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EPIDEMIC RESPIRATORY DISEASE
The Pneumonias and Other Infections of the Respiratory Tract Accompanying Influenza and Measles

BY

EUGENE L. OPIE, M.D.

COLONEL, M. R. C., U. S. ARMY; PROFESSOR OF PATHOLOGY, WASHINGTON UNIVERSITY SCHOOL OF MEDICINE

FRANCIS G. BLAKE, M.D.

MAJOR, M. R. C., U. S. ARMY; ASSOCIATE MEMBER OF THE ROCKEFELLER INSTITUTE FOR MEDICAL RESEARCH

JAMES C. SMALL, M.D.

FORMERLY FIRST LIEUTENANT, M. C., U. S. ARMY; BACTERIOLOGIST, PHILADELPHIA GENERAL HOSPITAL

THOMAS M. RIVERS, M.D.

FORMERLY FIRST LIEUTENANT, M. C., U. S. ARMY; ASSOCIATE IN BACTERIOLOGY, JOHNS HOPKINS UNIVERSITY

ILLUSTRATED

ST. LOUIS

C. V. MOSBY COMPANY

1921

Copyright, 1921, By C. V. Mosby Company

Press of

C. V. Mosby Company

St. Louis, U. S. A.

INTRODUCTION

Death from lobar pneumonia, bronchopneumonia and measles, fatal with few exceptions in consequence of complicating pneumonia, constituted in 1916 approximately one-sixth (16.8 per cent) of the mortality in the army,[^[1]] whereas in 1917 the same diseases were responsible for nearly two-thirds (61.7 per cent) of all deaths. During the first half of 1918 the incidence of pneumonia steadily increased and in some army camps there were extensive outbreaks of unusually severe pneumonia.

In July, 1918, the Surgeon General assigned a group of medical officers to the study of the pneumonias prevalent in the army and stationed them at Camp Funston, Kansas. At the base hospital of this camp all cases of pneumonia occurring among troops assembled in the camp were studied, but during the month of August there were few cases of pneumonia and these were of mild type.

Pneumonia which occurred at Camp Funston during August was almost wholly limited to recently recruited colored troops from southern states (Louisiana, Mississippi). There was a low rate of mortality, and few complications. This pneumonia exhibited a noteworthy difference in etiology from that usually seen in civil life, for it was associated with a high incidence of those types of pneumococci which occur in the mouths of healthy men, namely, Pneumococcus atypical II,[^[2]] Type III, and the group of microorganisms represented by Type IV. Pneumococcus Type I was encountered in only a few instances and Type II was not found, although these two microorganisms are responsible for two-thirds of the lobar pneumonia which occurs in civil life.

During the investigation at Camp Funston the Commission had the courteous cooperation of Major Willard Stone, Director of Medical Service, and received much valuable assistance from Lieutenant A. McGlory, Registrar of the Base Hospital.

A review of the accurately compiled records of the base hospital was made in order to obtain a history of the pneumonias and other respiratory diseases which had occurred throughout the existence of the camp, established in September, 1917. It soon became evident that a disease recognized as influenza had been prevalent throughout this period and its incidence had shown a close parallel with that of acute bronchitis. At the same time there had been much pneumonia and a high death rate from this disease. The chart[^[3]] which was constructed showed that the disease which had been designated influenza assumed epidemic proportions in March, 1918. Any doubt that may have been entertained concerning the nature of the disease is dispelled by the characters of this epidemic which, beginning at the end of February, reached its height on March 12 and rapidly subsided; 1,127 men with influenza entered the base hospital between March 4 and March 29 and many more were treated in the infirmaries of the camp. In April there was a second wave of influenza and in May a third, each in large part limited to newly drafted men brought into the camp shortly before these outbreaks. Corresponding to the epidemic of influenza there was a great increase of pneumonia, reaching a maximum about one week after the height of the incidence of influenza; subsequently the incidence of pneumonia increased after each one of the secondary waves of influenza. Pneumonia following measles occurred throughout the history of the camp; in November and December, 1917, there was a severe outbreak of pneumonia following measles and the mortality was high. Our conclusions in regard to the pneumonias which occurred during the history of Camp Funston were as follows:

1. Pneumonia of a relatively stationary camp population, such as that which occurred among white troops during the period of our investigation, was in considerable part caused by Pneumococcus Types I and II and resembled the pneumonia of civil life.

2. Pneumonia of newly drafted colored troops from southern states during the period of our investigation was caused in great part by pneumococci of those types which occur in the mouths of healthy men, namely, Types IV, III and atypical II.

3. Pneumonia caused by influenza occurred after the epidemic of influenza which we have described. The report states: “With the information available it is not possible to draw a sharp line between (1) the pneumonia of the stable camp population, (2) the pneumonia of the newly drafted southern troops, and (3) the pneumonia following influenza. It is possible that influenza, in greater or less degree, also acts as a predisposing factor in the production of the first and second varieties.”

4. Pneumonia with measles was a frequent and unusually fatal type of the disease. The most important causes of pneumonia during the history of the camp were influenza and measles.

Evidence is not lacking that influenza occurred in epidemic form in other widely separated camps in the United States during the spring of 1918. Vaughan and Palmer[^[4]] state that a disease strongly resembling influenza became prevalent in the Oglethorpe camps about March 18, 1918, and continued three weeks; during this time the number sent to hospital or to quarters with this disease was 1,468 in a total strength of 28,586. Pneumonia does not appear to have followed this epidemic.

Miller and Lusk[^[5]] found the ordinary type of pneumonia prevalent at Camp Dodge, Iowa, until March 18 to 20, 1918, when abruptly the streptococcus type predominated and there was a great increase in the rate of mortality. A mild tracheitis, they state, was widespread in the camp during March.

In March, 1918, one member of our commission saw an outbreak of influenza at Fort Sam Houston which was identical in its clinical characters with the disease which appeared as a pandemic in the fall of 1918.

The report of the Surgeon General[^[6]] for 1919 shows that there was a sharp increase of the incidence of influenza in the army during March, reaching a maximum in April. The rate of influenza for 1,000 troops fell to its original level through May and June and finally rose to a great height in September and October.

Influenza in epidemic form made its appearance in the army camps of the United States during March, 1918. The symptomatology of the disease associated with its peculiar epidemiology as seen at Camp Funston make its recognition unquestionable. The disease had doubtless been present in this camp since its establishment in September, 1917, but did not assume epidemic proportions until the spring of 1919.

Pneumonia followed the epidemics of influenza which occurred in the spring of 1918 and exhibited characters similar to those of the pneumonias which followed the pandemic of September and October, 1918. In both instances the height of the outbreak of pneumonia has been one week after the maximum incidence of influenza.

Influenza became epidemic in Spain about the middle of May and in other countries received the name “Spanish influenza” which is not more applicable than the designation “Russian influenza” often applied to the disease during the pandemic of 1889–90.

The studies of MacNeal[^[7]] have shown that the first epidemic of influenza in the American Expeditionary Force in France occurred about April 15, 1918, at a rest camp near Bordeaux, reached its height on April 22 and ceased May 5. The disease was of a mild character with few complications. Localized epidemics were reported from various camps and hospitals during May and June, when the disease, MacNeal states, had become widespread in all sections of the American Expeditionary Force in France and in the French and British armies as well. Influenza had become epidemic in the Italian navy in the first two weeks of May. The belief that the disease was introduced from America, the author thinks, is “probably completely disproved by the fact that the epidemic was subsequently introduced into America in August and September and found there a most fertile soil for its spread.” This view is disproved by the demonstration that influenza had appeared as scattered epidemics in the army camps in March, 1918. There is little reason to doubt that influenza in the American Expeditionary Force was brought from America.

At the end of August our commission was transferred from Camp Funston to Camp Pike, where throughout the history of the encampment pneumonia had been so prevalent that it had given the camp the rank of third in death rate from lobar pneumonia and fourth in death rate from bronchopneumonia among 32 camps established in this country. We arrived at Camp Pike September 5 and were stationed at the base hospital. Our work was facilitated by the hearty cooperation of the commanding officer, Major Morton R. Gibbons, who neglected no opportunity to promote the investigation. Our work was cordially aided by Major Carl R. Comstock, Director of the Medical Service, and by Major Henry H. Lissner, who later occupied this position. Work in the laboratory of the hospital received the valuable cooperation of Major Allen J. Smith, Director of the Laboratory, who placed at our disposal every facility available. Lieutenant James R. Davis, who was for a time in charge of the laboratory, effectively assisted the work.

The commission consisted of the following officers: E. L. Opie, Colonel, M. R. C.; Allen W. Freeman, Major, M. C.; Francis G. Blake, Major, M. R. C., James C. Small, Lieutenant, M. C. and Thomas M. Rivers, Lieutenant, M. C. Major Freeman acted as epidemiologist and will publish a report upon the epidemiology of influenza and pneumonia at Camp Pike. On October 11 the laboratory car “Lister” in charge of Lieutenant Warren H. Butz was assigned to the commission. Lieutenant Harry D. Bailey was attached to the commission on October 14 and later assisted in its work. Valuable technical assistance was given by Sergeant Charles Behre, by Wm. E. Hoy, detailed from the Army Medical Museum, and by Thomas Payne.

Study of the pathology of the lesions concerned was completed in the Pathological Laboratory of Washington University School of Medicine.

The existence of an epidemic of influenza at Camp Pike was recognized on September 23, when 214 cases of influenza were admitted to the base hospital. Preceding this date and beginning September 1 there had been a gradual increase of the number of patients admitted with the diagnosis of acute bronchitis. It is noteworthy that the demonstration of B. influenzæ had been regarded as essential for a diagnosis of influenza and since this microorganism had not been found, instances of acute inflammation of the respiratory passages with the symptoms of influenza were classified under a variety of names.

After September 23 influenza was recognized by its symptoms. The number of cases increased with great rapidity and on September 27 reached over 1,000 per day; this number was approximately maintained during one week and after October 3 the epidemic gradually subsided. Among 52,551 men in the camp, including those who arrived during October, 12,393 were attacked by influenza; of these 1,499 suffered with pneumonia and 466 died. The height of the outbreak of pneumonia followed approximately one week after that of influenza. The statistics from September 20 to October 14 collected by Major Freeman show that pneumonia following influenza, like the pneumonia at Camp Funston during the interepidemic period, has a conspicuous tendency to select men who have been in the camp less than one month, designated in Table I as new recruits:

New recruits were nearly two and a half times as susceptible to pneumonia as men who had been in camp more than one month. This statement does not take into consideration differences in the environment and mode of living of the new men.

In view of the existing uncertainty concerning the bacteriology of influenza and its associated pneumonias, the commission has availed itself of the opportunity afforded by the epidemic of influenza to determine what bacteria were present in the nasopharynx and sputum in these diseases. The examinations have been necessarily limited to a small proportion of the immense number of patients admitted to the hospital with influenza and pneumonia. Autopsies on those who have died with pneumonia have offered a more direct means of determining the relation of bacteria to inflammation of the bronchi and lungs. An attempt has been made to classify the pneumonias following influenza and to determine their relation to the complex bacterial flora of the injured respiratory passages. These studies have shown very early the threatening prevalence of streptococcus pneumonia, and appropriate measures have been taken to combat the spread of this infection. No better illustration could be furnished to demonstrate the value of routine performance of autopsies as a means for the recognition of obscure epidemic disease.

In view of the wide difference of opinion concerning the pathology of influenzal pneumonia special study has been given to the lesions of the disease, because the epidemic has furnished the unique opportunity of examining all instances of pneumonia accurately referable to an epidemic of influenza attacking a large but definitely defined group of individuals (50,000 troops). In a civil hospital there is often great difficulty in deciding, even in the presence of an epidemic, if death from pneumonia is the result of influenza, but at Camp Pike the relation of the heightened death rate to the epidemic has excluded all save a trivial error in determining the relation of fatal pneumonia to influenza.

At the direction of Col. F. F. Russell, who has promoted the work of the commission by unfailing aid, a special study has been made of the relation of hemolytic streptococcus to the complications of measles.

During the later period of the investigation at Camp Pike experiments were performed on monkeys to determine the pathogenicity of B. influenzæ and of microorganism isolated from the pneumonias following influenza. Typical lobar pneumonia was produced in monkeys by intratracheal injection of pneumococci. These experiments are described in an appendix.

The Surgeon General has approved the publication of this report but the authors alone are responsible for the views expressed.

Eugene L. Opie.

Washington University

School of Medicine

CONTENTS

ILLUSTRATIONS

EPIDEMIC RESPIRATORY DISEASE

THE PNEUMONIAS AND OTHER INFECTIONS OF THE RESPIRATORY TRACT ACCOMPANYING INFLUENZA AND MEASLES

CHAPTER I
THE ETIOLOGY OF INFLUENZA

Francis G. Blake, M.D.; Thomas M. Rivers, M.D.; James C. Small, M.D.

The bacteriologic investigation which will be described was made at Camp Pike, Arkansas, during the period of the influenza epidemic from September 6 to December 5, 1918. The data presented are limited to observations made during life in uncomplicated cases of influenza and to control studies in normal individuals, and in cases of measles. Bacteriologic studies made at autopsy will be described in a subsequent part of this report.

Because of the wide variations in opinion concerning the relationship of various bacteria to influenza that have arisen during the progress of the recent pandemic, a brief review of the salient features of the earlier literature seems advisable. In 1892 Pfeiffer[^[8]] found a small, Gram-negative, hemophilic bacillus in all cases of influenza, often in almost pure culture, both during life and at autopsy. He stated that the organism was found only in cases of influenza or in those convalescent from the disease. Similar bacilli occasionally found in other conditions he classified as pseudoinfluenza bacilli. He furthermore showed that freshly isolated cultures were pathogenic for monkeys, producing a disease not unlike influenza, though lacking in what he considered the characteristic lung lesions. He therefore felt justified in claiming that this bacillus, which he designated B. influenzæ, was the cause of epidemic influenza. Pfeiffer’s work, though hailed by many as unassailable, has failed to stand the test of time in two respects. It has been definitely shown, by Wollstein[^[9]] in particular, that there is no justification for recognizing a group of pseudoinfluenza bacilli, organisms so classified by Pfeiffer being indistinguishable from B. influenzæ. Furthermore, numerous investigations have demonstrated that B. influenzæ may frequently be found in a variety of diseases affecting the respiratory tract and in a small proportion of normal individuals. Kretz[^[10]] found it 47 times in 950 examinations, usually associated with disease of the respiratory tract. Süsswein,[^[11]] Liebscher,[^[12]] Jehle,[^[13]] Wollstein,[^[9]] Davis[^[14]] and many others have demonstrated its presence in cases of measles. Lord[^[15]] isolated B. influenzæ in 30 per cent of 186 sputums from patients with acute and chronic infection of the respiratory tract. Boggs[^[16]] found it in frequent association with chronic bronchiectasis. Wollstein[^[9]][^[17]] showed that it was often present in the respiratory diseases of infants, and was not an infrequent cause of meningitis. Rosenthal[^[18]] found that one in six of normal individuals harbors influenza bacilli and therefore considered it purely a saprophyte, a position, of course, thoroughly untenable in the face of indisputable evidence that it may be highly pathogenic. The widely accepted statement that B. influenzæ is nonpathogenic for animals has apparently served in considerable degree to shake belief in its etiologic relationship to epidemic influenza. It would appear, however, that this opinion is not founded upon fact. Reference is again made to the work of Wollstein[^[19]], who has shown that virulent strains of B. influenzæ, when freshly isolated from the human host, are highly pathogenic for rabbits and monkeys and that nearly all strains are more or less pathogenic for mice and guinea-pigs.

None of these modifications of Pfeiffer’s original work, however, would seem to constitute any valid reason for abandoning the conception of the etiologic importance of B. influenzæ. On the contrary, they are quite in harmony with well-established facts concerning other bacteria which cause infections of the respiratory tract. Such bacteria are frequently found in normal individuals leading a saprophytic existence, are often associated with other disease conditions, and tend to show marked variations in virulence.

Since the outbreak of scattered epidemics of influenza beginning in 1915–16, which finally culminated in the pandemic of 1918–19, a vast amount of literature on the subject has appeared. No attempt has been made thoroughly to analyze this, because much of it is not available, much of it abounds in contradictions which it is difficult to harmonize at the present time, and much of it has been written on the basis of insufficient data gathered under the handicap of war conditions by men without sufficient time to undertake special investigation, or it is feared, in many instances, not sufficiently qualified by previous bacteriologic training.

The sum and substance of opinion in 1918 would seem to be best summarized by quoting from the published report compiled by the British Medical Research Commission:[^[20]] “Although Pfeiffer may yet furnish reasons why the verdict should not be pronounced, there is already sufficient material to shake the orthodox conception out of its high altar. Two facts stand out prominently: the generally acknowledged, or by some reluctantly admitted, absence of B. influenzæ from organs on postmortem examinations, and the universally recorded findings of diplostreptococci, singly or in association with the Pfeiffer bacillus.” Comment on this opinion will be made in the general discussion at the end of this paper.

In undertaking a study of the bacteriology of influenza, it seemed essential to bear in mind certain clinical features of the disease which will be discussed in greater detail in a subsequent paper. It suffices to say for our present purpose that it is felt that influenza in itself should be regarded as a self-limited disease of short duration (two to five days in most instances), the most prominent local manifestation of which is a rapidly progressing attack upon the mucous membranes of the respiratory tract. Among the cases observed during the epidemic at Camp Pike uncomplicated influenza never proved fatal and death invariably was associated with a complicating pneumonia. In a large majority of cases pneumococci, S. hemolyticus, or less frequently other bacteria in addition to B. influenzæ were associated with the pneumonia. It is felt, therefore, that in any attempt to determine the primary cause of influenza bacteriologic studies made during life in early uncomplicated cases of the disease are of primary importance and that the bacteriology of the sputum of patients with complicating pneumonia and the bacteriology of autopsies can only properly be used as valuable supplements to data so obtained.

Since cultures from the respiratory tract must often of necessity contain many bacteria which play no part in the production of influenza, it is essential to have a working knowledge of the bacteria that may be encountered by the methods employed. It is also important that such knowledge as may have been gained in interepidemic periods be amplified by study of the bacterial flora present at various periods throughout the course of an epidemic, both in normal individuals and in other disease conditions. These points have been borne in mind throughout the present study and such observations have formed an essential part of the work.

Methods.—In an investigation of this nature the culture methods employed should be suitably directed to determine primarily what bacteria are present and in what relative proportion they exist. The use of culture or animal inoculation methods that are highly selective in character, enhancing the growth of certain bacteria and retarding or inhibiting the growth of others, are of great additional value, but can only properly be used secondarily in order to augment the results obtained by nonselective culture methods. As the most suitable medium for the purpose in hand plain meat infusion agar, titrating 0.1+ to 0.3+ to phenolphthalein, to which 5 per cent of sterile defibrinated horse blood was added, was used. Since growth on freshly poured plates is greatly superior to that on plates that have been stored, the agar was melted as needed, the blood being added when the medium had cooled to approximately 45° C. Cultures from the nose and throat were made by swabbing the mucous membranes with a sterile applicator, touching the applicator to a small area on the surface of a blood agar plate, and spreading the inoculum over the surface of the medium with a platinum needle, insuring as wide a separation as possible. Direct cultures of selected and washed specimens of sputum were made when possible. In many instances, of course, it was impossible to get sufficiently satisfactory specimens to permit of washing, especially when cultures were made very early in the disease. To supplement direct culture of the sputum the mouse inoculation method as employed for the determination of pneumococcus types was used. This is, of course, a highly selective method, of particular value in the detection of pneumococcus and B. influenzæ when they are present in relatively small numbers as compared with other bacteria. Plates were examined after twenty to twenty-four hours’ incubation and again at the end of thirty-six to forty-eight hours when necessary.

In the present study, attention has been centered upon B. influenzæ, S. hemolyticus, and the various immunologic types of pneumococci, other organisms encountered having played no significant part in the cases studied except in rare instances. B. influenzæ was identified by its morphologic, staining and cultural characteristics and conformed to the classical description given by Pfeiffer. S. hemolyticus was identified by its morphologic, staining, and cultural characteristics on blood agar, supplemented by a confirmatory hemolytic test with washed sheep corpuscles, and bile solubility test. Pneumococci were identified by morphologic, staining and cultural characteristics, bile solubility test, and agglutination with specific antipneumococcus immune sera. Note was made in most instances of the presence of other organisms, such as members of the Gram-negative diplococcus, staphylococcus, diphtheroid and streptococcus viridans groups, but no attempt was made further to isolate or identify them.

Bacillus Influenzæ in Cases of Influenza.—On October 10, 1918, at the height of the epidemic at Camp Pike, search for B. influenzæ was made in a group of 23 consecutive cases of uncomplicated influenza from one to six days after the onset of the disease. From each individual simultaneous cultures on blood agar plates were made (a) from the nose, (b) from the throat, and (c) from the sputum, and the sputum from each case was injected into the peritoneal cavity of a white mouse. A similar study of 5 consecutive cases was made on November 19. The results are presented in Table II.

By means of multiple cultures taken simultaneously from different portions of the respiratory tract no difficulty was encountered in demonstrating B. influenzæ in all these cases of uncomplicated influenza. Not only was B. influenzæ found in all cases, but often in very large numbers predominating over all other bacteria on at least one of the plates from each patient, and in occasional instances occurring in nearly pure culture. One culture made about two hours after onset of the initial coryza is of interest. There was at the time a profuse serous nasal discharge. One drop of this allowed to fall on the surface of a blood agar plate gave a practically pure culture of B. influenzæ.

During the latter part of November and in early December a small secondary wave of influenza occurred at Camp Pike. In a series of 48 consecutive cases, B. influenzæ was readily found in all by means of combined throat cultures and mouse inoculation of the sputum, 33 times (68.7 per cent) in the throat cultures, 39 times (81.3 per cent) in the sputum. These cases were cultured on admission to the receiving ward of the hospital within twenty-four to forty-eight hours after onset and were all early cases of influenza without complications at the time the cultures were made. In 90 more consecutive cases in this series 62 or 68.9 per cent showed B. influenzæ in a single throat culture taken on admission.

A summary of all cultures made in cases of uncomplicated influenza is presented in Table III.

Of any single method used the intraperitoneal inoculation of a white mouse with a specimen of the patient’s sputum proved the most efficient in demonstrating the presence of B. influenzæ. No single method served to demonstrate B. influenzæ in all cases, but by simultaneous cultures from the nose, throat, and deeper air passages no difficulty was met in showing that B. influenzæ was invariably present, usually in abundance somewhere in the respiratory tract during the acute stage of the disease. This result is not out of harmony with the rapidly progressive character of the attack upon the mucous membranes of the respiratory tract in influenza.

Of interest in this connection are certain observations which suggest that the presence of B. influenzæ in predominant numbers at least is in many cases coincident with the acute stage of influenza and that the organisms show a tendency rapidly to diminish in abundance with the progress of the disease to recovery. In 82 cases of influenza cultured on the day of admission to the hospital, B. influenzæ was present in 52 (63.4 per cent) of the throat cultures. Repeated throat cultures in this group of cases from the fourth to the eighth day after admission when the temperature had fallen to normal, showed that B. influenzæ was still present in demonstrable numbers in the throat of only 25 cases or 30.5 per cent. Not only was there a material reduction in the number of patients in whom B. influenzæ could be demonstrated by the throat culture method, but the contrast in the predominance of B. influenzæ on the plates made early in the disease with those made during convalescence was often very striking. It is only fair to say, however, that some cases continued to carry B. influenzæ in their throats in large numbers throughout the period of observation.

Presence of Pneumococcus in Cases of Influenza.—It seemed of some importance to determine the prevalence of pneumococcus in cases of influenza, not because of any possibility that pneumococci might bear an etiologic relationship to the disease, but more by way of comparison with the prevalence of B. influenzæ, since both organisms are found in the mouths of normal individuals and are also frequently found together in the pneumonias that complicate influenza. The results obtained in cases of influenza early in the disease before the development of either a purulent bronchitis or of pneumonia are presented. The presence of pneumococcus was determined by the intraperitoneal inoculation of white mice with the saliva or sputum.

Twenty-four cases examined on September 27 and 28 gave the results shown in Table IV. These patients had been in the hospital from two to five days at the time the determinations were made.

From November 27 to December 1, the pneumococci present in 47 consecutive cases of influenza were determined. In this group specimens of sputum were collected shortly after admission of the patients to the receiving ward of the hospital. The results are shown in Table V.

The results obtained show that pneumococci found in early uncomplicated cases of influenza, both early and late in the course of the epidemic, differ in no respect from those found in the mouths of normal individuals at any time.

Similar studies of the prevalence of S. hemolyticus as determined by throat cultures in early cases of influenza are shown in Table VI.

The only point of interest in these observations is the increased prevalence of S. hemolyticus in cases examined late in the epidemic of influenza as compared with that found early in the epidemic. The significance of this will be discussed in other parts of this report.

Presence of Bacillus Influenzæ in Normal Men.—For comparison with the results obtained in cases of influenza a fairly extensive study of the prevalence of B. influenzæ in normal individuals has been made at various times prior to and throughout the course of the epidemic. This was deemed of special importance, since it was obvious that the results obtained by previous workers during interepidemic periods would not in all probability coincide with those obtained in the presence of a widespread epidemic of influenza where the opportunity for the dissemination of B. influenzæ was almost unlimited.

From the results obtained in the multiple cultures in cases of influenza it is obvious that only like methods can be compared. The results obtained in normal individuals have, therefore, been tabulated in groups dependent upon the culture method employed. These groups have been subdivided according to the time and the place of the study, such explanatory notes as seem necessary being added. (See Tables VII-IX.)

The most striking feature of the figures presented in Table VII is the wide variation in the incidence of B. influenzæ in different groups varying all the way from 11.1 to 68 per cent. Analysis of these differences brings out certain points of great interest. It is apparent that the percentage of cases carrying B. influenzæ depended in large part upon the prevalence of respiratory diseases in the group from which the data were obtained. In the studies made at Camp Funston prior to the fall outbreak of influenza in epidemic proportions, it is noteworthy that “bronchitis” and pneumonia were prevalent throughout the summer in those groups showing a relatively high incidence of B. influenzæ. At the time these studies were made the presence of influenza in these organizations was not recognized, but in view of knowledge gained throughout the course of the epidemic at Camp Pike, it seems not improbable that influenza in mild form was present throughout the summer in certain organizations at Camp Funston. This would seem more likely in view of the fact that this commission has clearly demonstrated that a considerable epidemic of influenza swept through Camp Funston in March, 1918, and was followed by recurring smaller epidemics in April and May.[^[21]] In contrast with these groups showing a high incidence of B. influenzæ is that of the 210th Engineers, an organization entirely free from respiratory diseases during the period of our study.

On November 12 search was made for B. influenzæ in 50 normal drafted men who had assembled at Hot Springs, Ark., on that date preparatory to entraining for Camp Pike. These men were all from isolated farming communities where influenza was only moderately prevalent and where there was little opportunity for the wide dissemination of B. influenzæ such as occurs when large bodies of men are assembled in camps. Twelve of the 50 gave a history of influenza within the preceding eight weeks. The cultures were made by the same methods as those used at Camp Pike, the laboratory car “Lister” being taken to Hot Springs for that purpose. The incidence of B. influenzæ was only 22 per cent. In striking contrast with this figure are the figures of 50 and 68 per cent obtained in the last two groups studied at Camp Pike after the epidemic had swept through the camp: 24 of the 51 men in these groups had influenza during the epidemic.

It is of interest to record that the incidence of pneumococcus in these cases was approximately the same in all groups and bore no relation to the prevalence of influenza, bronchitis, or pneumonia.

The results obtained by throat culture are quite similar to those obtained by the mouse inoculation method. The entire absence of B. influenzæ in the group of 64 throat cultures made in the draft men assembled at Hot Springs as compared with the relatively high incidence in the last two groups examined at Camp Pike is very striking.

In consideration of the figures presented in Table IX it is important to remember that the group of 50 men from Hot Springs were all from isolated farm communities, had not previously been assembled and had not been in continuous contact with a widespread epidemic of influenza. On the other hand, the two groups of normal men at Camp Pike were studied immediately after the epidemic had swept through the camp and had been constantly in contact with epidemic influenza for a period of three months, 24 of the 51 actually having had the disease during this period. The fact that in the group of men from Hot Springs, B. influenzæ was found only by the mouse inoculation method is noteworthy, since it indicates that the organism was present in relatively small numbers and could be detected only by a highly selective method.

Summary of the results obtained in normal men shows that the incidence of B. influenzæ in normal individuals from isolated communities or in groups free from respiratory diseases prior to the occurrence of the fall epidemic was relatively low, namely, 10 to 20 per cent; that in observations made before the fall epidemic in groups in which “bronchitis” and pneumonia were fairly prevalent, B. influenzæ was found much more frequently, namely, in 25 to 50 per cent of the cases; and that in groups studied at intervals during the epidemic the incidence of B. influenzæ rapidly rose, reaching 85 per cent at the end of the epidemic. In contrast with this, B. influenzæ was found in 100 per cent of cases of influenza without reference to the time at which they occurred during the epidemic. It is obvious that the high percentage of normal men carrying B. influenzæ found at the end of the epidemic can depend only on the wide dissemination of B. influenzæ that must occur during epidemic times.

Bacillus Influenzæ in Measles.—Since the presence of B. influenzæ in other diseases than influenza has been advanced as an argument against its causal relationship to influenza, an extensive study of the incidence of B. influenzæ in the throats of measles patients was made during the period of the epidemic of influenza at Camp Pike from September 10 to October 20. In all a total of 830 throat cultures in 487 cases of measles were made, many cases being cultured repeatedly at weekly intervals. The results have been condensed as far as possible and are presented in Tables X, XI, XII.

The prevalence of B. influenzæ in cases of measles during the period of the influenza epidemic corresponded very closely with that found in normal individuals under similar circumstances. The increasing proportion of cases carrying B. influenzæ as the epidemic of influenza advanced is further evidence of the wide dissemination of the organism during the epidemic.

It is evident from the figures presented in Table XII that a large percentage of the measles cases studied were at one time or another carriers of B. influenzæ. In consideration of this fact, it must be borne in mind that all these cases were cultured during the period when the influenza epidemic was at its height and that many of these cases had influenza while in the hospital for measles. No data are available as to the exact number, since a definite diagnosis of influenza could hardly be made during the acute stage of measles. It is probable that approximately 25 per cent developed influenza, since that was the incidence of influenza in the total population of Camp Pike. The consistent increase in the percentage of influenza carriers clearly demonstrates that this was due to wide dissemination of B. influenzæ with the progress of the epidemic. Another point of exceeding interest is that the percentage of measles cases carrying B. influenzæ in the throat was lowest during the acute stage of the disease and increased during convalescence. This is in direct contrast with the results found in cases of influenza where the number of cases carrying B. influenzæ in the throat was highest during the acute stage and rapidly diminished in uncomplicated cases with the onset of convalescence.

Summary.—Multiple cultures made simultaneously from the nose, throat and lower respiratory tract showed that B. influenzæ was invariably present in all cases of influenza from the onset of the disease. Not only was B. influenzæ present in all cases, but it was frequently present in predominant numbers, sometimes in nearly pure culture. In the majority of cases that went on to rapid recovery without the development of an extensive bronchitis or complicating pneumonia, the predominance of B. influenzæ over other organisms rapidly diminished coincident with onset of convalescence. Many cases, however, continued to carry B. influenzæ in large numbers in the throat throughout convalescence. No data on the possible duration of the carrier state have been obtained. By the culture methods employed no other organism has been found that would suggest any etiologic relationship to the disease. The two organisms most frequently associated with B. influenzæ in postinfluenzal pneumonias, pneumococcus and S. hemolyticus, have not differed in their incidence in early uncomplicated cases of influenza from that found in normal individuals.

The incidence of B. influenzæ in normal men, in different groups studied, has varied between 11.1 and 88 per cent. This wide variation has depended upon the prevalence of respiratory diseases, more particularly influenza, in the groups studied and the opportunity thereby offered for the wide dissemination of B. influenza. With the progress of the epidemic, the number of normal men carrying B. influenzæ has steadily increased until it reached its maximum at the end of the epidemic.

The incidence of B. influenzæ in cases of measles studied during the epidemic of influenza has been relatively high though never equaling that found in cases of influenza. As in normal men, the incidence in cases of measles has steadily increased during the period of the epidemic. Repeated throat cultures at weekly intervals in cases of measles have shown that approximately 80 per cent became temporary carriers of B. influenzæ at one time or another during the period of the epidemic. Many of these cases had influenza during the time that they were in the hospital. The carrier state in cases of measles was found to bear no relation to the acute stage of the disease since the number of carriers at the time of admission to the hospital was considerably lower than that found during convalescence as determined by repeated cultures in the same cases.

Discussion

The bacteriologic studies in cases of influenza described in this report fully support Pfeiffer’s claim that B. influenzæ is invariably present in the disease. It is particularly important to note that these results were obtained in early uncomplicated cases of influenza and are not dependent upon cultures made from cases complicated by pneumonia or obtained at autopsy. In view of this fact the tendency so apparent in much of the recent literature to relegate B. influenzæ to a place of secondary or minor importance in the disease seems hardly justifiable. It would seem that this tendency is largely dependent upon three factors: first, the failure of many to find B. influenzæ either during life or at autopsy in any considerable proportion of cases; second, the frequent failure to draw a clear distinction between influenza itself and the pneumonia to which it predisposes with a consequent overemphasis upon autopsy bacteriology where a considerable variety of secondary organisms have attracted particular attention; and third, an incorrect interpretation of the undoubtedly large number of B. influenzæ carriers found among normal individuals and those with other diseases during the period of the epidemic and to less extent in interepidemic times.

Since the majority of workers who are thoroughly familiar with the technic of cultivating B. influenzæ have encountered little difficulty in finding it in a large majority of cases, it is felt that the considerable number of negative reports that have appeared can depend only upon the unfamiliarity of those who have failed to find it with the proper bacteriologic methods. This is quite apparent in many of the reports that have been published, and is not surprising in the face of the excessive demand for well-trained bacteriologists occasioned by the war.

One important feature in the successful isolation of B. influenzæ from all cases that has been brought out in the course of the work here reported, is the necessity of making simultaneous cultures from all portions of the respiratory tract, since by no single culture method was it found possible to find the organism in all cases. It has been pointed out that one of the most characteristic local phenomena of the disease is the rapidly progressing attack upon the mucous membranes of the respiratory tract. It seems quite possible that B. influenzæ in predominant numbers at least may be found in many cases only at the crest of the wave, if we may speak of it as such. By way of analogy is the well-recognized fact that the successful isolation of streptococcus from cases of erysipelas often depends upon taking cultures from the margin of the advancing lesion. While definite proof is lacking for this opinion, it would seem to receive some support from the observation that B. influenzæ rapidly disappears from the throat with the onset of convalescence in a considerable proportion of cases. It is felt that these observations, establishing the predominance of B. influenzæ in the early acute stages of the disease, are of considerable significance, especially when exactly the reverse condition was found in studying the incidence of the organism in cases of measles.

In consideration of the primary cause of influenza, attention has often been focused upon the many different bacteria found in autopsy cultures. The most prominent of these are the ill-defined diplostreptococci of the European writers, the various immunologic types of pneumococci, and S. hemolyticus. Other microorganisms less frequently found are staphylococci, M. catarrhalis, nonhemolytic streptococci, and B. mucosus capsulatus. It is not within the scope of this paper to discuss their relation to the various types of pneumonia found at autopsy, but their very multiplicity would seem sufficient prima facie evidence that they bear no etiologic relationship to influenza and must be regarded only as secondary invaders. If any further support for this opinion were necessary, it may be found in the studies upon the incidence of pneumococcus and S. hemolyticus in early cases of influenza described in this report. Both were found to occur in the same proportions in which they may be found in normal individuals at any time.

Although Pfeiffer maintained that B. influenzæ was found only in true epidemic influenza, the incorrectness of this contention has been thoroughly established by many reliable investigators and it has been shown beyond question that influenza bacilli may always be found in a small proportion of normal individuals and are not infrequently found in other respiratory diseases.

The fairly extensive study that has been made of the incidence of B. influenzæ in normal men and in cases of measles has clearly demonstrated that the proportion of carriers found in any group depends upon the prevalence of influenza in the group studied and that with the progress of the epidemic the percentage of carriers has steadily increased. When one considers that the opportunity for the dissemination of B. influenzæ by contact infection is almost unlimited during an epidemic of the proportions of that which has swept over the country, this is not at all surprising. That such a large number of normal individuals became carriers of B. influenzæ during the epidemic would seem to be sufficient evidence that actual dissemination does occur and to controvert the theory that in actual cases of influenza, conditions are established in the respiratory tract whereby B. influenzæ, always present in small numbers, is enabled to “grow out” and become the predominant organism. From a consideration of all the observations made as to the incidence of B. influenzæ in various conditions it would appear that the carrier condition is quite analogous to that found with many other bacteria, and may be divided into three groups: (a) acute carriers, those having influenza, (b) contact carriers, those who during epidemic times become temporary carriers of the organism without contracting the disease, and (c) chronic carriers, the relatively small number of normal individuals or those with chronic respiratory conditions who carry B. influenzæ over long periods of time. From the facts at hand this would seem to be the most probable explanation of the conditions found. It is certainly true that the established presence of pneumococcus, B. diphtheriæ, meningococcus and many other organisms in a varying proportion of normal individuals is not regarded as sufficient evidence to exclude them as the etiologic agents of the diseases which they cause.

It is quite obvious that if B. influenzæ is to be regarded as the cause of epidemic influenza, it must change quite rapidly under certain circumstances from a relatively saprophytic organism to a relatively virulent pathogenic organism, and conversely return to its avirulent state following the passage of an epidemic. Animal experimentation has taught us that virulence is acquired by the rapid passage of an organism from host to host. That an opportunity for the rapid transference of B. influenzæ from man to man was provided by the assembling of large groups of individuals relatively susceptible to respiratory diseases in our camps and cantonments is by no means impossible. It has been clearly shown by Vaughn and Palmer[^[22]] that men from rural districts are very susceptible to respiratory diseases and that the camps in which such men were assembled suffered most heavily in this respect during the winter of 1917–18. This Commission has clearly demonstrated that an epidemic of influenza swept through Camp Funston[^[21]] in the spring of 1918 and that a similar epidemic occurred at Camp Pike. Accumulating evidence will undoubtedly show that like epidemics existed in many of our southern camps (Vaughn and Palmer,[^[22]] Soper[^[23]]). It is of considerable interest that B. influenzæ was found in almost one-half of the cases of bronchopneumonia studied by Cole and MacCallum[^[24]] at Fort Sam Houston in February and March, 1918. This relation is especially noteworthy, since an epidemic of influenza was seen by one of us (Blake) among the troops at Kelly Field and Fort Sam Houston during these months. That similar conditions existed in European armies as early as 1916–17 is suggested by the reports of Hammond, Rolland, and Shore[^[25]] and of Abrahams, Hallows, Eyre, and French[^[26]] on epidemics of “purulent bronchitis” with bronchopneumonia in the British army. B. influenzæ was found abundantly in these cases.

Theoretically, under the conditions outlined above, ideal opportunities have been provided for B. influenzæ to build up sufficient virulence to enable it to produce the pandemic of 1918–19. While it is thoroughly recognized that these considerations are in the main hypothetical, it is felt that they are by no means beyond the bounds of possibility, and for that reason are offered as suggestions worthy of further investigation.

It is, of course, perfectly possible on the basis of the observations presented still to regard B. influenzæ as a secondary invader which makes its appearance in all cases of influenza simultaneously with the onset of clinical symptoms. Final proof of its causal relationship to the disease must depend upon the production of influenza by experimental inoculation. Results hitherto obtained in attempts to produce the disease experimentally have been contradictory. Pfeiffer[^[8]] claimed to have produced a disease in monkeys in some respects resembling influenza by the intratracheal injection of freshly isolated cultures of B. influenzæ. Wollstein,[^[19]] in studies upon the pathogenicity of various strains, has shown that B. influenzæ is generally pathogenic for mice and guinea-pigs without respect to source or virulence for man. Pathogenicity for rabbits and monkeys, on the other hand, was possessed only by strains that were highly virulent for man. She furthermore pointed out that for successful animal experimentation, it is imperative that inoculations be carried out immediately after the isolation of the bacilli because they rapidly lose virulence by subculture on artificial media. It is felt that failure to appreciate these facts has been responsible for the often repeated statement that B. influenzæ is not pathogenic for animals.

In a series of animal experiments carried out by this commission recorded in an appendix to this report, sixteen-hour cultures of B. influenzæ freshly isolated from early cases of influenza were demonstrated to be pathogenic for monkeys, both by inoculation of the nasal and pharyngeal mucosa and by intratracheal injection. Monkeys so inoculated developed coryza, epistaxis, tracheitis, bronchitis, and extreme prostration. Experiments with forty-eight-hour cultures of strains preserved by subculture during from ten to fifteen days failed to demonstrate pathogenicity for monkeys. Proof that these monkeys had influenza can depend only upon the demonstration that they suffered with a disease having the clinical character and pathologic lesions of influenza.

The reported failure to produce influenza in man by direct inoculation with freshly isolated cultures of B. influenzæ in experiments conducted on volunteers by the United States Public Health Service[^[27]] at Gallops Island, Boston, is interesting, but would seem to lack definite significance since attempts to transmit the disease from man to man by direct contact also failed. Since all the subjects of these experiments had been previously exposed to influenza during the epidemic, 30 per cent actually having contracted the disease, it would seem probable that the remaining 70 per cent were only very slightly if at all susceptible. It is noteworthy that the attack rate of influenza in most army groups was approximately 20 to 30 per cent during the epidemic, the remaining 70 to 80 per cent failing to contract the disease though equally exposed. No other explanation presents itself except that influenza is no longer transmissible when clinical symptoms have appeared.

Conclusions

1. Consideration of all the evidence available makes it seem highly probable that B. influenzæ is the specific etiologic agent of epidemic influenza, because (a) it is always present in early uncomplicated cases of influenza; (b) it is predominantly so during the acute stage of the disease in cases going on to rapid recovery without development of complications; (c) its presence in varying numbers in normal individuals and in other diseases of the respiratory tract is not valid evidence against its etiologic relationship to influenza, but on the contrary is quite in harmony with what should be expected from our knowledge of other bacteria known to be the etiologic agents of various respiratory diseases; (d) its rapidly increasing prevalence in normal individuals simultaneously with the progress of the epidemic indicates that actual dissemination of B. influenzæ readily occurs and is very widespread during pandemic times; (e) cultures of B. influenzæ freshly isolated from early acute cases of influenza are pathogenic for animals, and may produce in monkeys a disease closely resembling influenza.

2. Final proof of the exact relationship of B. influenzæ to influenza must depend upon (a) more definite knowledge of the immunology both of the organism and of the disease, and (b) knowledge of the pathologic lesions of influenza and the production of these lesions in animals by inoculation with B. influenzæ.

CHAPTER II
CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA AND ITS ASSOCIATED PURULENT BRONCHITIS AND PNEUMONIA

Francis G. Blake, M.D., and Thomas M. Rivers, M.D.

The material presented in this section of the report consists of clinical and bacteriologic observations made during the course of an investigation of influenza and its associated bronchitis and pneumonia at Camp Pike, Ark., between September 6 and December 15, 1918, comprising part of a correlated study of the epidemiology, bacteriology, pathology, and clinical features of these diseases. The bacteriologic studies are in the main limited to those made during life, those made at necropsy being reported in another section of this report.

Methods.—All cases upon which the clinical and bacteriologic data presented are based, were examined by the authors and our own clinical histories and physical examinations were recorded. This was considered of special importance, since in studying a group of diseases in which secondary infection of the respiratory tract might supervene at any time, it was essential to determine as far as possible the exact clinical condition of the patient at the time when bacteriologic examinations were made. The bacteriologic methods employed were the direct culture of nose and throat swabbings and of selected and washed specimens of sputum on the surface of 5 per cent defibrinated horse blood agar plates, the intraperitoneal inoculation of white mice with specimens of sputum according to the method described by Blake[^[28]] for the determination of pneumococcus types, and in some cases the method of Avery.[^[29]] B. influenzæ pneumococci and hemolytic streptococci were identified by the methods described elsewhere. Note was made in most instances of the presence of other organisms such as members of the Gram-negative diplococcus group, staphylococci, diphtheroids, and members of the streptococcus viridans group, but no attempt was made to further isolate or identify them since they played no significant part in the cases studied except in rare instances.

Influenza

The fall epidemic of influenza at Camp Pike began about September 1, 1918, and reached epidemic proportions on September 23 when 214 cases were admitted to the base hospital. The epidemic was at its height from September 27 to October 3, during which period there were in the neighborhood of 1,000 new cases daily. From this date until October 31 the number of new cases occurring daily steadily decreased and by the latter date the epidemic was over. Scattered cases continued to occur, however, throughout November, and during the last week of this month and the first week of December a second epidemic wave of relatively mild character occurred. From September 1 to October 31 the total number of cases of influenza reporting sick was 12,393. During the same period there were 1,499 cases of pneumonia with 466 deaths.

Influenza as observed at Camp Pike differed in no essential respects from that occurring elsewhere. In brief, it presented itself as a highly contagious, self-limited infectious disease of relatively short duration in most instances, the principal manifestations of which were sudden onset with high fever, profound prostration, severe aching pains in back and extremities, conjunctival injection, flushing of the face, neck, and upper thorax often amounting to a true erythema, and a rapidly progressing attack upon the mucous membranes of the respiratory tract as manifested by coryza, pharyngitis, tracheitis and bronchitis with a marked tendency to hemorrhage; in itself it is rarely serious, but in reality serious because of the large number of individuals attacked and temporarily incapacitated and because it predisposed to widespread and highly fatal secondary infection of the lungs.

Clinical Features.—A clinical study of 100 consecutive cases of influenza admitted during the height of the epidemic was made.

The onset was sudden, in most instances being initiated with marked sensations of chilliness in 82 cases. Although a severe chill was probably relatively uncommon, 44 of these patients considered the symptom of sufficient severity to describe it as such. This was accompanied by extreme general malaise with severe aching pains throughout the whole body. Intense backache was complained of in 40 cases, headache in 54 cases. A varying degree of prostration, sometimes leading to complete collapse, was almost universal; 5 patients complained of extreme asthenia and 2 of marked dizziness. At time of admission to the hospital the face, neck and upper chest exhibited a uniform erythematous flush, never macular in appearance. The conjunctivæ were deeply injected, but lacrimation was not noticeable and a true exudative conjunctivitis was not encountered. Onset was accompanied by a sharp elevation of temperature ranging from 100° F. to 106° F., in most cases being between 102° F. and 105° F., at the time of admission. No constant type of temperature curve was maintained. Excluding the 15 cases in this group that developed pneumonia, the temperature was well sustained throughout the course of the disease in 46, irregular in 33, and definitely remittent in 6. The duration of the fever varied between one and seven days, the temperature having returned to normal in all but 19 of the 85 cases by the end of four days. The duration of fever was one day in 18 cases, two days in 12, three days in 19, four days in 17, five days in 10, six days in 4, and seven days in 5. Of the 4 cases with fever for six days, 2 had a fairly extensive bronchitis, 1 a laryngitis. Of the 5 cases with fever of seven days’ duration, 3 had signs of an extensive bronchitis, 2 of only a mild bronchitis.

The pulse was relatively slow in rate as compared with the degree of temperature elevation, running between 90 and 100 beats per minute in the large majority of cases. At the height of the disease it was full and easily compressed. No irregularities were noticed. With recovery it fell promptly to normal. The respiratory rate showed only moderate elevation, being between 20 and 26 in most cases. In a few instances a rate as high as 32 was recorded at time of admission to the hospital, but this promptly fell with rest in bed. A respiratory rate rising above 26 after the third or fourth day of the disease nearly always indicated a beginning pneumonia. With recovery the rate promptly fell to normal. Cyanosis did not occur in the absence of pneumonia.

Aside from the manifestations of a profound toxemia, influenza was preeminently characterized by symptoms of respiratory tract infection. The appearance of respiratory symptoms occurred at varying intervals after the onset of the disease, being well developed by the end of twenty-four hours in most cases. A progressive attack upon the mucous membranes of the respiratory tract was universal, beginning with coryza and pharyngitis and progressing to tracheitis or vice versa. Further extension of the infection to the bronchi, however, was by no means universal, 49 cases in the group studied recovering without developing evidence of bronchitis. Sore throat was rarely complained of, and laryngitis, possibly due to secondary infection, occurred only once. The progress of the infection was marked subjectively by sensations of irritation, stinging, and a feeling of tightness. A profuse, thin, mucoid exudate appeared; the pharyngeal walls and the soft palate showed a characteristic deep red granular appearance. The onset of tracheitis began with a sense of burning and tightness beneath the sternum accompanied by a harassing cough, at first nonproductive, later with the outpouring of an exudate becoming productive. The sputum varied in character between a scanty, thin, mucoid sputum and a profuse, frankly purulent sputum in cases subsequently developing an extensive bronchitis. Hemorrhage from the mucous membranes was common. Epistaxis occurred in 12 per cent of the cases and was often profuse. The sputum contained fresh blood in varying amounts in 24 per cent of the cases; 51 per cent of the cases developed signs of bronchitis. In 15 of these the bronchitis was mild, probably limited to the larger bronchi, physical examination showing only inconstant sibilant and musical râles. The sputum in these cases was neither profuse nor frankly purulent; 36 cases developed a fairly extensive purulent bronchitis as manifested by more or less diffusely scattered moist râles and by moderately copious mucopurulent or frankly purulent sputum. This bronchitis was not accompanied by an increase in the respiratory rate or by cyanosis unless pneumonia subsequently developed.

Gastrointestinal symptoms were insignificant: 8 patients complained of nausea early in the disease and 6 of them vomited. Diarrhea occurred in only 1 case, constipation being the rule. The spleen was palpable in 21 cases, but this is of doubtful significance, since nearly all the patients came from malarial regions. Jaundice was not noted. Aside from the profound depression, sometimes amounting to stupor, mental symptoms were not noted except in 1 case which showed a mild delirium.

Influenza, although per se a self-limited disease of short duration, frequently leads to the development of serious complications, the most important of which are pneumonia and purulent bronchitis with a varying degree of bronchiectasis. In the group of 100 cases of influenza studied, purulent bronchitis developed in 36 instances, pneumonia in 15; in 3 cases there was lobar pneumonia, in 12 bronchopneumonia. Further discussion of these complications is reserved for the sections dealing with them in detail. Other complications were relatively rare. Otitis media occurred in one case and frontal sinusitis in one. No fatalities were observed among cases of uncomplicated influenza, the deaths that occurred being invariably associated with a secondary pneumonia due in nearly all instances to secondary infection with pneumococci or hemolytic streptococci.

Purulent Bronchitis

It has been stated that a considerable number of cases of influenza developed a more or less extensive purulent bronchitis. This term is used as descriptive of a group of cases showing clinically evidence of a diffuse bronchitis as manifested by numerous medium and fine moist râles scattered throughout the chest and evidence of a definitely purulent inflammatory reaction as indicated by the expectoration of fairly copious amounts of mucopurulent or frankly purulent sputum. This condition is regarded as quite distinct, on the one hand, from the common type of mucoid bronchitis frequently associated with “common colds” and a fairly common feature of uncomplicated cases of influenza, in which physical examination of the chest reveals only transient sibilant and musical râles without evidence of extension to finer bronchi, and, on the other hand, from bronchopneumonia.

Bacteriology.—Thirteen cases of purulent bronchitis following influenza in none of which was there any evidence of pneumonia at the time cultures of the sputum were made nor later were subjected to careful bacteriologic study. Specimens of bronchial sputum were collected in sterile Petri dishes and selected portions thoroughly washed to remove surface contaminations before bacteriologic examinations were made. The results are shown in Table XIII.

From the data presented in Table XIII it is evident that a mixed infection existed in all cases. The results obtained by stained sputum films and by direct culture on blood agar plates are of special significance. B. influenzæ was present in all cases, being the predominant organism in 6 cases, abundantly present in others, and few in number in 2. Of other organisms the pneumococcus was most frequently found, occurring in 11 of the 13 cases, in all but 2 instances being present in considerable numbers. S. viridans was encountered twice, once in association with a Gram-negative micrococcus resembling M. catarrhalis culturally. S. hemolyticus was found once, together with M. catarrhalis and a few pneumococci, Type IV, coming through in the mouse only and of doubtful significance. The stained sputum films and direct cultures always showed these organisms present in sufficient abundance to indicate that they were present in the bronchial sputum and were not merely contaminants from the buccal mucosa.

It seems quite probable from these results that purulent bronchitis following influenza is, in most cases at least, due to mixed infection of the bronchi and should be looked upon as a complication of influenza. Whether the condition may be caused by infection with B. influenzæ alone is difficult to say. No evidence that it may be caused by B. influenzæ alone was obtained in the cases studied. It is not intended to enter here into a discussion as to whether B. influenzæ should be regarded as a secondary invader or not; the other organisms encountered certainly are. It would seem most probable that purulent bronchitis is caused by the mixed infection of B. influenzæ and various other organisms, commonly the pneumococcus, but that the condition is initiated by the invasion of the bronchi by these other organisms in the presence of a preceding infection with B. influenzæ.

Clinical Features.—Purulent bronchitis following influenza began insidiously without any prominent symptoms to mark its onset. About the third or fourth day of influenza, when recovery from the primary disease might be looked for, the patient would begin to cough more frequently, raising increasing amounts of mucopurulent sputum. This sputum was yellowish green in color, copious in amount, and often somewhat nummular in character, sometimes streaked with blood. These symptoms were accompanied by the appearance of coarse, medium and fine moist râles more or less diffusely scattered throughout the chest and usually most numerous over the lower lobes. The percussion note, breath and voice sounds, and vocal and tactile fremitus remained normal. There was no increase in the respiratory rate or pulse rate, and cyanosis did not develop in the absence of a beginning pneumonia. Many such cases, of course, developed bronchopneumonia; in this event areas showing diminished resonance, suppressed breath sounds, and fine crepitant râles with the “close to the ear” quality would appear, the respiratory rate would become increased and cyanosis would become evident. In those cases of purulent bronchitis not developing pneumonia, a moderate elevation of temperature, rarely above 101° F., and irregular in character usually occurred and persisted for a few days or a week.

Many cases maintained a persistent cough, raising considerable amounts of sputum throughout the period of their convalescence in the hospital, which was often considerably prolonged when this complication of influenza occurred. Although no clinical data are available on such cases over a prolonged period of observation, it seems probable that some of them, at least, had developed some degree of bronchiectasis. This would seem all the more probable, since many cases of pneumonia following influenza showed at autopsy extensive purulent bronchitis with well-developed bronchiectasis. Bronchiectasis will be discussed in greater detail in another section of this report. It is this group of cases with more or less permanent damage to the bronchial tree that makes this type of bronchitis following influenza a serious complication of the disease.

Pneumonia

The opportunity presented for a correlated study of the clinical features, bacteriology, and pathology of pneumonia following influenza throughout the period of the epidemic at Camp Pike from September 6, 1918, to December 15, 1918, made it evident that this pneumonia could be regarded as an entity in only one respect, namely, that influenza was the predisposing cause. Clinically, bacteriologically, and pathologically it presented a very diversified picture ranging all the way from pneumococcus lobar pneumonia to hemolytic streptococcus interstitial and suppurative pneumonia with the picture modified to a varying extent by the preceding or concomitant influenzal infection.

One hundred and eleven consecutive cases in which careful clinical and bacteriologic studies were made form the basis of the material presented. Of these cases, 38 came to necropsy so that ample opportunity was presented to correlate the clinical and bacteriologic studies made during life with the pathology and bacteriology at necropsy. It has seemed advisable to group the cases primarily on an etiologic basis with secondary division according to clinical features in so far as this can be done. Bacteriologic studies showed that at the time of onset these pneumonias were either pneumococcus pneumonias or mixed pneumococcus and influenza bacillus pneumonias in nearly all instances. Certain of these cases later became complicated by a superimposed hemolytic streptococcus or a staphylococcus infection. In a few instances hemolytic streptococcus pneumonia directly followed influenza without an intervening pneumococcus infection. B. influenzæ was present in varying numbers in nearly all cases. In only 2 instances however, was it found unassociated with pneumococci or hemolytic streptococci, once alone and once with S. viridans.

Clinically the cases fell into four main groups: (1) Lobar pneumonia; (2) lobar pneumonia with purulent bronchitis; (3) bronchopneumonia (pneumococcus); (4) bronchopneumonia (streptococcus). It should be borne in mind, however, that the picture was a complex one and that correct clinical interpretation was not always possible, since many cases did not conform sharply to any one type and superimposed infections during the course of the disease often modified the picture.

Pneumococcus Pneumonia Following Influenza.—Bacteriologic examination of selected and washed specimens of sputum coughed from the lungs at time of onset of pneumonia showed the various immunologic types of pneumococcus to be present in 105 cases. The incidence of the different types is shown in Table XIV.

The most noteworthy feature of the figures in Table XIV is the high proportion of pneumonias due to types of pneumococci found in the mouths of normal individuals, 93 cases or 88.6 per cent, being caused by Pneumococcus Types II atypical, III, and IV. This is in harmony with the results generally reported and is in all probability due to the fact that in patients with influenza pneumococci, which under normal conditions would fail to cause pneumonia, readily gain access to the respiratory tract and produce the disease. It is also of interest that with one exception the highly parasitic pneumococci of Types I and II were associated with pneumonias clinically lobar in type.

Superimposed infection of the lungs with other types of pneumococci than those primarily responsible for the development of pneumonia occurred not infrequently in this group of cases either during the course of the disease or shortly after recovery from the first attack of pneumonia. Pneumococcus Type II infection was superimposed upon or shortly followed pneumonia caused by Group IV pneumococci in 4 instances, by Pneumococcus II atypical in 1 instance. In 1 case pneumonia due to Pneumococcus II atypical occurred three days after recovery from a Pneumococcus Type I pneumonia, in another case Pneumococcus Type III infection was superimposed upon a pneumonia originally due to a pneumococcus of Group IV. These cases are presented in detail in another section of this report, and in several instances were shown to be directly due to contact infection from patients in neighboring beds.

In a similar manner, superimposed infection with S. hemolyticus at some time during the course of the pneumonia occurred in 13 cases in this group, with fatal result in all but one. Streptococcus infection occurred in pneumonia due to Pneumococcus II atypical once, to Pneumococcus Type III once, and to pneumococci of Group IV eleven times. Nine of these cases were free from hemolytic streptococci at the time of onset of the pneumonia, 4 showed a very few colonies of hemolytic streptococci in the first sputum culture made.

B. influenzæ was found in the sputum coughed from the deeper air passages in the majority of cases, being present in 80, or 76.2 per cent, of the 105 cases. In the 58 cases of lobar pneumonia it was found 41 times, or 70.7 per cent, in the 47 cases of bronchopneumonia 39 times, or 82.9 per cent. The abundance of B. influenzæ in the sputum varied greatly in different cases. Microscopic examination of stained sputum films and direct culture of the sputum on blood agar plates showed that in general it was more abundant in the mucopurulent sputum from cases of bronchopneumonia than in the mucoid rusty sputum from cases of lobar pneumonia. This was by no means an invariable rule, however, since in the former the bacilli were sometimes very few in number, in the latter quite abundant. Whether B. influenzæ shared in the production of the actual pneumonia in these cases is difficult to decide and cannot be stated on the basis of the bacteriologic and clinical observations which have been made.

Clinical Features.—One of the most striking aspects of pneumococcus pneumonia following influenza was the diversity of clinical pictures presented. These varied all the way from the classical picture of lobar pneumonia to that of bronchopneumonia of all grades of severity from the rapidly fatal coalescing type to that of very mild character with very slight signs of consolidation. For this reason it is questioned whether there is any real justification for speaking of a typical influenzal pneumonia, an opinion that seems well supported by the diversified picture found at the necropsy table.

For purposes of presentation, pneumococcus pneumonia following influenza may be divided into three clinical groups: (1) Lobar pneumonia; (2) lobar pneumonia with purulent bronchitis; (3) bronchopneumonia. No accurate data are available as to the relative frequency with which these three types occurred at Camp Pike. In the group of 105 cases studied there were 58 cases of lobar pneumonia, 11 of which had purulent bronchitis, and 47 cases of bronchopneumonia. The majority of these cases, however, occurred during the early days of the epidemic of influenza and probably show a considerably higher proportion of lobar pneumonias than actually occurred in the total number of pneumonias throughout the epidemic. This is indicated by the fact that of 100 consecutive cases of influenza selected for observation at the height of the epidemic, 3 developed clinical evidence of lobar pneumonia and 12 of bronchopneumonia.

(1) Lobar pneumonia presenting the typical clinical picture with sudden onset, tenacious rusty sputum, sustained temperature, and physical signs of complete consolidation of one or more lobes occurred in 47 cases; 36 cases in this group definitely followed influenza. In 11 cases no certain clinical evidence of a preceding influenza was obtained, and it is probable that some of these represent cases of pneumonia occurring independently of the epidemic of influenza.

The onset of pneumonia in this group of cases occurred from four to nine days after the onset of influenza and with few exceptions was ushered in by a chill and pain in the chest. In several instances the patient had apparently recovered from influenza as evidenced by fall of temperature to normal. After twenty-four to seventy-two hours of normal temperature the patient would have a chill and develop lobar pneumonia. In the majority of cases, however, lobar pneumonia developed while the patient was still sick with influenza. The course of the disease, symptomatology and physical signs were quite characteristic of lobar pneumonia and require no special comment. Recovery by crisis occurred in 21 cases, by lysis in 8. Pneumococcus empyema developed in 3 cases, fibrinopurulent pericarditis in 3 and all but 1 of these 6 cases terminating fatally.

In Table XV 5 fatal cases of lobar pneumonia, which illustrate some of the unusual features of the disease when it follows influenza, have been summarized. The first 2 cases represent examples of recurring attacks of pneumonia which developed shortly after recovery from the first attack, in both instances being due to types of pneumococci different from those causing the first attack. The third case represents an example of superimposed infection of the lungs with hemolytic streptococci and staphylococci during the course of a pneumonia due to Pneumococcus IV and disappearance of the latter organism from the tissues so that it was not found at time of necropsy. The last 2 cases are examples of fulminating rapidly fatal cases of lobar pneumonia associated with mixed infections of pneumococci and hemolytic streptococci, the streptococci probably being secondary in both cases. Cases like the few examples cited above, which occurred not infrequently throughout the epidemic of influenza, serve to illustrate the difficulties which may be met in attempting to correlate the clinical, bacteriologic and pathologic features of pneumonia following influenza unless careful bacteriologic examinations are made both during life and at the necropsy table in the same group of cases.

(2) There were 11 cases of lobar pneumonia with purulent bronchitis in the group studied. Clinically, they closely resembled the cases in the preceding group except in so far as the picture was modified by the presence of the purulent bronchitis. All directly followed influenza. The sputum, instead of being rusty and tenacious, was profuse and mucopurulent, usually streaked with blood. Stained films and direct culture on blood agar plates showed pneumococci in abundance and B. influenzæ in varying numbers, in only two instances the predominant organism. The physical signs were those of lobar pneumonia with, in addition, those of a diffuse bronchitis as manifested by medium and coarse moist râles throughout both chests. Five cases recovered by crisis; 6 terminated fatally and in all of them the clinical diagnosis of lobar pneumonia with purulent bronchitis was confirmed at necropsy.

(3) Forty-seven cases in the group studied presented the clinical picture of bronchopneumonia. The onset of pneumonia in these cases was in most instances insidious and appeared to occur as a continuation of the preceding influenza. The temperature, instead of falling to normal after from three to four days, remained elevated or rose higher, the respiratory rate began to rise, a moderate cyanosis appeared, the cough increased, and the sputum became more profuse, usually being mucopurulent and blood streaked, sometimes mucoid with fresh blood. The pulse showed little change at first, being only moderately accelerated. Pleural pain, so characteristic of the onset of lobar pneumonia, was rarely complained of, but a certain amount of substernal pain was common, probably due to the severe tracheobronchitis. Physical examination at this time revealed small areas showing relative dullness, diminished or nearly absent breath sounds, and fine crepitant râles. These areas usually appeared first posteriorly over the lower lobes.

The subsequent course of the disease showed the widest variation from mild cases with limited pulmonary involvement going on to prompt recovery in four or five days with defervescence by lysis or crisis to those presenting the picture of a rapidly progressive and coalescing pneumonia with fatal outcome. In the milder cases the diagnosis of pneumonia depended in considerable part upon the general symptoms of continued fever, increased respiratory rate, and slight cyanosis. Definite pulmonary signs were always present if carefully looked for, though sometimes not outspoken. Areas of bronchial breathing and bronchophony often appeared late, sometimes not until the patient was apparently recovering. In the severe cases cyanosis became intense and an extreme toxemia dominated the picture. In certain of these cases there was an intense pulmonary edema. The respiratory rate showed wide variation, the breathing in some cases being rapid and gasping, in others comparatively quiet. Progressive involvement of the lungs occurred with the development of marked dullness, loud bronchial breathing and bronchophony. Abundant medium and coarse moist râles were heard throughout the chest, probably due in considerable part to the extensive bronchitis almost universally present. An active delirium was not uncommon. Signs of pleural involvement, even in the most severe and extensive cases, rarely occurred, except in those cases in which a hemolytic streptococcus infection supervened.

Of the 47 cases in this group, 29 recovered; 14 by crisis, 15 by lysis. The average duration of illness from the onset of influenza until recovery from the pneumonia was ten days, the majority of these cases being relatively mild in character with pneumonia of three to six days’ duration. Empyema with ultimate recovery occurred in 1 of these cases, Pneumococcus Type II being the causative organism.

There were 18 fatal cases in the group. Nine of these are summarized in Table XVI as illustrative of the frequently complex character of bronchopneumonia following influenza and because of the interest attaching to the bacteriologic examinations made during life and at necropsy. Case 70 is a typical instance of the rapidly progressive type of confluent lobular pneumonia with extensive purulent bronchitis, intense cyanosis, and appearance of suffocation, with which pneumococci, in this case Pneumococcus IV, and B. influenzæ are commonly associated. Case 59 is illustrative of the small group of bronchopneumonias following influenza which die, often unexpectedly, after a long drawn out course, in this instance three weeks after onset. Examination of the sputum at the time the pneumonia began, showed Pneumococcus Type IV and B. influenzæ. At necropsy there was a lobular pneumonia with clustered small abscesses, probably due to a superimposed infection with S. aureus. There was a well-developed bronchiectasis in the left lower lobe. Cultures taken at autopsy showed a sterile heart’s blood, which is not infrequently the case in cases of pneumococcus lobular pneumonia after influenza. Cultures from the consolidated portions of the lung showed no growth, the pneumococcus having disappeared as might be expected from the duration of the case. B. influenzæ together with staphylococci were found in the bronchi. In Cases 50 and 56 a second attack of pneumonia caused by a different type of pneumococcus from that responsible for the first attack occurred, the second attack in both instances being due to contact infection with Pneumococcus Type II from a patient in a neighboring bed suffering with Pneumococcus Type II pneumonia. Both cases showed at necropsy the type of confluent lobular pneumonia so commonly found in pneumococcus pneumonias following influenza. Case 107 illustrates well the extent to which mixed infections may occur, especially when cases are treated in crowded hospital wards. The sputum at time of onset showed Pneumococcus IV in abundance and a few staphylococci. At necropsy there was a confluent lobular pneumonia with clustered abscesses, purulent bronchitis, and bronchiectasis in the left lower lobe. The heart’s blood was sterile, the lungs showed Pneumococcus Type III and staphylococci. B. influenzæ was not found, but through oversight, no cultures were taken from the bronchi. Cases 92, 99, 102, and 104 are all examples of superimposed hemolytic streptococcus infection occurring in the presence of a Pneumococcus Type IV pneumonia, with the picture of interstitial suppuration, abscess formation, and empyema due to S. hemolyticus on the background of a pneumococcus lobular pneumonia found at necropsy. All showed abundant pneumococci and B. influenzæ in the sputum and were free from hemolytic streptococci at time of onset of pneumonia, except Case 92 which showed 2 colonies of S. hemolyticus in the first sputum culture made. At time of death the pneumococci had disappeared in all cases and were replaced by hemolytic streptococci.

The cases cited in the preceding paragraph are illustrative examples from a series of over 250 necropsies which are described in another section of this report. They serve to indicate clearly the extent to which mixed and superimposed infections of the lungs may occur in pneumonia following influenza and leave little doubt that a considerable proportion of the deaths from influenzal pneumonia are due to this circumstance.

Hemolytic Streptococcus Pneumonia Following Influenza

But 4 cases of hemolytic streptococcus pneumonia directly following influenza without an intervening pneumococcus infection of the lungs occurred in the group of cases studied clinically. Superimposed infection with S. hemolyticus, however, occurred not infrequently during the course of pneumococcus pneumonia following influenza, as has been stated above. This occurred 3 times in lobar pneumonia and 10 times in bronchopneumonia, with fatal outcome in all but 1 case.

Bacteriology.—Bacteriologic examination of the sputum in the 4 cases of streptococcus pneumonia directly following influenza showed S. hemolyticus present in abundance. B. influenzæ was also present in large numbers in 3 cases, but was not found in the fourth. In 1 case a Gram-negative micrococcus resembling M. catarrhalis was also present in large numbers in the sputum. Pneumococci were not found either by direct culture on blood agar plates or by inoculation of the sputum intraperitoneally in white mice.

In the 13 cases of superimposed hemolytic streptococcus infection occurring during the course of pneumococcus pneumonia, bacteriologic examination of the sputum by direct culture and by mouse inoculation shortly after onset of the pneumonia showed Pneumococci (atypical II once, Type III once, Group IV eleven times) B. influenzæ present in large numbers, and no hemolytic streptococci except in 4 instances in which a very few organisms were present. Subsequent invasion of the lower respiratory tract by S. hemolyticus was shown to occur by means of cultures of empyema fluids or by cultures made at necropsy.

Clinical Features.—The 4 cases of hemolytic streptococcus pneumonia following influenza that occurred in this series resembled in all respects the secondary streptococcus pneumonias of the winter and spring of 1918 and presented no features requiring special comment. The onset resembled that of pneumococcus bronchopneumonia, the disease appearing to develop as a continuation of the preceding influenza. The sputum was profuse and mucopurulent in 3 cases, mucoid and bloody in the other. Two cases ran a severe and rapid course with the development of empyema early in the disease and fatal outcome. The other 2 cases ran only moderately severe courses without developing empyema and recovered by lysis in twenty and fifteen days, respectively, after the onset of influenza. Clinical differentiation between streptococcus and pneumococcus bronchopneumonia following influenza did not seem possible without bacteriologic examination of the sputum except in those cases of the streptococcus group which developed an extensive pleural effusion early in the disease.

The advent of superimposed hemolytic streptococcus infection of the lower respiratory tract during the course of pneumococcus pneumonia following influenza presented no clinical features that made diagnosis certain without bacteriologic examination. The sudden occurrence of a pleural exudate during the course of the disease seemed of particular significance, especially since empyema in the bronchopneumonias following influenza was exceedingly rare in the absence of hemolytic streptococcus infection. Other suggestive symptoms were a chill during the course of the disease, a sudden turn for the worse in cases apparently doing well, or the development of a cherry red cyanosis. None of these features, however, was sufficiently constant or distinctive of streptococcus invasion to be depended upon and when they occurred, were merely indications for further bacteriologic examination.

Bacillus Influenzæ Pneumonia Following Influenza

Bacteriologic evidence that cases of pneumonia following influenza might be due to B. influenzæ alone was very meager in the group of cases studied clinically at Camp Pike; in fact, no convincing evidence was obtained that such cases occurred. In one case B. influenzæ alone was found in the sputum coughed from the deeper air passages, and in another case B. influenzæ with a few colonies of S. viridans was found. Both were cases of bronchopneumonia, mild in character, and recovered promptly. They presented no clinical features by which they could be distinguished from cases of pneumococcus bronchopneumonia.

It has been previously stated that B. influenzæ was found in all early uncomplicated cases of influenza somewhere in the respiratory tract; that it was present together with other organisms, notably pneumococcus in the sputum from cases of purulent bronchitis following influenza; and that it was found in the sputum coughed from the lung in approximately 80 per cent of cases of pneumonia complicating influenza. In 35 cases it was very abundant, often being the predominating organism. In all these cases, however, pneumococci or hemolytic streptococci were also present in considerable numbers at the time of onset of the pneumonia. It is impossible to say merely from the clinical and bacteriologic data under consideration what part B. influenzæ played in the development of the actual pneumonia in these cases. Discussion of this subject is therefore reserved for the section of this report dealing with the pathology and bacteriology of pneumonia following influenza.

Summary

Influenza as observed at Camp Pike presented itself as a highly contagious infectious disease, the principal clinical manifestations of which were, sudden onset with high fever, profound prostration with severe aching pains in the head, back and extremities, erythema of the face, neck and upper chest with injection of the conjunctivæ, and a rapidly progressive attack upon the mucous membranes of the respiratory tract as evidenced by coryza, pharyngitis, tracheitis and bronchitis with their accompanying symptoms. In the majority of cases it ran a short self-limited course, rarely of more than four days’ duration, and was never fatal in the absence of a complicating pneumonia.

Bacteriologic examination in early uncomplicated cases of the disease showed the B. influenzæ of Pfeiffer to be present in all cases, often in predominating numbers. It was found more abundantly present during the acute stage of the disease than during convalescence in uncomplicated cases. No other organisms of significance were encountered by the methods employed.

Purulent bronchitis of varying extent developed in approximately 35 per cent of the cases and often prolonged the course of the illness to a considerable extent. Bacteriologic studies showed that it was invariably associated with a mixed infection of the bronchi with B. influenzæ and other bacteria, in most instances the pneumococcus, and indicated that it should be regarded as a complication rather than as an essential part of influenza. Its clinical features consisted of a mild febrile reaction, frequent cough with the raising of considerable amounts of purulent sputum, and the physical signs of a more or less diffuse bronchitis. It led to a varying degree of bronchiectasis in at least some instances.

Pneumonia complicating influenza presented a very diversified picture and appeared to have only one constant character, namely, that influenza was the predisposing cause. It may be best classified on an etiologic basis since the clinical features to some extent and the pathology to a much greater extent depended upon the infecting bacteria in a given case.

Bacteriologic examination showed that a very large proportion of the cases was due to infection with the different immunologic types of pneumococci or to a mixed infection with B. influenzæ and pneumococci. The types of pneumococci commonly found in normal mouths, namely, II atypical, III, and IV, comprised approximately 88 per cent of these, the highly parasitic Pneumococci Types I and II, but 12 per cent. A small number of cases were due to hemolytic streptococci or to mixed infection with B. influenzæ and S. hemolyticus. No certain evidence was obtained that pneumonia was due to B. influenzæ alone. This organism was present in varying numbers, however, in approximately 80 per cent of the sputums examined, and it seems fairly certain that it must have played at least a part in the development of the pneumonia in many of the cases in which it was found. Superimposed infections with other types of pneumococci than those primarily responsible for the development of pneumonia, with hemolytic streptococci and with Staphylococcus aureus occurred frequently in cases of pneumococcus or mixed pneumococcus and B. influenzæ pneumonia and undoubtedly contributed to a considerable extent in increasing the number of deaths.

Three clinical types of pneumococcus pneumonia following influenza occurred: lobar pneumonia, lobar pneumonia with purulent bronchitis, and bronchopneumonia. Lobar pneumonia was usually sudden in onset and ran the characteristic course of the primary disease. Lobar pneumonia with purulent bronchitis similarly ran the characteristic course of the primary disease but presented the unusual picture of lobar pneumonia with mucopurulent rather than rusty, tenacious sputum and numerous moist râles throughout the unconsolidated portions of the lungs. The cases of bronchopneumonia ran a very variable course from mild cases of a few days’ duration and meager signs of consolidation to rapidly progressive cases with signs of extensive pulmonary involvement. Purulent bronchitis was very frequently associated with bronchopneumonia.

Hemolytic streptococcus pneumonia following influenza presented the clinical picture of bronchopneumonia and was not readily distinguished on clinical grounds from pneumococcus bronchopneumonia except in those cases which developed a pleural exudate early in the disease. The advent of tertiary infection of the lower respiratory tract with hemolytic streptococci in cases of secondary pneumococcus pneumonia presented no symptoms sufficiently constant or certain to make clinical diagnosis easy. The development of empyema in pneumococcus bronchopneumonia usually meant streptococcus infection.

Pure B. influenzæ pneumonia, if such cases existed, presented no diagnostic features by which it could be distinguished from pneumococcus bronchopneumonia following influenza. It was impossible to determine on clinical and bacteriologic grounds alone what part the prevalent influenza bacilli played in the causation of the actual pneumonia.

Discussion

That wide variations in the conception of influenza have arisen during the recent pandemic, even a hasty review of the literature makes clear. In its essence this divergence of opinion seems to depend upon whether pneumonia is considered an essential part of influenza or a complication due either to the primary cause of influenza or to secondary infection. One extreme is expressed by Dunn[^[30]] who says “the so-called complication is the disease,” the other by Fantus[^[31]] who finds influenza a relatively mild disease with pneumonia a relatively infrequent and largely preventable complication.

A similar divergence of opinion prevails with respect to the bacteriology of influenza. There is fairly general agreement that the members of the pneumococcus and streptococcus groups and to a less extent other organisms are responsible for a large proportion of the secondary pneumonias, and but few observers hold that they possess any etiologic relationship to influenza. No such uniformity of opinion exists, however, with respect to the relation of B. influenzæ to influenza and to the complicating pneumonia. By some it is considered the primary cause of influenza, by others it is regarded as a secondary invader responsible for a certain proportion of the secondary pneumonias, and by still others it is not considered to bear any relation either to influenza or its complications.

A limited number of references to the extensive literature of the recent pandemic will amply serve to illustrate the various points of view that have developed.

Keegan[^[32]] regards pneumonia as a complication and considers that B. influenzæ, the probable cause of influenza, is the primary cause of the pneumonia which may or may not be still further complicated by pneumococcus or streptococcus infection as a terminal event. Christian[^[33]] states that epidemic influenza causes a clinically demonstrable bronchitis and bronchopneumonia in the larger proportion of cases, and lays particular emphasis upon the fact that it is quite incorrect to consider fatalities in the epidemic as due to influenza uncomplicated by bronchopneumonia. Blanton and Irons[^[34]] speak of influenza as an “antecedent respiratory infection” of undetermined etiology, and believe that pneumonia when it occurs is due to autogenous infection by a variety of secondary invaders, principally of the pneumococcus and streptococcus groups. Hall, Stone, and Simpson[^[35]] regard pneumonia strictly as a complication and quite distinct from influenza itself. Synnott and Clark[^[36]] believe that the infection is characterized by a progressive intense exudative inflammation of the respiratory tract often terminating in an aspiration pneumonia with a variety of conditions found at autopsy and a multiplicity of secondary organisms responsible for the fatal termination. B. influenzæ was usually found but always with other organisms. Friedlander and his collaborators[^[37]] speak of a fulminating fatal type of influenza with acute inflammatory pulmonary edema, but regard true bronchopneumonia as secondary, due to infection with pneumococcus or S. hemolyticus. B. influenzæ was not found more frequently than under normal conditions. Brem[^[38]] and his collaborators present a clear cut clinical picture both of influenza and the secondary pneumonia to which it predisposes, regarding the latter as definitely due to secondary infection with pneumococcus, streptococcus or B. influenzæ, the virus of influenza being unknown. Ely[^[39]] and his collaborators make no distinction between influenza and pneumonia, and apparently consider the epidemic due to a hemolytic streptococcus of indefinite and inconstant characters. The Camp Lewis Pneumonia Unit[^[40]] states “the process [influenza], whether mild or severe, is etiologically and pathologically the same; * * *.” B. influenzæ was not found. In a report of The American Public Health Association[^[41]] it is stated that deaths resulting from influenza are commonly due to pneumonias resulting from an invasion of the lungs by one or more forms of streptococci, by one or more forms of pneumococci, or by the so-called influenza bacillus. This invasion is apparently secondary to the initial attack. Wolbach[^[42]] found B. influenzæ in a high proportion of cases, not infrequently in pure culture in the lung, and believes that there is a true influenzal pneumonia whether B. influenzæ is the cause of the primary disease or not. Spooner, Scott and Heath[^[43]] isolated B. influenzæ in a high percentage of cases and consider it reasonable to suppose that it was the prime factor in the epidemic. Kinsella[^[44]] found B. influenzæ infrequently and regards it as a secondary invader. MacCallum[^[45]] regards B. influenzæ as a secondary invader and believes that it is responsible for a form of purulent bronchitis and bronchopneumonia following certain cases of influenza. Pritchett and Stillman[^[46]] found B. influenzæ in 93 per cent of cases of influenza and bronchopneumonia. Hirsch and McKinney[^[47]] state that B. influenzæ played no rôle in the epidemic at Camp Grant and apparently consider it due to a specially virulent pneumococcus.

No further references to the extensive literature of the recent pandemic seem necessary, since those cited above serve to illustrate the various points of view that exist. A similar diversity of opinion may be found in the reports from foreign sources.

It would appear that much of the divergence of opinion that has been formed has depended to a considerable extent upon the conditions under which cases have been observed. This is clearly brought out by contrasting the experience of Fantus[^[39]] dealing with private cases in civilian practice, where pneumonia was relatively uncommon, with that of others dealing only with cases in large hospitals, where those admitted have been in large part selected seriously ill patients with a high incidence of pneumonia, the milder cases comprising from 60 to 90 per cent of those attacked by influenza never reaching the hospital. Variations in opinion with respect to the bacteriology of the epidemic, especially in regard to B. influenzæ, would appear to be due for the most part to differences in bacteriologic technic, in some degree to differences in interpretation. Accumulating evidence can leave little doubt that B. influenzæ was at least extraordinarily and universally prevalent throughout the period of the epidemic and thereafter, and that earlier reports of failure to find it were due to the use of methods unsuitable for its detection and isolation.

The opportunity afforded the commission at Camp Pike to devote their full time to a systematic and correlated group study of the epidemic simultaneously from many aspects throughout its whole course made it apparent that influenza per se is in the large majority of instances, in spite of the initial picture of profound prostration, a relatively mild disease which tends to rapid spontaneous recovery. This opinion is supported by the fact that the disease during the first waves of the epidemic in this country, which it is now recognized occurred pretty generally in the army camps during the spring of 1918, was so mild that it attracted only passing attention, since the disease at that time was not sufficiently virulent to predispose to any alarming amount of pneumonia. With the return of the epidemic in the late summer and early fall, however, the disease had attained such a high degree of virulence that it predisposed to an appalling amount of severe and often rapidly fatal pneumonia, which often detracted attention from the real nature of the preceding disease. Yet even during the fall epidemic from 60 to 90 per cent of the cases of influenza proceeded to rapid recovery without developing complications. On this ground alone it would seem only logical to regard pneumonia strictly as a complication of influenza rather than as an essential part of the disease, irrespective of whether the pneumonia may be caused by the primary cause of influenza or not. The complexity of the clinical features, the bacteriology and pathology of the pneumonias following influenza lend further support to this opinion.

It seems better, therefore, to consider influenza first as a disease by itself and subsequently to take up the question of pneumonia and the relation of influenza to it.

The most striking clinical features of influenza are its epidemic character, its involvement of the respiratory tract, its extremely prostrating effect, and the often surprising rapidity with which the individual cures himself. These features strongly suggest that the etiologic agent of the disease is an organism subject to rapid changes in virulence; that it is confined to the respiratory tract where it produces a superficial inflammatory reaction giving rise to the characteristic symptoms of coryza, pharyngitis and tracheitis; that it elaborates a poison, possibly a true toxin, readily absorbed by the lymphatics, the effect of which is manifested in the profound prostration, severe aching pains, erythema, and leucopenia; and that it may either disappear promptly from the respiratory mucous membrane at time of recovery or may persist, leading a relatively saprophytic existence for an indefinite period of time, being no longer harmful to the individual, at least more than locally, because of an acquired immunity. Furthermore, in our opinion, the very brief incubation period suggests that the disease is bacterial in origin, rather than that it is analogous to the exanthemata, the majority of which present a comparatively long, fairly constant, incubation period.

B. influenzæ has characteristics in accord with the clinical features of influenza. It is an organism of very labile virulence; it is always present in our experience on the mucous membranes of the respiratory tract in early uncomplicated cases of influenza, often in overwhelming numbers; in only very exceptional instances, in adults at least, does it invade the body producing a general infection, as the numerous reports of negative blood cultures testify; recent investigations by Parker[^[48]] and others indicate that it is capable of producing a toxin quickly fatal for rabbits; it is predominantly present in the respiratory tract during the active stage of the disease and disappears in a considerable proportion of cases at time of recovery, while in others, more particularly those that develop an extensive secondary bronchitis and bronchiectasis it may persist for an indefinite period of time.

It is, of course, fully appreciated that the foregoing is in the main merely argumentative reasoning and it is put forth only to suggest that B. influenzæ merits a much closer scrutiny with respect to its etiologic relationship to influenza than the trend of present opinion has awarded it.

Although there remains some difference of opinion as to the relation of influenza to pneumonia, the majority of observers concur in regarding pneumonia as a complication and this would seem to be the only logical interpretation of the facts available. The same may be said with respect to purulent bronchitis and bronchiectasis. It is of considerable significance in this connection that pneumonia following influenza presents no uniform clinical picture, no uniform bacteriology and no uniform pathology. Whether the predisposition of patients with influenza to contract pneumonia is preponderantly due to lowering of general resistance to infection by the extremely prostrating effect of the disease and the inhibition of leucocytic defense, or to a destruction of local resistance against bacterial invasion by reason of profound injury to the bronchial mucosa, or to a combination of both factors, is difficult to say. It seems most probable that both are concerned. At any rate it seems clear that in the presence of influenza a considerable variety of organisms which under ordinary conditions do not find lodgement in the lungs are able to gain access to the lower respiratory tract and produce pneumonia.

CHAPTER III
SECONDARY INFECTION IN THE WARD TREATMENT OF INFLUENZA AND PNEUMONIA

Eugene L. Opie, M.D.; Francis G. Blake, M.D.; James C. Small, M.D.; and Thomas M. Rivers, M.D.

One of the most pressing problems that presented itself in the care of influenza and pneumonia patients in the army cantonments during the recent epidemic was the danger of secondary contact infection because of the overcrowding of the base hospitals, nearly all of which were taxed far beyond the limits of their capacity. That this danger was very real was fully demonstrated by certain studies in ward infection that this commission was able to make at Camp Pike[^[49]]. It is the purpose of the present section of the report to present these studies and to discuss the means whereby this danger may be most successfully met.

It is perhaps well, first to define exactly what is meant by secondary contact infection in influenza and pneumonia. In our experience at Camp Pike it was found that a very large percentage of the pneumonias following influenza were accompanied by secondary infection with pneumococcus, some few being caused by hemolytic streptococcus. The types of pneumococcus encountered were almost entirely those that are found normally in the mouths of healthy men, approximately 85 per cent being Types II atypical, III, and IV. It has been generally accepted that infection with these types of pneumococci is usually autogenous—that is, that under the proper conditions of lowered resistance an individual becomes infected with the pneumococcus that he carries in his own mouth. Many observations made during the course of the present work have suggested that this is probably not so in many instances and that the influenza patient may not be so much in danger from the pneumococcus that he normally carries in his own mouth as he is from that carried by his neighbor, in other words, he is in danger from contact infection. The same considerations hold true with respect to hemolytic streptococcus infection. Secondary contact infection in cases of already existing pneumonia following influenza were found to occur frequently. These were for the most part caused by hemolytic streptococcus infection superimposed upon a pneumococcus pneumonia. Many instances of double pneumococcus infection, however, either coincident with or following one another were encountered.

Secondary Infection with S. Hemolyticus in Pneumonia

Pneumonia caused by streptococci was repeatedly observed[^[50]] during the pandemic of influenza which occurred in 1889–90. With clearer recognition of the characters which distinguish varieties of streptococci several observers have shown that secondary infection with hemolytic streptococci may occur during the course of pneumonia and though definite evidence has been lacking have suggested that it may be acquired within hospital wards. That a similar secondary infection with S. hemolyticus in pneumococcus pneumonias following influenza occurred not infrequently at Camp Pike during the epidemic was shown by bacteriologic studies made during life and at autopsy in a considerable series of cases. During the early days of the epidemic of influenza, secondary streptococcus infection was almost entirely limited to certain wards which were opened for the care of the rapidly increasing number of patients with pneumonia. During this period these wards were overcrowded, organization was incomplete, and the opportunities for transfer of infection from patient to patient were almost unlimited. The spread of streptococcus contagion and its fatal effect may be clearly brought out by comparison of these wards with wards that had long been organized for the care of patients with pneumonia.

Ward 3 had been in use for the care of patients with pneumonia for some time prior to the outbreak of influenza. It was provided with sheet cubicles and conducted by medical officers, nurses and enlisted men accustomed to the care of patients with pneumonia, ordinary precautions being taken against transfer of infection from one patient to another. The data in Table XVII show the average number of patients in the ward, the number of new cases of pneumonia admitted, and the number of deaths among patients admitted during the corresponding period, for three periods of ten days each from September 6 to October 5. The types of infection in fatal cases as determined by cultures taken at autopsy are also shown.

During the period from September 6 to 15, just prior to the outbreak of influenza in epidemic proportions, the ward had an average population of 18.6 patients. The total number of new patients admitted was 11, of whom 3 died, a mortality of 27.2 per cent. All these cases were pneumococcus pneumonias as determined by bacteriologic examination of the sputum at time of admission. The 3 fatal cases showed pneumococcus infection at autopsy. During the second period, from September 16 to 25, with the outbreak of the epidemic of influenza, the ward rapidly filled with new cases of pneumonia, attaining an average population of 46.1 patients. Of the 52 new cases admitted 16 died, a mortality of 30.7 per cent. Again all the cases admitted during this period in which bacteriologic examination of the sputum was made, were found to be pneumococcus pneumonias with one exception. This case, admitted on September 21 and dying two days later, had a hemolytic streptococcus pneumonia. Fortunately, though quite by accident, he was placed in a bed at one end of the porch and no transmission of streptococcus infection to other cases in the ward took place. At autopsy 13 cases showed pneumococcus infection; the foregoing case, hemolytic streptococcus. During the third period from September 26 to October 5 the ward became even more crowded, having an average of 58.6 patients; 23 new cases were admitted, 8 of whom died, a mortality of 34.7 per cent. Autopsy showed that 5 of these were pneumococcus pneumonias and 1 was caused by hemolytic streptococcus infection. It is noteworthy that the death rate from pneumonia gradually increased as the ward became more and more crowded. This may possibly be attributed in part to the increasing severity of the pneumonia during the early days of the influenza epidemic. That it was in part directly due to secondary contact infection with pneumococcus will be shown when the transmission of pneumococcus infection is discussed. In spite of the overcrowding of the ward the introduction of 2 cases of streptococcus pneumonia did not cause an outbreak of streptococcus infection. Whether this was due to precautions taken against the transfer of infection or was merely a matter of good luck is difficult to say, in view of the fact that a considerable amount of transfer of pneumococcus infection from one patient to another did occur.

Ward 8 had long been used for the care of colored patients with pneumonia. As in Ward 3 cubicles were in use and ordinary precautions against the transfer of infection were used. The data are presented in Table XVIII.

During the period from September 6 to 20, prior to the outbreak of influenza in epidemic proportions among the colored troops, the ward had an average population of 25.5 patients; 18 new cases of pneumonia were admitted during this period, all of whom were pneumococcus pneumonias as determined by bacteriologic examination of the sputum at time of admission to the ward. Only 2 died, a mortality of 11.1 per cent, autopsy cultures showing pneumococcus in both cases. All these patients were treated on the porch of the ward while they were acutely sick. During the second period from September 21 to October 5, when the influenza epidemic was at its height, the ward rapidly filled with active cases of pneumonia and became distinctly crowded. It contained an average of 46.1 patients, but had actually reached a population of 64 patients at the end of the period. Of the 59 new cases admitted, 20 died, a mortality of 33.9 per cent, 10 with pneumococcus pneumonia, one with hemolytic streptococcus pneumonia. In 9 there was no autopsy. The conditions in Ward 8 were quite analogous to those in Ward 3. In spite of the overcrowding during the second period no outbreak of secondary infection with S. hemolyticus occurred, but secondary pneumococcus infection did occur as will be shown below.

In contrast with these two wards are Wards 1 and 2 in which widespread secondary contact infection with S. hemolyticus took place. Ward 2 was opened September 26, at the beginning of the period when 20 new wards for pneumonia were organized. From September 26 to October 1 the cubicle system was not in use, the ward was crowded, organization was imperfect, and few precautions were taken to prevent transfer of infection from one patient to another. On October 2 the cubicle system was installed and precautions against transfer of infection were instituted. The data are shown in Table XIX.

During the first three days 40 patients with pneumonia were admitted to the ward. Of these 40 patients, 27 died, a mortality of 67.5 per cent. Cultures at autopsy showed that 23 of these died with hemolytic streptococcus infection, none of pneumococcus infection. In four there was no autopsy. To appreciate the full significance of these figures it must be emphasized that these patients at time of admission to the ward in no way differed from those admitted to Ward 3 during the corresponding period and were not in any sense selected cases. The type of infection in 9 of these patients had been determined by bacteriologic examination of the sputum just prior to or immediately after admission to the ward before opportunity for secondary contact infection in this ward had occurred. All 9 were shown to have pneumococcus pneumonia free from hemolytic streptococci at that time. All 9 died, 7 with secondary streptococcus infection as shown by cultures taken at autopsy, 1 with a secondarily acquired Pneumococcus Type III infection—sputum showed a Pneumococcus Type IV on admission—and in 1 there was no autopsy. In view of the fact that bacteriologic examination of the sputum in cases of pneumonia following influenza had shown that the large majority of them were due to pneumococcus infection, it is probable that most of the other cases of pneumonia admitted to this ward were pneumococcus pneumonias at time of admission, and that they acquired the streptococcus infection after admission.

During the next three days 17 new patients were admitted, of whom 6 died, a mortality of 35.3 per cent. Cultures at autopsy showed pneumococcus infection in 2, streptococcus in 2. It is noteworthy that the porch was first put into use on September 29. Of the 12 patients admitted on this date, 8 were treated throughout the acute stage of their illness on the porch. Of these 8 patients but one died, of a Pneumococcus Type IV infection and none became infected with S. hemolyticus. From October 4 to October 6, 10 patients were admitted, of whom 4 died. Cultures at autopsy showed pneumococcus infection in 2, hemolytic streptococcus in 1.

The widespread prevalence of hemolytic streptococcus infection in this ward as compared with its almost entire absence in Wards 3 and 8 is very striking. Cultures made during life and at autopsy have shewn clearly that it was due to rapid spread of contagion throughout the ward. The almost unlimited opportunities for transfer of infection from patient to patient, during the first six days the ward was in use, undoubtedly greatly facilitated this spread. From the data available it is impossible to state exactly when and by which patients hemolytic streptococcus infection was introduced into the ward, but it must have been very early since the death rate was very high from the beginning, and the first 23 cases coming to autopsy died with streptococcus infection.

Ward 1 was opened on September 24. From that date until October 2 no cubicles were in use and few precautions were taken against transfer of infection. On October 2 cubicles were installed and ordinary precautions to prevent transfer of infection were instituted. On October 6 the ward was closed to further admissions. The data presented in Table XX are divided into two periods, because on September 29 and 30, 4 patients with streptococcus pneumonia were admitted to the ward.

During the first period from September 24 to 29 the ward contained an average of 35.8 patients, being only moderately crowded; 34 cases of pneumonia were admitted, of whom 11 died, a mortality of 32.3 per cent. It is noteworthy that deaths among this group which occurred prior to September 30 were due to pneumococcus infection with one exception, a patient entering the ward on September 26 and dying the following day. Of the other 2 patients in this group who died with hemolytic streptococcus pneumonia, 1 was admitted to the ward on September 25, was shown to be free from S. hemolyticus on September 30, and died on October 12 with a secondarily acquired streptococcus pneumonia and empyema; the other was admitted on September 29 with streptococcus pneumonia and died the following day.

During the second period from September 30 to October 5 the ward contained an average of 55.3 patients, being very overcrowded; 40 new cases of pneumonia were admitted of whom 24 died, a mortality of 60 per cent. Cultures taken at autopsy showed that 6 died of pneumococcus pneumonia, 14 with hemolytic streptococcus infection. As in Ward 2, patients admitted to this ward were in no way selected and were probably, as experience has shown, in large part pneumococcus pneumonias at time of admission. The widespread dissemination of hemolytic streptococcus and its fatal effect following the introduction of the organism on September 29 and 30 is only too evident.

Secondary Infection with Pneumococcus in Pneumonia

The foregoing studies have shown that hemolytic streptococcus infection may spread by contagion throughout an entire ward with great rapidity. Other observations have demonstrated that pneumococcus infection may be transmitted in the same way. Only three instances of this nature will be cited. The first occurred in Ward 3 (Table XXI). Between September 6 and 16 no cases of pneumonia caused by Pneumococcus Type II had been admitted to the ward. On September 16 Pvt. Swain was admitted to the ward and placed in Bed 3. Bacteriologic examination of his sputum showed that his pneumonia was caused by Pneumococcus Type II. At this time Pvt. Pullam, who had been admitted to the ward on September 9 with a pneumococcus Type IV pneumonia, occupied Bed 5 separated from Bed 3 by one intervening bed. He had had his crisis on September 14 and was doing well, his temperature being normal. On September 24 he developed a second attack of pneumonia and died on September 30. Cultures at autopsy showed Pneumococcus Type II in heart’s blood and lung, Pneumococcus Type II and B. influenzæ in the right bronchus. Pvt. Wolfe was admitted to the ward with bronchopneumonia on September 17 and placed in Bed 6 next to Pvt. Pullam. Pneumococcus Type IV and B. influenzæ were found in his sputum. His temperature had fallen to normal by lysis on September 21 and he was doing well. On September 23 his temperature suddenly rose and he developed a second attack of pneumonia. Pneumococcus Type II was isolated by blood culture on this date. He recovered. In both instances Pneumococcus Type II was acquired after the admission of a patient with a Pneumococcus Type II pneumonia, the opportunity for contact infection having been favored by the association of these patients in adjoining beds.

The second instance is almost identical and occurred on the opposite side of Ward 3 at about the same time (Table XXII). Pvt. Linehan was admitted on September 16 and placed in Bed 30. Pneumococcus Type IV was found in his sputum. Pvt. Thompson was admitted the following day with a Pneumococcus II atypical pneumonia and placed in Bed 28. The next day Pvt. Smith was admitted and placed in Bed 26. Pneumococcus Type II was found in his sputum. On September 19 Pvt. Thompson recovered by crisis and was doing well. On September 21 he had a chill, his temperature rose to 104.4° F. and he developed a second attack of pneumonia. He died on September 29; cultures at autopsy showing Pneumococcus Type II in heart’s blood and left pleural cavity, Pneumococcus Type II and B. influenzæ in bronchus and lung. Pvt. Linehan had begun to improve on September 24 and his temperature was falling by lysis. On September 26 he became worse, developed signs of pericarditis and died on September 30. Cultures from lungs and bronchus at autopsy showed Pneumococcus Type II and B. influenzæ. In both instances the fatal secondary infection with Pneumococcus Type II was undoubtedly acquired from Pvt. Smith in the nearby bed.

The third instance occurred in Ward 8 (Table XXIII). Pvts. Lewis and Scott were admitted on September 21 and were placed in adjoining beds, 50 and 51. Lewis showed Pneumococcus Type I in his sputum, Scott Pneumococcus II atypical. The following day Pvts. Pighee, Jones, and Columbus were admitted and given Beds 48, 49 and 53 respectively. All showed Pneumococcus II atypical in the sputum. Pvt. Lewis with Pneumococcus Type I pneumonia recovered by crisis on September 29. His temperature remained normal until October 2 when it suddenly rose to 104.2° F. He developed a second attack of pneumonia and died on October 8. Cultures at autopsy from heart’s blood and lung showed Pneumococcus II atypical, from the bronchus Pneumococcus II atypical and B. influenzæ. It is, of course, impossible to say from which one of his neighbors Pvt. Lewis acquired his second pneumococcus infection.

It is noteworthy that these instances of secondary contact infection with pneumococci occurred in wards where every precaution was supposedly taken to prevent transfer of infection from one patient to another. It is true however that the wards were greatly overcrowded at the time. Many other instances of secondary pneumococcus infection in cases of pneumonia following influenza were encountered in which it was impossible to trace the source of infection, many combinations of different types of pneumococcus being found. There were two instances in which Pneumococcus Type IV was found in the sputum by inoculation of white mice shortly after onset of pneumonia, whereas secondary infection with other types was found at autopsy, one with Pneumococcus Type II, one with Pneumococcus Type III. In 2 cases by inoculation of white mice, two types of pneumococcus were found simultaneously in the sputum coughed from the lung, in one Pneumococcus Types III and IV, in the other Pneumococcus Types I and IV. There were 5 cases in which two types of pneumococcus were found in cultures at autopsy as shown in Table XXIV. Combined pneumococcus infections of this nature are almost never encountered in pneumonia occurring under normal conditions in the absence of epidemic influenza.

The foregoing data show that infection with one type of pneumococcus may readily be superimposed upon or closely follow infection with another type. Cases have been cited in which it was clearly demonstrated that this was due to contact infection. It is furthermore evident that pneumonia caused by one type of pneumococcus affords no reliable immunity against pneumonia caused by another type. The same conditions that favored the spread of hemolytic streptococcus infection also favored the transfer of pneumococcus infection from patient to patient.

Secondary Contact Infection in Influenza

The material so far presented has dealt with contact infection in cases of pneumonia following influenza. That a similar contact infection in cases of influenza treated in crowded hospital wards is responsible in considerable degree for the development of pneumonia in cases of influenza seems quite probable. It has already been stated that this pneumonia was found in large part to be caused by infection with types of pneumococcus that are found in the mouths of normal individuals. It has been fairly definitely established by Stillman[^[52]] that lobar pneumonia caused by pneumococcus Types I and II is in all probability due to contact infection, and definite instances of such infection by Pneumococcus Type II have been reported above. In a recent communication Stillman[^[53]] has furthermore shown that of the various groups of Pneumococcus II atypical those most frequently associated with pneumonia are rarely found in normal mouths, while those infrequently associated with pneumonia are more commonly found. Whether similar considerations will hold true for pneumococci of Group IV can only be determined by further investigation. It has been stated that certain observations made during the course of this work have suggested that cases of pneumonia which complicate influenza may be due to contact rather than to autogenous infection. The data available are far too limited to establish this fact and it would require a very extensive study to furnish conclusive evidence.

Certain general observations have suggested this point of view. It is well recognized that the incidence of pneumonia in patients with influenza has been much higher where overcrowding has existed. It would seem probable that this has been in large part due to the greater opportunity for the dissemination of organisms capable of producing pneumonia and the consequently increased opportunity for secondary contact infection among patients treated under such conditions. The not infrequent occurrence of influenzal pneumonia due to combined infections of the different types of pneumococci, hemolytic streptococci, staphylococci, and other bacteria, instances of which have been cited, is in harmony with this view, especially since pneumonia under ordinary conditions is rarely found to be associated with mixed infections of this nature. It is true that healthy individuals occasionally carry more than one type of pneumococcus simultaneously in the mouth, though this is very infrequent, and autogenous infection occurring in such individuals might account in some instances for the mixed pneumococcus infections encountered. By way of analogy it has been clearly shown in other studies by the Commission on the relation of hemolytic streptococcus carriers to the complications of measles, that secondary infection of the respiratory tract with S. hemolyticus is in very large part due to contact infection, the chronic carrier rarely developing complications due to this organism.

To obtain further light on this question the type of pneumococcus present in the mouths of 46 consecutive cases of early uncomplicated influenza was determined by the mouse inoculation method at time of admission to the receiving ward of the hospital before the patients had been associated, with the purpose of determining if cases among this group which subsequently developed pneumonia might be shown to have acquired a pneumococcus which they did not carry at time of admission. This group of patients was treated in a special ward set apart for the purpose. The patients were assigned to beds in rotation and confined in bed until thoroughly convalescent. Beds were well separated and cubicles, masks and gowns were in use. Cultures were made from the ward personnel. By these procedures an accurate record was kept of all sources of pneumococcus infection. The types of pneumococcus found in the mouths of these patients at time of admission are shown in Table XXV.

Only 1 patient in this group developed pneumonia. At time of admission he had no pneumococcus in his mouth as determined by inoculation of a white mouse with his sputum. Examination of the sputum by the same method at time of onset of pneumonia three days after admission showed Pneumococcus Type III. The only ascertainable source of infection in this case was one of the ward attendants who carried Pneumococcus Type III in his throat in sufficiently large numbers to be demonstrable by direct culture and who frequently came in contact with the patient. In this instance the development of pneumonia was probably due to contact infection. An extensive study of this nature would be necessary to determine in what proportion of cases pneumonia following influenza is caused by secondary contact infection and in what proportion to autogenous infection. It is at least evident that contact infection with a type of pneumococcus found in the mouth of normal individuals may occur in influenza and be responsible for the development of pneumonia. Therefore every precaution should be taken to prevent it.

Methods for the Prevention of Secondary Contact Infection in Influenza and Pneumonia

The methods at present in vogue for preventing the spread of contagion in wards devoted to the care of patients with influenza and pneumonia may be briefly enumerated: The separation of patients by means of sheet or screen cubicles, the wearing of masks and gowns by the ward personnel and to some extent by convalescent patients who are up and about the ward, and in some hospitals the separation of streptococcus carriers from noncarriers as determined by throat culture at time of admission. That these methods are of some value in preventing spread of infection cannot be denied, and it is probable that they are fairly effective under ordinary conditions when conscientiously carried out. That they inevitably break down in the presence of an overwhelming epidemic when hospital wards become overcrowded is only too evident. Under such conditions the sheets hung between the beds are constantly being displaced and are slight proof against a patient’s curiosity as to the identity and condition of the man in the adjoining bed; masks cannot be worn by patients seriously ill with pneumonia, during the very time when they are most dangerous and in greatest danger and those worn by the ward personnel are very rarely sufficiently well made to prevent spread of contagion by droplet infection as the studies of Haller and Colwell[^[54]] and Doust and Lyon[^[55]] have shown; the separation of streptococcus carriers from noncarriers as at present carried out cannot keep pace with the ever increasing influx of patients nor with the rapidity of the spread of the hemolytic streptococcus, in part because of the time required to make the bacteriologic diagnosis, in part because the amount of work involved cannot be accomplished by the laboratory personnel available. That this is so will be shown in data presented below. Not only do these methods break down in the face of an epidemic, but they often provide a false sense of security.

In searching for a solution of the problem it is essential to have the following considerations clearly in mind. Every patient with influenza must be considered a potential source of pneumococcus or hemolytic streptococcus infection for his neighbor until he is proved otherwise by bacteriologic examination. Every person engaged in the care of patients with respiratory diseases must also be regarded as a potential source of danger. Pneumonia cannot be regarded as one disease but must be looked upon as a group of different diseases, with more or less similar physical signs and symptoms, it is true, but caused by a considerable variety of bacteria, infection with any one of which not only provides no protection against infection with another, but may even render the individual more susceptible to secondary infection. Therefore, every patient with pneumonia must be regarded as an actual source of danger to his neighbor, at least until it is established that he has the same type of infection. All these considerations are especially true in the presence of influenza, for it has become evident that many organisms readily gain access to the lung and produce pneumonia in patients with influenza which under ordinary circumstances fail to cause disease of the respiratory organs.

Since secondary infection in respiratory disease is undoubtedly spread in large part by droplet and contact infection, the prevention of secondary infection must depend upon the elimination of these methods of transmission. Three solutions present themselves: (1) Ward treatment with absolute elimination of overcrowding and much wider separation of patients than has hitherto been deemed necessary; (2) segregation of patients according to type of bacterial infection; (3) effective individual isolation of every patient.

It has been clearly shown that treatment of influenza and pneumonia in overcrowded wards even with the use of such precautions to prevent transfer of infection as cubicles, masking of attendants and patients, etc., is attended by serious danger of contact infection and that such infection will almost inevitably occur. This is not at all surprising when it is remembered that we are treating in the same ward, in the case of pneumonia, a group of what are in reality entirely different diseases, all of which may be transmitted from one patient to another, and in the case of influenza a group of individuals who carry a variety of potentially pathogenic bacteria. No one would expect to treat cases of scarlet fever, measles, and diphtheria together in a hospital ward without having contact infection result. Among patients ill with influenza and postinfluenzal pneumonia, certainly streptococcus pneumonia and to some extent pneumococcus pneumonia may be transmitted quite as readily as any of these diseases. In view of these considerations it must be apparent if ward treatment of these diseases is to be continued without respect to type of bacterial infection, not only that overcrowding is absolutely contraindicated but also that much wider separation of patients than has hitherto been regarded as necessary is imperative. Furthermore, beds should be separated by permanent cubicles that cannot readily be displaced. Patients should be confined to their cubicles until thoroughly convalescent and when up and about should not be allowed to enter cubicles occupied by patients still sick. Medical officers, nurses and attendants who come into contact with the patients should use the same rigid precautions that are used in the care of patients with typhoid or erysipelas or meningitis with the additional use of means to prevent droplet infection of the patients, always bearing in mind that the respiratory tract in patients with influenza or postinfluenzal pneumonia is as susceptible to secondary infection as the postpartum uterus or an open surgical wound. In other words, the most rigid aseptic technic should be maintained. The recognition of a case of streptococcus pneumonia in a ward should be an indication for immediate quarantine of the ward until it has been shown by bacteriologic examination that there is no longer danger of spread of streptococcus contagion. This is done in the case of meningitis or diphtheria, neither of which diseases is comparable with streptococcus pneumonia in rapidity of spread or in resulting fatality.

Segregation of patients in wards according to type of bacterial infection while theoretically an improvement over the indiscriminate mixing of patients with many different types of infection presents many practical difficulties which make it impossible to carry out in the presence of an overwhelming epidemic. It is quite obvious that grouping of influenzal patients on the basis of the types of pneumococci that they carry in their mouths is impossible since the great majority of mouth pneumococci belong to Group IV and comprise a heterologous immunologic group. The separation of influenza patients who carry S. hemolyticus from those who do not would appear to offer a more hopeful field. Since we cannot make an immediate distinction between streptococcus carriers and noncarriers by inspection of the patient, this procedure requires the taking of throat cultures at time of admission to the hospital, the holding of patients for eighteen to twenty-four hours in receiving wards until the bacteriologic diagnosis has been made, and their subsequent distribution to streptococcus and nonstreptococcus wards. This is feasible when the admission rate is low and the number of streptococcus carriers found at time of admission is small. In the presence of an influenza epidemic it immediately becomes impossible to carry out in base hospitals as now constituted, since the demand for beds under such conditions at once converts a large part of the hospital into a group of receiving wards with little room remaining for subsequent separation of patients. The amount of bacteriologic work involved at once becomes prohibitive and the time required to make the bacteriologic diagnosis defeats its purpose since it allows the spread of hemolytic streptococcus to occur in the receiving wards during the interval.

The foregoing statements are based on results obtained in an attempt to separate streptococcus carriers from noncarriers in a limited group of cases of influenza at Camp Pike, the investigation being conducted during a secondary wave of influenza between November 27 and December 5. A special group of five wards consisting of one receiving ward and four distributing wards were set aside for the study. Cubicles, masks and gowns were in use and the wards were not crowded. The personnel on these wards did not carry S. hemolyticus in their throats. Patients entering the receiving ward were assigned to beds in rotation. Throat cultures were made on blood agar plates at time of admission. The plates were examined promptly the next morning, the diagnosis of S. hemolyticus being made by the characteristic hemolytic colonies and microscopic examination of stained smears. By this method a report reached the receiving ward at 9:30 a.m. and patients were promptly evacuated to the streptococcus and nonstreptococcus wards, where they were again assigned to beds in rotation, remaining confined in bed until convalescent. Confirmation of all strains of hemolytic streptococcus was subsequently carried out by isolation in pure culture, bile solubility test, and hemolytic test with washed sheep corpuscles. All cases free from hemolytic streptococci at time of admission who were sent to the “clean” wards were recultured daily throughout the period of study, those acquiring a hemolytic streptococcus being transferred to a streptococcus ward as soon as the bacteriologic diagnosis was made. The results are shown in Table XXVI.

One hundred and sixty-five cases were admitted to the receiving ward during the period of study as cases of influenza. Of these, 137 had influenza; 4 of those with influenza had pneumonia at time of admission, 23 had acute follicular tonsillitis, 3 epidemic cerebrospinal meningitis, 1 scarlet fever, and 1 Vincent’s angina. Sixty-six cases (40 per cent) showed hemolytic streptococcus in the throat at time of admission and were sent to the streptococcus wards; 99 cases (60 per cent) were negative for hemolytic streptococcus on admission, and of these 91 were sent to the “clean” influenza wards. Twenty-four of these clean cases subsequently became positive for S. hemolyticus. It is especially noteworthy that 14 of them acquired a hemolytic streptococcus during the short period that they were held in the receiving ward awaiting the report of the culture taken at time of admission, the first culture taken shortly after admission to the “clean” wards being positive. This result was undoubtedly due to the fact that these cases were unavoidably associated in the receiving ward with many carriers of hemolytic streptococcus. It is evident that cases which were supposedly free from streptococci but which in reality had picked up the organism in the receiving ward were constantly being sent to the “clean” wards. It is furthermore evident that if the precaution had not been taken of reculturing all clean cases on day of admission to the “clean” wards and daily thereafter these wards would soon have become saturated with hemolytic streptococci. Even under these conditions, 10 cases, after varying periods in the “clean” wards, acquired the organism in their throats. When it is stated that it required the full time of two men under very special conditions to carry out this work in a very limited number of cases and that it failed to keep “clean” wards free from hemolytic streptococci, it is only too apparent that the efficient separation of carriers from noncarriers in the presence of an epidemic of influenza is an impossible task.

The segregation of pneumococcus pneumonias following influenza according to type of infection is obviously impossible, since they are caused by an almost unlimited variety of immunologic types as far as present knowledge goes.

Even the efficient separation of streptococcus pneumonias from pneumococcus pneumonias would require a considerable team of workers and the closest cooperation between laboratory and ward staffs, so that no case of pneumonia would be sent to a pneumonia ward until the bacteriologic diagnosis had been made. In our experience this is rarely considered feasible even under ordinary conditions, and in the presence of an epidemic is nearly impossible because of the volume of work involved and the delay necessitated by bacteriologic methods. It is, nevertheless, absolutely essential if highly fatal ward epidemics of streptococcus pneumonia are to be prevented.

In view of the considerations discussed above, it is believed that the clear and most fundamental indication for the management of epidemic respiratory diseases in the army is to scatter patients as widely as possible instead of following the time-honored custom of concentrating them. In brief, abandon open ward treatment and adopt effective individual isolation of every case, maintaining as strict a quarantine as is demanded in other highly contagious and infectious diseases. The adoption of a strict aseptic technic in the handling of these patients is an evident corollary. Only by this means can the serious and highly fatal secondary hospital infections, which occur in influenza and pneumonia when these diseases are present in epidemic form, be prevented.

The prevention of secondary infection, prior to admission to the hospital, is another and more difficult problem. That opportunity for secondary contact infection in cases of influenza before patients reach the hospital is great seems unquestionable, since many cases have already developed these infections at time of admission. During the epidemic patients were crowded in regimental infirmaries, in ambulances, and in the receiving office of the hospital with every opportunity for droplet infection present. No study has been made of this question, but it seems reasonable that the same methods of prevention should apply, namely, effective separation of patients.

It is not within the scope of this paper to discuss details of method, but anything that is possible becomes feasible as soon as sufficient evidence can be brought to bear that it is a necessity. In the present instance it would seem that any means that can be used to reduce materially the terrific toll taken by respiratory diseases is an absolute necessity.

Summary

1. Secondary contact infection with pneumococci not infrequently occurs in patients with pneumonia following influenza when they are treated in hospital wards.

2. Secondary contact infection with S. hemolyticus readily occurs in patients with pneumonia and may spread rapidly throughout an entire ward with highly fatal results.

3. Secondary contact infection may be responsible for the development of pneumonia in patients with influenza.

4. Ward treatment of these diseases is fraught with serious danger which is greatly increased by overcrowding, by imperfect separation of patients by cubicles, and by imperfect aseptic technic of medical officers, nurses, and attendants.

5. It is probable that secondary contact infection can be effectively prevented only by individual isolation and strict quarantine of every patient.

CHAPTER IV
THE PATHOLOGY AND BACTERIOLOGY OF PNEUMONIA FOLLOWING INFLUENZA

E. L. Opie, M.D.; F. G. Blake, M.D.; and T.M. Rivers, M.D.

Many observers have described isolated phases of the recent epidemic and of past epidemics of influenza. Few have had an opportunity to follow the pathology of influenza from the onset of an epidemic through a period of several months and to observe the succession of acute and chronic changes which occur in the lungs. Our commission arrived on September 5, 1918, at Camp Pike two weeks before the outbreak of influenza. The commission had previously made a careful study of the clinical course, the bacteriology and to a limited extent the pathology of pneumonia occurring at Camp Funston where there was little if any influenza. Study of the records preserved at the base hospital at Camp Funston had convinced us that this camp had passed through an epidemic of influenza during the spring of 1918, this epidemic being followed by a very severe outbreak of pneumonia. Our investigation at Camp Funston had brought to our attention those phases of pneumonia which with the facilities of a base hospital laboratory could be most profitably studied with a view to determining the causation, the epidemiology and the prevention of the pneumonias prevalent in the American army.

Study of pneumonia after death offers the only opportunity of determining the relation of pulmonary lesions to the considerable variety of microorganism associated with them. Clinical diagnosis furnishes no certain criterion for distinguishing lobar and bronchopneumonia; suppurative pneumonia is rarely recognizable during life. The relation of pneumococci, streptococci, staphylococci or B. influenzæ to one or other type of pneumonia can be determined with accuracy only after death; for the demonstration of one or more of these microorganisms in material obtained from the upper respiratory passages in life, though of value, furnishes us no definite evidence that the organism which has been identified has entered the lung and passed from the bronchi to produce pneumonia.

Study of autopsies following examination of the sputum during life has shown that an individual primarily attacked by influenza may suffer with a succession of pneumonias, one microorganism having prepared the way for another. The complexity of the subject is much increased by the truth that pyogenic microorganisms, like the tubercle bacilli, are capable of producing a considerable variety of pulmonary lesions.

Examination of the lungs of a large number of individuals who have died as the result of pneumonia following influenza has disclosed a succession of acute and chronic diseases. Immediately succeeding the height of the epidemic of influenza, death occurred with acute lobar pneumonia or with diffusely distributed hemorrhagic bronchopneumonia caused in the majority of instances by Pneumococcus IV in association with B. influenzæ. Superimposed infection with hemolytic streptococci increased in frequency and in individuals who had occupied certain wards was almost invariable. At a later period, from one to two months following the maximum incidence of influenza chronic lesions, namely, bronchiectasis, unresolved pneumonia, and chronic empyema were common and often occurred as the result of influenza which had had its onset at the height of the epidemic.

When influenza attacked the encampment, about 50,000 troops were quartered in it, and for a considerable period no more troops were brought into the camp and none left it. All cases of pneumonia occurring among these troops were brought to the base hospital so that the autopsies which were studied were representative of all the pneumonias following influenza in this limited group of men. It is noteworthy that autopsy disclosed no instance of fatal influenza unaccompanied by pneumonia.

Pneumonia of Influenza.—Knowledge concerning the bacteriology of the pneumonia of influenza dates from the study of the epidemic of 1889–90. The frequency with which Diplococcus lanceolatus occurred in association with influenzal pneumonia was well recognized, although several observers, notably Finkler[^[57]] and Ribbert,[^[58]] found Streptococcus pyogenes so often that they attributed the pneumonia of influenza to this microorganism.

During a subsidiary outbreak of influenza occurring in 1891–92 Pfeiffer[^[59]] discovered the microorganism which he believed was the cause of the disease. Pneumonia, he believed, was caused by the invasion of this microorganism into the lung, and the pneumonia of influenza, if death occurred at the height of the disease, was characterized not only by the presence of the bacillus of influenza, but was recognizable by its anatomic peculiarities. He described lobular patches of consolidation which were separated from one another by air containing tissue or were confluent, so that, although the lobular character was still recognizable, whole lobes might be affected. The consolidated tissue was dark red and within each lobular area were small, yellowish gray spots varying in size from that of a pinhead to a pea. In the mucus of the larynx and trachea were numerous microorganisms, including diplococci and streptococci, among which influenza bacilli were predominant; in the larger bronchi, bacteria other than influenza bacilli were less abundant, whereas in the finer bronchi filled with purulent fluid and in the lung tissue influenza bacilli had undivided sway. Pfeiffer stated that the changes described were found when death occurred at the height of the disease, whereas other pulmonary lesions might be sequelæ of this typical influenzal pneumonia.

Observations upon the pathology of influenzal pneumonia made during the epidemic of 1889–92 have been collected in the monograph of Leichtenstern[^[60]] published in 1896. He combats the opinion held by some observers that pneumonia with influenza is always catarrhal and cites many writers to prove that lobar pneumonia not infrequently accompanies the disease. Indeed, some have found “croupous” pneumonia more often than “catarrhal.” Krannhals[^[61]] at Riga found typical fibrinous pneumonia in 53 instances, doubtful forms in 22 and bronchopneumonia in 37. Cruickshank[^[62]] in England found croupous forms predominant. Among 43 autopsies performed upon individuals dead with influenza Birch-Hirschfeld[^[63]] found 11 instances of croupous lobar pneumonia, 8 instances of croupous lobular pneumonia and 24 instances of catarrhal pneumonia. Leichtenstern thinks that the atypical symptomatology of lobar pneumonia with influenza—for example, the purulent character of the sputum—has led many physicians to believe that lobar pneumonia rarely occurs. It is equally true that many instances of confluent lobular pneumonia are mistaken for lobar.

There appears to be no comprehensive description of the pneumonias of influenza based upon the epidemics of 1889–92. Descriptions dating from this period are much obscured by attempts to separate croupous or fibrinous from catarrhal pneumonias. Croupous lobular pneumonia has been recognized, for example, by Birch-Hirschfeld. Leichtenstern describes a form of pneumonia which he regards as neither lobar nor lobular although it implicates whole lobes; the consolidated tissue is homogeneous and varies in color from fleshy red to bluish red; it is tough and elastic in consistency. The author thinks that it is an error to regard this lesion as a confluent lobular pneumonia.

Kuskow[^[64]], who has discussed the pathology of influenza in considerable detail, has seldom seen lobar pneumonia but has almost invariably found, even when there is lobar distribution of the lesion, lobular patches of consolidation involving groups of lobules, single lobules or only parts of lobules; the lung tissue has been hyperemic and in places edematous.

Opinions concerning the pathology and bacteriology of the pneumonias of influenza, published since the recent epidemic, have varied almost as much as those just cited. Few observers have had the opportunity of making a considerable number of observations under conditions which determine the relation of the pulmonary lesions to the primary disease.

Keegan[^[65]] has found with influenza a massive and confluent bronchopneumonia, frequently resembling lobar pneumonia but distinguishable particularly in its early stages when the cut section of the consolidated lung has a finely granular character and each bronchiole stands out as a grayish area with intervening dark red alveolar tissue.

Symmers[^[66]] states that the pneumonia of influenza is a confluent lobular exudative and hemorrhagic pneumonia which bears a close resemblance to the pneumonic variety of bubonic plague.

Our commission[^[67]] published a preliminary report on pneumonia following influenza observed at Camp Pike. The occurrence of purulent bronchitis, distention of lungs, peribronchial hemorrhage and bronchiectasis were described. B. influenzæ was isolated from the bronchi in approximately 85 per cent of instances of influenzal pneumonia but from the consolidated lung in less than half this number of autopsies. Lobar pneumonia was present in a large proportion of autopsies but was less frequent than bronchopneumonia. Bronchopneumonic consolidation is in part red, lobular and confluent, in part nodular; pneumococci have a predominant part in the production of these lesions. Three types of suppurative pneumonia are described: (a) Abscess caused by hemolytic streptococci usually in contact with the pleura and accompanied by empyema; (b) Suppuration of interstitial tissue of the lung caused by hemolytic streptococci and accompanied by empyema; (c) multiple foci of suppuration clustered about a bronchus of medium size and caused by staphylococci. We have expressed the opinion that B. influenzæ descends into the bronchi; pneumococci, usually Type IV, may enter the lung and produce either lobar or bronchopneumonia. Hemolytic streptococci may descend and infect the pneumonic lung causing death often before suppuration has occurred. Epidemics of such superimposed streptococcus pneumonia in wards of the hospital were described.

LeCount[^[68]] says: “The pneumonia of influenza is commonly referred to as bronchopneumonia. It may be so designated, but it differs from other bronchopneumonias in its predilection for the periphery of the lungs and in the extent to which the inflammation is hemorrhagic.”

MacCallum[^[69]] states that the following types of pneumonia following influenza may be recognized. 1. Pneumococcus pneumonia. The lobular character of the consolidation is in these cases well marked, although it tends to lose its definiteness through the confluence of adjacent areas. The cut surface of the lung shows in the more acute cases a peculiar lobular or confluent consolidation which corresponds well with what is commonly written of the stage of engorgement in the description of lobar pneumonia. Later stages in the pneumonia show within these areas patches of rough gray consolidated tissue from which definite plugs of exudate project. 2. Staphylococcal pneumonia. 3. Streptococcal pneumonia. There is lobular pneumonia, the interlobular septa are edematous and, microscopically, bronchi and alveoli are loaded with streptococci. Whole areas of lung, though retaining their form, are entirely necrotic. Lymphatics are distended with exudate containing streptococci in great numbers, but in none of these cases is interstitial bronchopneumonia found. 4. Pneumonia produced by B. influenzæ of Pfeiffer. The lung is studded with palpable shot-like grayish yellow nodules; the bronchi exude thick yellow pus, which contains influenza bacilli. Microscopically, the walls of the bronchi are found to be thickened by mononuclear infiltration and new formation of connective tissue. The walls of the alveoli are thickened and indurated and the alveoli often contain fibrin in process of organization. Absence of conspicuous changes in lymphatics, absence of intense pleural infection and relatively scant numbers of polynuclear leucocytes in the exudate within the alveoli and bronchial walls are, MacCallum states, all that distinguish this pulmonary change from the interstitial bronchopneumonia caused by the hemolytic streptococcus and described by him in previous papers.

Lyon[^[70]] designates the pulmonary lesion following influenza, hemorrhagic pneumonitis, the lung tissue containing serous fluid loaded with red blood corpuscles; in many instances there was such scant consolidation that the process could not be regarded as a true pneumonia. In 35 instances the lesion was lobular in distribution and in 16 instances was sufficiently extensive to be designated lobar, but it was not typical lobar pneumonia, and, often associated with lobular patches of consolidation, appeared to be a confluent lobular pneumonia.

Goodpasture and Burnett[^[71]] say: “The difficulties of analyzing the pulmonary lesions in any group of influenza pneumonias as they have appeared in this epidemic, are very apparent to anyone who has had an opportunity to observe the bacteriology and pathology of this accompaniment of the disease.” There is an acute outflow of the fluid elements of the blood and of hemorrhage into the lung tissue filling the alveoli in lobular areas and not infrequently in an entire lobe. By a special method of staining these authors have studied the distribution of Gram-negative bacilli with the morphology of B. influenzæ. The fact that in certain very early cases demonstrable bacteria of any kind are scarce or not found at all, has lead them to believe “notwithstanding the demonstration of influenza bacilli in pure culture in the lung in all but one instance, that at this stage organisms are comparatively few within the alveoli, and the primary injury is due to a very potent toxic agent elaborated in and disseminated through the larger air passages. In the later stages or from the beginning, if the injury be slight, the infection focalizes about the bronchi or their terminations, so that the bronchial and lobular distribution becomes very conspicuous.” Typical lobar pneumonia with “croupous” exudate within the alveoli occurs in cases complicated by secondary pneumococcus infection.

Wolbach[^[72]] has found that two types of pneumonia are characteristic of influenza. In cases in which death has occurred within a few days after onset of pulmonary signs, the lung tissue is dark red and “meaty in consistency” and contains abundant blood-tinged serous fluid which drips from the cut surface. The other type of lesion is found in patients who have lived for ten days or more after onset of the disease; there is extensive bronchitis, bronchopneumonia, discrete or confluent, and peribronchitis. The lungs are voluminous and the smaller bronchi are distended. Microscopically, there is peribronchitis with extensive infiltration of the interlobular septa and organization in alveoli and bronchioles. This lesion is that designated by MacCallum as “interstitial bronchopneumonia.” Wolbach thinks that the two types of lesion represent different stages of the same process. He regards as distinctive of the pneumonias of influenza the presence of hyalin fibrin lining distended air spaces. With the two types of lesion which have been described, B. influenzæ was the only organism which could be cultivated, and the author associates these distinctive conditions with that microorganism.

Streptococcus Pneumonia.—Finkler emphasized the importance of streptococcus pneumonia as a complication of influenza. In 1888 he described instances of acute primary streptococcus pneumonia observed in 1887 and 1889. This form of pneumonia, Finkler thought, occurred in Bonn in epidemic form before the influenza epidemic of 1889–90 and, he states, exhibited an astonishing similarity to the pneumonia of influenza. He thought that later there was in Bonn a mixed infection of influenza and primary streptococcus pneumonia. In one type of streptococcus pneumonia, described by Finkler, there was lobular consolidation which in multiple patches produced “pseudolobar” consolidation; the consolidated lung was smooth and red, and similar to spleen, rather than hepatized. In another group of instances the lesion merited the name “erysipelas of the lung.” The lesion was an acute interstitial pneumonia in some places, a cellular or occasionally fibrinous pneumonia with involvement of the interstitial tissue in other places. There was edematous swelling and accumulation of leucocytes in the interstices between the alveoli and about the blood vessels and bronchi. Finkler stated that the similarity to erysipelas might suggest that the lymphatics contain streptococci, but this relation did not exist although large lymphatic channels were occasionally filled with coagulum. He asserted that the disease was contagious and cited cases which he believed had their origin in hospital wards.

The widespread occurrence of streptococcus pneumonia in the army camps in this country attracted attention during the first months of 1918. Cummings, Spruit and Lynch[^[73]] at Fort Sam Houston, Texas, recognized the prevalence of streptococcus pneumonia, both as a complication of measles and in association with lobar pneumonia, and showed that the microorganism concerned was a hemolytic streptococcus. In 7 autopsies upon individuals with lobar pneumonia, they found pneumococcus alone in 2 instances and pneumococcus and hemolytic streptococcus or hemolytic streptococcus alone in 5 instances. Hemolytic streptococcus was found in all of 24 instances of bronchopneumonia, three-fourths of which followed measles. They recommend the bacteriologic examination of the throat of patients with measles and the segregation of those who harbor hemolytic streptococci.

Cole and MacCallum[^[74]] have published almost simultaneously, with that just cited, a report upon the pneumonia which has occurred at Fort Sam Houston and have shown the importance of hemolytic streptococci in its causation. They have found two varieties of pneumonia, namely, acute lobar pneumonia which does not differ essentially from that which occurs elsewhere and bronchopneumonia which in most cases has followed measles and is caused by S. hemolyticus. They think this infection is usually acquired in the hospital. They believe that the pulmonary lesions are characteristic. In this publication and elsewhere MacCallum has designated the lesion “interstitial bronchopneumonia.”

The epidemic of streptococcus pneumonia and empyema occurring at Camp Dodge, Iowa, from March 20 to May 10 is described by Miller and Lusk[^[75]]. During this period there were 400 cases of pneumonia, whereas from September 20, 1917, to March 20 there had been only 276 instances of lobar pneumonia. The type of pneumonia changed, there was more severe intoxication and empyema became very frequent; in 85 of 95 exudates streptococci were found. The outbreak of pneumonia bore no relation to measles. The authors state that a mild tracheitis was prevalent in the cantonment during March, and whenever a large group of soldiers congregated coughing was noticeable.

MacCallum[^[76]] studied the pneumonia at Camp Dodge during May and found 17 instances of the lesion which he had designated interstitial bronchopneumonia; of these, 9 followed measles, although in the earlier part of the epidemic there appear to have been, he states, few such cases. Cultures made at autopsy, except in a few fatal cases of uncomplicated lobar pneumonia caused by the pneumococcus, showed the hemolytic streptococcus in every situation throughout the respiratory tract and pleura.

The pneumonia which occurred at Camp Funston is of special interest to our commission because we were for a time stationed at this camp and had the opportunity of following in the excellent records of the hospital the history of the occurrence of pneumonia during the year following the establishment of the camp in September, 1917. Stone, Phillips and Bliss[^[77]] have described the outbreak of pneumonia which occurred in March, 1918. At this time there was, the authors state, severe pneumonia with frequent empyemas due to hemolytic streptococci. This condition which did not follow measles was responsible for the greatly increased death rate in March; 9 deaths occurred in February, 45 in March, 25 in April and 14 in May. They found during March 26 instances of multiple pulmonary abscess. In 29 autopsies they found a pleural lesion which they designate “subcostosternal pus pockets”; it occurs only in association with empyema caused by hemolytic streptococci.

Our commission[^[78]] has shown that an epidemic of influenza, well characterized by its epidemiology and symptoms, preceded and accompanied the outbreak of pneumonia just described. Between March 4 and 29 1,127 men from Camp Funston, which then contained 29,000 men, were sent to the base hospital with influenza and many more were treated in the infirmaries of the camp; on March 11 107 patients with influenza were admitted to the hospital. The greatest incidence of pneumonia in the history of the encampment up to this time occurred between March 9 and 29, immediately following the outbreak of influenza, the maximum incidence of pneumonia occurring five days after the maximum for influenza.

The foregoing observations are cited to prove that streptococcus pneumonia, which occurred during the spring of 1918 at Camp Funston and doubtless at other camps, had its origin in influenza and did not differ in character from that which occurred on a much larger scale in the fall of 1918.

Table of Autopsies.—In order to present as briefly as possible the data upon which the present study has been based, autopsies have been assembled in tabular form in the order of their performance (Table XXVII). During the early period of the epidemic autopsies were performed on all who died with pneumonia, but later, with increase in the number of deaths, this became impossible and autopsies were performed on all those who died in certain wards.

Comparison of charts representing incidence of influenza and of deaths from pneumonia furnishes evidence that fatal pneumonia during the period of investigation was with few exceptions referable to influenza. During two weeks, namely, from September 1 to 14, before the presence of the epidemic was evident, there were only 2 fatal cases of pneumonia. In most instances the relation of pneumonia to influenza is established by a definite history of influenza having its onset during the epidemic. Bronchopneumonia usually develops gradually as a sequence of influenza in which purulent bronchitis has occurred. Lobar pneumonia may develop in cases of influenza complicated by purulent bronchitis. In some instances there is apparent recovery from influenza indicated by return of temperature to normal; after from one to three days of normal temperature there is typical lobar pneumonia with rusty sputum. In many instances of pneumonia having their onset at the height of the epidemic of influenza, the history indicates that pneumonia was present immediately after the onset of symptoms, so that the onset resembled that of pneumonia rather than of influenza.

Cases of pneumonia following measles have been excluded from the table in order that they may be studied separately and compared with the pneumonias of influenza. It is noteworthy that the lesions of pneumonia following measles have shown a very close resemblance to the pneumonias of influenza, with regard both to pathologic characters and to bacteriology.

Five instances of pneumonia following typhoid fever (Autopsies 245 and 329), scarlet fever (Autopsy 311) or mumps (Autopsies 403 and 417) have been excluded from the table. These secondary pneumonias are grouped as an appendix to the section on pneumonia following measles. It is not improbable that individuals with the diseases named are just as susceptible as others to influenza. Included in the table is an instance (Autopsy 487) in which a definite attack of influenza preceded scarlet fever.