Part 25

There has never been in the history of medicine so many experiments on human beings as have been carried out in the attempts to discover the etiological factor in the recent pandemic of influenza. Davis has called attention to a successful human inoculation with pure cultures of B. influenzæ which he performed in 1906. During the present investigation at least 200 men have volunteered as experimental subjects, and the results of many different methods of attempting to transmit the disease, have been disappointing and inconclusive. I will not attempt to review the reports at present available, as a great deal of the work done has not yet appeared in print. The important point is that the results do not affect the various views held as to the causative agent in pandemic influenza nor the massive evidence for transmission of the disease under natural epidemic conditions.

It is my opinion, as expressed above, that practically all of the population are rapidly infected during such a pandemic as we have had. The resistant have escaped, and it would appear to be very difficult to break down this resistance. The human experiment carried out by Pettenkofer on himself and his assistant with vibrion choleræ is an example, but we have numerous others demonstrating the same kind of phenomena in most of our diseases of established bacterial origin. In diphtheria we have an explanation in the varying antitoxic content of the sera, but we really know very little of what are the actual factors in preventing or determining infection among exposed individuals in the natural history of most diseases. The reports of Leonard Hill and Gregor are well worth reading in this connection, as well as the editorial in the same number of the British Medical Journal. We are not in a position to be very dogmatic on the causes of epidemics. The mere presence of the bacteria or any other living virus is not in itself sufficient to explain the phenomenon, and one of the chief objects of this paper is to indicate from the collected facts, that in the words of Flexner, “the case against the influenza bacillus is not proved.”

Conclusions

1. B. influenzæ is one of a group of hemophilic bacteria and there are probably strains of this organism which may be differentiated which will lead to further subdivisions of the group.

2. B. influenzæ as we understand it today, is distinguished by its morphological and staining characters; its requiring hemoglobin in some form for its development; its showing symbiotic reactions with other bacteria which stimulate its growth; the production of a toxine and its usual low pathogenicity for animals.

3. The media found most favorable for its growth are those containing blood with the hemoglobin content altered in certain ways, (1) by heating, (2) the addition of various chemicals, (3) by the action of other bacteria or their products. The heated blood agar I have found to be a most efficient and readily prepared medium.

4. Since B. influenzæ is so difficult to isolate, it is necessary to be very cautious in interpreting results unless the greatest effort has been made to demonstrate the presence of this organism.

5. B. influenzæ should be considered, from the evidence at hand, as the bacterial causative agent in epidemic influenza, and it should be recognized that secondary infections following the primary attack by this organism are both frequent and important. This view I believe the logical one, unless much more convincing evidence than we have today may demonstrate another more probable living virus as the cause.

6. B. influenzæ is a frequent etiological factor in purulent and chronic bronchitis, broncho-pneumonia and other acute and chronic respiratory infections, in meningitis, endocarditis, sinusitis, conjunctivitis and other conditions, as well as in complications of many other diseases.

7. There are many carriers of the bacillus among our population, both in apparently normal individuals and in those suffering from chronic infections of bronchi, sinuses or other parts.

8. The problem of what constitutes resistance or susceptibility to this infection are as far from solution as they are in most other respiratory diseases, and the attempts to explain the reasons for epidemics have been as futile as they are for meningitis and many other respiratory epidemics.

9. It would not appear that the immunological reaction against this infection has been discovered, but the possibility of its being of an antitoxic nature opens an interesting field for investigation.

BIBLIOGRAPHY

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THE PATHOLOGY OF EPIDEMIC INFLUENZA

By OSKAR KLOTZ, M. D., C. M.

The discussion to be entered into in this report will be limited to an experience dealing with epidemic influenza as it was met with in the emergency Military Hospital in Pittsburgh. We shall largely confine our attention to the observations which came directly under our supervision, and in as much as this investigation was continued during the epidemic as it swept over this district, the intensive study was limited to a time period of about five weeks. During this period much material was collected, which since then, has taken us a considerable time to analyze. We have thought it more valuable to restrict our discussion to this material in that it illustrates the pathological lesions as they occurred during the acute stage of the disease. We have not entered upon a discussion of the sequelæ or the chronic lesions which are not uncommonly found following in the wake of an acute epidemic nor do we deal with the lesions arising in cases of sporadic influenza, such as are always with us. As is so well illustrated in the literature, there is probably no disease which has so many late complications and sequelæ as influenza. The investigations upon the protean lesions have been fully reported in numerous papers during the intervals between epidemics. A comprehensive bibliography upon influenza will be found at the end of the extensive report by Leichtenstern (1905). There is very much less accurate information available upon the actual lesions present during the acute disease when present in epidemic or pandemic form, than upon the many clinical complications in various systems and organs. In fact, our knowledge of the pathology of influenza lies more largely in the field of associated lesions such as the late events in the bronchi, the sinuses of the head, abscesses, meningitis and other conditions, rather to be viewed as complications than as portions of the disease. There are relatively few thorough pathological analyses of the influenza lesions as they are found in the acute epidemic disease.

A fair literature has already appeared upon epidemic influenza from the many countries and regions over which the present pandemic (1918) has swept. These reports by various authors are offered from different viewpoints, some investigators being impressed with certain features which they bring into marked prominence in their reports. It thus happens that up to the present there is a decided lack of uniformity in the opinions expressed upon different phases of the subject. The nature of the pathology of the past epidemic has given rise to many expressions of opinion as well as dogmatic statements, which are found to differ from those of others. It seems to us that this apparent confusion arises partly through the somewhat different characteristics of the disease as it has made its appearance in different centers. We hear it repeatedly stated that the types found in different military camps and urban communities were quite unlike those of other regions. It is evident that such differences in the clinical course actually did exist and that the epidemic though having a common foundation upon which the disease process was built differed in what might be looked upon as symbiotic complications during the early and acute stages. Differences in the nature of the findings in various communities also probably lay in the fact that the bacterial flora associated with the causative agent of influenza was quite different in different regions. We mention this here so that a full appreciation will be obtained for the differences in the pathological characters of the disease as they are found in one region or another. We appreciate, of course, that if the concomitant bacterial flora associated with the underlying cause of influenza, differs in different regions, so, too, will the bodily reactions differ within certain degrees. We are becoming more familiar with different types of bacteria, and the resulting inflammatory reaction which is often unique or at least particular, and that not uncommonly the nature of the inflammatory process suggests the type of bacterium involved. This argument, of course, must not be driven too far, for we well know that the same micro-organisms under different conditions can cause types of inflammatory reactions wholly divergent.

In as much as our observations are confined to a particular group of cases and the study of these was undertaken during the five weeks of the acute epidemic, these results are not to be compared with the collected statistics on influenza as they shall be made over a period beginning with the onset of the epidemic and ending with the last vestiges remaining after months or it may be years of time. Our observations are to be considered only in the light of the events taking place during the height of an epidemic wave. In as much as influenza presents itself during an epidemic in different forms, we shall again mainly limit the report upon our investigations of those cases having respiratory lesions. Our acute observations were made upon the tissues of those who had died of this disease. It is impossible, or nearly so, to fully study the tissues of those with lesser lesions and who recover. Hence, if we divide the influenza cases into those (1) without pulmonary lesions and (2) those with pulmonary lesions, we must state that all of our cases coming to autopsy fall in the second group. It is true that one of these having pulmonary lesions was not brought to his fatal termination by them but by a septicæmia arising in the middle ear. He had distinct lesions in his lungs. In other words, our autopsy material represents epidemic influenza in which the lung was definitely involved in an inflammatory state. In all but one of these the pulmonary lesion was the cause of death.

No doubt, if opportunity had presented itself to follow a large epidemic through months of its progress, during which late complications in various portions of the body would make their appearance, our analysis would give a different picture and the pulmonary factor for the fatal termination would not be in such prominence.

Of the first group, those cases of epidemic influenza not showing pulmonary lesions, we will have very little to say, in as much as the pathological investigations of them is impossible, or nearly so, during the height of the disease.

Such cases apparently do not die at this period. I am willing to admit that individuals without pulmonary involvement may succumb, but I question whether their death has been due to the result of the influenzal lesions, be it in nose, pharynx, larynx or trachea, or be it in the intestine, but rather that the fatal termination occurred later in the course of this complex disease, when distant vital organs became involved or incapacitated in a toxemia or secondary bacterial invasion. We must clearly distinguish these cases from the clear-cut ones of epidemic influenza, looking upon the new circumstances as complications aside from the original disease. Such, for example, is the case we have mentioned where a fatal streptococcus bacteriæmia followed in the wake of an otitis media. In our experience we have not had a fatal case of the acute epidemic disease in which the lung was not involved.

In types of epidemic disease such as we have just had, where the epidemic wave has passed over in a period of four or five weeks, there is always much to be regretted which has been left undone. We tried as far as possible to gain all the information available at the time of collecting our materials and of laying aside such of the work which could be accomplished at a subsequent date. The materials were collected from divergent sources in the cadaver, and the more perishable substances were analyzed immediately. During the period of the epidemic 32 autopsies were performed and as much use as possible was made of each for a thorough comprehension of the lesions.

Materials

During the period of our work 639 patients were admitted to the hospital suffering from clinical influenza. The cases varied in type from the very mild to the extremely ill. The majority of the cases were of the type of “three-day fever.” Clinically 81 cases developed pneumonia, and of these, 35 died. It would, of course, be impossible to say how many other individuals had a pulmonary involvement which could not be recognized clinically. In fact, some of the cases which did come to autopsy were only recognized as having a pulmonary involvement when the lungs were examined outside of the body. The physicians freely admitted that the physical signs were quite unusual and unlike those of the ordinary forms of pneumonia. In fact, except for the fact that we were living in the midst of an epidemic of respiratory infections, there was nothing to make the clinician suspect that many of these cases had a pulmonary involvement. Obviously, when the recognized signs of different types of pneumonia made their appearance, the clinician did not fail to make proper interpretation of the lung involvement. This, as we shall discuss later, is an event superadded to a lung condition which pathologically must be recognized as pneumonia (inflammation) and which differs so decidedly from what we know of as croupous or lobar pneumonia, as well as ordinary broncho-pneumonia that it would be incorrect to include them under this heading, although the distribution of the lesion may have lobar, bronchial or lobular characters.

TABLE I

════════════════════════════════════════════════════════════════════ DATE 1918 PATIENTS PATIENTS CASES IN DEATHS ADMITTED DISCHARGED HOSPITAL ──────────────────────────────────────────────────────────────────── October 5 65 0 65 0 〃 6 23 0 88 0 〃 7 61 0 149 0 〃 8 77 0 225 1 〃 9 42 1 266 0 〃 10 35 1 300 0 〃 11 9 0 307 2 〃 12 2 16 290 3 〃 13 10 0 298 2 〃 14 1 18 278 3 〃 15 4 13 266 3 〃 16 9 23 248 4 〃 17 10 19 235 4 〃 18 16 34 217 0 〃 19 38 29 225 1 〃 20 27 0 252 0 〃 21 37 43 245 1 〃 22 33 7 270 0 〃 23 14 20 263 2 〃 24 20 17 266 0 〃 25 27 21 272 0 〃 26 10 29 250 0 〃 27 18 3 265 1 〃 28 10 31 243 3 〃 29 6 16 231 0 〃 30 11 27 215 1 〃 31 2 15 202 2 November 1 2 18 185 0 〃 2 4 18 170 1 〃 3 5 1 174 0 〃 4 2 19 156 1 〃 5 5 0 161 0 〃 6 4 16 149 0 ——— —— Admissions. 639 35 ────────────────────────────────────────────────────────────────────

The individuals admitted to this hospital were obtained from the two military camps at the University of Pittsburgh and the Carnegie School of Technology. All of them were enrolled in the army service and ranged from the ages of 18 to 30. They were vigorous individuals, who had passed their physical examinations for the army. The epidemic made its appearance in these camps on October 2, rapidly ascending from a report of two ill on October 2, four on October 3, eight on October 4, to 65 on October 5. On October 11 there were 307 cases in the hospital.