Part 22

It will be impossible to review the numerous reports on the recent epidemic that have appeared. Many of these can be discounted, as far as the finding of B. influenzæ is concerned, for the reasons mentioned above. The often quoted report of Little, Garofalo and Williams, who did not even use a hemoglobin medium, will serve as an example. Little attention should be given to others where the large numbers of cases precluded the requisite time and media necessary for such a difficult problem. Friedlander and his co-workers in their report from Camp Sherman made no mention of the number of sputa, throat swabs or autopsies which they examined bacteriologically. The incidence of influenza showed a total of 10,979 cases, 2,001 of pulmonary œdema or pneumonia and 842 deaths. They recorded one culture from the sputum with pneumococcus predominating which gave two colonies of B. influenzæ, and this bacillus was grown from the lung exudate at one autopsy. Their conclusions that “B. influenzæ (Pfeiffer) has not been demonstrated as the causative organism” is certainly true from their results, but that “the frequency of its detection has not exceeded the frequency of its existence under normal conditions” can hardly be considered as established, if we accept the many results mentioned above as indicating its presence during inter-epidemic times, unless they mean by normal conditions practically complete freedom from this organism.

The prevalence of B. influenzæ in various sections of this country may be indicated by the following reports chosen from many available ones. Keegan, from the First Naval District Hospital, found B. influenzæ 19 times from 23 in cultures grown from the lungs. In 6 cases these cultures were pure. Medalia reported from Camp McArthur the following. Out of 2,279 sputa of influenza suspects, 76.8 per cent. showed “B. influenzæ” in smears, and 445 sputa from cases of broncho-pneumonia showed it in 54 per cent. It was found in culture in only 10.6 per cent. of these last cases. He considered sputum smears of practical diagnostic help. He further grew B. influenzæ twice from the blood during life, once with a pneumococcus and once alone. Necropsy cultures gave B. influenzæ in 2 of 3 cultures from the brain, 19 of 34 from the heart, 19 of 36 from the spleen, 54 of 65 from both lungs, 50 of 62 from the right pleura and 47 of 62 from the left pleura. The percentage of positive results ranged from 53 in the spleen to 83 in the lungs. Nuzum and his associates only found B. influenzæ in 4 of 100 cases from the bronchial secretions, but it is interesting to note that he grew it in practically pure culture from both lungs of one case at autopsy. Synnott and Clark in Camp Dix found streptococci and pneumococci predominating, and, although making no particular effort to study the B. influenzæ or determine its frequency, they found it in the majority of cases when it was looked for. Blanton and Irons reported as follows from Camp Custer. From cultures of the nose and throat of 357 examined before the epidemic struck, B. influenzæ was found in 5.1 per cent.; in 366 throat cultures of influenza cases without physical signs of pneumonia the same organism was grown in 44, or 8 per cent.; sputa typed for pneumococci 740 times from influenza cases with pneumonia gave isolations of B. influenzæ 38 times, or 5 per cent.—8 times alone, but here it should be remarked that these latter isolations were only attempted after the organism was suspected from the morphological picture of the smears; from 280 autopsies B. influenzæ was recovered 8 times from the lung and 3 times from the heart’s blood. This report covered the period from the outbreak of the epidemic, October 5 (or as given by Soper, September 30) to October 22, at the outside a period of 22 days. During this time 366 throat cultures, 510 blood cultures, 740 sputa typed for pneumococci, 280 autopsies with cultures from both lung and heart’s blood, made a total of primary cultures of well over 2,000. The technical difficulties would make it almost impossible to handle such a mass of material and get reliable results for the incidence of B. influenzæ.

Brem, Bolling and Casper in Camp Fremont found B. influenzæ in 259 from 537 selected cases in swabs from the nasopharynx. It was also noted in a fair number of other examinations. Opie and his co-workers found B. influenzæ to be very frequent at Camp Pike. Spooner, Scott and Heath isolated B. influenzæ at Camp Devens from the sputa of 104 cases, from nasopharyngeal swabs in 11 out of 18 attempts and from the pleural fluid 8 times out of 45, twice pure. From 37 autopsies they found B. influenzæ in 23 and in pure culture in at least 1 lobe of the lung in 16. From 82 blood cultures at autopsy B. influenzæ was recovered twice. Nichols and Stimmel studied lung punctures during life and grew the B. influenzæ from 7 out of 10 attempts, 5 times in pure culture. Stone and Swift at Fort Riley found B. influenzæ in 18.7 per cent. of 928 sputa and in 5.2 per cent. of 77 sputa from fatal cases. He recovered it from autopsy material; 21 times from 51 lungs, once alone; twice from 26 pleural fluids; twice from 30 heart bloods; 19 times from the sinuses of 40, and 9 times from the ear and mastoid of 17 cases.

Lamb and Brannin at Camp Cody examined 80 typical cases early in the epidemic. They found B. influenzæ predominated in 46 per cent. being present with pneumococci on 41 per cent. of the plates. They also grew the influenza bacillus from a fair number of other cases.

Wollstein and Goldbloom in the Babies Hospital of the City of New York found the B. influenzæ in 13 of 17 sputa during life and in both lungs of all 18 autopsies as well as in the heart’s blood of one. Kotz found it in half of his 30 cases. Pritchett and Stillman grew the influenza bacillus from 41 of 49 cases of influenza, from 40 of 43 cases of influenza with broncho-pneumonia, from all of six other broncho-pneumonia cases and from 11 of 20 cases of lobar pneumonia, making a total of 98 positive findings from 118 or 82 per cent. They further found 25 positives from 54 convalescent and 74 from 177 normal sputa. Wolbach found this organism in pure culture in one or more lobes of the lungs of 9 from 23 cultured cases. It was demonstrated in 23 of 28 either by culture or in section.

Similar results are to be found in reports from Great Britain. Martin noted a great increase in the numbers present as the sputum became more purulent. Hicks and Gray found B. influenzæ by culture in 75 per cent. of their cases. They were seen in direct smears in only 70 per cent. Gotch and Wittingham considered M. catarrhalis to be the etiological factor as it was found in all of their 50 cases. B. influenzæ was grown in 8 per cent., although B. influenzæ-like bacilli, were seen in 62 per cent. of their smears. Averill, Young and Griffiths studied the sputum from 41 cases and found B. influenzæ in 32. It is interesting that Macdonald and Lyth determined the incubation period to be 41 hours as a minimum in their own experience and that from the posterior nares of one of them B. influenzæ was obtained.

Schofield and Cynn found the B. influenzæ in Korea. Kraus in Brazil found it in the sputum in 62 per cent. of his cases of influenza. It was also found in the organs of 27 who had died, being in pure culture in five. It has further been found in France, Italy and practically all parts of the world where investigations have been made. The German literature is at present only available in the report of the British Medical Research Committee which is written in a more or less popular manner with a rather strong tendency against the importance of B. influenzæ. Dietrich, Simmonds, Bergmann and others, however, found B. influenzæ rather frequently. Such quotations as “Uhlenhuth, a diehard of bacteriologic orthodoxy, has clearly shown signs of uneasiness” and “one empyema and one throat swab yielded the looked for growth” will indicate why this review is of little use. It is certainly necessary to “look for” the B. influenzæ to get results of any worth.

Secondary, ancillary or symbiotic bacteria are of cardinal importance in these infections. It has been considered by some writers as characteristic for the influenza bacillus to be followed so frequently with such a variety of secondary invaders. Sahli looked upon the complex of B. influenzæ, pneumococcus and streptococcus as the true etiological cause of influenza. Abrahams and his associates discussed the symbiotic effect of the B. influenzæ in raising the virulence of pneumococci previously present in the patient and many other investigators lay stress on these symbiotic relationships.

Pneumococci appear to be the commonest of these secondary micro-organisms judging from the various published reports, but the fact must not be overlooked that, particularly in America, the typing of pneumococci has drawn a disproportionate attention to this group. Hemolytic streptococci have received much attention (Ely and his co-workers and several others). M. catarrhalis (Gotch and Wittingham and several of the British writers), members of the B. mucosus capsulatus group (Nichols and Stimmel, Rucker and Wenner), staphylococcus aureus (Patrick), various ill-defined streptococci (Rosenow and several British writers), capsulated cocci apparently different from pneumococci, B. pestislike forms and many others have been given more or less attention, often as clearly recognized secondary infections, but not infrequently as of primary significance.

B. influenzæ, however, is the organism most regularly found in this pandemic where carefully looked for, and the evidence of its lowering the general resistance to bacterial invasion is very strong. The experiments of Ghedini and Fedeli showing the effect of the toxine on muscular tone and those of Ghedini and Breccia who found a similar effect on blood vessels are worthy of note.

The fact that the flora differs so widely in various regions is what one might expect and many investigators have emphasized the significance of this. Bacteria in the mouth and throat are readily transmitted from individual to individual and under the conditions in the training camps and our modern life, the development of local flora is not surprising. That it is of very great importance is recognized by all and it is often a determining factor in the severity of the infection. Nevertheless, influenza in this pandemic has been almost equally severe whatever the secondary organism may have been.

I have discussed in another place the suggestion of the stimulating effect of various bacteria on the growth and toxine production of B. influenzæ. Huntoon showed the effect of hemolytic streptococci in cultures to be helpful in toxine production. An important point, however, is that no one bacterium has been shown to be exclusive in thus affecting the growth on media of the influenza bacillus, and in the animal experiments in raising the invasive and pathogenic power of this organism the same appears to be true. The infection in influenza, in the vast majority of cases, rapidly becomes a mixed one. The secondary organisms at times completely dominating the field, at least as far as numbers go, most frequently invade the blood stream and it would appear often play the important role in many of the secondary conditions.

_Chronic Infections_

B. influenzæ is a frequent finding in the sputum of patients with chronic bronchitis, pulmonary tuberculosis and other chronic conditions in the respiratory tract. Boggs recovered this bacillus from two cases of bronchiectasis, Richards and Gurd had a similar case and Tedesko reported several. The literature is filled with references to the finding of B. influenzæ in cases of chronic bronchitis. Those reported by Lord, Madison and Tedesko quoted above will serve as examples. The frequent positive cultures in cases of pulmonary tuberculosis so often referred to in reviews of the literature and the significance of these findings, as pointed out by Scheller, are important as bearing on the much debated subject of the effect of influenza on this disease. These types of chronic infection by the influenza bacillus should be more generally recognized as they undoubtedly will become more numerous following this last epidemic if we can judge from the experience of the past.

_Infections of the Pleura_

The recovery of B. influenzæ from the pleural cavity is not uncommon as is shown in the above review. The findings of MacCallum, Cole and others during the spring of 1918 are particularly interesting. Beall in 1906 reported a case of empyema with large quantities of green pus in which B. influenzæ was found in pure culture.

_Sinuses of the Head_

Infection of the accessory sinuses of the head has long been recognized as occurring in influenza. Frankel found B. influenzæ in 4 from 40 infected antra. Lindenthal, who was particularly interested in the question of sporadic influenza, found the bacillus in one or more of the head sinuses in six of eight carefully studied cases. He considered that the B. influenzæ remained in these areas during inter-epidemic times and from hence caused the sporadic outbreaks of influenza. Howard and Ingersoll reviewed the literature up to 1898 and grew B. influenzæ from one of three acute antral diseases. They did not find it, however, in 12 chronic cases. Clemens believed the influenza bacillus to be present in the sinuses rather frequently in cases where it was overgrown or difficult to culture from the lower respiratory secretions. Moszkowski grew it in one case from the pus of the antrum. Tedesko recorded several positive results and many others are reported in the literature.

The two cases reported by Lacy (1918), the findings during the present epidemic by Stone and Swift of B. influenzæ in 13 of 28 sphenoidal and 6 of 12 ethmoidal sinuses cultured at necropsy, those by Spooner, Scott and Heath, of B. influenzæ in four frontal sinuses and in eight sphenoidal, and the recovery by Wolbach of B. influenzæ in cultures from the sinuses in certain cases where the lung cultures were negative, emphasize the importance and frequency of the infection by this organism in these cavities. Keegan, who laid particular stress on lung punctures and autopsy examinations, pointed out that in throat cultures the probability that the influenza focus is often not in the pharynx but in some recess of the nasal cavity.

H. E. Robertson in the spring of 1918 reported the infection of the sinuses in seven cases of tracheo-bronchitis with patches of broncho-pneumonia and the growth of B. influenzæ from sphenoid, ethmoid or frontal sinuses of all these cases. He also found this organism in the sphenoid of six cases dying with various diseases as well as in two accident cases with death under 24 hours. The importance of these results was laid stress on by the author, not only on account of the probable toxic absorption and the general menace of spread, but, more particularly, because such individuals, acting as carriers, could furnish foci for the spread of epidemics.

_Eye and Ear_

Infections of the eye by the influenza bacillus are quite common. This subject is fully discussed by Axenfeld (text-book, “The Bacteriology of the Eye”). Giani and Picchi found it in the eye in 66 per cent. of influenza cases, in 90 per cent. of epidemic conjunctivitis, and in the normal eye of 5.8 per cent. Wynekoop, in 1903, reported having found this organism in cases of conjunctivitis in 1899. Guiral, in the recent epidemic, found influenza bacillus constantly present in the secretions in cases of what seemed to be Week’s conjunctivitis. Ulceration of the cornea was rather common. One such case is mentioned in which there was no pain in the eyes, but general symptoms of influenza. The middle ear is also sometimes infected. Between the report of Kossel in 1893 and that of Stone and Swift in 1918, who found the middle ear and mastoid to contain B. influenzæ in 8 of 17 cases, there have been many references in the literature to this complication by the influenza bacillus. The evidence indicates, however, that in the middle ear, as in the pleural cavity, the secondary bacteria are far more often the important ones.

_Meninges_

Influenzal meningitis seems to stand by itself as a manifestation of the pathogenic effects of B. influenzæ. The literature is too voluminous to review in this place, but the evidence would seem to point to a more invasive and pathogenic type of this organism, if not to a separate member of the group.

_Invasion of the Blood Stream_

The evidence in clinical influenza would suggest at times a bacteremia in addition to the severe toxemia, which is such a constant feature of the disease. Simultaneously with the discovery of B. influenzæ, Canon reported finding bacilli of similar morphology in blood smears, but was unable to grow them, and it would appear at least doubtful that he was dealing with the influenza bacillus. Meunier is probably the first who grew this organism from the blood. He recovered it from 8 blood cultures out of 10 in cases of broncho-pneumonia following measles, and in one other case of broncho-pneumonia. A very full discussion of this question is to be found in Canon’s book on “The Bacteriology of the Blood in Infectious Diseases.” Of particular interest are the results of Ghedini, who made a careful study of 28 influenza patients. B. influenzæ was grown from the blood in 18 of these at the height of the fever, while in the 10 negative cases the disease was milder or the blood was taken only after the temperature had fallen. The amount of blood used was 20-30 c.c., and it was cultured in lecithin broth. In practically all of his cases several cultures were taken, and in a number of the positive cases negative results were obtained both before and after the acme of the fever. He also grew the bacillus from 8 of 14 spleen punctures of these patients. Madison (1910) reported the recovery of this bacillus from the blood of a patient with a primary broncho-pneumonia who recovered. This author also used about 30 c.c. of blood. Thursfield, in 1910, also reported two cases of B. influenzæ bacteremia in which the organisms were recovered at the height of the temperature. One had influenza, the other phlebitis, and both recovered. Tedesko and several others have found it in the heart’s blood in many cases, more especially in broncho-pneumonia after measles.

During the present epidemic the positive cultures of this bacillus from the blood have been rather infrequent. J. S. Fleming had 2; 2 are quoted in the report of the Influenza Committee of the Advisory Board to the D. G. M. S. (Peters and Cookson); Medalia had 2 during life and 19 of 34 at autopsy; Orticoni, Barbie and Leclerc in 5 of 10 blood cultures in one series, and 7 of 19 in another; Stone and Swift 2 at autopsy; McKeekin, in Australia, influenza-like bacilli in 4; Blanton and Irons three times in the heart’s blood, one of these pure; Spooner, Scott and Heath twice in the heart’s blood at autopsy, and Wollstein and Goldbloom from the heart’s blood in one child. In the majority of these findings the bacillus was not found in pure culture. Abrahams and his associates found the B. influenzæ along with a pneumococcus and M. catarrhalis from the heart’s blood in one case. In our positive blood culture there was evidence of the same mixture being present.

Before drawing sweeping conclusions against the invasion of the blood by B. influenzæ it must be remembered that the quantity of blood used has been generally only about 10 c.c., and often much less, the difficulty of observing growth if the culture is pure has been largely overlooked, the use of more favorable media than blood agar and the possible inhibitory action of influenzal blood, as suggested by Wittingham and Sims, Rivers and others, has not been considered, and further that sufficient care has not been exercised to obtain blood at the most favorable period in the disease. It may be recalled that the problem is quite similar to that of demonstrating the organisms in the blood in patients with streptococcus viridans bacteremia.

All the available evidence, however, points to the invasion of the blood in influenzal infections as being a very fleeting one. Unless this is true, it would be surprising in the many hundreds of blood cultures which have been taken in the concentrated study of patients during the recent pandemic, if more successful cultures had not been obtained. General infections with localization of B. influenzæ in different parts of the body are here of interest—such as that reported by Slawyk and others. Whether the strains causing meningitis, and which apparently more frequently invade the blood, are really different members of the hemophilic group or only forms with a higher invasive power is still, I believe, an open question.

_Endocarditis_

In endocarditis the B. influenzæ is probably, after streptococci, the organism most frequently isolated from the blood. Rosenthal from heart’s blood at autopsy, Schlangenhaufer, Jehle two cases, Horder (1907) six cases, and who believed he was the first to isolate B. influenzæ from the blood, Tedesko in a number at autopsy, Spat, F. J. Smith, Saathoff, Libman four cases, Sacquepee, McPhedran, Mann, Rainaford and Warren three cultures from two patients, and a number of others all bear witness to its frequency.

Other organs of the body are sometimes found to contain B. influenzæ. Adrian, Schultes, Basile and Tedesko have all recovered this organism from the diseased appendix. Several years ago a bacillus, considered, to be B. influenzæ, was grown from the pus of an appendix abscess in our laboratories. Wright found it in pyelonephrosis. Klieneberger found influenza-like bacilli in cases of cystitis. Menko reported the bacillus from orchitis, and Cohn found numerous influenza-like bacilli in the discharge from urethritis. Meunier found it in pure culture in a case of osteoperiostitis. Huyghe, Besancon and Griffon recovered it from infected joints, as did Pacchioni in a general infection. Weil found it in the pus about the hip joint one month after an attack of influenza. This short review serves to illustrate that the influenza bacillus, although generally limited to infections in the respiratory tract, is, nevertheless, capable of infecting other parts.

_Immunity—Phagocytosis_

Phagocytosis of the B. influenzæ has been very frequently noted in the study of sputum smears. It has been observed, moreover, that this phenomenon occurs most frequently when the patient is on the road to recovery (Pfeiffer, Martin, and others), and it may indicate an important reaction on the part of the body to this organism. Tunnicliff in a recent report, however, did not find the opsonic index to be raised above the normal in her patients, and Tunnicliff and Davis had difficulty with a spontaneous phagocytosis of this bacillus. This difficulty was to a large extent absent in her later study.

_Agglutination_