CHAPTER I_Epidemic Respiratory Disease The pneumonias and other infections of the repiratory tract accompanying influenza and measles

EPIDEMIC RESPIRATORY DISEASE

The Pneumonias and Other Infections of the Respiratory Tract

Accompanying Influenza and Measles

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

_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:

TABLE I

════════════════════════════════╤══════════╤═════════════╤═════════════

│POPULATION│ INFLUENZA │ PNEUMONIA

────────────────────────────────┼──────────┼──────┬──────┼──────┬──────

„ │ „ │ No. │ Per │ No. │ Per

│ │ │cent. │ │cent.

────────────────────────────────┼──────────┼──────┼──────┼──────┼──────

Men in camp more than one month │ 27,782│ 4,462│ 15.6│ 493│ 1.7

New recruits │ 23,769│ 7,263│ 30.6│ 1006│ 4.2

Total │ 51,551│11,725│ 22.7│ 1499│ 2.9

────────────────────────────────┴──────────┴──────┴──────┴──────┴──────

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

CHAPTER I

PAGE

THE ETIOLOGY OF INFLUENZA. (BY FRANCIS G. BLAKE, M.D.; THOMAS M.

RIVERS, M.D.; JAMES C. SMALL, M.D.) 25

Discussion, 43; Conclusions, 49.

CHAPTER II

CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA AND ITS ASSOCIATED

PURULENT BRONCHITIS AND PNEUMONIA. (BY FRANCIS G. BLAKE, M.D.,

AND THOMAS M. RIVERS, M.D.) 51

Influenza, 52; Purulent Bronchitis, 56; Pneumonia, 59;

Hemolytic Streptococcus Pneumonia Following Influenza, 70;

Bacillus Influenzæ Pneumonia Following Influenza, 72; Summary,

73; Discussion, 76.

CHAPTER III

SECONDARY INFECTION IN THE WARD TREATMENT OF INFLUENZA AND

PNEUMONIA. (BY EUGENE L. OPIE, M.D.; FRANCIS G. BLAKE, M.D.;

JAMES C. SMALL, M.D.; AND THOMAS M. RIVERS, M.D.) 83

Secondary Infection with S. Hemolyticus in Pneumonia, 84;

Secondary Infection with Pneumococcus in Pneumonia, 91;

Secondary Contact Infection in Influenza, 95; Methods for the

Prevention of Secondary Contact Infection in Influenza and

Pneumonia, 98; Summary, 106.

CHAPTER IV

THE PATHOLOGY AND BACTERIOLOGY OF PNEUMONIA FOLLOWING INFLUENZA.

(BY E. L. OPIE, M.D.; F. G. BLAKE, M.D.; AND T. M. RIVERS, M.D.) 107

Bronchitis, 142; Lobar Pneumonia, 154; Bronchopneumonia, 162;

Peribronchial Hemorrhage and Pneumonia, 189; Suppurative

Pneumonia with Necrosis and Abscess Formation, 199;

Interstitial Suppurative Pneumonia, 209; Suppurative Pneumonia

with Multiple Clustered Abscesses Caused by Staphylococci,

225; Empyema, Pericarditis and Peritonitis, 232;

Bronchiectasis, 239; Unresolved Bronchopneumonia, 261.

CHAPTER V

SECONDARY INFECTION IN THE WARD TREATMENT OF MEASLES. (BY JAMES C.

SMALL, M.D.) 282

Hemolytic Streptococci with Measles at Camp Pike, 297;

Complications of Measles, 303; The Dissemination of Hemolytic

Streptococci in Wards, 315; Carriers of Hemolytic

Streptococci, 321.

CHAPTER VI

THE PATHOLOGY AND BACTERIOLOGY OF PNEUMONIA FOLLOWING MEASLES. (BY

EUGENE L. OPIE, M.D.; FRANCIS G. BLAKE, M.D.; JAMES C. SMALL,

M.D.; AND THOMAS M. RIVERS, M.D.) 334

Changes in Bronchi, 336; Lobar Pneumonia, 337;

Bronchopneumonia, 340; Suppurative Pneumonia, 347; Pneumonia

Associated with Acute Infectious Diseases other than Influenza

and Measles, 353.

CHAPTER VII

SUMMARY OF THE INVESTIGATION AND CONCLUSIONS REACHED. (BY EUGENE

L. OPIE, M.D.) 359

Lobar Pneumonia, 362; Bronchopneumonia, 363; Streptococcus

Pneumonia, 365; Staphylococcus Pneumonia, 366; Empyema, 366;

Bronchiectasis, 367; Unresolved Bronchopneumonia, 368; B.

Influenzæ, 369; Pneumococcus, 372; S. Hemolyticus, 374;

Nonhemolytic Streptococci, 376; Staphylococci, 377; Pneumonia

of Measles, 378; The Transmission of Streptococcus Pneumonia,

381; Transmission of Pneumococcus Pneumonia, 383; Prevention

of the Transmission of Pneumonia, 383.

APPENDIX

EXPERIMENTAL INOCULATION OF MONKEYS WITH BACILLUS INFLUENZÆ AND

MICROORGANISMS ISOLATED FROM THE PNEUMONIAS OF INFLUENZA. (BY

EUGENE L. OPIE, M.D.; ALLEN W. FREEMAN, M.D.; FRANCIS G. BLAKE,

M.D.; JAMES C. SMALL, M.D.; AND THOMAS M. RIVERS, M.D.) 387

Inoculation of the Nose and Pharynx with B. Influenzæ, 389;

Introduction of Bacillus Influenzæ into the Trachea, 391;

Introduction of B. Influenzæ and S. Hemolyticus into the

Trachea, 392; Introduction of B. Influenzæ and of Pneumococcus

or of Pneumococcus Alone into the Trachea, 393.

ILLUSTRATIONS

CHARTS PAGE

1. The onset of cases of pneumonia shown by autopsy to be

uncomplicated by secondary infection with hemolytic

streptococcus and of cases of streptococcus pneumonia 141

2. The date of onset of cases in which autopsy demonstrated

lobar pneumonia 161

3. Shows the relation of the epidemic of measles to that of

influenza at Camp Pike, and the relations of the

pneumonia following measles to both measles and influenza 293

4. Shows the time interval between the onset of measles and

the onset of the subsequent pneumonia in the 56 cases of

pneumonia following measles at Camp Pike 306

5. Shows the time relation between the identification of

hemolytic streptococci in the throats and the development

of otitis media in 27 cases shown to be due to hemolytic

streptococci 314

FIG.

1. Acute bronchitis showing engorgement of blood vessels of

mucosa and elevation of epithelium by serum and blood 146

2. Acute bronchopneumonia with nodules of peribronchiolar

consolidation and purulent bronchitis 167

3. Acute bronchopneumonia with peribronchiolar consolidation 169

4. Acute bronchopneumonia with peribronchiolar consolidation 170

5. Bronchopneumonia with hemorrhagic peribronchiolar

consolidation 174

6. Acute bronchopneumonia with confluent gray lobular

consolidation in lower part of upper lobe and hemorrhagic

peribronchiolar pneumonia in lower lobe; purulent

bronchitis 180

7. Bronchopneumonia with purulent bronchitis and peribronchial

hemorrhage 190

8. Streptococcus pneumonia with massive necrosis 201

9. Abscess below pleura with perforation caused by hemolytic

streptococci 202

10. Interstitial suppurative pneumonia; interstitial septa are

the site of suppuration and lymphatics are distended with

purulent fluid; empyema 211

11. Suppurative interstitial pneumonia 212

12. Suppurative interstitial pneumonia 216

13. Suppurative interstitial pneumonia showing a dilated

lymphatic 217

14. Endophlebitis occurring in association with suppurative

pneumonia 219

15. Abscesses in two clusters caused by S. aureus in upper part

of right upper lobe 227

16. Abscesses in cluster caused by S. aureus at apex of right

lobe 228

17. Acute bronchiectasis showing fissures penetrating into

bronchial wall and at one place entering alveolar tissue 246

18. Acute bronchiectasis showing fissures in the bronchial wall

extending into neighboring alveoli which in zone about

are filled with fibrin 247

19. Acute bronchiectasis; the bronchial wall indicated by

engorged mucosa shows a varying degree of destruction,

fissures extending into and through the bronchial wall 248

20. Acute bronchiectasis with destruction of bronchial wall

exposing alveoli filled with fibrin 249

21. Bronchiectasis with fissures extending through the

bronchial wall into alveolar tissue which is site of

fibrinous pneumonia 251

22. Regeneration of epithelium over fissures which have been

formed in the wall of a bronchus 252

23. Squamous epithelium growing over the defect in the

bronchial wall 253

24. Acute bronchiectasis with fissures extending through

bronchial wall which is marked by great engorgement of

blood vessels 255

25. Advanced bronchiectasis throughout lower left lobe 258

26. Unresolved bronchopneumonia with tubercle-like nodules of

peribronchiolar consolidation best seen in lower lobe;

bronchiectasis 268

27. Unresolved pneumonia with peribronchial formation of

fibrous tissue; bronchiectasis 270

28. Unresolved pneumonia with bronchiectasis showing new

formation of fibrous tissue about a greatly dilated

bronchus of which the epithelial lining has been lost 271

29. Lobar pneumonia following measles 338

30. Unresolved bronchopneumonia with measles showing new

formation of fibrous tissue about a bronchus and in

immediately adjacent alveolar walls 342

31. Unresolved bronchopneumonia with measles showing a nodule

of chronic fibrous pneumonia surrounding a respiratory

bronchiole 343

32. Unresolved bronchopneumonia with measles showing chronic

pneumonia about a respiratory bronchiole and alveolar

duct 344

33. Experimental lobar pneumonia in the stage of gray

hepatization produced by injection of Pneumococcus III

into the trachea of a monkey 395

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.

TABLE II

PRESENCE OF B. INFLUENZÆ IN 28 CASES OF INFLUENZA

═══════════╤═══════════╤═══════════╤═══════════╤═══════════╤═══════════

NO. │ DAY OF │ NOSE │ THROAT │ SPUTUM │ SPUTUM

│ DISEASE │ │ │ CULTURE │ PASSED

│ │ │ │ │ THROUGH

│ │ │ │ │ MOUSE

───────────┼───────────┼───────────┼───────────┼───────────┼───────────

1│ 1 │ + │ + │ + │ +

2│ 4 │ − │ + │ + │ +

3│ 5 │ − │ − │ + │ −

4│ 4 │ − │ − │ + │ +

5│ 3 │ − │ − │ + │ +

6│ 4 │ − │ + │ + │ c

7│ 2 │ − │ + │ − │ c

8│ 4 │ + │ + │ + │ −

9│ 5 │ − │ + │ + │ +

10│ 2 │ + │ − │ − │ −

11│ 2 │ − │ + │ c │ +

12│ 3 │ c │ + │ + │ +

13│ 3 │ − │ − │ − │ +

14│ 2 │ − │ − │ + │ +

15│ 3 │ c │ − │ − │ +

16│ 1 │ − │ + │ + │ +

17│ 3 │ − │ + │ − │ +

18│ 4 │ + │ + │ c │ +

19│ 6 │ − │ − │ + │ +

20│ 1 │ − │ + │ + │ +

21│ 2 │ − │ + │ − │ +

22│ 4 │ + │ − │ + │ +

23│ 3 │ c │ − │ − │ +

24│ 2 │ + │ − │ − │ −

25│ 1 │ − │ − │ + │ +

26│ 5 │ − │ − │ + │ +

27│ ? │ − │ + │ − │ +

28│ 1 │ − │ − │ + │ +

│ │ 6 │ 14 │ 17 │ 22

───────────┴───────────┴───────────┴───────────┴───────────┴───────────

c indicates that the plate was contaminated.

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.

TABLE III

PRESENCE OF B. INFLUENZÆ IN CASES OF INFLUENZA

════════════════════════════════════════════╤════════╤═════════════════

│ NUMBER │

METHOD │OF CASES│ B. INFLUENZÆ

│CULTURED│ FOUND

────────────────────────────────────────────┼────────┼────────┬────────

„ │ „ │ NUMBER │PER CENT

────────────────────────────────────────────┼────────┼────────┼────────

Nose culture │ 28│ 6│ 21.4

Throat culture │ 166│ 109│ 65.7

Sputum culture │ 28│ 17│ 60.7

Sputum (mouse passage) │ 76│ 61│ 80.3

Combined nose, throat and sputum cultures │ │ │

and sputum inoculation │ 28│ 28│ 100

Combined throat cultures and sputum │ │ │

inoculation │ 48│ 48│ 100

────────────────────────────────────────────┴────────┴────────┴────────

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.

TABLE IV

PNEUMOCOCCUS IN CASES OF INFLUENZA

═══════════════════════════════════╤═════════════════╤═════════════════

│ NUMBER │ PER CENT

───────────────────────────────────┼─────────────────┼─────────────────

Pneumococcus, Type I │ 0│ 0

Pneumococcus, Type II │ 0│ 0

Pneumococcus, Atypical II │ 0│ 0

Pneumococcus, Type III │ 2│ 8.3

Pneumococcus, Group IV │ 15│ 62.5

No pneumococci found │ 7│ 29.2

───────────────────────────────────┴─────────────────┴─────────────────

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.

TABLE V

PNEUMOCOCCI IN CASES OF INFLUENZA

│ NUMBER │ PER CENT

Pneumococcus, Type I │ 0│ 0

Pneumococcus, Type II │ 0│ 0

Pneumococcus, Atypical II │ 2│ 4.3

Pneumococcus, Type III │ 0│ 0

Pneumococcus, Group IV │ 25│ 53.2

No pneumococci found │ 20│ 42.5

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.

TABLE VI

S. HEMOLYTICUS IN CASES OF INFLUENZA

══════════════╤══════════════╤═════════════╤═════════════╤═════════════

│ │ S. │ S. │ PER CENT

DATE │ NUMBER OF │ HEMOLYTICUS │ HEMOLYTICUS │POSITIVE FOR

│CASES CULTURED│ FOUND │ NOT FOUND │ S.

│ │ │ │ HEMOLYTICUS

──────────────┼──────────────┼─────────────┼─────────────┼─────────────

Sept. 25–26 │ 100│ 6│ 94│ 6

Nov. 27–Dec. 5│ 138│ 39│ 99│ 28.3

──────────────┴──────────────┴─────────────┴─────────────┴─────────────

=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.

TABLE VII

INCIDENCE OF B. INFLUENZÆ IN NORMAL MEN AS DETERMINED BY

INTRAPERITONEAL INOCULATION OF WHITE MICE WITH SALIVA OR SPUTUM

════╤═════════╤═════════════╤════════╤═════════╤═════════╤═════════════

DATE│ PLACE │ORGANIZATION │ NUMBER │ B. │PER CENT │ REMARKS

│ │ │EXAMINED│INFLUENZÆ│POSITIVE │

│ │ │ │ PRESENT │ FOR B. │

│ │ │ │ │INFLUENZÆ│

────┼─────────┼─────────────┼────────┼─────────┼─────────┼─────────────

1918│ │ │ │ │ │

Aug.│Camp │22 Prov. │ 25│ 6│ 24│Bronchitis

13│Funston, │Colored Co. │ │ │ │and pneumonia

│Kans. │164th Depot │ │ │ │were

│Detention│Brigade │ │ │ │prevalent in

│Camp, No.│ │ │ │ │this

│2 │ │ │ │ │organization

│ │ │ │ │ │of recently

│ │ │ │ │ │drafted

│ │ │ │ │ │negroes

│ │ │ │ │ │during July

│ │ │ │ │ │and August,

│ │ │ │ │ │1918

Aug.│Camp │Co. D. 3rd │ 25│ 11│ 44│Recently

18│Funston, │Dev. Bn. │ │ │ │drafted

│Kans. │ │ │ │ │southern

│Detention│ │ │ │ │negroes not

│Camp, No.│ │ │ │ │fit for full

│2 │ │ │ │ │military

│ │ │ │ │ │duty.

│ │ │ │ │ │Bronchitis

│ │ │ │ │ │and pneumonia

│ │ │ │ │ │were

│ │ │ │ │ │prevalent in

│ │ │ │ │ │this

│ │ │ │ │ │organization

│ │ │ │ │ │during July

│ │ │ │ │ │and August,

│ │ │ │ │ │1918

Aug.│Camp │70th Inf. │ 25│ 11│ 44│25 men

20│Funston, │ │ │ │ │presenting

│Kan. │ │ │ │ │themselves at

│ │ │ │ │ │sick call for

│ │ │ │ │ │various

│ │ │ │ │ │complaints;

│ │ │ │ │ │not strictly

│ │ │ │ │ │normal;

│ │ │ │ │ │respiratory

│ │ │ │ │ │diseases not

│ │ │ │ │ │prevalent

Aug.│Ft. │Quarters 4 M │ 32│ 16│ 50│Recently

22│Riley, │M.O.T.C. │ │ │ │drafted white

│Kan. │ │ │ │ │men of 4 to 8

│ │ │ │ │ │weeks’

│ │ │ │ │ │service.

│ │ │ │ │ │Pneumonia

│ │ │ │ │ │fairly

│ │ │ │ │ │prevalent in

│ │ │ │ │ │this

│ │ │ │ │ │organization

Aug.│Camp │210th Eng. │ 27│ 3│ 11.1│About one

26│Funston, │ │ │ │ │mile distant

│Kan. │ │ │ │ │from Camp

│ │ │ │ │ │Funston

│ │ │ │ │ │proper. No

│ │ │ │ │ │sickness in

│ │ │ │ │ │this

│ │ │ │ │ │organization

Nov.│Hot │Drafted men │ 50│ 11│ 22│50 men

12│Springs, │assembled to │ │ │ │selected from

│Ark. │entrain for │ │ │ │isolated farm

│ │camp │ │ │ │communities;

│ │ │ │ │ │12 gave a

│ │ │ │ │ │history of

│ │ │ │ │ │“influenza”

│ │ │ │ │ │within the

│ │ │ │ │ │preceding 8

│ │ │ │ │ │weeks

Nov.│Camp │Miscellaneous│ 26│ 13│ 50│12 of this

25│Pike, │ │ │ │ │group had

│Ark. │ │ │ │ │influenza

│ │ │ │ │ │during the

│ │ │ │ │ │epidemic

Dec.│Camp │Miscellaneous│ 25│ 17│ 68│12 of this

10│Pike, │ │ │ │ │group had

│Ark. │ │ │ │ │influenza

│ │ │ │ │ │during the

│ │ │ │ │ │epidemic

│Summary: │Normals │ 235│ 88│ 37.4│

│ │Cases of │ 76│ 61│ 80.3│

│ │influenza │ │ │ │

│ │(for │ │ │ │

│ │comparison) │ │ │ │

────┴─────────┴─────────────┴────────┴─────────┴─────────┴─────────────

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.

TABLE VIII

INCIDENCE OF B. INFLUENZÆ IN NORMAL MEN AS DETERMINED BY THROAT CULTURES

ON BLOOD AGAR PLATES

═══════╤════════╤═════════════╤════════╤═════════╤═════════╤════════════

DATE │ PLACE │ORGANIZATION │ NUMBER │ B. │PER CENT │ REMARKS

│ │ │EXAMINED│INFLUENZÆ│POSITIVE │

│ │ │ │ PRESENT │ FOR B. │

│ │ │ │ │INFLUENZÆ│

───────┼────────┼─────────────┼────────┼─────────┼─────────┼────────────

Sept. │Camp │Med. │ 82│ 14│ 17.1│82 throat

14–Oct.│Pike, │Detachment, │ │ │ │cultures in

5 │Ark. │Base Hos.; │ │ │ │42

│ │personnel on │ │ │ │individuals

│ │measles wards│ │ │ │

Nov. │Camp │Miscellaneous│ 296│ 71│ 23.9│Number among

5–9 │Pike, │ │ │ │ │this group

│Ark. │ │ │ │ │who had had

│ │ │ │ │ │influenza

│ │ │ │ │ │not recorded

Nov. 12│Hot │Drafted men │ 64│ 0│ 0│Men, in

│Springs,│assembled to │ │ │ │large part

│Ark. │entrain for │ │ │ │from

│ │camp │ │ │ │isolated

│ │ │ │ │ │farm

│ │ │ │ │ │communities;

│ │ │ │ │ │13 gave a

│ │ │ │ │ │history of

│ │ │ │ │ │“influenza”

│ │ │ │ │ │within the

│ │ │ │ │ │preceding 8

│ │ │ │ │ │weeks

Nov. 25│Camp │Miscellaneous│ 26│ 13│ 50│12 of this

│Pike │ │ │ │ │group had

│ │ │ │ │ │influenza

│ │ │ │ │ │during the

│ │ │ │ │ │epidemic

Dec. 10│Camp │Miscellaneous│ 25│ 13│ 52│12 of this

│Pike │ │ │ │ │group had

│ │ │ │ │ │influenza

│ │ │ │ │ │during the

│ │ │ │ │ │epidemic

│Summary │Normals │ 493│ 111│ 22.5│

│ │Cases of │ 166│ 109│ 65.7│

│ │influenza │ │ │ │

│ │(for │ │ │ │

│ │comparison) │ │ │ │

───────┴────────┴─────────────┴────────┴─────────┴─────────┴────────────

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.

TABLE IX

INCIDENCE OF B. INFLUENZÆ IN NORMAL MEN CONTRASTED WITH THAT IN EARLY CASES OF

INFLUENZA AS DETERMINED BY MULTIPLE CULTURES FROM NOSE, THROAT, AND SPUTUM

════╤════════╤═════════╤════════╤══════════════════════════════════════════════

DATE│ PLACE │ GROUP │ NUMBER │ PER CENT SHOWING B. INFLUENZÆ

│ │ │EXAMINED│

────┼────────┼─────────┼────────┼────────┬────────┬───────┬───────────┬────────

„ │ „ │ „ │ „ │ NOSE │ THROAT │SPUTUM │ SPUTUM │ BY

│ │ │ │ │ │DIRECT │ MOUSE │MULTIPLE

│ │ │ │ │ │CULTURE│INOCULATION│CULTURES

────┼────────┼─────────┼────────┼────────┼────────┼───────┼───────────┼────────

Nov.│Hot │Normal │ 50│ 0│ 0│ 0│ 22│ 22

12 │Springs,│draft men│ │ │ │ │ │

│Ark. │assembled│ │ │ │ │ │

│ │to │ │ │ │ │ │

│ │entrain │ │ │ │ │ │

│ │for camp │ │ │ │ │ │

│ │ │ │ (4 │ (31 │ │ │

│ │ │ │cultures│cultures│ │ │

│ │ │ │ only) │ only) │ │ │

Nov.│Camp │Normal │ 26│ 38.6│ 50│ 34.6│ 50│ 80.8

25 │Pike │men; 12 │ │ │ │ │ │

│ │had │ │ │ │ │ │

│ │influenza│ │ │ │ │ │

│ │during │ │ │ │ │ │

│ │the │ │ │ │ │ │

│ │epidemic │ │ │ │ │ │

Dec.│Camp │Normal │ 25│ 48│ 52│ 24│ 68│ 88

10 │Pike │men; 12 │ │ │ │ │ │

│ │had │ │ │ │ │ │

│ │influenza│ │ │ │ │ │

│ │during │ │ │ │ │ │

│ │the │ │ │ │ │ │

│ │epidemic │ │ │ │ │ │

Oct.│Camp │Patients │ 28│ 21.4│ 50│ 60.7│ 78.6│ 100

10 │Pike │with │ │ │ │ │ │

and │ │influenza│ │ │ │ │ │

Nov.│ │in Base │ │ │ │ │ │

19 │ │Hos. │ │ │ │ │ │

────┴────────┴─────────┴────────┴────────┴────────┴───────┴───────────┴────────

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.

TABLE X

INCIDENCE OF B. INFLUENZÆ IN 400 CONSECUTIVE CASES OF MEASLES AS

DETERMINED BY THROAT CULTURE AT TIME OF ADMISSION TO THE BASE HOSPITAL

═════════════════╤═════════════════╤═══════════════════════════════════

DATE │ NUMBER OF CASES │ B. INFLUENZA FOUND

─────────────────┼─────────────────┼─────────────────┬─────────────────

„ │ „ │ NUMBER │ PER CENT

─────────────────┼─────────────────┼─────────────────┼─────────────────

Sept. 16–Oct. 4 │ 100│ 27│ 27

Oct. 4–Oct. 10 │ 100│ 32│ 32

Oct. 10–Oct. 15 │ 100│ 32│ 32

Oct. 15–Oct. 19 │ 100│ 48│ 48

─────────────────┴─────────────────┴─────────────────┴─────────────────

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.

TABLE XI

INCIDENCE OF B. INFLUENZÆ IN 830 THROAT CULTURES IN 487 CASES OF

MEASLES; CULTURES REPEATED AT WEEKLY INTERVALS

DATE │ NUMBER OF CASES │ B. INFLUENZA FOUND

„ │ „ │ NUMBER │ PER CENT

Sept. 10–15 │ 47│ 15│ 31.9

Sept. 16–29 │ 106│ 33│ 31.1

Sept. 30–Oct. 6 │ 122│ 38│ 31.1

Oct. 7–13 │ 235│ 96│ 40.8

Oct. 14–20 │ 320│ 157│ 49.1

Total │ 830│ 339│ 40.8

TABLE XII

TOTAL NUMBER OF B. INFLUENZÆ CARRIERS AMONG 223 CASES OF MEASLES AS

DETERMINED BY REPEATED THROAT CULTURES AT WEEKLY INTERVALS AFTER

ADMISSION TO HOSPITAL

══════════╤══════════╦═════════╤═══════════════════╦═══════════════════

TIMES │NUMBER OF ║NUMBER OF│B. INFLUENZÆ FOUND ║ TOTAL CARRIERS IN

CULTURED │ CASES ║CULTURES │ ║ ONE OR MORE

│ ║ │ ║ CULTURES

──────────┼──────────╫─────────┼─────────┬─────────╫─────────┬─────────

„ │ „ ║ „ │ NUMBER │PER CENT ║ NUMBER │PER CENT

──────────┼──────────╫─────────┼─────────┼─────────╫─────────┼─────────

2│ 129║ 1st│ 37│ 28.7║ 82│ 63.6

│ ║ 2nd│ 63│ 48.8║ │

3│ 69║ 1st│ 20│ 28.9║ 52│ 75.4

│ ║ 2nd│ 31│ 44.9║ │

│ ║ 3rd│ 33│ 47.8║ │

4│ 25║ 1st│ 6│ 24║ 21│ 84.0

│ ║ 2nd│ 10│ 40║ │

│ ║ 3rd│ 13│ 52║ │

│ ║ 4th│ 14│ 56║ │

──────────┴──────────╨─────────┴─────────┴─────────╨─────────┴─────────

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.

Epidemic Respiratory Disease The pneumonias and other infections of the repiratory tract accompanying influenza and measles · 第 1 / 10 章