becomes -swollen, softened and indefinite. At times a homogeneous precipitate -occurs along its free surface giving rise to an appearance resembling a -false membrane. This deposit is, however, distinctively different from -the diphtheritic membrane of other infections. It is interesting, -however, that where such deposits and degeneration occur in the basement -membrane more or less degeneration and necrosis also occur in the -connective tissues immediately neighboring to it. These tissues show a -peculiar granular destruction and alter their staining qualities. -Moreover, and what is more important, under these conditions the dilated -blood vessels are found to suffer from the injuries taking place in -their neighborhood. We have repeatedly found partially or completely -thrombosed capillaries, arterioles and venules in these surface layers. -These thromboses took place while the vessel was in its distended state -and thus produced a mold of the dilated vessel. This observation is of -importance in indicating the severity of the effect of the virus and -toxin upon the tissues of the trachea, and it is also of importance to -appreciate that this damaging influence is very different from that -which we encounter in pneumococcus infections, and we shall point out in -our discussion on lung a reaction very similar to that which takes place -very superficially in the trachea may also occur in the alveolar walls -of the lung. - -Having referred to the intensity of the responses of the blood vascular -system, we must also indicate the part played by the lymphatics. -Simultaneously with the reactions taking place about the blood vessels -of the trachea we observed similar responses in the lymphatic channels. -At first these dilated structures contained only fluid. Later the -migration of the lymphocytes took place along these routes, and rarely -micro-organisms could be demonstrated either free or within an -occasional leucocyte. The sharp response of the lymphatics during the -serous inflammation is noteworthy, inasmuch as we have found that the -lymph glands lying about the respiratory tubes and lungs were early in -their response to the irritating virus. - -Bacteria were demonstrated in the secretions lying upon the surface of -the trachea. In those specimens in which the mucous membrane was still -intact we attempted to demonstrate the clustering of the micro-organisms -about the ciliated cells as was described by Mallory in whooping cough. -Although the organisms, and particularly small Gram negative bacilli, -could be demonstrated lying about these cells no characteristic -arrangement was found. Furthermore where the mucosa was still attached -to its basement membrane we were never able to demonstrate organisms -below the surface of the epithelial layer. In several cases where the -mucosa was lifted in bleb-like structures a number of organisms were -detected below the epithelial layer and in contact with the basement -membrane of the submucosa. We have rarely demonstrated bacteria in the -interstitial spaces of the submucosa, even where large numbers of -organisms were lying upon the inner denuded surface. - -The distinction which was made by the gross examination of the trachea -between the acute tracheitis with serous exudate, subacute tracheitis -and mucopurulent tracheitis was not so readily distinguished in the -microscopic sections. In the gross the character of the exudate lying -upon the surface was the main guide suggesting the nature and intensity -of the inflammatory reaction. In the microscopic sections this exudate -was largely wanting, or was not sufficiently characteristic to confirm -the gross findings. On the other hand, differences in the nature of the -injury were to be found mainly in the reaction of the submucosa. As we -have indicated above, the early inflammatory reaction of the trachea is -mainly evident in an intense congestion accompanied by an inflammatory -œdema of the submucosal tissues, hemorrhage sometimes accompanying this -response. In the later stages of the reaction a cellular deposit takes -the place of the inflammatory œdema and usually consists of lymphocytes -and plasma cells. It is only in those cases where the intensity of the -irritant continues to act over a longer period of time that a -superficial necrosis with leucocytic infiltration makes its appearance. -The epithelial layer of the trachea is desquamated early in the acute -reaction, and hence a denudation of the surface is to be found in all -stages of the acute lesion. The mucous glands have not been found to -show any particular involvement in the inflammatory process, and in the -majority of instances they were found to have escaped entirely the -damaging effect of the virus. Their response in an over-secretion of -mucus may be the outcome of a stimulation by toxins or soluble -irritants; but on the other hand, may also probably be a reflex response -to the injury of the mucosal surface, which being bared of its covering -is highly sensitive. The increased discharge of mucus from the deep -glands may well be a protective response to such injury. - - - _Bronchi_ - -The lesions in the bronchi were in every way comparable to those in the -trachea. The main bronchial tubes differ in no material way from the -structure of the trachea, and the extension of the inflammatory process -from above downwards leads to a reaction in their walls similar to what -has been above described. As we follow the subdivisions of the bronchi -we gradually lose some of the characteristics contained in the larger -tubes. The mucous glands gradually become fewer and eventually -disappear. The cartilage rings become smaller and no longer completely -encircle the bronchus, and with the further diminution in the size of -these structures disappear entirely. A relatively greater amount of -muscle tissues takes the place of the cartilage rings. This change in -the anatomy of these structures has a certain influence in modifying the -character and distribution of the inflammation. - - - TABLE V - - BRONCHITIS AND TRACHEITIS - - ═════════════════════════════════════ - Acute bronchitis and tracheitis 26 - Subacute bronchitis and tracheitis 1 - Acute mucopurulent tracheitis 5 - Acute purulent bronchitis 2 - Acute mucopurulent bronchitis 7 - Ulcers of trachea 1 - Acute bronchiectasis 1 - ───────────────────────────────────── - -Thus whereas we have indicated that the inflammation of the trachea and -of the large bronchi is of a peculiar kind and remains confined to the -tissue lying inwardly from the cartilage rings, we found that where -these structures give place to a loose muscle tissue with a more -extensive lymphatic drainage the zone of inflammation is not so limited, -but proceeds outwardly into the neighboring tissues. We often use the -terms bronchus and bronchioles very freely without clearly -distinguishing any real difference. In a study of the inflammatory -reactions of the respiratory tubes in epidemic influenza (as well as in -other infections) it is best to accept the anatomical definition that -the bronchioles not only represent the minute tubules passing to the -alveoli, but also those small air passages which devoid of cartilage, -mucous glands and heavy connective tissue stroma are in close relation -to the parenchymatous tissues of the lung. These soft muscular tubes -possess blood and lymphatic vessels which freely communicate with the -blood vessels of the lung alveoli. It is in association with these -distant tubes that concomitant inflammatory reactions are found in the -alveoli and in the bronchial tubes. - -Desquamation of the epithelial lining is to be found in every size of -bronchial tube where the infection has caused an acute inflammatory -reaction. Throughout the pulmonary tissues where the lung is found in -some stage of influenzal pneumonia the bronchial tubes, both large and -small, are either entirely denuded of the mucosa or show only remnants -attached to irregular areas. In the smaller passages dense clusters of -desquamated cells are sometimes found within the lumen and indicate the -accumulation of a desquamated epithelium obtained from portions of the -tubular system in deeper portions of the lung. In the early stages, this -desquamation is accompanied by a serous exudate and a certain amount of -hemorrhage. Later we find masses of leucocytes which fill up the tube, -and though appearing to arise from these structures have in fact largely -come from the lung alveoli. Like the larger bronchial tubes the distant -ramifications show relatively little cellular reaction in their walls in -the early period. It is only when the neighboring lung tissues are -extensively implicated in a purulent inflammation that we find a similar -exudate occupying the tissues of the bronchioles. Polymorphonuclear -leucocytes are equally distributed through the region of the basement -membrane, submucosa, muscular coat and outer connective tissue layer. -Some grades of degeneration may occupy the inner surface wherein the -basement membrane first shows a homogeneous swelling and later a -granular degeneration. In a few instances where the small bronchioles -have communicated with regions with abscess formation an ulcerating -surface occupied the inner boundary. - -The evidence in the smaller bronchial tubes, both those with cartilage -and those without, that an inflammatory reaction of some degree may -occupy the muscular coat is of importance. We have found reactions of -inflammation in the muscular coat varying from a mild œdema and cellular -exudate to an intense polymorphonuclear leucocyte involvement. In the -latter the muscle fibers showed evidence of degenerative change and -suggested an acute weakening of this layer. We lay particular importance -upon this finding as indicating a causative factor in the development of -acute bronchiectasis as was met with in one of our cases. In this -particular instance the bronchi passing to the lower lobes of each lung -were unusually dilated and could be followed, in the gross, to their -distant extremities. The dilatation was more or less uniform and no -large pouches or cavities had developed. A mucopurulent exudate was -found occupying these dilated tubes. Others have likewise observed the -development of acute bronchiectasis under these conditions. Goodpasture -and Burnett found that as early as the second to the fourth day one of -the striking appearances was the gaping dilated condition of the -infundibula, and the tendency to dilatation of the air passages was -manifested in a bronchiectasis in 4 out of 30 cases. Boggs as well as -Lord have reported upon chronic bronchiectasis associated with the B. -influenzæ and there appeared to be evidence that a certain percentage of -cases recovering from influenza permanently develop irregular -dilatations of the bronchial tubes. - -The recognition of inflamed bronchi or bronchioles was never difficult. -In the gross the presence of the abnormal exudate and the intense -injection of the mucosal surfaces always attracted attention to the -inflammatory state. Furthermore where the mucosa had been desquamated -the surface of these tubes was found to be quite granular if closely -observed. With moderate magnification by means of a hand lens the -granular appearance was shown to be due to the engorged vessels. Much -easier, of course, was the recognition of the inflammatory reaction by -the microscope. The importance, however, of the bronchitis and -bronchiolitis lay in the amount of involvement which had occurred in the -neighboring tissues. As we, however, indicated elsewhere, we do not -doubt that many of the cases of three-day fever have a state of -tracheitis and bronchitis equal to that which we have observed in many -of our cases. Whether the inflammatory reaction progressed beyond the -firmer bronchial tubes to the softer and more vascular structures would -be difficult to say where our evidence rests upon the clinical findings -alone. It is, however, probable that a certain number of the severe and -sharp attacks of influenza not only cause a tracheitis and bronchitis of -the larger tubes, but also extend more deeply into the smaller -ramifications tending to simulate the reactions which we have above -described. When we ask ourselves, however, how distantly must the -infection invade the smaller bronchial tubes before involving the -parenchymatous tissues of the lung we are at a loss to enunciate a -general rule. It is more than probable that there are modifying -influences which determine whether the bronchitis with a certain amount -of its bronchiolitis will progress to a true pneumonia or will remain -localized to these tubular systems. I can well appreciate that in the -event that a bronchitis has an inflammatory reaction accompanied by much -serous exudate there is great danger of flooding the neighboring alveoli -with this inflammatory fluid and of carrying the large numbers of the -micro-organisms within the tubes to the air sacs of the lung. Under -these conditions the virus has an unusual ability to develop the disease -from one localized in the air passages to that of a true pneumonia. It -is probable that the peculiar early acute reaction which is present in -the air passages in epidemic influenza is responsible for the extensive -involvement of the lung in the severe and dangerous form of -inflammation. - - - TABLE VI. - - EXTENT AND DISTRIBUTION OF PNEUMONIA. - - ═══════╤════╤════════════════════════════╤════════════╤══════════════════════ - AUTOPSY│AGE.│ RIGHT LUNG. │ TYPE OF │ LEFT LUNG. - NUMBER.│ │ │ LESION. │ - ───────┼────┼──────┬─────────────────────┼────────────┼────────┬───────────── - │ │WEIGHT│INVOLVEMENT OF LOBES.│ │ WEIGHT │ INVOLVEMENT - │ │ OF │ │ │OF LUNG.│ OF LOBES. - │ │LUNG. │ │ │ │ - ───────┼────┼──────┼──────┬───────┬──────┼────────────┼────────┼──────┬────── - │ │ │UPPER.│MIDDLE.│LOWER.│ │ │UPPER.│LOWER. - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 741│ 18│720 G.│ + │ + │ ++ │Lobar S. & │ 850 G.│ + │ ++ - │ │ │ │ │ │ H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 743│ 20│825 G.│ + │ + │ + │Lobular S. &│ 1375 G.│ +++ │ +++ - │ │ │ │ │ │ H. │ │ │ - │ │ │ │ │ │ │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 744│ 30│900 G.│ + │ – │ ++ │Lobar and │ 900 G.│ ++ │ ++ - │ │ │ │ │ │ Lobular S.│ │ │ - │ │ │ │ │ │ & H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 745│ 18│575 G.│ + │ – │ ++ │Lobular S. &│ 480 G.│ – │ ++ - │ │ │ │ │ │ H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 746│ 21│900 G.│ + │ ++ │ +++ │Lobar S. & │ 650 G.│ + │ +++ - │ │ │ │ │ │ H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 747│ 27│ 1510│ +++ │ ++ │ +++ │Lobar S. & │ 1000 G.│ +++ │ +++ - │ │ G.│ │ │ │ H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 748│ 22│900 G.│ + │ + │ +++ │Lobar and │ 1250 G.│ + │ +++ - │ │ │ │ │ │ Lobular S.│ │ │ - │ │ │ │ │ │ & H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 749│ 23│ 1480│ ++ │ ++ │ +++ │Lobar S. & │ 1250 G.│ ++ │ +++ - │ │ G.│ │ │ │ H. Slight │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 750│ 24│ 1200│ +++ │ + │ +++ │Lobar and │ 825 G.│ + │ +++ - │ │ G.│ │ │ │ Lobular. │ │ │ - │ │ │ │ │ │ Early │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 751│ 22│ 1250│ – │ – │ +++ │Lobar │ 610 G.│ ± │ ± - │ │ G.│ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 752│ 27│ 1125│ +++ │ + │ +++ │Lobar S. & │ 775 G.│ ± │ +++ - │ │ G.│ │ │ │ H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 756│ 22│ 1000│ ++ │ ++ │ ++ │Lobar S. & │ 820 G.│ +++ │ ++ - │ │ G.│ │ │ │ H. Slight │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 757│ 21│815 G.│ ++ │ – │ ++ │Lobular S. &│ 1075 G.│ +++ │ +++ - │ │ │ │ │ │ H. │ │ │ - │ │ │ │ │ │ │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 758│ 22│ 1150│ +++ │ + │ + │Lobar │ 1400 G.│ +++ │ +++ - │ │ G.│ │ │ │ Purulent │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 761│ 21│ 1250│ +++ │ ++ │ +++ │Lobar S. & │ 550 G.│ + │ + - │ │ G.│ │ │ │ H. and │ │ │ - │ │ │ │ │ │ Lobular │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 762│ 21│680 G.│ + │ + │ + │Lobular S. &│ 750 G.│ + │ +++ - │ │ │ │ │ │ H. │ │ │ - │ │ │ │ │ │ │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 763│ 22│920 G.│ + │ – │ + │B. P. and │ 540 G.│ – │ + - │ │ │ │ │ │ Lobar S. &│ │ │ - │ │ │ │ │ │ H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 764│ 23│725 G.│ – │ + │ + │Lobular S. &│ 550 G.│ + │ + - │ │ │ │ │ │ H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 765│ 25│ 1100│ ++ │ – │ ++ │Lobar S. & │ 1400 G.│ – │ +++ - │ │ G.│ │ │ │ H. │ │ │ - │ │ │ │ │ │ │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 767│ 25│ 1075│ + │ +++ │ +++ │Lobar and │ 850 G.│ – │ ++ - │ │ G.│ │ │ │ Lobular S.│ │ │ - │ │ │ │ │ │ & H. and │ │ │ - │ │ │ │ │ │ Lobular │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 770│ 21│900 G.│ ++ │ ++ │ ++ │Lobar S. & │ 750 G.│ ++ │ ++ - │ │ │ │ │ │ H. and │ │ │ - │ │ │ │ │ │ Lobular │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 773│ 22│ 2050│ +++ │ ++ │ +++ │Lobar S. & │ 780 G.│ – │ +++ - │ │ G.│ │ │ │ H. and │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 778│ 22│ 1100│ ++ │ + │ ++ │Interstitial│ 975 G.│ ++ │ ++ - │ │ G.│ │ │ │ Pneumonia.│ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 781│ 21│ 1000│ +++ │ ++ │ +++ │Lobar S. & │ 540 G.│ + │ +++ - │ │ G.│ │ │ │ H. │ │ │ - │ │ │ │ │ │ │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 782│ 18│650 G.│ + │ – │ ++ │Lobular S. &│ 875 G.│ ++ │ +++ - │ │ │ │ │ │ H. Slight │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 783│ 21│ 1250│ +++ │ +++ │ +++ │Lobar S. & │ 580 G.│ + │ ++ - │ │ G.│ │ │ │ H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 784│ 21│ 1590│ +++ │ +++ │ +++ │Lobar │ 1400 G.│ +++ │ +++ - │ │ G.│ │ │ │ Purulent. │ │ │ - │ │ │ │ │ │ │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 786│ 20│ 1100│ ++ │ +++ │ +++ │Lobar S. & │ 700 G.│ – │ ++ - │ │ G.│ │ │ │ H. Slight │ │ │ - │ │ │ │ │ │ Lobular │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 787│ 21│750 G.│ ++ │ – │ ++ │Lobular S. &│ 1125 G.│ +++ │ +++ - │ │ │ │ │ │ H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 791│ 21│775 G.│ + │ ++ │ ++ │Lobular S. &│ 1050 G.│ ++ │ +++ - │ │ │ │ │ │ H. and │ │ │ - │ │ │ │ │ │ Purulent. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 792│ 21│ 1050│ + │ + │ +++ │Lobar and │ 950 G.│ + │ ++ - │ │ G.│ │ │ │ Lobular S.│ │ │ - │ │ │ │ │ │ & H. │ │ │ - ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼────── - 793│ 18│500 G.│ – │ – │ + │Slight │ 435 G.│ - │ + - │ │ │ │ │ │ Lobular S.│ │ │ - │ │ │ │ │ │ & H. │ │ │ - ───────┴────┴──────┴──────┴───────┴──────┴────────────┴────────┴──────┴────── - - ═══════╤════════════╤════════════╤════════════╤══════════ - AUTOPSY│ TYPE OF │ PLEURA. │ ABSCESS OF │ DAY OF - NUMBER.│ LESION. │ │ LUNG. │ DISEASE. - ───────┼────────────┼──────┬─────┼────────────┼────────── - │ │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - │ │RIGHT.│LEFT.│ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 741│Lobar S. & │S.F. │S.F. │ │ 3d. - │ H. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 743│Lobar S. & │F. │S.F. │ │ 5th - │ H. Early │ │ │ │ - │ P. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 744│Lobar S. & │S.F. │S.F. │ │ 7th - │ H. │ │ │ │ - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 745│B.P. with │S.F. │– │ + │ 10th - │ Necrosis. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 746│Lobar S. & │– │– │ │ 5th - │ H. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 747│Lobar S. & │S.F. │– │ │ 6th - │ H. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 748│Lobar S. & │– │– │ │ 4th - │ H. and │ │ │ │ - │ B.P. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 749│Lobar S. & │F. │– │ │ 4th - │ H. Slight │ │ │ │ - │ P. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 750│Lobar and │F. │F. │ │ 9th - │ Lobular. │ │ │ │ - │ Early P. │ │ │ │ - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 751│B.P. slight.│S.F. │– │ │ 7th - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 752│B.P. and │F. │S.F. │ │ 13th - │ Lobar P. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 756│Lobar and │F. │S.F. │ │ 8th - │ Lobular S.│ │ │ │ - │ & H. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 757│Lobar S. & │F. │F. │ │ 6th - │ H. and │ │ │ │ - │ Purulent. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 758│Lobar │F. │F. │ │ 14th - │ Purulent. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 761│Lobular S. &│– │– │ │ 7th - │ H. │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 762│Lobar S. & │S.F. │S.F. │ │ 10th - │ H. and │ │ │ │ - │ Lobular P.│ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 763│B.P. │F.P. │– │ │ 11th - │ │ │ │ │ - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 764│B.P. │– │– │ │ 9th - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 765│Lobar S. & │– │– │ │ 9th - │ H. and │ │ │ │ - │ Early P. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 767│Lobar S. & │– │F. │ │ 10th - │ H. Lobular│ │ │ │ - │ P. │ │ │ │ - │ │ │ │ │ - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 770│Lobar S. & │S.F. │F. │ + │ 11th - │ H. Lobular│ │ │ │ - │ P. │ │ │ │ - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 773│Lobar S. & │F. │F. │ │ 20th - │ H. Lobular│ │ │ │recurrence - │ P. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 778│Interstitial│S.F. │S.F. │ │ 23d - │ Pneumonia.│ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 781│Lobar S. & │S.F. │S.F. │ + │ 5th - │ H. │ │ │ │ - │ Purulent. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 782│Lobar S. & │F. │F. │ │ 8th - │ H. and │ │ │ │ - │ Early P. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 783│Lobar S. & │S.F. │S.F. │ │ 8th - │ H. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 784│Lobar S. & │S.F. │S.F. │ │ 8th - │ H. and │ │ │ │ - │ Purulent. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 786│Lobar S. & │S.F. │– │ │ 4th - │ H. and │ │ │ │ - │ Early P. │ │ │ │ - │ │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 787│Lobar S. & │S.F. │S.F. │ │ 8th - │ H. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 791│Lobar S. & │F. │S.F. │ │ 6th - │ H. and │ │ │ │ - │ Slight P. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 792│Lobar and │S.F. │S.F. │ │ 6th - │ Lobular S.│ │ │ │ - │ & H. │ │ │ │ - ───────┼────────────┼──────┼─────┼────────────┼────────── - 793│Slight │– │F. │ Strep. │ 10th - │ Lobular │ │ │Bacteriemia.│ - │ Purulent. │ │ │ │ - ───────┴────────────┴──────┴─────┴────────────┴────────── - - S—Serous. H—Hemorrhagic. P—Purulent. B.P.—Broncho-pneumonia. - S.F.—Serofibrinous. F.—Fibrinous. F.P.—Fibrinopurulent. - -It was very evident that the smaller bronchi and bronchioles were much -more readily involved in a severe inflammatory reaction than the larger -tubes. A purulent inflammation was not uncommonly found in the -bronchioles of the lung when a pneumonic state with leucocytic -infiltration was present. Even where such purulent infiltration of the -walls of the bronchioles was readily demonstrable the trachea and main -bronchi were devoid of this intense reaction. These purulent -inflammations were not uniformly distributed in the bronchioles of the -lung, but only occurred in those regions where the parenchymatous -tissues were in themselves involved in a purulent reaction. It was -difficult to find the evidence whether the purulent bronchitis preceded -or followed the presence of a purulent pneumonia. The intimacy of the -lung tissues with those of the small bronchioles makes it impossible for -one or other of these structures to escape when one of them is -implicated in a purulent reaction. It is equally important to appreciate -that to a considerable extent the lung tissue surrounding the small -bronchioles becomes involved by a direct radial extension through the -walls of the thin respiratory tubes. Such extension laterally is -assisted by the free lymphatic communication lying about the bronchioles -and stretching into the lung parenchyma. Purulent processes of the small -air tubes always showed a similar reaction in the interstitial tissues -of the neighboring air sacs. - -Our material did not permit of following the bronchial reactions to -their conclusion. In some instances we have found that where abscesses -developed within the lung the contiguous bronchi and bronchioles either -became eroded or suffered intense suppurative inflammatory lesions on -their inner surface. The manner in which repair of the more common -inflammatory processes of the bronchi is accomplished could not be -demonstrated in the cases dying during the acute stage. In one case an -organizing bronchitis was associated with an organizing lobular -pneumonia. In this instance the connective tissues were proliferating -freely from the inner wall of the bronchi, there being no evidence of a -basement membrane at the point where the connective tissue was growing. -The development of the connective tissue appeared to be spontaneous and -was not taking place within an unresolved fibrinous exudate. In as much -as the fibrosing process was largely scattered through all of the lobes, -the numerical involvement of the respiratory tubes was quite great. In -this instance the amount of obstruction which was imposed upon the -respiratory tissues by the fibrosing pneumonia and bronchitis was -sufficient to cause considerable distress and dyspnœa during the last -few days of the patient’s life. The amount of dyspnœa was out of -proportion to the clinical manifestations of pulmonary involvement, and -from a clinical point of view it was difficult to arrive at a conclusion -of the nature of the lung lesion. - -Undoubtedly during the subsidence of the inflammatory process within the -bronchi the gradual restitution of the tissues with little or no -fibrosis is accompanied by a reproduction of the lining membrane arising -from the epithelial remnants in the small mucous crypts. In a few cases -lately coming to autopsy where the patients had suffered an influenza -five or six weeks previously, the mucosa of the trachea and bronchi had -assumed its normal appearance and was fully clothed by a normal -epithelial covering. - - - _Lung—Early Stage_ - -We have just discussed the importance of the inflammation of the trachea -and bronchi in the cases of influenza. It is our belief that every case -of influenza has some tracheitis, and a great many have both tracheitis -and bronchitis. This is true in the absence of localizing signs and -symptoms, as was evident even in these cases in which the simple -influenza passed into its more severe type with its pulmonary lesions. -In many of these instances clinical evidences of an inflammatory -reaction in the respiratory tubes were wanting, while the reactions -observed at autopsy were often astounding. - -Just as we feel that simple influenza and inflammation of the -respiratory tubes go hand in hand, or better that these respiratory -localizations are the all-important ones in every case of simple -influenza, so, too, we are of the belief that the pulmonary lesions bear -the same relation to all cases of severe and fatal epidemic influenza. -We hold that no case comes to his death through acute epidemic influenza -without having a lesion in the lung. The pulmonary condition, therefore, -is of first importance and its analysis is imperative for a proper -understanding of this disease. There has been divided opinion as to the -part played by the pulmonary lesion in epidemic influenza, some holding -that it is to be looked upon as a part of the disease and others that it -must be viewed as a complicating lesion. Complications of various kinds -are very common, and there are a number of conditions arising in the -lung (abscess, gangrene, necrosis) which must be viewed as -complications. There is, however, a type of pneumonia, and here I use -the term in its broad sense, which is not in truth a complication but -merely a wider extent of involvement of the respiratory tract by the -same virus which is always present to cause lesions in the respiratory -tubes. The reaction within the lungs is distinctive and differs from the -pneumonias which are met with under other conditions and with various -bacterial agencies. Nor are our findings in this matter unique for this -epidemic. They have been described and discussed in the past. True it is -that, like in the epidemic which has just passed us, the incidence of -clinical and pathological pneumonia varied quite widely in different -communities, so, too, the reports of past epidemics do not give a -uniform description of a pulmonary lesion. Where, however, the analysis -has been made during the four weeks’ period of the acute epidemic and -where the descriptions have been recorded by painstaking observers, the -similarity with our present findings is very striking. I would refer in -particular to one report made in 1893 in Petrograd by Kuskow. His report -deals with 40 carefully studied cases in which records both macroscopic -and microscopic were accurately made. - -One of the great difficulties in placing an accurate interpretation upon -the pulmonary findings lies in the fact that true pneumonia as seen in -epidemic influenza in man has not been reproduced in animals. -Furthermore, as the majority of the fatal human cases of epidemic -influenza with their associated pneumonias present a mixed infection of -the lung tissues, it is difficult, if not impossible, to indicate the -lesions which have resulted through the activity of one of these as -against those induced by the other bacteria present. In our own -carefully studied cases wherein bacteriological cultures were taken from -every lung there was not a single instance in which the influenza -bacillus was present in pure culture. This is more fully commented upon -in the studies by Dr. Holman, but the point we wish to make here is the -difficulty in arriving at a conclusion in our material as to the actual -effects induced by any one type of organism. As it is fully discussed by -Dr. Holman we are convinced of the importance of the influenza bacillus -in this epidemic. We also appreciate that pneumonia lesions in animals -have been induced by a variety of materials gained from influenza -patients, but yet in view of the abnormal manner of producing such -lesions these are hardly comparable to those in man. We may well expect -severe œdema, inflammation and hemorrhage, if in guinea pigs, rabbits -and monkeys we introduce by intra-tracheal insufflation large quantities -of fluid suspensions of bacteria. And thus we find positive results -obtained by the use of a filtrable virus, streptococci, influenza -bacilli and other organisms. The lung is a sensitive tissue which quite -readily responds to a variety of irritants. In many respects some of -these lesions simulate those in influenza, but still we are far from the -conclusion that the disease, influenza, with all its manifestations has -been actually reproduced. - -The pathology of the pulmonary lesions in acute epidemic influenza is so -distinctive that except for the late purulent stage which may resemble -types of reinfected and unresolved pneumonia the condition cannot be -confused with the stages of frank lobar pneumonia. We appreciate that -this is a very positive statement, and that opposition will be taken by -those who resting their opinion upon individual factors may claim that a -clear distinction from other forms of pneumonia is not available. We, -however, base our opinion not upon a single feature, but upon the -combined pathological complex observed in many individual cases. These -features are mainly those seen in the type of the lesion, the character -of the distribution, extent of involvement and the multiple stages so -commonly present at one time in different portions of the lung. The type -lesion that has become so well known in pneumococcus lobar pneumonia has -its distinctive stages which for teaching purposes are divided into the -stage of (1) congestion, (2) red hepatization, (3) gray hepatization and -(4) resolution. In dealing with lobar pneumonia from the standpoint of -illustrating these stages the majority of teachers annually confess -their inability to present for the student’s study the stage of -congestion. The student is impressed that the congestive stage of lobar -pneumonia is very transient and rapidly passes into the stage of red -hepatization. Patients do not die with pneumococcus pneumonia in the -stage of congestion. And this is also largely true of the stage of red -hepatization, which is but rarely seen at the autopsy table. This -community (Pittsburgh) gives its large quota to the mortality statistics -of pneumococcus pneumonia, but it is most unusual to meet with a -specimen of red hepatization except for the borders of the advancing -gray area. And, furthermore, red hepatization even when found in the -unusual cases shows remarkably little of this character when seen under -the microscope. True it is that a certain number of red blood cells will -be found in the alveoli and a certain degree of congestion will occupy -the alveolar walls, but its extent is far less than what we may have -hoped to demonstrate to others. So that broadly speaking the intensely -congested lung with or without red hepatization is unusual in our frank -lobar pneumonia. This was quite the reverse in our cases of acute -epidemic influenza-pneumonia. Furthermore lobar pneumonia in the great -majority of instances illustrates a distribution distinctive for the -name. Massive lobar, or pneumococcus pneumonia is found to occupy one or -more lobes or parts of lobes. The involved lobe is fairly uniform in the -stage of the inflammatory process. If it is in the early gray stage, -this will be seen with equal intensity in the different areas of the -lobe. Patches of pneumonia in different stages within the same lobe are -not to be found, while this finding is not uncommon in the pneumonias of -acute epidemic influenza. And lastly, the frequency with which an -inflammatory œdema occupied the lungs in the cases of influenza was in -quite striking contrast with the dry fibrinous lesion of common -pneumonia. This wet state of the lung was but a stage in the -inflammatory process varying in its extent in the different periods, but -nevertheless inducing a character in the early pulmonary lesions which -was quite foreign to our usual finding. This wet state also assisted in -modifying the subsequent picture so that when the lung assumed its gray -appearance it was rather of a slimy character than of the firm dry -nature. In this late gray stage the slimy lung somewhat resembled the -appearance of unresolved pneumonia where this condition had been brought -about by a new infection upon the original cause of the pneumonia. - -It is incorrect in influenza pneumonia to speak of the lesions as lobar -pneumonia or broncho-pneumonia if by these terms we have in mind the -pathological characters observed in the pneumococcic pneumonia with its -lobar or bronchial distribution. Influenza-pneumonia appeared with both -lobar and lobular characteristics. Nearly every case had both types of -lesions present, but the nature of the inflammatory process is so -decidedly different from that of the ordinary endemic pneumonia that a -confusion in the interpretation is likely to arise and in fact has -already raised a considerable polemic. Influenza-pneumonia is commonly -lobar, lobular or bronchial in distribution. It is, however, not of the -characters that are associated with the lesions designated under these -terms. When, therefore, we here use the word “lobar” we mean lobar _in -distribution_ but not lobar in type. As will be seen from our table, it -was usual to have multiple lobes involved. But the lesions, not only in -the different lobes varied in their character and distribution, but even -within the same lobe a variety of types was present. - - - TABLE VII - - ═══════════════════════════════════════════════╤═══════════════════════ - Day of Pneumonia on Which Death Occurred │ No. of Cases - ───────────────────────────────────────────────┼─────────────────────── - Second │ 2 - Third │ 4 - Fourth │ 7 - Fifth │ 6 - Sixth │ 7 - Seventh │ 3 - Eighth │ 1 - Tenth │ 1 - Twentieth │ 1 - ───────────────────────────────────────────────┴─────────────────────── - -To a certain degree we were able to analyze the types of the lesions as -they occurred in the different stages and progress of the pulmonary -inflammation. Briefly, these were as follows: the earliest stage of -congestion following rapidly upon the infection from the bronchi was -followed by (1) inflammatory œdema, (2) hemorrhage, (3) cellular exudate -(a. mononuclear cells, b. leucocytes, c. interstitial infiltration) and -(4) resolution or organization, abscess, infarct and gangrene. The -majority of our cases died during the stages of congestion, hemorrhage -or early purulent infiltration. In the early stages the amount of fibrin -was small or entirely absent, later, with the appearance of leucocytes, -some fibrin was present. - -For the estimation of the time elapsing between the onset of the -pneumonia and death we are dependent upon the clinician. This is often -quite difficult to do, in as much as with a primary respiratory disease, -such as epidemic influenza represents, it is very difficult to determine -the time when there is a transition from the inflammatory process of the -upper respiratory tubes to that of the pulmonary tissue. In many of the -cases where from the onset there was intense prostration and every -evidence of marked intoxication the clinical manifestations of localized -processes taking place in the respiratory system were very much in the -background and often of insidious progress. In four of our cases it -appeared as if the pulmonary manifestations had made their appearance -with the first sudden and severe onset of the influenza. On the other -hand, also, the clinical signs and symptoms of lung involvement were -different from those of frank lobar pneumonia. We would, from our -experience at the autopsy table, say that where in the cases of epidemic -pneumonia there are present the signs of pulmonary consolidation like -those of true lobar pneumonia, that there has been an antecedent period -of a pulmonary lesion which passed unrecognized by the clinician. To -more clearly state the case, whereas in lobar pneumonia the stage of -congestion preceding the stage of red hepatization gives rise to no -signs whereby the clinician can indicate the time of its onset or -determine the time when it has passed into the succeeding stage, and -moreover, the stage of congestion is of short duration to be measured in -a period of a few hours, this stage in epidemic influenza though equally -indefinite in its clinical manifestations is much prolonged, lasting not -only a period of hours but even a period of several days. It is this -pulmonary state which is difficult or even impossible to recognize in -the living. All gradations of it occur and the clinician can only -broadly suggest from all the evidence at hand, the period when -inflammation with definite exudate began in the lung. In as much as the -total length of illness of a number of cases was only three, four and -five days, whereas there was nothing at the onset to suggest pulmonary -involvement, we can estimate approximately, at least, the duration of -the lung condition. This makes it possible to give a relative estimate -of the character of the lesions present at different periods of time. -The outstanding finding, as we will discuss again, was that a distinct -and peculiar pulmonary reaction was primarily imposed upon the lung, -which made its appearance at periods different from those of frank lobar -pneumonia. - -We were repeatedly surprised at finding death to have occurred during -the stage of acute congestion with some hemorrhage and inflammatory -œdema of lung and in the absence of any sign of grey hepatization or -purulent infiltration. In many of these cases the involved areas of lung -though heavy and œdematous, were still partly air-containing and the -amount of lung involvement was insufficient, on the basis of mechanical -interference, in accounting for the severity of the clinical symptoms -and the fatal outcome. This must have impressed everyone dealing with -the autopsies during the acute epidemic. It immediately suggests that in -some cases at least the pulmonary lesion, in as far as incapacitating -the external respiratory system, was not the sole or even the important -cause of death, but that a condition of intoxication, borne out by the -evidence of damage in muscles, blood and kidney is a large factor of -danger in this disease. - -We shall briefly describe the important pulmonary findings as we have -met with them in the successive stages of influenza-pneumonia. This, we -hope, will make clear the interpretation of the pathology of the lung -lesion of the epidemic as it came under our observation. - -The earliest pulmonary lesion which we encountered was one of -congestion, inflammatory œdema and hemorrhage. These three conditions -were usually present at the same time and were found in the height of -intensity in all of the cases dying within the first four days of -illness. During this early period these manifestations of inflammation -were not accompanied by definite red or grey hepatization as might -ordinarily be expected. The lesions varied greatly in their intensity, -the œdema always being very prominent, while the hemorrhage varied from -a diffuse infiltration of the involved lobe or added to this, was -localized in massive collections four or five cm. in diameter and -commonly occupying the central portions of the lobes. We have seen -several hemorrhages lying in close proximity to each other with their -borders coalescing and leading to a larger central involvement. In the -regions where the hemorrhage and inflammatory œdema were diffuse, air -was still present within the lung tissue, sometimes to an extent -permitting the lung tissue to float on water but more often in quantity -sufficient only to suspend the tissue at various depths. On pressure the -fine air bubbles were recognized amidst the blood-stained fluid. Acute -compensatory emphysema often occupied the anterior borders of the lobes -or formed interstitial blebs beneath the pleura. The quantity of fluid, -inflammatory œdema and hemorrhage, contained within these bulky lobes -was often very surprising. A lobe when compressed would leak fluid with -the ease that it could be obtained from a sponge. Out of the lower lobe -on one occasion we pressed 700 c.c. of limpid blood-stained exudate. The -acute emphysema which may make its appearance suddenly, is - - - TABLE VIII - - DISTRIBUTION OF PNEUMONIC LESIONS AND GRADES OF SEVERITY - - ═════════════════════════════════════ - DEGREE OF INVOLVEMENT + ++ +++ Total - Left upper lobe 10 6 7 23 - Left lower lobe 4 10 17 31 - Right upper lobe 12 8 9 29 - Right middle lobe 10 9 4 23 - Right lower lobe 5 9 18 3 - ───────────────────────────────────── - - All lobes were simultaneously - involved in some grade of pneumonia - in 18 cases—56 per cent. - -at times quite remarkable. It may appear very early in disease. We have -not met with a single case where the emphysema of the lung led to a -rupture of the air sacs and an interstitial infiltration of air through -lung, mediastinum, neck and subcutaneous tissues. Some very remarkable -cases are reported by different authors where this emphysema was of -astounding grade leading to a crepitating infiltration throughout the -mediastinum, neck and the subcutaneous tissues over the thorax and -abdomen as low as the pubis. The milder grade of emphysema consisted -mainly of an abnormal expansion of the air sacs which were not -infiltrated by exudate and which probably had some effect in preventing -the diffusion of the inflammatory fluid from entering certain regions. -These emphysematous areas could be readily recognized by the naked eye -along the anterior borders of the lung as well as between the involved -pneumonic patches within the lung. - -These lungs, involved in this early serous and hemorrhagic exudate -varied considerably in their appearance according to the regional and -quantitative involvement. As is seen from Table viii, the lower lobes -were more commonly occupied by massive exudate than the upper, and the -involvement of multiple lobes was the usual. Still more remarkable is -the fact that all lobes were simultaneously involved in some grade of -reaction (pneumonia) in 56 per cent. of cases. In complicated -influenza-pneumonia Goodpasture and Burnett found the inflammatory -reaction in both lungs and involving to a greater or less degree the -lobes on each side. Most commonly this involvement consisted of a lobar -distribution in one or two lobes with a lobular or patchy disposition of -exudate in one or more of the remaining lobes. Where the distribution -was lobar the involved lobe was distended to its fullest and the pleura -tightly stretched over the lung tissue which, heavy with fluid, was not -solid but flabby. The lung could be moulded under the finger and could -be compressed into various shapes. At first sight this flabby, heavy -lung tissue suggested the appearance of the waterlogged lung which one -encounters in renal disease or failing circulation. A closer analysis, -and particularly when the lung was sliced, showed an entirely different -character. - -Where the inflammatory œdema was accompanied by much focal hemorrhage -the distribution was nodular and suggested the appearance of the -hemorrhagic lung of plague pneumonia. It was this appearance which led -to the suggestion that the pandemic was not one of influenza but -possibly of an infection related to the eastern plague. The nodular -masses of hemorrhage at times occupied areas varying from the size of a -walnut to that of a golf ball and were localized amidst a relatively -mildly involved lung tissue making a sharp contrast between the involved -and relatively normal tissue. With the removal of the lung from the body -and the partial collapse of the aerated tissues these nodules became -still more prominent. The greater the amount of hemorrhage within these -areas the more solid became the occupied tissue. Such sporadic -distribution of hemorrhagic lesions occurred in the two most intense and -rapidly fatal cases. Both of these individuals died within 48 hours of -the time of onset of the lung conditions. In these two cases we do not -believe that the pulmonary lesions had been prolonged over a time even -as long as 36 hours but with the difficulty of estimating the onset of -the lung involvement we are giving a liberal estimate of this time. - -Besides meeting with the stages of congestion, œdema and hemorrhage -during the earliest days of the pulmonary lesions we have found that -they are to be encountered virtually through all the stages of the fatal -cases either as remnants of the original reactions which had not been -entirely obliterated by the succeeding purulent process or as was so -commonly found, new reactions occurred in other regions of the lung so -that, in the same individual, inflammatory reactions of different stages -of development could be defined. I do not recollect a single autopsy of -a case dying during the acute period which did not show evidence of some -areas in the stages of this early acute reaction. Naturally where -resolution is well advanced within the lung all trace of inflammatory -exudate of various kinds is removed and where such individuals with -their resolved pneumonia are brought to death through succeeding -complications the above finding will not be borne out. We limit, -however, our statement to the findings in the acute deaths. - -We have previously intimated that the œdema present in the early stages -of the reaction is to be looked upon as an inflammatory œdema or better -as a true serous exudate, and must not be confused with the transudation -of fluids in non-inflammatory conditions. We have on several occasions -collected the fluid expressed from the soggy lungs and have made some -determinations of their chemical qualities. The difficulty immediately -arises in separating the materials arising from cellular degeneration -from the natural constituents of the serous exudate. We were unable to -obtain specimens in which laked blood was not present, so that even -though the cellular constituents and fibrin were removed, decomposition -products could not be separated. The analyses, however, gave a -differentiation from the transudate seen in renal and cardiac -conditions. - -During the period of the accumulation of this inflammatory fluid the -clinician could often recognize a profuse watery exudate within the lung -or even observed an abundant serous discharge arising in bronchi and -trachea. At times the quantity of expectoration was great. Frothy serous -fluid accumulated in the air passages and would periodically be -expectorated. At other times the hemorrhage was of quite serious extent -and the patient would suddenly bring up several mouthfuls or more of -bright blood. This pulmonary hemorrhage was without manifestations -different from the acute illness with cyanosis of other individuals. The -two most acute cases, which we have referred to above, were of this -kind, both of them having marked hæmoptysis with the loss of upwards of -a pint of blood at a time. - -The early pulmonary lesion which we have described, we have called acute -serous pneumonia and acute hemorrhagic pneumonia (or we might speak of -it as an acute sero-hemorrhagic pneumonia) and is one which is -distinctive for epidemic influenza. The cut surface of a lobe involved -in this reaction is wet, glassy, meaty and oozes much blood-stained -fluid. It contains no visible fibrin and presents no characters of a -“cellular consolidation.” As a serous inflammation of the lung it is -unique. The further remarkable character to the pulmonary lesion is that -in advancing through the other stages, it never passes through a stage -of “red hepatization.” Here again we have a distinctive difference from -the pneumococcus-pneumonia. From what we have previously said about the -nature of this early acute inflammation of the lung in this disease it -is apparent that red hepatization has no place in its process. The stage -of red hepatization is attained only when the inflammatory reaction is -accompanied by certain constituents in the exudate, which upon -coagulation (separation out of the fibrin) renders the lobe dry and -solid, while there is a sufficient abundance of red blood cells and -congestion to maintain a dark red color. The hepatized lung on section -is dry, more or less granular, containing fibrin, red cells and -leucocytes within the alveoli. Extensive œdema is unusual except in the -cases of hypostatic pneumonia, which in well marked cases bears some -resemblance to the gross appearance of the early influenza pneumonia. We -have not encountered a single case of the red meaty lung of influenza -which showed evidence of true red hepatization in the gross. - -The _microscopical_ examination of the lung tissue confirmed the -observations which were made in the gross. In the early stages of -congestion the reaction was much more extensive than what could be -spoken of as a broncho-pneumonia. The capillary dilatation in the -alveolar walls occupied diffuse areas varying from multiple lobules and -areas several cm. in size to the common diffuse congestion of an entire -lobe. Capillaries were distended to their full capacity and often this -engorgement was associated with the leakage of blood or a serous fluid. -Not uncommonly a clear serous fluid was exuded into the interstitial -tissues of the alveolar wall and collected within the air sacs. The high -albuminous content of this fluid was seen in the homogeneous coagulation -which occurred when the tissues were placed in fixatives. The -microscopical sections of such parts demonstrated the coagulum occupying -the alveoli as a clear homogeneous substance containing relatively few -cells and looking not unlike the colloid deposit of the thyroid. The -alveolar walls, themselves, were infiltrated with fluid so that the -distended tissues and vessels made these structures thick and bulky. In -our own observations we were impressed by the differences of the early -inflammatory reaction from those ordinarily seen in pneumonia. Amongst -these differences was the quantity of fluid extruded into the lung with -a relative absence of fibrin. In some instances fibrin was completely -wanting, although small quantities could be demonstrated in isolated -areas. This observation upon the quantity of fibrin can be made only -during the early stage of the disease in as much as after secondary -infection of various kinds has become implanted the presence of fibrin -has become a variable quantity often exceeding that seen in the early -stages. This is one of the points upon which the older authors have laid -stress in differentiating influenza pneumonia from others. In this we -fully concur. Whether this lack of fibrin in the inflammatory exudate is -a characteristic to be associated with the infection by the B. influenzæ -alone is hard to say, but in as much as it was such a prominent finding -we are led to lay some stress upon it. It is, of course, to be realized, -as with all other micro-organisms that under certain conditions fibrin -will form an important part of the exudate even when the B. influenzæ is -present. This is true in the inflammatory reactions of the meninges -present in infections due to this bacillus. Under the conditions of -epidemic influenza where the lung lesion is the prominent and unique -reaction this micro-organism fails by itself to bring out this quality -in the exudate. - -Not uncommonly this stage of inflammatory œdema was accompanied by -various grades of hemorrhage, varying from the presence of small -aggregations of red cells to a complete flooding of the lung tissue -making it look not unlike a red infarct of lung, save that the alveolar -walls still showed an active circulation and living cells. It was -remarkable that even though there was such an intense reaction taking -place in the lung tissue there was little or no evidence of a cellular -exudate during this stage of the process. Where much blood was extruded -into the alveoli occasional fibrin threads were found in the coagulum. -In these early cases the bronchicles and small bronchi were found to -contain an exudate similar to that in the alveoli. Not uncommonly the -vessels from which the red blood was escaping, could be demonstrated in -sections. The appearance of the vascular wall suggested that a definite -opening had occurred in the side of the capillary from which the blood -escaped. We were not able to demonstrate a fatty or other type of -degeneration in the cells of the capillary walls. It is probable that -the process of injury was much too acute to permit of the demonstration -of the products of degeneration within the surviving cells. - -The hemorrhagic lesions which had existed for a longer period of time -gradually showed a varying infiltration by wandering cells. The earliest -cells not belonging to those of the hemorrhage or œdema appearing within -the alveoli were mononuclear elements partly arising from the alveolar -walls and partly coming from the circulation. Numerous mononuclear cells -of epithelial type desquamating from the inner surface of the alveoli -accumulated in the œdematous fluid and the hemorrhage within a short -time after their occurrence. These cells either appeared in clusters or -as single elements. Accompanying this were also large mononuclear cells -loaded with different quantities of pigment which had apparently escaped -from the lymphatic channels within the alveolar walls. These latter -cells belong to the wandering endothelial type which are active in -phagocytosis for foreign material and which assist so largely in -inducing the deposit of carbon in the lungs and lymph glands. A third -mononuclear cell appearing early in the reaction was the lymphocyte. The -numbers and extent of distribution of this cell were not constant. We -have seen it in some of the reactions where very few leucocytes were to -be seen, and where it constituted the main infiltrating cell of the -alveolar wall or the air sacs. We have previously mentioned its presence -in the inflammatory reactions of the bronchi. Here we find it in the -early response within the lung tissue and appearing amidst a reaction -which is intensely acute. It is not long after the finding of these -various cell elements that the polymorphonuclear leucocyte wanders in -large droves to numerically overshadow the mononuclear cells. -Nevertheless, the three types above mentioned can be recognized in the -exudate through the succeeding stages of reactions in the lung. The -large macrophage shows its phagocytic properties in taking up numerous -red blood cells, lymphocytes and occasional leucocytes. - -It is not difficult to demonstrate that the inflammatory reaction within -the bronchi and bronchioles precedes the responses within the alveoli. -Quite often one may find an acute bronchiolitis with desquamation of the -lining epithelium and the early serous exudate lying amidst the lung -parenchyma unaffected by any irritant and reaction. There is every -evidence that the bacteria reach the lung tissue by extending along the -walls of the respiratory tubes and eventually reaching the air sacs -either in the distant extremities of the bronchioles or when they have -arrived at the thin-walled structures extend through them into the -neighboring air sacs. - -It is during this early period that we are able to observe the -characteristics of the initial inflammatory exudate as we have described -it above. The serous exudate and the infiltration by mononuclear cells -appear early while the absence of fibrin also attracts attention. In -place of fibrin there appeared in a certain number of cases a peculiar -material of a hyaline nature which becomes plastered against the borders -of the air sacs forming a fairly thick laminated structure and within -which thread-formation is not to be seen. Occasionally a few cells lie -within this hyaline substance. Some have referred to this as a type of -fibrin. We have found, however, that it does not give the staining -reactions for fibrin and does not appear to be of the same composition. -These masses are tightly welded to the alveolar walls and the borders -are often indistinguishable. In part this material appeared to be made -up of necrotic cells of the septum which previously had suffered œdema -and circulatory interference. We have found in a number of cases hyaline -thromboses of the fine capillaries with more or less necrosis of the -alveolar septum. At times the septum was entirely destroyed so that a -thick hyaline mass alone separated neighboring air sacs. This hyaline -necrosis resembles in part the superficial necrosis which was observed -along the borders of the denuded bronchi. There is, however, more than -necrosis of cells constituting this deposit for the bulk of material -eventually deposited is much greater than could arise from tissue cells -alone. These hyaline masses have never been found to lie upon the -alveolar wall with an intact lining, but it is always accompanied by a -loss of the lining cells and more or less destruction of the wall -itself. As to the nature of the hyaline deposit which is laid down in -lamellae we do not know. Fibrin threads occasionally appear to arise -from these hyaline deposits and extend amidst the exudate in the air -sac. One cannot assume, however, that the fibrin and the hyaline -material have any relation to each other as their chemical -characteristics (and mode of deposition) appear to be quite different. -It has been suggested by some that this hyaline material represents an -imperfectly formed fibrin which has formed a jelly-like clot, not having -the property of developing the usual threads. - -It is of importance to appreciate that the deposition of these hyaline -structures indicates a severe injury of the alveolar walls not commonly -observed in ordinary pneumonias. - -In different areas of the same lung these constituents of the early -exudate may be observed in all proportions of admixture. Each one of the -elements of the exudate may largely overshadow the others and -prominently modify the appearance of the lesions. Broadly speaking, -however, the inflammatory œdema and hemorrhage occupying the greatest -part of the exudate in the lungs and the absence of marked leucocytic -response as well as the absence of the characteristic fibrinous meshwork -in the alveoli give to the early influenza-pneumonia a character -different from those which we ordinarily see. - -It is during this early phase of the reaction that the influenza bacilli -can be shown within the lung structures. The distribution of bacteria is -not uniform. Clusters of these minute bacilli are found in the alveoli -at irregular intervals, many of the air sacs containing much exudate -being quite free from organisms. When present the bacteria appeared in -tightly aggregated schools lying free amongst cells of the exudate, but -also certain numbers being incorporated within the large mononuclear -cells. In some regions organisms of the type of the influenza bacilli -were alone seen, while elsewhere again, and particularly where the -exudate was assuming purulent characters other bacteria of the nature of -streptococci, staphylococci and micrococcus catarrhalis, were also -found. - - - _Lung—Secondary Stage_ - -Following upon the primary reaction in the lung as above described, a -secondary reaction makes its appearance at variable periods. This -reaction is one in which the inflammatory exudate resembles more closely -but is not identical with the responses which are observed in ordinary -lobar, lobular and pneumococcus-pneumonia. Whereas in the earlier -period, the reaction is largely one of a serous and hemorrhagic exudate -accompanied by peculiar hyaline deposits along the inner borders of the -alveoli, later there is seen a change in the quality of the exudate with -the accumulation of more cellular elements and some fibrin. The naked -eye appearance of the involved tissue changes considerably. The lung -tissue loses in weight but becomes more solid. The lung contains less -fluid and the cut surfaces are drier and the color of the reaction -changes from the dark congested appearance to one showing all varieties -of red and gray. This change from the flabby and soggy pneumonia to the -more definite type of consolidation occurs in the regions which have -been previously involved and is not to be found in the lung areas which -have escaped the early reaction. The gray consolidation appears to be -either a stage of the influenza-pneumonia or is a new reaction -superadded to those pulmonary lesions induced by the primary infection. - -It is sometimes difficult to recognize the beginning of this pneumonic -stage inasmuch as the gray color does not make its appearance even with -the presence of fairly large quantities of cellular exudate. The amount -of hemorrhage that originally lay in the affected areas for a long time -overshadows the presence of the color of the cellular exudate. This is -also true of the characters that may be impressed by the presence of -fibrin. Small quantities of fibrin scattered through the congested and -œdematous lung are not readily recognized and the beginning of this -secondary reaction is also easily overlooked if one relies upon evidence -of consolidation. More or less solid exudate may occupy a flabby lung -without permitting one to appreciate its presence in the gross specimen. -When, however, the deposit is of sufficient quantity to change the color -of the involved lobe and to alter its consistency, one has little -difficulty in recognizing the changes now taking place. The earliest -development of this change in the inflammatory reaction was on the -fourth day. In the majority of instances the gray color and the -consolidation made its appearance about the sixth day. We have, however, -on several occasions observed hemorrhagic lesions as late as the seventh -and eighth day, at which time it was impossible to recognize a gray hue -to the exudate or the character of granular consolidation to the -involved lung. - -The reaction naturally suggests the stage of gray hepatization as we so -well appreciate it in ordinary pneumococcus-pneumonia and from the -standpoint of its color and the greater solidification of the lung -tissue we might speak of it as such. Here, however, it must be clearly -distinguished from the gray hepatization of ordinary pneumonia. This -secondary lesion of influenza-pneumonia has but little in common other -than its color and the development of a consolidation with true lobar -pneumonia. It is never as clear cut as we see it in the latter and the -degree of the “gray hepatization” is not uniformly distributed through -the involved lobe. One portion of the lobe will show a diffuse gray hue -while in other parts more decided lobular or patchy areas are picked out -in the advanced reaction. There is not the uniformity of lobar -involvement nor is the distribution as regular as one obtains it in -broncho-pneumonia. Furthermore, the character of the consolidation -differs very decidedly in showing such a variety of hues in reds and -grays and the cut surface is not the picture of the dry granular -consolidation of our endemic disease. The gray areas are in all states -of wetness and ooze a slimy fluid on the cut surface. In the later -stages this exudate is most profuse resembling a sticky pus. In its -appearance we were reminded of the character seen in unresolved -pneumonia as well as in the pneumonias produced by the pneumococcus -mucosus, and the B. mucosus capsulatus. We would, therefore, avoid the -use of the term gray hepatization and in place of it, as the evidence -with the microscope confirms, use the term _purulent pneumonia_. - -There are three other characters which differentiate this gray stage -from those of ordinary pneumonias—(1) the irregular distribution, (2) -the friability of the involved tissue and (3) the interstitial reaction. -We have never observed such an irregularity in the distribution of a -gray stage of pneumonia as we have seen it develop in acute -influenza-pneumonia. All types of involvement of the lobes are found in -different cases and even sometimes in the same case. The least frequent -type has been the broncho-pneumonia in its true form. Broncho-pneumonia -as we see it in children and the cases following measles is usually -fairly uniformly seeded through several lobes and the size of the -individual patches is about that of a split pea. The small bronchus can -be recognized about the center of the involvement. In those instances -one has studded through the lung tissue numerous small swollen areas -which are granular, dry and gray. Differing from this the patchy -distribution of the gray stage of influenza-pneumonia had no regularity -either in the size of the areas nor the distribution. A lobe may show -one or more patches. The patches may be distributed toward one portion -of the lobe more than another. Furthermore the areas do not always -encircle the small bronchi but involve the terminal portion so that an -entire lobule is more commonly affected. The lobular type rather than -the peribronchial type is most commonly seen and it is often remarkable -how sharply the gray lobule is demarcated from the surrounding congested -lung tissue. On several occasions we observed a single lobule in the -gray stage while the remaining portion of the lobe was in the serous and -hemorrhagic condition. However, multiple lobules are commonly seen -closely associated in the advancing inflammatory process. Such lobules -show peculiar geographical patches or leaflet-like configuration. -Varying with the number of lobules involved the extent of the gray -change in the lobes assumed more or less a lobar distribution. There was -no uniform position to this pneumonic state sometimes appearing in the -peripheral tissues of the lung, at other times lying centrally with less -involved or less advanced inflammatory reactions surrounding it. -Nevertheless, the gray stage made its appearance more rapidly in the -lower lobe than the upper and it was not uncommon to find this condition -appearing quite early in the upper posterior portion of the lower lobes. -This latter position is the one which is recognized during life by the -clinician as one of the earliest localizations of the demonstrable -pneumonia. It is reported by many that the first physical signs of -consolidation are to be obtained close to the lower angles of the -scapulae. - -There is no doubt that the character of the pneumonic process in the -epidemic influenza was not the same in all localities. There have been -not a few who have reported a large proportion of their pulmonary -lesions as a definite broncho-pneumonia with an interstitial purulent -involvement. The prominent reaction was a small circumscribed yellow -focus about the bronchioles from which a bead of pus could be expressed. -These pea-sized foci were scattered through several or all lobes. It is -this type of reaction which appears to develop by a direct extension -through the bronchial walls and to remain quite localized in the alveoli -about these tubes. This reaction seems to be purulent from its very -beginning and does not pass through the stages as we have described them -above. There is more or less fibrin present in the exudate, but usually -not in the quantity observed in lobar pneumonia. These lesions closely -resemble those observed in the post-measles pneumonia, and it is claimed -are the result of the same agent; the hemolytic streptococcus. In only -one case did we observe a lesion of this kind. The small areas of -broncho-pneumonia were confined to the left lower lobe and in the lower -portion of the upper lobe. Each area was about the size of a split pea, -was quite yellow and in fairly sharp contrast to the background of an -acute sero-hemorrhagic pneumonia. The subsequent history of these -interstitial purulent broncho-pneumonias is like that in measles, where -the tendency toward an organizing pneumonia has been shown. The -importance of the hemolytic streptococcus in inducing purulent -interstitial lesions of the lung (and also of other organs) cannot be -over-impressed. It is not so much the type of the reaction during its -acute stage which attracts our attention, but the manner of the healing -process. It is more than probable that the organizing pneumonias of -influenza, not only of this distinct bronchial type, but also the -lobular, confluent and lobar variety have had an associated -streptococcus infection. The more intimate discussion of this type of -pneumonia has been given by MacCallum. - -Our autopsy experience has led us to believe that the definite clinical -signs of pneumonia are associated with the development of this gray -consolidation of the lung. The lung tissue develops characters which -permit the physical signs to be recognized. The tissue is more solid and -more readily transmits the bronchial sounds. This is not true of the -earlier stages where the inflammatory process is contained within a lung -tissue which still is partially crepitant and when the so-called -consolidation is due to an inflammatory œdema and not to the more solid -fibrinous and cellular exudate. With the protean distribution of the -gray lesion one does not wonder at the clinical difficulties in mapping -out or even finding the consolidated tissues. - -As soon as the lobes show this gray character and with the progressive -development of an acute interstitial purulent pneumonia, the lung tissue -becomes friable. All gradations of flabbiness may still be obtained and -in the early stages while the cellular exudate is accumulating to change -the color of the lung, little variation from the tough character of the -pulmonary tissues can be recognized. When, however, a true gray -character is assumed by a portion of the lobe, the tissue becomes so -soft that it is handled with difficulty without rupture. The thumb can -be pressed into the gray mass and pus will well up around the invading -phalanx. The consistency in the late stages reminds one of the pulpy -tissues in acute splenitis. In cutting such lobes it is almost -impossible to obtain slices of the tissues, their own weight often -breaking such a segment. When allowed to rest on the table for a few -moments, the cut surface becomes coated with a dirty yellow slime -representing pus and products of disintegration arising from the lung. -The stroma and alveolar tissues are themselves involved in the -inflammatory process and many of them have suffered complete or partial -destruction so that they offer but little resistance to pressure and -serve as a poor supporting stroma to the pulmonary tissues. The reaction -which has taken place within the lung producing both the gray color and -the destruction of the tissues is, indeed, an active suppurative one. -One would not be surprised to obtain not only a purulent lesion wherein -the cellular exudate occupies the air sacs and their walls but also a -further stage leading to a destruction of the tissues to the extent that -abscess cavities are produced. These we have met with in several -instances, some of them being small while others were several -centimeters in diameter. An abscess of larger extent and having a -destructive process which involved the surrounding tissues so that one -would speak of it as a process of gangrene, was observed by Dr. McMeans -in one of his cases. A lobar distribution of the purulent lesion takes -place where multiple involved lobules have fused in their periphery or -where a suppurative flooding of the tissues in this violent late -reaction has taken place. - -The question at once comes to mind whether this gray stage is but the -late event of what we have previously spoken of as influenza-pneumonia -or whether this condition is superadded to what may begin as an -influenza-pneumonia but end in a pulmonary inflammation with a mixed -infection. Dr. Holman was not able to demonstrate a sufficient -difference in the bacteriology of the lobes in the gray stages from -those in the early acute stage to be able to say that the flora changes -at a certain time during the progress of the disease in the individuals. -It is possible, and there is some evidence in support of this, that the -earlier stages of the pneumonic process represent the reaction to the -influenza bacillus and that during this period the response is fairly -uniform and similar owing to the fact that this infection has but a -short incubation period and a high pathogenicity. In such an event the -particular micro-organism may bring about a peculiar response of its own -before the other organisms with which it is associated have the -opportunity of producing damage. Subsequently, however, these secondary -organisms impose their peculiar reactions upon an altered lung, thus -inducing an inflammatory lesion which differs from the preceding -reaction and also differs from the reaction usually induced by those -organisms upon relatively healthy tissues. It is difficult to account -for the very irregular distribution of the gray lesions by an -explanation concerning the influenza bacillus alone, or by the -characters peculiar to the secondary infection. There is an entire want -of character to these gray lesions which makes them differ from other -types of pneumonia known to us. - -It is well to lay particular stress upon this peculiarity in the -distribution and extent of the lesions within the lobes; and it is also -important to appreciate the difference in the appearance of these gray -areas from those of true lobar or broncho-pneumonia. - -Finally there is another point in which this stage of the pneumonic -process differs from that of pneumococcus lobar pneumonia. In frank -lobar pneumonia the reactions taking place in the involved portion of -the lung are fairly uniform in all its parts. The stage of red -hepatization occupies about that amount of lung which subsequently shows -itself in the state of gray hepatization. In other words, all of those -areas which appear gray are preceded by this peculiar red consolidation, -and all of the area occupied by the red hepatization will pass through -the phases of gray hepatization before entering upon the final stage of -resolution. - -In influenza-pneumonia, on the other hand, the events taking place in a -given lobe are not uniform and various stages and grades of the -inflammatory reaction may be recognized at the same time, some appearing -red, some congested, some flooded with blood in hemorrhage and others -showing the purulent infiltration by the appearance of gray patches upon -the background of red. Not only do the various reactions within the same -lobe fail to show similar grades of intensity and similar stages or time -of involvement, but we find that all of the red and hemorrhagic areas -are not destined to pass through the gray stages. At times it is true an -entire lung will enter into the purulent phase and if this becomes -extreme abscess and gangrene are almost certain to develop. But often -the purulent infiltration occupies only a few or scattered lobules and -resolution may take place in a lung where the greater part of the lobes -is occupied by the inflammatory œdema and hemorrhage and has never -become truly consolidated by cellular and fibrinous exudate. This -feature that the involved lung tissues need not pass through the -sequence of events which is usually observed in frank lobar pneumonia is -so distinctive that it differentiates the character of the inflammatory -reaction very clearly. It may be that this is an indication of the -unequal distribution of the micro-organism and that the first infection -presumably by the _bacillus influenzæ_ has been much more diffuse and of -wider extent than the secondary invading bacteria which being -distributed through the bronchial tree are more or less localized to -those lobules most severely involved. It is impossible to claim for -influenza-pneumonia as clear and sharp-cut stages as we obtain them in -the pneumococcus lobar pneumonia. - -During the period of the intense purulent reaction in certain portions -of the lung, the intrinsic structures within the area also partake in -the damage and response. The suppurative infiltration not only occupies -the alveolar walls but also extends through the tissues of the -bronchioles, the arteries and the veins. The polymorphonuclear -leucocytes seem to migrate into all of the parenchyma indicating some -damage by bacterial invasion. On more than one occasion have we observed -partial or incomplete thrombosis of arterioles and capillaries whose -walls showed an acute suppurative reaction. Some of these thromboses are -of importance, being associated with the interference with a blood -supply not compensated by adequate anastomosis. Necrosis and small areas -of gangrene and abscess are to be found in the region of the circulatory -disturbances. It is also during this period of the disease when the -bronchi and their ramifications contain pus or muco-pus, that the -exudate from the alveoli readily finds its way into the air passages and -becoming mixed with the mucus from these tracts forms a tenacious -discharge. - -The presence of large amounts of exudate within the bronchi brought -these structures into unusual prominence. This was particularly true in -the purulent stage of the reaction when beads of sticky pus would well -up from the cut bronchioles. We were tempted on a number of occasions to -speak of this in terms of bronchiectasis but with the intense -inflammatory reaction occupying the bronchial wall and modifying its -contour on this account we avoided this diagnosis. In one instance, -however, the lesion was unmistakable. This was a case of purulent -pneumonia (764) dying on the ninth day of the disease. The distribution -of his pulmonary lesions was distinctly lobular, apparently following -the course of the bronchial distribution. The bronchi were followed -longitudinally and irregular pouchings of the lumen were very apparent. -The bronchi had suffered marked inflammatory reaction which had also -infiltrated the muscular tissues of the tubes. Goodpasture and Burnett -report finding two cases of acute bronchiectasis associated with abscess -and ulceration of the bronchi. In our case the bronchiectasis was found -bilateral but was more marked in the lower lobes than the upper. - -The lymphatic channels within the lung tissue are found active in -establishing an internal drainage to the neighboring thoracic glands. -The lymph vessels were often found filled with leucocytes and variable -amounts of serum. During this late stage only a few of the endothelial -leucocytes were observed wandering to or from the lung with a load of -pigment or cell debris. These wandering endothelial cells, however, -appeared to become loosened from their normal situations and in the -vicinity of lymphatic nodes or communicating channels where these cells -are prone to localize with their carbon pigment, again assumed their -spherical form and took on migratory properties entering into the nearby -tissues and scattering themselves in the looser structures. It is an -interesting point to note that these pigment carrying cells, ordinarily -assuming a latent existence when their cytoplasm has been crowded with -foreign particles will assume all the activities of migrating cells when -the œdema of the tissues alters the physical properties not conducive to -a stationary existence. These cells will then be found to enter the lung -alveoli, often appearing as cells which have only recently picked up -their carbon load. When, however, the conditions of the experiment, that -is, the production of an inflammatory œdema in the lung, are produced in -the tissues of an individual with much anthracosis, he will, during the -period of his pneumonia and for some time during convalescence, bring up -a greater number of these cells in his sputum than are ever obtained -during the times when the lung is not involved. We are convinced that -inflammatory conditions of the lung tend to reduce the total number of -latent pigment bearing cells present in the involved tissues, and in -this way somewhat reduce the grade of anthracosis. - -A considerable discussion has arisen concerning the proper nomenclature -for the pneumonia or pneumonias found in epidemic influenza. From some -quarters have come the reports of a true lobar pneumonia, from others a -lobular or broncho-pneumonia and others again claim that the reaction is -an interstitial pneumonia of varying distribution. It appeared to us -that the gross distribution of the lesions is not alone the criterion -for a proper appreciation of the inflammatory states which may arise -within the lung. I believe it has been amply demonstrated that the -pneumonic reactions appearing in different regions of the United States -as well as in different countries are not of a constant kind when viewed -alone in the light of the gross picture nor are they constant from the -standpoint of their bacteriology. We are of the opinion that the earlier -phases of the pulmonary reaction are fairly constant in different places -and that this constancy is dependent upon the common virus which -initiates the respiratory lesion and which then permits a variety of -micro-organisms invading as secondary agents. The secondary agents vary -with the community and depending upon their nature the character of the -reaction differs from that in other places. It has been well -demonstrated that in some regions the hemolytic streptococcus is the -important organism following the primary injury by the initial virus. In -other places the pneumococcus or the staphylococcus or the M. -catarrhalis is found to be of primary importance. Up to the present it -has not been shown that the influenza bacillus is not the important -organism causing the initial reaction and being responsible for the -opportunity of secondary invaders leading to such diverse reactions in -the lung. In our series we have met with lobar, lobular, interstitial -and broncho-pneumonic types. We have not observed a case of the miliary -bronchial reaction as described and illustrated by Goodpasture and -Burnett and fully investigated by MacCallum. Moreover we have not met -with the type of purulent bronchitis as a characteristic lesion -preceding pulmonary involvement. The occurrence of pus within the -bronchi occurred not early in the pulmonary lesion but later after the -bronchi and bronchioles had passed through their stages of acute, serous -and hemorrhagic pneumonia and were entering upon their secondary stage -with pus production. The pulmonary lesion had long preceded the -appearance of pus in the bronchi. We do not hold, however, that such -relations between the pulmonary lesion and the purulent bronchitis do -not exist for there is evidence that in particular regions this sequence -of events was closely observed. - -We cannot, however, correlate our findings with the classification of -pneumonias as given by MacCallum. His claim for specific types of -pneumonia as a sequel to influenza is based upon his statement that “no -satisfactory evidence has been brought forward to show that the epidemic -influenza is a bacterial infection. It is evidently a general or -systematic infection not especially affecting the respiratory tract and -analogous in many respects, as Bloomfield has pointed out, to the acute -exanthematic diseases.” Thus we are confronted by two schools concerning -the nature of influenza. The one claiming that epidemic influenza is -essentially a disease of the respiratory system and the other completely -denying this. - -I am unable to understand the claims which are put forward to -substantiate the second view. - -The classification of the pneumonias as suggested by MacCallum would be -valuable if it could be applied in a practical manner. We find, however, -that his description for the pneumococcus-pneumonia hardly coincides -with common observations on endemic pneumonia and if the description is -to apply only to the pneumonias associated with influenza wherein -pneumococcus alone is isolated we find that our own observations do not -coincide with this. The picture offered by MacCallum under this heading -was reproduced when the bacteriological findings illustrated the -presence of organisms other than the pneumococcus or combinations of -these. The most characteristic of his description is the one for the -streptococcus-pneumonia which when present alone gives quite a unique -picture. The picture, however, is to a certain degree modified by the -reactions which precede the streptococcus in the lung. Furthermore to -offer as a characteristic picture for the influenza infection of the -bronchi the presence of a thick yellow pus is hardly complete inasmuch -as this exudate appeared only as a stage in the inflammatory process. -The intense serous and hemorrhagic response observed early in this type -of infection is more unique than the presence of pus which appears -somewhat later and which may occur with infections other than the B. -influenzæ. It has long been the hope in pathology to be able to -establish by the character of the tissue reaction, the nature of the -infecting agent. Up to the present this has been possible only with a -very few types of bacteria. - - - _Lung—Stage of Resolution_ - -The removal of the infection and the inflammatory exudate from the lung -tissue is accomplished slowly. Clinically the pulmonary process clears -up by lysis, and it is quite unusual to have a crisis with the rapid -disappearance of the serious manifestations. It is difficult to obtain a -clear conception of what takes place in any individual case recovering -from an influenza-pneumonia, but if we have an understanding of what may -occur in the inflamed lung tissue in any one of the stages or varieties -of kind, we may visualize the changing character of the lung condition -tending toward the final restoration. - -We have previously pointed out that the early stage of -influenza-pneumonia is one of congestion, œdema, hemorrhage and more or -less leucocytic infiltration, and that this reaction differs materially -from that observed in pneumococcus lobar pneumonia. There being no stage -of true red hepatization, it has also become apparent that this peculiar -primary reaction need not pass into the stage of gray consolidation. -Scattered areas in the lung pass from the condition of acute serous and -hemorrhagic pneumonia to a type of purulent pneumonia while much of the -remaining tissue continues in the state as seen in the early reaction. A -certain amount of cellular exudate makes its appearance but not -sufficient to lead to a true consolidation. This variety of reaction is -present from the fifth day of the pneumonia onwards and may continue -with all of its varieties through until the tenth or twelfth day or even -longer when recovery from the infection is beginning. Thus the stage of -resolution makes its appearance before the inflammatory reaction in the -involved lobes has assumed a common character and where we are able to -recognize different grades of severity and different stages of -inflammation within the same lobe. Resolution taking place in such a -lobe has responses occurring in the different parts determined by the -nature of the antecedent reaction. We have found that those portions -which have not advanced beyond the stage of œdema and hemorrhage may -clear up with the disappearance of this early exudate and its infection. -In a neighboring portion the purulent inflammation passes through phases -differing somewhat from the preceding but also tending toward the -restoration of the parenchyma and the disappearance of the inflammation. -It would be incorrect to consider the resolution of the early type of -inflammatory reaction as an abortive process inasmuch as it is not yet -clear whether this serous and hemorrhagic process is not the -characteristic inflammation of a peculiar micro-organism or organisms -and that when acting alone these bacteria do not in themselves stimulate -a further inflammatory response. Hence if it is true that there is a -peculiar inflammatory reaction of a non-suppurative and non-fibrinous -kind the manner of resolution will differ somewhat from that where these -other constituents of the exudate are present. It becomes clear, -therefore, that in influenza-pneumonia all of the lung involved in the -early peculiar inflammatory reaction need not pass through those stages -and reactions as we recognize them in pneumococcus lobar pneumonia. - -The resolution taking place in the areas of serous and hemorrhagic -pneumonia is accomplished largely by a reabsorption of the fluid, -autolytic disintegration of the red blood cells and a certain amount of -phagocytosis of red blood cells and their debris. This resolution is -quite rapidly accomplished, and the clearing up of such an area may take -place in a remarkably short period of time. The leucocytes and -endothelial cells which are present with every such reaction become -active in phagocytosis of bacteria, and we have repeatedly observed them -crowded with small Gram negative bacilli, whose morphology is similar to -that of the B. influenzæ. These areas contain but few bacteria of other -kinds. The exudate in the alveolar walls is also simple in character and -is readily removed. Slight suffusion of blood, serous fluid, and -migrating cells may occupy portions of the alveolar walls during the -acute reaction, but these, too, are easily removed and the tissue -rapidly resumes its normal character. The vascular and lymphatic -congestion again disappear and the tissues which once were soggy return -to a normal state without leaving behind evidence of the pulmonary -incapacity. The lining epithelium of trachea, bronchi and alveoli is -restored by proliferation from the neighboring less injured parts. - -If this early stage in influenza-pneumonia is to be compared with the -early reactions of endemic pneumonia, it is interesting to note with -what ease the resolution may be accomplished in the former, whereas in -the latter a further sequence of stages must apparently be passed -through before the lung is cleared of its inflammatory products. As we -have intimated before, the early exudate in these two types of pneumonia -differs very essentially, the one being accompanied by much fibrin and -leucocytes which are present only in small quantities in the pulmonary -lesion of influenza. - -Resolution of the other portions of the involved lobes in influenza is -not so easily accomplished. Where a progressive lesion with its -development of pus occupying both the air sacs and the tissue of the -lung, the outcome of attempts at repair are uncertain. Complete -resolution with complete disappearance of the purulent exudate may take -place as we see it in many other regions occupied by a similar reaction; -and where the purulent response is not accompanied by material damage to -the tissue the restoration of the lung is so complete that upon its -recovery no evidence is left behind of the former injury, but in as much -as the presence of a purulent reaction in the lung is often of more -severe grade than this, a certain amount of tissue destruction having -been accomplished, the repair does not completely restore the tissue to -its former normal state. The purulent lesion, however, is not uncommonly -accompanied by minute capillary thromboses, tissue derangement, organic -destruction, with even tissue alteration amounting to abscess or -gangrene, and it is too much to hope that the lung may be completely -restored. Minute abscesses varying from microscopic size to large -cavities, several centimeters in diameter, were not unusual in the -tissues severely involved in the purulent reaction. Thus in these areas, -resolution can be accomplished only by a process of slow organization of -the damaged parts with the final production of fibrosis. These fibroses -are of variable extent depending upon the initial damage. We have been -very much struck with the speed with which this process of organization -may take place and the extent of the lung tissue which may become -involved in this late lesion. In one of our cases we have evidence of -marked fibrosis present on the twenty-third day of his illness. Patches -of organization varying from one to four centimeters in diameter -occupied the different lobes of the lung. The new fibrous tissue was -well developed and the purulent reaction had largely disappeared. The -fibrosis obliterated the normal architecture of alveoli and bronchioles, -leaving only irregular islands of epithelium which assumed grotesque -glandular shapes and looked not unlike a new growth. One of the -interesting features of these late fibroses which come to occupy various -extents of the lung and bronchial tissues is that the individual after -recovering from his acute influenzal lesions again passes, in about his -third week, into a stage of dyspnœa with manifestations out of -proportion to the physical signs or constitutional derangements which -can be determined. The dyspnœa is often the outstanding sign and the -patient may die in a state of asphyxia. - -We have observed evidence of organization in its earlier reactions -taking place in the patches of gray consolidation. This organization of -the lung tissue takes place as an interstitial fibrosis and as an -alveolar organization. Masses of granulation tissue grow out into and -come to occupy the lumen of the air sacs, while in other instances the -new growth of tissue takes place mainly in the alveolar walls converting -them from thin partitions to thickened and tough structures. In the -cases in which a purulent pneumonia was present for some time, and where -some of these tended towards repair, this type of restoration with the -new development of connective tissue was found. The amount of fibrosis -varied very much, and in many instances there was no evidence that -obstruction to the bronchioles occurred to a material degree. Hence, -although we believe that more or less organization occurs in all of -those cases which have passed through a purulent pneumonia, and that a -permanent mark is left upon the lung tissue, it is not probable that the -amount of involvement and final damage by fibrosis is sufficient to -seriously influence the pulmonary respiration. There is, however, a -certain percentage of cases in which this organization and fibrosis does -involve sufficient of the lung parenchyma and bronchioles to interfere -with the pulmonary ventilation. - -Where the purulent pneumonia has markedly involved the parenchyma, and -particularly where vascular channels both large and small have suffered, -some of them by thrombosis, others by a sclerotic thickening, the -circulatory disturbance may be sufficiently interfered with to infarct -the area. The infarction usually occupies the purulent area itself, and -with the complete occlusion of the circulation the resulting necrosis -gives rise to an appearance different from that usually seen in -pulmonary infarcts. The area may lie in the peripheral portion of the -lobe or may occupy deeper parts. The infarct is of a cream-white color, -quite homogeneous, and resembles the appearance of a local area of -caseous pneumonia. This appearance is brought about through the local -purulent consolidation undergoing necrosis. Some of these areas rapidly -develop a cavity through liquefaction of the exudate. - -The localization of the inflammatory products not only upon the surface -of the air sacs but also in the stroma of the alveoli; the interlobular -trabeculæ, and about the vascular channels indicates the intense effect -of the virus of this disease. The exudate is largely an indication of -the point of action of the irritant upon the tissues, and in influenza -with its variety of bacteria in the lung this is not limited to the -surface membrane of the air sacs. During this second stage of the -reaction the purulent exudate was found occupying all structures of the -involved area. Damage upon the component tissues was to be seen in the -endothelium of the capillaries, the muscle tissue of the bronchioles and -arterioles, the connective tissues and the epithelium. It was seldom -that bacteria were demonstrated in the interstitial parts, and it would -appear that the damage was the result of their toxins. - -Hence, broadly speaking, the end result of the pneumonic process in -influenza is far more complex and indefinite than that in lobar -pneumonia. Resolution may take place early with the clearing up of the -first products of the exudate; or it may be delayed in association with -the secondary purulent process which not uncommonly occupies multiple -lobes. Where the resolution begins in purulent regions the final outcome -is most variable, depending upon the amount of damage which has been -imposed upon the lung tissue during the suppurative inflammation, ending -either in complete restoration or slight fibrosis of the lung, or -passing on to focal scarring of various degrees, sufficient to alter the -pulmonary capacity. In other instances the resolution is delayed by the -development of abscess, infarct and gangrene. Here the final outcome is -determined by the amount of tissue involved in the destructive process, -and the persistency with which the infecting micro-organisms attack the -local tissues and the constitutional resistance of the individual. Those -individuals in whom resolution begins before there is much purulent -pneumonia stand the best chance of having the lung return to its normal -characteristics. - - - _Pleura_ - -Inflammation of the pleura was a complication which varied in its extent -and appearance. It appeared to us that a definite interval lapsed -between the development of the lesions in the lung and the appearance of -an inflammatory reaction upon the pleural surfaces. Although we have -recorded evidence of a pleural reaction in 27 cases, this does not -indicate that we have met with that number of pleurisies of clinical -severity. In this group we include all gradations of pleural reaction -from the merest evidence of irritation and slight dulling of the surface -to the cases in which definite and marked inflammatory exudate -accumulated within the cavity. In many cases we observed a slight -increase in the amount of the fluid present in one or other pleural -cavity, while there was little or no macroscopic evidence of a cellular -or fibrinous exudate. An examination of the fluid showed the presence of -lymphocytes and endothelial cells in small numbers, and sections of the -pleural surface at points where a slight dulling of the serous membrane -was seen at autopsy showed the presence of a very thin layer of a -hyaline fibrin. By taking these reactions as indicative of pleurisy we -have recorded 6 cases of acute fibrinous pleurisy, 20 of acute -serofibrinous pleurisy, and 1 of acute fibrino-purulent pleurisy. - -An increase in the quantity of fluid in the pleural sacs was the most -common indication of pleural irritation. The quantity varied from 50 to -500 c.c. of a clear or slightly turbid fluid. Not uncommonly this fluid -was blood stained and evidence of superficial extravasation of blood -could be recognized directly beneath the pleural membrane. These serous -reactions accompanied the early acute stage, while hemorrhage was the -accompaniment of the early period of the influenzal pneumonia when -similar hemorrhages were found in the lung substance. The pleural -reactions were almost entirely confined to the visceral pleura, and only -in the very severe responses did we obtain a marked inflammatory -reaction with hemorrhage upon the chest wall. Goodpasture and Burnett -state that “there is commonly a moderate serous effusion in one or both -pleural cavities amounting to 50 or 250 cubic centimeters. The fluid is -clear and has the color of blood-stained serum. The pleural surfaces are -smooth, shiny and wet, though occasionally a thin, granular fibrinous -exudate may be seen by reflected light over limited areas. Often -numerous small, red, discrete, or confluent pleural hemorrhages are -present over consolidated portions, especially posteriorly on the -surface of the lower lobes.” Where organisms other than the influenza -bacillus had invaded the pleural sac and had been present for a -sufficient time to obtain a reaction, the serous type of exudate -observed in the early lesions changed to the turbid type of fluid -accompanied by more or less fibrin deposit. There was one case where the -intense reaction with fibrin and leucocytes gave rise to a new character -to the pleural exudate, a fibrino-purulent pleurisy or empyema. - -As we have subsequently learned the pleurisies developing late in the -course of the influenza and those which persist after the pulmonary -inflammation has passed are prone to be of a purulent kind. There have -been a fair number of cases of empyema brought to our attention by the -surgical department in the bacteriological laboratory of the hospital, -subsequent to the wave of epidemic influenza. If one were to base his -finding alone upon observations obtained in the operating room, he would -be impressed by the fact that the pleurisy accompanying the epidemic of -influenza is of a purulent type. On the other hand, if one were alone to -consider the findings at the autopsy table during the five weeks of the -epidemic, one would be of the opinion that the pleurisy is of very minor -consequence and of a serous type. It is this changing picture which is -particularly to be kept in mind. And our experience indicates that -during the height of the influenzal lesions of the lung when the -pulmonary lesions develop so rapidly that we obtain a pleural reaction -closely resembling the inflammatory conditions in the lung and also -containing bacteria not unlike the pulmonary flora. Dr. Holman has -obtained the influenza bacillus and other varieties from the pleura -during these early periods of the pulmonary inflammation. It is more -than probable that just as in the infection of the lung tissue where -there is a change in the type of the bacteria present, so, too, the -flora of the pleura alters in the succeeding stages of the pulmonary -reaction. In the late event of empyema we have not observed the -influenza bacillus. The majority of the empyemas possess hemolytic -streptococci and occasionally pneumococci. - - - _Heart_ - -During the acute epidemic and while the disease was at its height it was -remarkable how few cases showed involvement of the heart. It was the -common observation that even during intense illness the heart action -remained fairly stable and did not indicate an effect by intoxication as -might be expected from the severity of the illness. In as much as the -majority of deaths occurred within relatively few days of the onset of -the severe infection, the type of lesion that would be looked for in the -heart would be either bacterial inflammatory products within the -pericardium, myocardium or endocardium or toxic lesions of musculature -alone. - -In our series we have encountered no cases of pericarditis. This lesion -in the experience of others has also been unusual, and it would appear -that bacterial invasion of this sac is accomplished mainly in the -presence of secondary infections localizing in the neighboring pleura. -It was not uncommon to find a slight increase in the serous fluid in the -sac, but this on no occasion amounted to a hydropericardium. The fluid -was always clear and with no evidence of fibrin or cellular exudate. -Petechial hemorrhages scattered over the epicardium were noted in seven -cases. In the majority of instances these minute hemorrhages were -scattered in small numbers over the ventricular walls. In one instance -these petechial hemorrhages were also present through the myocardium, -suggesting the influence of an intoxication not upon the tissues of the -heart as much as upon the finer structures of the vascular channels. -This is furthermore borne out in the presence of petechial hemorrhages -confined not to one organ, but to various tissues and structures in the -body. - -More or less cloudy swelling or granular degeneration of the muscle -elements of the heart was not uncommon. It was sufficiently pronounced -in 12 cases to be readily detected by the naked eye. A lesser amount was -also observed in other cases on microscopical examination. In only one -instances was the myocardial degeneration of such extent to lead to a -definite and recognizable weakening of the musculature. In this instance -the autopsy showed a flabby myocardium which was relatively soft and -easily broken and in which all the chambers of the heart were decidedly -dilated. This was the only case in which we were convinced of a -sufficient influence of the toxic effects upon the musculature to permit -a stretching of the walls, with failure of function. - -In a number of other instances, however, in which there was more or less -granular degeneration and cloudy swelling we found that the right -ventricle ceased in diastole without, however, the capacity of the -chamber being enlarged. We would make this differentiation in speaking -of dilatation of the heart. We have met with 11 cases in which the right -heart died in diastole, but in which there was no evidence that the -right ventricle had been unduly expanded. In four cases there was -evidence of an old compensatory hypertrophy of the left ventricle in -which the cavity of this chamber was also slightly larger than normal. -The lesions in these four cases, however, bore no direct relation to the -results from the influenza infection. The appearance of the musculature -with moderate grade of cloudy swelling suggested some œdema of the -tissues. In the myocardium, œdema is difficult to recognize, and we -would not place great stress upon its presence in mild degree. - -The microscopic examination of the myocardium showing cloudy swelling -gave the usual picture as is seen with a variety of infections. The -muscle fibers showed a fine granular deposit in their cytoplasm and the -staining quality of the tissue was somewhat altered. The transverse -striæ were less distinct than normal, while not uncommonly the -longitudinal fibrils became more evident. Fatty degeneration was not -encountered. - -In the single case showing a definite and acute dilatation of the -ventricles the cause of the myocardial lesion could not be placed at the -door of the influenzal infection. This was the case suffering from a -secondary streptococcal bacteriæmia arising in the middle ear. It is -more than probable that the streptococcus was the immediate cause of the -acute muscle change and weakening. In a number of cases we have studied -the tissues of the bundle of His, but we were unable to note any -definite change. - -It is interesting that the intoxication associated with acute influenza -is selective in localizing in certain muscle tissues. We have previously -indicated the intensity of muscle degenerations occurring in the -abdominal recti. Even in these cases where these striped voluntary -muscles were markedly affected the myocardium showed nothing more than a -mild or moderate grade of cloudy swelling. We can only account for this -in a difference in the constitution of these muscular structures, some -being of such composition permitting of the localizing and damage by the -unknown intoxicant. It does not appear that the reason for localization -in certain tissues is in any way related to the character of the blood -supply, nor is it related to the activity of the part. - -In three cases we have found an inflammatory lesion of the endocardial -tissues. In all of them this consisted of a slight acute verrucose -mitral endocarditis. The lesions were very small, consisting only of a -fine granular deposit looking like grains of sand localized along the -border of the mitral leaflets. In no instance was the leaflet injured or -incapacitated. Unfortunately the lesion not being suspected was -encountered after the heart had been removed and opened and when it was -too late to make bacteriological analyses. This point is greatly to be -regretted, in as much as it is of great importance to know whether some -distant lesions are induced through the influenza bacillus or its -symbiotic flora. - -The majority of authors report but little upon the heart lesions in -influenza. Many deny that a heart involvement is to be found, a few -report an occasional endocarditis. Wallis and Kuskow found more or less -myocardial change similar to what is usually described as cloudy -swelling. This reaction they point out differs in no way from the -degenerations arising from other types of intoxications. Keegan in a -series of about 23 autopsies found only a single case with acute -dilatation. - -Abrahams, Hallows and French had an opportunity of observing over 400 -autopsies upon the influenza patients, and they comment upon the -infrequency of cardiac dilatation. A slight dilatation of the right -ventricle was seen in a few cases, and in no instance did they find -pericarditis or endocarditis. They comment upon the heart condition as -follows: “The most remarkable feature about the heart is the general -absence of dilatation. In quite a large proportion of cases there has -been no trace of dilatation; in a fair number of others there has been -some dilatation of the right side, but this has seldom been extreme, -perhaps enough to cause the apex of the heart to be formed about equally -by right and left ventricles. Most often the heart has appeared of -normal dimensions and the apex has been formed entirely by the left -ventricle. This absence of dilatation accounts for the clinical absence -of orthopnœa.” In direct contradiction to the above findings, the -Advisory Board to the D. G. M. S., France, report the findings in 30 -autopsies of clinical influenza. Twenty-nine of these 30 cases showed -dilatation of the heart, chiefly of the right side, but very commonly of -the left side as well. Twenty-one showed myocarditis and two -endocarditis. In this report it is stated that these patients showed -evidence of obsolete tuberculosis. It is possible that the condition of -the patients and the presence of an unusual complicating infection led -to the high incidence of cardiac involvement. The figures in this last -series are much too high when compared with the frequency of heart -involvement as found by the majority of other investigators. - -A number of heart lesions not resulting from influenza were observed. -For none of them was there an antecedent history, but in some cases the -condition may have had an influence in causing accessory cardiac -embarrassment. One case had a chronic interstitial myocarditis of the -rheumatic type, three had mild grades of chronic sclerotic mitral -endocarditis, one a bicuspid pulmonary valve and three showed old -pericardial adhesions, one of them having a complete obliteration of the -sac. The foramen ovale was patent in six of the hearts. - - - _Arteries_ - -The arteries in these young adults were remarkably healthy, and in none -of them did we observe the characters of arteriosclerosis or leutic -lesions. On the other hand, evidence of superficial fatty streaks lying -in the intima of the aorta and some of its large branches were not -uncommon and are believed to have had a relation to the acute infection -of which they died. In only four cases in the series of 32 autopsies was -evidence of these fatty streaks wanting. In about one-half of the -remaining number these fatty streaks were only slight or moderate in -extent, while in the rest of them these lesions were particularly -prominent and striking. They formed linear markings on the posterior -wall of the aorta, aggregating with particular prominence about the -intercostal arteries. The anterior wall was quite free from them. The -greater extent of these lesions lay in the descending thoracic and was -less marked in the arch and the abdominal aorta. At times these fatty -streaks were found to extend into the large vessels of the neck and into -the intercostal arteries, and they were also found in the coronaries of -the heart. It was uncommon to observe their presence in the arteries of -the abdominal viscera. - -This type of lesion has been discussed from the standpoint of its -etiology and its possible bearing upon true arteriosclerosis. Some -believe that the frequency of its finding in autopsy material suggests -the non-importance of its presence. This we can hardly agree with. It is -true that the presence of these lesions does not materially incapacitate -the aorta in acting as the main channel for the distribution of blood. -The lesions are quite superficial in the intima and cause but little -elevation on the surface. The amount of roughening which the intima -presents to the blood is not great. Nevertheless, the presence of these -fatty streaks is an index of the disturbed metabolism of the cholesterin -products of the body. Under certain conditions they make their -appearance when there is a true hypercholesterinemia such as is readily -produced in the animal experiments by feeding cholesterin. Under these -circumstances the various tissues of the body, including the adrenal, -the corpus luteum, the spleen, liver and arteries, all participate in -localizing cholesterin in the form of cholesterin-ester in peculiar -cells which have been termed cholesterin-ester phagocytes. It has been -shown that cholesterin metabolism is quite readily altered in the human -and that the blood content will vary from the normal. In chronic kidney -disease, pregnancy, diabetes, chronic heart disease and arteriosclerosis -the blood cholesterin rises, while in many of the acute infectious -diseases the cholesterin in the blood is materially diminished. It is -particularly in these latter cases where fatty streaks of the intima are -prone to occur. Hence in human pathology we more often meet with the -development of fatty streaks of the intima associated with a -hypocholesterinemia than with a hypercholesterinemia. - -The fatty streaks of the intima of the aorta to which we are referring -are lesions quite aside from true endarteritis as well as atheroma. In -naked eye appearance the lesion is of a fatty nature and suggests -atheroma, but it differs from this well-known lesion in the fact that -the fatty materials, cholesterin-esters, are contained within cells -which are of uniform type and have no reaction in their immediate -vicinity. True atheroma may occur in definite levels of the intima, most -commonly in the deepest portion, and is characterized by the fact that -we are dealing with a variety of fatty materials, neutral fat, fatty -acids, soap, cholesterin-ester and free cholesterin which lie between -the tissue cells forming a detritus following a process of true -degeneration. It is possible that some of the superficial fatty streaks -do give rise to a small atheromatous area by death of the cells which -primarily contain the fatty substances. Most commonly, however, the -fatty streaks do not progress directly to atheroma but may entirely -disappear, as we have seen it occur in our experimental animals. At -other times these fatty streaks are followed by a slight thickening of -the surface of the intima so that the resemblance to early endarteritis -is obtained. We do not believe that these fatty streaks in themselves -lead to the chronic nodular thickening of the aorta, but that other -factors giving rise to a low grade inflammatory reaction must be -present. - -There appears to be a relation between the development of these fatty -streaks and the altered cholesterin metabolism, brought about by -pathological change in the blood, adrenal cortex and it may be in the -liver. It is under these conditions where these tissues are altered -particularly by bacterial toxins in a process of marked cloudy swelling -that these intimal fatty streaks arise. Analyses in other diseases have -shown that such organic changes lead to a diminution in the cholesterin -content of the blood, while at the same time there is neither an -increased intake nor an excessive output. It would appear that certain -types of tissues and cells are stimulated into activity to become depots -for the cholesterin which is not being properly handled by the adrenal -and other organs. These cells in the intima which become active in -taking up cholesterin-esters are types of endothelial cells whose origin -is not entirely clear. In these lesions it is observed that the most -superficial cells of the intima do not show an overloading with the -fatty compound, but that the cells active in absorption lie at a level -slightly beneath the endothelial lining and form colonies as if arising -through active division of cells which are present in these parts. -Active migration on the part of these cells is not to be observed. They -do not appear to wander far from the location where they are found -during the acute process. The plaque may enlarge by proliferation and -thus enlarge the extent of the involved area. We have failed to find, -however, that these cells migrate into the lowermost portion of the -intima or into the media. The possibility that these cells do arise from -the endothelium lining the blood vessels has, up to the present, not -been excluded. If such is the case, the cells appear to adopt a function -which is not commonly observed in normal arteries nor present in the -endothelial cells lying immediately above the fatty plaque. - -We have searched various arterial systems in the cases of acute epidemic -influenza for inflammatory lesions lying in the adventitia and media. -These, up to the present, we have not discovered. Some years ago a -number of French authors reported the development of acute -non-suppurative influenza lesions in the outer coats of arteries which -at times had aneurysm as the outcome. These cases, however, occurred -during non-epidemic periods, when the type of influenza of which the -patient suffered was quite different from that seen in pandemics. As far -as we know none of the reported cases of arteritis and aneurysm -occurring under these conditions has shown the presence of the influenza -bacilli in the arterial lesion. It is possible that sporadic influenza -has complicating secondary infections which are of importance in -localizing in the arterial wall. - -Occasional reports have been made upon the occurrence of thrombosis -immediately following an attack of influenza. These thromboses have -occurred in diverse regions, the brachial, femoral, the mesenteric, and -other arteries. It is possible that the development of the deep -hemorrhagic lesions of muscles in the extremities are associated with -thrombosis. It is impossible, however, to demonstrate within such blood -masses the presence of thrombosed vessels which had preceded the -hemorrhagic state. It was, however, possible to demonstrate capillary -thromboses through the lung and in the submucosa of bronchi and trachea. -In these instances the damage to the vascular walls was brought about by -the action of the infection immediately surrounding them, and was not -associated with a process beginning within the lumen of the channel. The -type of thrombosis within the lung to which we have referred in a -previous discussion is interesting in that it does not show the usual -type of fibrin clotting, but in place of fibrin threads a gummy -homogeneous material is deposited upon the vessel walls within which the -red blood cells soon undergo dissolution. It would appear that these -thromboses within the lung are dependent upon a toxic action on the -vessel wall and its plasma content. - -Thromboses within venous channels are met with more often than in -arteries. The veins of the lower extremities are most frequently -affected, and yet amidst the many cases of influenza it is an unusual -occurrence. The various thromboses of larger vessels usually occur as -post-influenzal complications rather than as accompaniments of the acute -disease. It is possible that factors other than those present during the -acute stage play an important part, and that the virus of influenza is -not directly the cause of the thrombosis. - - - _Lymphatics of Lung and Mediastinum_ - -One of the prominent reactions which was almost constantly present as -the inflammatory reaction involving the lymphatic system of the chest. -The lymph glands within the chest responded to a marked degree in -hyperplasia and commonly showed enlargement quite out of proportion to -what is usually observed in lobar pneumonia. These reactions were in -direct relation to the inflammatory processes of the lung and appeared -to be involved in proportion to the inflammation occupying the tissues -drained by them. Elsewhere in the body the lymph glands responded but -slightly, and often no change was observed in the lymphatics of the -abdomen, axilla and lower extremities. The systemic intoxication thus -had no effect upon distant lymph glands, and even the presence of -micro-organisms in the circulation did not appear to cause responses in -these tissues other than in the neighborhood of the chest. Within the -chest the lymphatic system became involved through the presence of the -various bacteria migrating along the lymphatic channels as well as -through its activity in removing products of inflammation. - -The response of the thoracic lymphatics, including those within the lung -and mediastinum, is observed in all stages of pneumonia. But in epidemic -influenza the reaction was much more prompt, appearing in the early -stages and rapidly developing tissue changes along the channels and in -the lymph nodes. The lymph channels during the period of the early -serous pneumonia became dilated and filled with fluid with relatively -few cells. The stroma immediately surrounding became œdematous, so that -in the gross specimen the connective tissue between the lobules of lung -were sometimes easily seen as gray strands. At this time this tissue was -not increased in quantity and did not project above the level of the cut -lung. The fibrous tissue remained soft and pliable, but formed quite -wide strands. When the pulmonary reaction became hemorrhagic, red blood -cells, leucocytes and large mononuclears were found mixed with the fluid -in the lymphatics. We had no way of determining the direction of the -lymph flow from the pulmonary tissues, but it was assumed that as there -was no excessive loss of serous fluid from the lung and the lymphatics -beneath pleura into the chest cavities that the fluid was draining -through the channels lying about the bronchi and vessels. The further -evidence of the direction of flow was seen in the rapid and comparable -responses which occurred in the lymph glands along these routes. The -glands about the bronchi and at the hilus became enlarged, red and -succulent. The glands were often two and one-half centimeters in -diameter. Their capsule was thin and stretched and the gland was quite -soft. Many of them when cut open were almost diffluent. - -This acute lymph hyperplasia occurred in 30 of our cases. It is -impossible to indicate any particular type of infection as being -responsible for these lymphatic lesions. The nature of the bacteria -present in these 30 cases differed quite considerably: 25 showed -influenza bacilli, 15 pneumococci, 18 streptococci, 8 M. catarrhalis and -17 staphylococci. In as much as the pulmonary reaction was fairly -constant in certain characteristics in all of our cases, and as we -believe that the influenza bacilli were the very important factor in -these reactions, it would appear that the lymphatic responses are only a -part of the general inflammation of the respiratory organs. Comparison -can also be made of the character of the lymphatic changes with that -occurring within the pulmonary tissues. The lymphatics were filled with -fluid which dilated all the available sinuses; the lymph nodes were -œdematous and within them the reaction often had numerous small -hemorrhages. - -The lesion within the lymph nodes following the early serous -inflammation was of a non-suppurative kind. The lymph follicles lost -their outline, and the lymphocytes were diffused through the stroma so -that no recognition of the germinal centers could be found. The dilated -sinuses within the lymph nodes were filled with large mononuclear cells, -of the type of endothelial cells, along with some lymphocytes and -leucocytes. Subsequently the leucocytes increased very materially so -that the lymphatic fluid became purulent. Smears obtained from larger -lymphatics showed leucocytes and varieties of bacteria. This was -particularly true in those cases where the pulmonary lesion had itself -become purulent either localized in a patchy pneumonia or with lobar -involvement. Under these circumstances focal areas of purulent -infiltration were found within the tissues of the gland occupying the -regions of the former follicles and leading to necrosis or abscess. -Where such purulent reaction and abscess formation were found within the -lymph nodes there was remarkably little reaction in the tissues of the -immediate vicinity. No attempt at the development of a pyogenic membrane -or granulation tissue was observed, though this probably does take place -in the cases recovering. - -In only one instance did we observe the development of the peculiar -fibrosis along the lymphatic channels where the freshly cut section of -lung reveals prominent and raised demarcation between the lobules. This -response has been described by MacCallum as unique for the streptococcus -inflammation of the lung. The character of the exudate within the -lymphatics with many mononuclear cells and blood is not to be considered -singular for the influenza pneumonia. It has been found that in ordinary -lobar pneumonia, as well as in the pneumonia following measles, the -early pulmonary reaction is accompanied by the dilatation of the -lymphatic channels along the bronchi, containing serous fluid, -mononuclear cells, blood and leucocytes, while occasionally thrombosis -entangling bacteria is also encountered. It would seem, however, that -the lymphatics in epidemic influenza can more readily recover their -normal character when a streptococcus infection is wanting. - -In the late purulent lesions of the lung we have encountered dilated -lymphatic channels whose yellow contents could be recognized by the -naked eye. At times this could be followed for short distances along the -bronchi as narrow yellow cords, or when cut transversely appeared as -small dots close to the bronchi or vessels. On pressure small droplets -of pus may be evacuated, or again where fibrin has led to a coagulation -of the exudate a yellow plug can be withdrawn from the channel. These -small plugs resembled the thick exudate seen within the bronchi and -often were misleading when first viewed. The distribution of the -purulent lymphatic masses was most irregular occupying only local or -patchy fields in the lung, particularly associated with the purulent -confluent pneumonia. In one instance such a lymphatic appeared to be -associated with the development of a small abscess lying close to the -bronchus. - -Too much stress cannot be placed upon the importance of the lymphatics -in all forms of pneumonia. They play an important role in the drainage -of the lung during inflammation. In the normal lung we hardly appreciate -the lymphatic distribution except in our observations upon anthracosis. -But even under these conditions when much carbon is deposited in -conjunction with the lymphatic system we do not gain a true appreciation -of the activity of the lymph channels and nodes during an acute process. -Bacteria may be demonstrated in acute infections of the lung within the -fluid and cells of the lymph channels. Less easily may we demonstrate -bacteria in the lymph nodes under similar conditions, although when -abscess has occurred their presence is readily recognized. The transport -of bacteria is accomplished not only by a passive migration of -micro-organisms in the fluid as it drains from the lung, but organisms -are also found within the leucocytes as they travel with the current. -Only occasionally have we demonstrated bacteria within the wandering -large mononuclear cells, although we have observed them in a few -instances within the cells lining the sinuses of the nodes. - -Whether the inflammation of the pleura is directly related to the -involvement of the pleural lymphatics we have not been able to -determine. In our series of cases pleurisy has not been a prominent -feature of the disease, and in many instances the grade of involvement -was so slight that it was not easily recognized by the naked eye and -showed only a slight reaction microscopically. That the presence of -bacteria within the intricate plexus of lymphatics beneath the pleura -may be responsible for the development of an inflammation of this -membrane may well be the case, and in this way simulate the mode of -transmission of the infection as seen in lobar pneumococcus pneumonia -and in the streptococcus type of infection. - - - _Abdominal Viscera_ - -The lesions occurring in the abdominal viscera were of less importance -than those within the thorax. In none of the cases of the epidemic was -the intestinal type of the disease, described in previous years, -encountered. The changes found in the various viscera were concomitant -with evidences of intoxication as observed clinically or at autopsy in -other regions of the body. We found no evidence that the bacteria of the -disease localized in the tissues of the abdominal viscera, and we were -led to believe that the alterations in morphology and function were the -result of diffusible toxins. The action of these toxins was either upon -the parenchymatous cells of the organs, as in the liver and kidney, -resulting in granular degeneration, or upon the capillaries with the -development of petechial or diffuse hemorrhage as was encountered in the -stomach, intestines and bladder. The absence of definite localized -inflammatory processes in these distant tissues, including the abdominal -lymphatics, speaks against the probability of a bacteriæmia playing an -important role in the disease. That transient bacteriæmias by the -influenza bacillus do occur has been repeatedly demonstrated, and that -the organisms associated with this bacillus may also enter the blood -stream has likewise been found. But these states are accessory to the -disease, and must be viewed as complications rather than the rule. Hence -the occasional observations by some, of bacterial inflammatory reactions -in liver and kidney must not be considered a part of epidemic influenza, -for in many cases it is wanting. The majority of lesions of the -abdominal viscera probably arise through the action of the unknown toxin -in the blood. - -In the _stomach_ and _intestines_ the lesions were of two kinds, (1) -hemorrhage and (2) erosions. Petechial hemorrhages were present in the -stomach 15 times, in the intestines 4 times. These small dots of blood -extravasation, lying in the mucosa and submucosa, differ in no way from -those observed in other acute infections and intoxications, save that -the tendency for the leakage of blood into the lumen of the viscera was -more pronounced. Often we could observe the presence of free and more or -less altered blood in the stomach and intestines, and in 12 cases the -amount was considerable, sufficient to be spoken of as melena. It is -probable that the oozing of blood takes place not only from the areas -visible to the eye as petechial hemorrhages, but also from the more -normal-looking mucosa of stomach and bowel. The tendency to hemorrhage -was not necessarily accompanied by visible alterations in the epithelial -layer of the mucosa, though at times erosions were found. When -hemorrhage could be observed, the extravasation of blood occupied the -superficial layers of stroma, causing a separation of the tissues -beneath the epithelial layer. At times the submucosa was also -infiltrated, and in one instance the musculature. The lesions were -isolated and sporadic, but always about small capillary loops. It -appeared to us that the damage was primarily upon the vascular tissues -and particularly upon the endothelial walls of the fine channels. -Inflammation was not present, and the hemorrhage was more or less -passive—that is, a slow oozing rather than acute hemorrhage by rhexis. - -The second type of lesion of the gastro-intestinal canal was erosion. -This was of the nature of a defect in the mucosa, usually multiple, -small and well circumscribed. The tissue loss was superficial. In their -appearance these lesions were similar to those encountered in these -parts in other infections, and also as described by McMeans in -experimental infections of animals. The erosions appear to arise in a -process of bland necrosis, limited in the periphery by healthy tissue -and not tending to enlarge. It is probable that these erosions are -associated in their development with the petechial hemorrhages, being a -sequel to the vascular disturbance of the mucosa and subsequent -digestion of the injured tissue. Multiple lesions of the stomach were -found 10 times and twice in the intestine. The largest was 1.25 cm. in -diameter. They are more common on the posterior than anterior wall, and -usually toward the lesser curvature. It is probable that these defects -are limited in their progress and heal readily. - -The changes occurring in the _liver_ were not of striking account. -Cloudy swelling was observed 13 times, usually of moderate grade. The -usual appearances with enlargement of the organ, bulging of the -parenchyma on section and a dull gray cut surface were all that could be -found. The one case with icterus was the only one in which the natural -discharge of bile from the liver was interfered with through the -swelling. Even in this case the obstruction to the outflow of bile in -the small channels was not demonstrable in the microscopic sections, nor -was there evidence of unusual bile staining of the liver-points -suggesting the possible origin of the icterus in an unusual hemolysis. -On no occasion did we meet with recent inflammatory reactions in the -gall bladder or bile ducts, and we have no evidence that the organisms -of the infection are discharged from the body by these routes. The -cloudy swelling of the liver was accompanied by slight œdema of these -tissues in seven cases; and in six instances focal necroses were -observed. These focal necroses were similar in appearance to those seen -in typhoid fever, but were much less frequent in the tissue. Only -careful search revealed isolated pinhead gray dots with depressed -centers. They were most commonly in the mid-zone of the lobule, and in -the early stage were without inflammatory reaction. Subsequently, -leucocytes infiltrated the area, but not in an amount to form pus. -Bacteria were never demonstrated in the areas of focal necrosis. Four -cases showed old adhesions about the gall bladder and in one a gall -stone was present. - -Lesions of the _pancreas_ were not encountered. In a few cases the lymph -glands about the head of the pancreas were slightly enlarged. - -The _spleen_ showed relatively little reaction and in only two cases was -it enlarged. Fourteen times a diagnosis of acute splenitis was made on -examination of the gross specimen. This diagnosis rested upon the -finding of a swollen spleen with tense capsule and with a dark bulging -pulp. The Malpighian bodies were usually in part or completely -obliterated, though in a few instances these grayish nodules seemed even -larger than normal. These spleens contained an excess of blood within -the pulp. In one case several isolated areas appeared hemorrhagic as if -a local rupture of the tissues had occurred. The microscopic examination -of these specimens showed mainly a marked congestion of the sinusoids, a -diminution in the size of the lymphoid corpuscles and some increase in -the number of leucocytes within the blood spaces and reticulum. Only -occasionally did we observe a proliferative reaction of the large -mononuclear cells lying in the reticulum. This proliferation was not -sufficiently marked nor uniformly present to be considered as -characteristic. We did not find abnormal deposition of blood pigment -indicating an unusual destruction of red blood cells within the spleen. -It is interesting to note that 5 of the 32 cases showed obsolete miliary -tubercles in the spleen. - -Our analysis of the changes occurring in the _kidney_ bore out the -clinical findings observed in the wards. Like in so many acute -infectious diseases urinary changes were commonly present. These are in -part dependent upon systemic changes in the metabolism of tissues and -not entirely the result of renal lesions. In acute epidemic influenza -there was no common characteristic in the urinary output. The amount -excreted in 24 hours was usually diminished to a small extent, the color -was darker, the specific gravity slightly increased, as well as the -total solids. There was no marked change in the total quantity of output -of any one of the constituents as far as they were analyzed by us. -Albumin was present in the urine in variable amounts and in the more -severe cases casts were also present. There was only one case in which -the quantitative output was much diminished and where some fear was -entertained of development of acute uremic manifestations. This -individual, however, died before these made their appearance and before -there was any evidence that the retention of waste products was causing -definite clinical symptoms. - -In 30 cases coming to autopsy more or less cloudy swelling was to be -observed in the kidney. This reaction varied from a very mild swelling -and granular degeneration of the tubules of the cortex to a decided -parenchymatous degeneration with loss of nuclear structure and erosion -of some of the cells lining the tubules. The convoluted tubules were -always most markedly involved. Occasionally this tubular degeneration -was accompanied by a desquamation of the lining cells of the glomerular -capsules. We were, however, unable to recognize an acute inflammatory -reaction in the interstitial tissue or in the glomeruli in any of the -cases, except the one which had developed a streptococcus bacteriæmia as -a sequel to an otitis media. The kidney lesion reminded one very much of -the toxic lesion which is observed in the kidney in typhoid fever. -Differing, however, from the latter there was a variable congestion of -the fine vessels associated with the cyanosis which was present in a -certain percentage of these cases. At times the kidneys were quite wet -with blood from the venous engorgement. - -The lesions in the kidney were of a toxic type and did not resemble -reactions following the presence of the bacteria in the stroma of the -organ. In the majority of instances in other diseases where bacteria -themselves locate in tissues we are able to recognize focal lesions of -acute necrosis or inflammation. In epidemic influenza where a variety of -micro-organisms within the lung are able to reach distant structures in -a bacteriæmia, we would, because of their type, expect to find -inflammatory reactions of a definite kind. The absence of such reactions -is very suggestive that the bacteria do not commonly localize in the -kidney, but that their toxins alone affect it during its elimination. We -have also entirely missed the finding of any vascular lesions in the -renal system. Neither degeneration nor inflammatory reactions of any of -the coats of the blood vessels could be distinguished. - -The partial incapacity on the part of the kidneys must, therefore, be -viewed as a complication resulting from the effect of a diffusible toxin -reaching them by the blood stream. The damage performed in this manner -may be quite extensive upon the secreting tissues of the tubules leading -to an increased or decreased output of the urinary constituents. Because -of the nature of the lesion, it is probable that the kidney damage -incurred during the acute epidemic influenza is only temporary and not -permanent. Tubular degeneration is readily repaired, and in the absence -of an inflammatory reaction in the interstitial tissue or the glomeruli -avoids the development of a permanent mark or derangement in the system. -This is as we find it in typhoid fever. - -In two cases we observed very interesting lesions in the _bladder_. -These two individuals during life had been excreting markedly -blood-stained urine for some days preceding death. In the one case the -hemorrhage was so marked that on standing, about one-tenth of the urine -was composed of sedimented red blood cells. It was assumed that the -hemorrhage was of kidney origin until the autopsy revealed a simple -cloudy swelling of the kidney associated with a hemorrhagic state of the -submucosa of the bladder. In both cases the posterior wall of the -bladder was heavily infiltrated with blood so that the mucosa was raised -from the surface and the prominent folds showed a superficial erosion -with small points of greenish necrosis. This bladder hemorrhage was -concomitant with hemorrhagic foci elsewhere in the body, pericardium, -pleura, stomach and intestine. Alone in the bladder however, the -hemorrhage formed a distinct mass and allowed a considerable escape from -the lesions on the surface. These areas of hemorrhage were not infected -and showed no local inflammatory reaction. They also appeared to be -toxic in origin and resembled the hemorrhages occurring in the muscles -of the abdomen. - -Changes in the _adrenal_ gland were noted in 14 instances. In all of -these there was the picture of what is commonly known as cloudy swelling -of the cortex and, in addition to this, in three cases small petechial -hemorrhages were observed. The so-called cloudy swelling of the adrenal -consists largely in a loss of the bright golden appearance of the -cortical tissues accompanied by soft œdematous swelling. The tissues -change color to a brown or clay color, and it is not uncommon to observe -that the inner zone of pigmentation is more diffuse. There is no sharp -demarcation between the layers of the cortex. With this alteration in -the outer structure of the adrenal, the medulla not uncommonly appears -smaller. This change is more apparent than real, and we have not been -able to observe any definite lesion in the nervous portion. At times we -believed that the inner tissue appeared more cellular, but it was not -possible to determine any specific alteration in the cells. - -The changes in the adrenal cortex are comparable to those observed in -typhoid fever. The analyses of these tissues showed that the cells were -almost devoid of cholesterin bodies and few doubly refractile globules -could be demonstrated. This change in the adrenal is by no means -specific for any acute disease, it being found in many of the severe -infections. We regret that systematic analysis of the blood serum in -these cases was not made to determine the cholesterin content. If the -comparison bears out with typhoid fever, we would expect to find that -the quantitative cholesterin of the blood is diminished. Some importance -attaches itself to the study of the cholesterin metabolism, particularly -in regard to the development of the peculiar fatty streaks which develop -in the aorta and other arteries during these acute infections. It has -been claimed that in the human these streaks bear an analogy to those -produced in the experimental animals and that the arterial lesions are -associated with an altered activity on the part of the adrenal cortex in -handling the cholesterin compounds. In influenza there is evidence that -the adrenal does not function in a normal fashion and that the storage -of cholesterin-esters does not take place. From this, however, we cannot -conclude that the blood content is increased, and, in fact, it is more -than probable in comparing the other reactions of the disease that it -follows the changes as seen in typhoid fever where the blood content of -cholesterin is lowered. In this way comparison with the experimentally -produced arterial lesions in animals is not clear, in as much as in the -experimental work a true hypercholesterinemia was induced. Nevertheless -it is possible that with the abnormal function on the part of the -adrenal the cholesterin materials are made more available for absorption -by other tissues and that a true hypercholesterinemia is not necessarily -a constant factor, even with the abnormal accumulation of these -substances in the intima. It may well be that the normal activity of the -adrenal is related to the presence of toxins in the circulation and an -attempt by mobilizing cholesterin to diminish the activity of these -harmful substances. - - - OBSERVATIONS UPON THE PATHOLOGY OF EIGHTEEN CASES OF INFLUENZA - - By J. W. MCMEANS - -The recent epidemic of influenza has afforded a series of interesting -autopsies in view of the very extensive and peculiar involvement that -occurred in the lungs of the cases examined. Ordinary lobar pneumonia, -as we know it, was not observed, although it must be said that the lungs -many times exhibited a consolidation of a lobar distribution. The usual -dry granular lung of the more common pneumonia was absent, and in its -stead a most unusual series of pictures was observed in the several -cases. A common feature of all cases was the œdema of the lung tissue, -which in the majority of instances contained such an amount of fluid -that it ran freely from the cut surface in almost unlimited quantity. -This fluid varied in its color and consistence depending upon the age of -the process. In the very early cases the lungs were boggy, very -congested, and a thin serosanguinous fluid poured forth from the cut -surface. It actually appeared as though the fluid within the tissue was -under considerable pressure. At times blotchy deep red hemorrhages -occurred in the lung substance, and hemorrhages of a bright red color -were not infrequent in the pleura. That the circulation of the lungs was -much embarrassed was often prettily demonstrated by the dilatation of -the fine capillaries and lymphatics beneath the pleura. These small -vessels stood out prominently as a meshwork more or less outlining the -areas supplied by them. Not only was the peculiar consolidation in lobar -arrangement, but also in many cases was there evidence of a lobular -distribution. Even in some cases where the entire lobe was consolidated -the cut surface presented a peculiar lobulation with patches of lung -tissue projecting above the general surface. The wet trabeculated -structure of the lung in this stage did not give the impression of true -red hepatization, but rather a structure resembling spleen and at times -a meaty, compact, glassy picture not unlike thyroid. - -As the process advanced the appearance of the lung changed from deep red -to yellowish red and finally to a quite yellowish gray color, still -retaining, however, the very moist characters. The fluid found in the -lung changed its consistency from the thin red type to a sticky, glairy -variety which could be pulled out in long strings. It was noted that the -change in the character of the fluid was accompanied by similar changes -in the lung structure, advancing in two cases to abscess formation of a -grape-bunch type. Here there was a rather extensive necrosis and -cavitation of lung substance in communication with the bronchioles. -However, there was also marked softening and necrosis of lung in a -number of cases where abscesses did not develop, but the lesion was so -advanced that the lung substance was almost diffluent. An accompaniment -of these advanced cases were irregular yellow islands which appeared -beneath the pleura. At times they reached the size of a circle 2 cm. in -diameter and were slightly raised above the surrounding pleural surface. -When these were opened they were found to be areas of softened lung -substance. This reaction was so extensive in some lungs that it -resembled to a degree the appearance of a caseous pneumonia. However, -the former process appeared to be brought about by the interference with -the lymphatic drainage, as it was not uncommon to see engorged yellow -channels beneath the pleura as well as enlarged lymph nodes at some -distance from the hilus. Another feature of the advanced cases were the -plugs of ropy yellow material which were contained within the -bronchioles, while in the early cases the bronchi and bronchioles showed -intense congestion of the mucosa with blood-stained fluid in their -lumina. - -Of the more unusual reactions observed in the lungs an infarct was found -occupying a considerable part of the lower left lobe in one case. There -was a marked softening of the lung tissue with reddish, mucky-looking -lung substance arranged about small irregular cavities. This reaction -extended into the lung for a distance of 4.5 cm. Bordering close on -these softened areas there was a dry mottled yellowish gray and deep red -lung tissue. Surrounding this area again were noted a number of small -blood vessels in which there were found yellowish granular plugs. One -plug in a vessel was found at a distance of 3 cm. from the base of the -lobe, and another was found at a distance of 8 cm. from the apex of the -lobe. On further examination it was observed that the base of this -softened area was situated on the pleural surface and that the apex was -directed inward about a distance of 6 cm. from the pleura. Bathing the -cut surface there was a glairy and very sticky material of a reddish -yellow color. Near the apex of this softened area in the lung there was -found a vessel about the size of a goose-quill in which there was a -grayish yellow granular plug. This plug was adherent to the vessel. -Within the small bronchioles there were plugs of a soft yellowish brown -material. The striking feature in addition to the softening of the lung -in a number of places was the glairy material of a sticky nature which -bathed the cut surface. A white infarct was present in the spleen. The -lung described above as well as another showed gangrenous change. In the -second of these two abscesses had formed, and there was a communication -between the lung and pleural cavity in which there was a large amount of -sanguino-purulent fluid and a pyopneumothorax. - -In a description of these reactions it must be added that the early and -late changes were not always observed independently, but in most cases -occurred together, giving the lung a peculiar mottled red and yellow -glassy appearance. More frequently the congested œdematous reaction was -observed singly, while the purulent alteration usually was in -combination with the former type. The acute serous pneumonia was noted -13 times, 6 times in combination with the purulent reaction and 7 times -alone, while the acute purulent pneumonia was found in 9 cases, 3 times -alone and 6 times with an acute serous process. In all but 3 of 18 cases -there was evidence of a bronchial distribution. Two of these three cases -showed a massive œdematous lung with in one case an extensive -hemorrhage, while the third presented an advanced purulent reaction with -marked necrosis and softening. An acute bronchitis which varied in -character from a hemorrhagic to a purulent one was present in all the -cases. The reaction observed within the bronchi in the individual cases -corresponded closely to the picture found in the lungs. - -In all cases except one there was an exudate in one or both pleural -cavities. A serofibrinous pleurisy was noted in 11 cases with, in 2 of -this number, a fibrino-purulent reaction present in the opposite pleural -cavity, while fibrino-purulent pleurisy occurred alone in 6. In 6 cases -pleurisy occurred on one side only with the incidence equally divided in -each cavity. Both pleurae were involved in 9 cases. Seventeen of the 18 -cases showed both lungs involved. One case was an individual who had had -clinical influenza and during convalescence developed gangrenous colitis -and acute ascending myelitis which terminated fatally. B. influenzæ was -isolated from the bronchioles in the lung of this individual. - -The reaction of the body generally was evidenced by a widespread -distribution of petechial hemorrhages over serosal and mucosal surfaces. -However, certain other important lesions were noted such as one acute -vegetative mitral endocarditis, two acute serofibrinous pericarditis, -three cases in which focal necroses were prominent in the liver and two -examples of infarct of spleen. Further, there were four cases of slight -dilatation of the right heart. The liver was usually swollen and -œdematous and the spleen presented evidence of an acute reaction, -softening and reddening of its pulp with at times slight enlargement. - -As evidence of the virulent character of the infection from which these -patients suffered, there was not only present in the lung a peculiar -hemorrhage and purulent process, but also a more or less widespread -distribution of hemorrhages in other parts of the body. The -gastro-intestinal tract was most affected with the stomach showing -petechial hemorrhages in 17 of 18 cases and the small intestine in 15 of -the same number. In the gastric mucosa of three cases there were -definite erosions, while in two instances the duodenum presented an -intense œdematous and hemorrhagic appearance of its mucosa. Further -hemorrhages were observed on one occasion each in the mesentery and in -the mesenteric and retroperitoneal lymph nodes. In the latter the -mesenteric glands were so distended with hemorrhages that a soft pulp -spurted out when the glands were sectioned. Next in order of frequency, -hemorrhages were noted 9 times in the pleura, 8 in the pelvis of the -kidney, 6 in heart muscle and 3 each in pericardium and bladder. In one -case of widespread distribution of petechial hemorrhages there was a -massive loose hemorrhage into the lower recti abdominis. Further another -case showed a large amount of a blood-stained fluid in the peritoneal -cavity. - - - _Summary_ - -In the analysis of the cases of acute epidemic influenza two important -features of the disease present themselves, (1) a marked systemic -intoxication with localized manifestations in certain organs, and (2) -inflammatory lesions of the respiratory tract. These manifestations -present themselves both to the clinician and to the pathologist, and to -each they have demonstrated their importance in the disease. The -pathologist not in touch with the clinical manifestations of the toxæmia -has more closely linked the occurrence of these two factors with the -actual findings in the cadaver. But there are those who look upon these -factors as separate and distinct, viewing the toxæmia as an individual -process and as illustrating the uninvolved influenza, while the -inflammatory reaction of the respiratory tract is taken to be a -complication arising through the activity of secondary invading -organisms. This is the view held by MacCallum, who compares influenza -with the acute exanthemata wherein the respiratory lesions are but -secondary to the production of a lowered resistance and an invasion by a -variety of bacteria. Such confusion presupposes an undetermined virus -for influenza. In confirmation to such views we have the reports upon a -filterable virus. Up to the present, however, the latter has been on -insecure grounds. - -It would appear to us that, as has been discussed by Dr. Holman, the -case against the B. influenzæ not being the important causative agent -has not been proved. The demonstration by others of a potent toxin from -the B. influenzæ cannot be overlooked, and although the actual disease -has not been reproduced in animals, there is evidence that this toxin -will induce acute degenerations in various tissues. Furthermore, the in -vitro symbiotic relation demonstrated for the B. influenzæ with other -organisms, as the pneumococcus, streptococcus, staphylococcus pyogenes -aureus and M. catarrhalis, gives ample support to the claim for a -similar symbiosis in the human tissues. The evidence for the important -primary relation of the B. influenzæ to epidemic influenza is such that -we cannot disregard it—at least, not before we can produce some definite -positive evidence that another demonstrable virus precedes it and -produces those constitutional effects which initiate the remaining -sequelæ. - -We must agree with Christian in the statement that all cases dying -during the acute stage of epidemic influenza have inflammatory lesions -in the respiratory tract and largely in the lung (pneumonia). It is -difficult to conceive of a disease comparable to the acute exanthemata, -which beginning as a separate and distinct process ends fatally within -48 hours with a pneumonia which is claimed to be secondary. - -Epidemic influenza is an acute infectious process of the respiratory -tract, usually localizing in the upper respiratory system, but often and -in a fairly constant percentage of cases extending into the lower -portion of the same system and causing a type of broncho-pneumonia. -Accompanying the initial invasion there is a marked systemic -intoxication with lesions of degeneration arising in a variety of -tissues. These lesions of degeneration are to be seen both locally in -the respiratory system as well as in distant parts, as in the muscles, -kidney and liver. The primary damage arising in the respiratory organs, -and which we believe to be the result of infection by the B. influenzæ, -facilitates attacks by such other bacteria as are available and -pathogenic to man. The secondary invaders are not constant in type, but -we find variations according to the localities where the epidemic takes -place. Just as there is a difference in the bacterial flora which -constitutes the secondary invasion, so, too, there is a variation in the -picture of the inflammatory process which appears in the lungs. The -occurrence of the miliary streptococcal broncho-pneumonia has been met -with in certain localities much more frequently than in others; lobular -and confluent pneumonia has been the prevailing type in certain regions, -while a lobar purulent pneumonia with abscess and gangrene was most -frequent with others. There does not appear to be an individual and -constant character in the mode of distribution of the pneumonia in the -lungs. That the pneumonias were not the usual type otherwise seen, is -fairly agreed upon by all. The most astonishing feature presenting -itself to us was the frequency of death occurring in the early stages of -the inflammatory process and before the gray stage had definitely -developed. The gray stage of influenza pneumonia is a purulent pneumonia -which often also constitutes an acute interstitial pneumonia. - -The extensive hemorrhage and inflammatory œdema of the lung are striking -during the early stages of the lung involvement. The mononuclear -infiltration which appears early and remains for a variable time, until -the purulent process is well under way, is also unique. The hyaline -deposit in the lung alveoli; the capillary thrombosis and necrosis of -the alveolar walls and bronchi are important; while the tendency to -abscess, infarct, gangrene and incomplete resolution with fibrosis -differentiates this type of pneumonia from the common lobar variety. - -As an organic evidence of the acute intoxication, none stands out more -prominently than the degeneration of the voluntary muscles. These -resemble the waxy degeneration of other bacterial intoxications, and -particularly that of typhoid fever. The finding of these acute -degenerations does not assist us in arriving at a conclusion as to the -nature of the poisonous body, whether a true exotoxin. The presence, -however, of such widespread degenerative lesions in cases showing no -naked eye change suggests, at least, that the peculiar muscle weakness -associated with pain has its origin in this definite process and not in -primary nerve lesions. - -Very interesting it is that the different muscular structures are not -equally affected by the intoxication. This is particularly noteworthy in -the heart and intestine. In neither of these structures have we met with -lesions comparable to those in the voluntary muscles. Wherein this -immunity resides we cannot state. In our own series, as well as in the -majority of others, there was an unusual absence of evidence of -myocardial weakness. In most of those dying during the acute illness, -the heart muscle was found firm and the cavities not dilated. This -finding was in striking contrast to that found in acute lobar pneumonia -where dilatation of the right ventricle and auricle, along with muscle -degeneration, is almost the rule. In but one case of the present series -did we find myocardial degeneration leading to dilatation of the -cavities and causing death. And in this particular case the intoxication -was due to a streptococcus septicæmia arising as a late sequel from the -middle ear. The heart in influenza withstands remarkably well the -effects of an intoxication from the disease and carries the extra load -imposed upon it by the involved lung with little evidence of fatigue. - -It is also worthy of attention to note that the kidney suffers so little -in this severe disease. Bacterial localization with inflammatory -concomitants does not occur, and there is no lasting damage upon its -structure. As in so many conditions of bacterial poisoning, tubular -degeneration, varying from a cloudy swelling to a more acute damage, is -to be found in a percentage of cases, but complete restoration is -rapidly obtained in convalescence. It is unusual to find such severe -renal damage to incapacitate function to a degree to endanger life. - -Finally we can add our evidence, gained from a study of the pathology of -epidemic influenza, that the primary disease induced by the invasion of -the B. influenzæ opens the way for secondary infections of a variety of -kinds, whose subsequent effect may be more serious than initial lesions. -The many late complications which arise in this manner we have not -investigated. - - - BIBLIOGRAPHY - - Abrahams, Hallows and - French Lancet., 1919; i, p. 1. - Advisory Board to the - D. G. M. S Brit. Med. Jour., 1918; ii, p. 505. - Blanton and Irons Jour. A. M. A., 1918; lxxi, p. 1988. - Boggs Johns Hop. Bull., 1905; xvi, p. 288. - Brooks and Cecil Brit. Med. Jour., 1918; ii, p. 496. - Chickering and Park Jour. A. M. A., 1919; lxxii, p. 617. - Christian Jour. A. M. A., 1918; lxxi, p. 1565. - Cole Brit. Med. Jour., 1918; ii, p. 566. - Cole Canadian Med. Assoc. Jour., 1919; ix, p. 41. - Dever, Boles and Case Jour. A. M. A., 1919; lxxii, p. 265. - Fildes, Baker and - Thompson Lancet., 1918; ii, p. 697. - Fletcher Lancet., 1919; i, p. 104. - Friedlander, McCord, - Sladen and Wheeler Jour. A. M. A., 1918; lxxi, p. 1652. - Goodpasture and Burnett U. S. Naval Med. Bull., 1919; xiii, No. 1. - Hall, Stone and Simpson Jour. A. M. A., 1918; lxxi, p. 1986. - Hunt Lancet., 1918; ii, p. 419. - Keegan Jour. A. M. A., 1918; lxxi, p. 1051. - Kuskow Virchows Archiv., 1895; cxxxix, p. 406. - Le Count Jour. A. M. A., 1919; lxxii, p. 650. - Lord Boston Med. and Surg. Jour., 1905; cl, p. 537. - Lyon Jour. A. M. A., 1919; lxxii, p. 924. - MacCallum Jour. A. M. A., 1919; lxxii, p. 720. - MacCallum Monog. Rock. Inst. for Med. Res., 1919; No. 10. - Muir and Wilson Brit. Med. Jour., 1919; i, p. 3. - McMeans Archives of Int. Med., 1917; xix, p. 709. - Nuzum, Pilot, Stangl - and Bonar Jour. A. M. A., 1918; lxxi, p. 1562. - Oertel Canadian Med. Assoc. Jour., 1919; ix, p. 339. - Opie, Freeman, Blake, - Small and Rivers Jour. A. M. A., 1919; lxxii, p. 556. - Speares Boston Med. and Surg. Jour., 1919; clxxx, p. - 212. - Stone and Swift Jour. A. M. A., 1919; lxxii, p. 487. - Symmers Jour. A. M. A., 1918; lxxi, p. 1482. - Synnott and Clark Jour. A. M. A., 1918; lxxi, p. 1816. - Torrey and Grosh Amer. Jour. Med. Sci., 1919; clvii, p. 170. - Weber British Med. Jour., 1919; i, p. 8. - Wittingham and Sims Lancet., 1918; ii, p. 865. - - - - - EXPLANATION OF PLATES - - - Fig. i. Cyanosis of head and neck. - - Fig. ii. Acute tracheitis with desquamation of epithelium and - superficial necrosis. - - Fig. iii. Acute serous and hemorrhagic pneumonia. - - Fig. iv. Acute serous pneumonia with massive hemorrhage. - - Fig. v. Acute hemorrhagic and purulent lobular pneumonia. The - purulent process is seen to be advancing from the focal - type to the more diffuse lobar by fusion of the - neighboring lobules. - - Fig. vi. Acute purulent pneumonia. - - Fig. vii. Lobular fibrosing pneumonia. In this specimen the patches of - new scar tissue formed irregular islands. The final stage - of contraction of the scar had not taken place. - - Fig. viii. Acute serous pneumonia with some infiltration by mononuclear - cells. - - Fig. ix. Acute hemorrhagic pneumonia. - - Fig. x. Hyaline deposits upon alveolar walls. In some areas the wall - itself has suffered necrosis. - - Fig. xi. Acute purulent pneumonia. In other areas of the same lung - the interstitial infiltration by leucocytes was more - intense. - - Fig. xii. Acute lymph adenitis, showing the unusual numbers of - endothelial cells while leucocytes are relatively - infrequent. - - Fig. xiii. Rupture of abdominal rectus muscle with hemorrhage. The - degeneration antecedent to the rupture is shown in the - belly of the muscle. - -[Illustration: Fig. i] - -[Illustration: Fig. ii] - -[Illustration: Fig. iii] - -[Illustration: Fig. iv] - -[Illustration: Fig. v] - -[Illustration: Fig. vi] - -[Illustration: Fig. vii] - -[Illustration: Fig. viii] - -[Illustration: Fig. ix] - -[Illustration: Fig. x] - -[Illustration: Fig. xi] - -[Illustration: Fig. xii] - -[Illustration: Fig. xiii] - ------------------------------------------------------------------------- - - - - - TRANSCRIBER’S NOTES - - - 1. Silently corrected typographical errors and variations in spelling. - 2. Anachronistic, non-standard, and uncertain spellings retained as - printed. - 3. Footnotes have been re-indexed using numbers. - 4. 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