Influenza and Other Diseases.
Influenza and tuberculosis.—Following the 1918 and 1920 epidemics of influenza, there has arisen in the literature some controversy regarding the effect, if any, of influenza on tuberculous individuals. This has centered particularly on the question whether tuberculosis produces some degree of immunity to influenza, and whether the latter, on the other hand, predisposes either to the lighting up of a latent tuberculosis, or to a new infection with the tubercle bacillus. Keen observers in the field of tuberculosis who have had apparently equal opportunities to study the effects of the pandemic differ radically in their conclusions.
The first mention of consumption following influenza was made in 1580 by Thomas Short.
After the 1889–1893 epidemics, Leichtenstern recorded that the mortality tables of all countries agree in showing considerable rise in the mortality from pulmonary tuberculosis in influenza periods. The clinicians of that time made the frequent observation that the course of tuberculosis in the lungs is markedly and unfavorably influenced by grip and its pneumonic complications. Latent quiescent cases often became active, and healed and healing foci broke out anew. Afebrile cases were changed to the hectic type and frequently hemoptysis was induced. In London, during the height of the 1889 epidemic, the weekly death reports from phthisis rose to double the average. The increase in death rate during the epidemic period was not limited entirely to tuberculosis, but there was almost a doubling of deaths due to all acute respiratory infections. After the cessation of the epidemic, however, there was some decrease in the general mortality, as well as in the mortality from respiratory infections. This was especially true of deaths from pulmonary tuberculosis, which decreased to such an extent that the total mortality rate for the year for this disease was little greater than for preceding years.
Similar observations have been made following the 1918 pandemic. Jordan remarks that in New York City in 1918 during the two weeks of maximum epidemic mortality, the deaths reported from pulmonary tuberculosis numbered 430, as compared with 264 for the corresponding weeks of 1917. Vaughan and Palmer found that the deaths from tuberculosis in the army were higher in the autumn of 1918 than in the two previous four months’ periods, the death rate rising from 18 per 100,000 during the summer to 46 per 100,000 in the autumn. The rate for the same time of the preceding year had been 15 per 100,000. They assume that the most plausible explanation for this increase in deaths is that dormant and incipient cases introduced into the army during the preceding year had accumulated and possibly were hastened into the acute stage, both by the duties of camp life, and the prevalence of the epidemic of grip and pneumonia. Quite naturally there had been from the time of the first assembling of troops an accumulation of tuberculous individuals, inasmuch as such men were not discharged, but were kept in the army and under Government control and supervision. Sir Arthur Newsholme in reviewing the relationship between influenza and tuberculosis in England concludes that many deaths from tuberculosis are undoubtedly hastened during an influenza epidemic. Abbott wrote of the epidemic of 1889 in Massachusetts that the chief diseases which followed in its train and were intimately associated with it were bronchitis and pneumonia, and that phthisis when already existing in the victim of the attack was undoubtedly aggravated, and in many cases a fatal termination was hastened. Baldwin says that influenza is a frequent and important agent in bringing latent tuberculosis to life. “Allowing for mistakes in diagnosis, influenza must be classed as an important exciting cause, if not a true predisposition.”
In frank opposition to the foregoing authorities, Fishberg claims that influenza has had no effect whatever on the course of tuberculosis. He says that a large proportion of tuberculous patients under treatment in New York City in 1918–1919 contracted the disease and not a single one succumbed. This appears as rather an inclusive statement. He goes on to say that some were in far advanced stages of the disease, with large cavities in the lungs, and yet they passed through the acute symptoms and recovered, the tuberculous process then pursuing its course as if no complicating disease had affected them. He believes that the prognosis was, if anything, better in those who suffered from tuberculosis or any other chronic pulmonary disease, such as asthma, bronchitis, emphysema, bronchiectasis, than in those in whom the lungs and bronchi had been apparently in healthy condition. Fishberg observes that, instead of lighting up the tuberculosis, the influenza runs a milder course than when attacking healthy persons, and the old lung lesion remains in about the same condition as could be expected if no complicating process had attacked the patient. He says that authors who have asserted the contrary have based their arguments mainly on the facts first, that many tuberculous patients date the onset of their tuberculosis as concurrent with an attack of influenza; that many patients suffering from phthisis state that ever since an intercurrent attack of influenza the symptoms of tuberculosis have become more pronounced; that the Pfeiffer bacillus has been found quite frequently in the sputum of tuberculous patients, especially that derived from pulmonary cavities; and finally that in some countries it has been noted that during and soon after an epidemic of influenza the mortality from tuberculosis was increased.
He believes that many of the conditions diagnosed as influenza have been no more than ordinary colds, and that the average patient will call any upper respiratory tract infection grip during or around the time of an epidemic. He further believes that a misdiagnosis of tuberculosis is frequently made in influenza convalescents who show some signs of moisture in their lungs which does not clear up for some time, causing doubt in the mind of the examiner, but which is not truly tuberculous in origin. Fishberg cites P. J. Murphy, Hawes, Armstrong, McRae, and Dickinson, as well as Geiber and Schlesinger, in Vienna, and Rickmann and Ladeck in Germany, as having observed the same phenomenon of relative insusceptibility of tuberculous patients and failure of influenza to hasten the progress of tuberculosis. He also calls attention to the low incidence of influenza in tuberculosis sanatoria, but apparently compares this incidence with the incidence for the public at large, and not with that in similar institutions devoted to the care of invalids with diseases other than tuberculosis, or with other institutions in general.
Amberson and Peters, as well as Minor, take sharp exception to the statement of Fishberg, and the former have collected the evidence against Fishberg’s view. They first point out that a comparison of the incidence of 5.4 per cent. among hospitalized tuberculous patients at Chicago cannot be compared with a much higher incidence of the epidemic in the various military camps. As Heiser has pointed out, the mere quartering of men in barracks seems to have a tendency to increase the risk from acute respiratory diseases. Furthermore, the incidence at some sanatoria was low, while at others it was high, nearly as high as for the community at large. In Hawes’ report of the epidemic among the Massachusetts sanatoria, Lakeville had escaped entirely, while Rutland which consisted chiefly of ambulatory cases, less easily controlled, had an influenza incidence of 18.3 per cent. among the patients, and 21.3 per cent. among the employees. At Montefiore Home, the proportion of tuberculous patients and employees contracting the infection was practically the same as among the nontuberculous employees, and about the same percentage of both groups developed evidence of bronchopneumonia.
Still another fallacy in the comparison of incidence in institutions and the like is proven by the work done by Jordan, Reed and Fink, who found that in the various Chicago telephone exchanges the attack rate varied from five per cent. to twenty-seven per cent., although the working conditions were approximately the same. The attack rate in one section of the students’ army training corps in Chicago was 3.9 per cent., while in another section particularly exposed to infection it was 39.8 per cent. Similarly Frost found the incidence in Louisville, Kentucky, to be 15 per cent., and in San Antonio, Texas, 53.3 per cent. All these figures show the difficulty of comparing rates for various institutions and various groups of individuals. Although Fishberg quoted Rickmann in support of his contention that influenza has no effect whatever upon tuberculosis, Amberson and Peters used his work in support of their contention, and call attention to the fact that in thirty out of forty tuberculous persons reported by him who had contracted the grip, the attack did not produce any aggravation of the lung condition. Presumably it did in the other ten. If even 25 per cent. of tuberculous patients who contract influenza have their pulmonary condition aggravated, this should be regarded as a notable number. According to Stivelman, 11.4 per cent. of tuberculous influenza cases died at Montefiore Home. In a survey of convalescents from the Loomis Sanatorium, Amberson and Peters found that seventy had contracted influenza, or 5.7 per cent. of the number surveyed, and that 11.4 per cent. of these had had relapses of their pulmonary condition, apparently due to the acute disease, while 22.9 per cent. had died from the intercurrent infection. 2.8 per cent. were deaths due to tuberculosis after convalescence from the influenza.
Tubercle bacilli have been found in the sputa of convalescent grip patients, whose sputa had previously been negative, by Amberson and Peters, as well as by Berghoff, at Camp Grant. The latter found that 50 per cent. of his cases showed a reactivation and a positive sputum after an attack of influenza.
Amberson and Peters agree with Fishberg in the observation that there has been no increase in the general mortality from tuberculosis within the recent months, and suggest as an explanation the possibility that during the epidemic enough of the old cases were carried off to account for a temporary lull until new cases developed, or others had time to reach later stages of the disease. As we have previously remarked, Leichtenstern observed this same phenomenon following the 1889–1890 epidemic.
The state of our knowledge of influenza and tuberculosis is considerably clouded by divergent opinions such as those quoted above. To further complicate the picture, there are other authors who assume a middle ground and believe that there is some truth in both lines of contention. Thus, Amelung believes that the morbidity among patients with pulmonary tuberculosis is slight, and that the grip takes a milder course in such patients than in the nontuberculous, unless the disease is far advanced, but that pulmonary tuberculosis may and sometimes does follow the disease in patients whose lungs were previously sound, and that in the last mentioned cases the prognosis is relatively bad. Peck finds that in some tuberculous patients the disease has been aggravated, but in the majority the intercurrent influenza did not appear to have been the causative factor in the acute exacerbation of the tuberculosis.
Debré and Jacquet have reviewed the European literature on the subject pro and con, and though they admit that there are exceptions, as at l’hôpital Tenon, where, in a barracks reserved entirely for female tuberculosis patients there was a veritable epidemic of grip, 29 per cent. of the twenty-eight being attacked in a few days; and at the sanatorium de La Tronche, where 83 per cent. took ill between the 25th of September and the 20th of October; they conclude that as a rule tuberculous individuals are less heavily attacked by the influenza than are the nontuberculous. As they suggest, the first explanation that comes to mind is that the tuberculous are isolated in the hospitals where general hygienic conditions are good, but we have all seen other institutions, hospitals, etc., in which the inmates were not spared as they were in tuberculosis hospitals. Furthermore, in certain sanatoria, such as the sanatorium of the Côte Saint-André, and Bligny, and several German sanatoria, the proportion of tuberculous individuals attacked was very much less than that of the professional attendants, the physicians and nurses. Again, where cases have occurred in these hospitals, and little precaution was taken to prevent its spread, very few other individuals took sick. Finally, many have noted the infrequency of the disease even in those tuberculous individuals who were living at home. It has been suggested that rest in bed from the beginning of the attack explained the mildness, or that the immunity resulting from the infection with pneumococcus, streptococcus, etc., in tuberculous individuals explained the absence of pulmonary complications. Marfan, who observed this same phenomenon in 1890, suggested that it might be due to a refractory state of the tubercle bacillus against the virus of influenza. Debré and Jacquet conclude that none of these explanations is satisfactory.
Having concluded that tuberculosis does protect in some measure against influenza, Debré and Jacquet next discuss whether the latter has increased the severity of tuberculosis in the subjects who were already tuberculous. They review the literature and make their conclusions, not from statistical records, but from general observations. They consider first those cases of phthisis which are open cases when attacked, and second, latent tuberculosis. Their conclusion concerning the first group is that influenza does not have any effect on the rapidity of evolution of the tuberculous process, except in very rare instances, such as an occasional case of miliary tuberculosis following grip. As regards latent tuberculosis, however, they do believe that the intercurrent acute infection does cause in many cases a lighting up of a previously entirely dormant tuberculosis. It seems rather difficult to reconcile the two ideas. If one type of tuberculous individual is rendered more susceptible to the ravages of consumption, it would seem reasonable to expect that all types would be so affected.
The greatest difficulty in reaching a conclusion regarding the effects of influenza on tuberculosis, and vice versa, is due to the fact that the individuals studied are in all stages of the disease, and that each individual reacts differently and in his own way. Opinions have been based chiefly on clinical observations, and not on statistical study of large series of cases, while from the nature of the conditions, even statistical studies would not be without great fallacy.
Armstrong, found in a survey made in Framingham, Massachusetts, that 16 per cent. of the entire population was affected with influenza, but only 4 per cent. of the tuberculous group in the community. Most of these latter were of the arrested type and were going about taking their part in industry and exposed to the same degree of contact as was the case with the normal population. The fatality rate was equally in contrast. Armstrong concluded that there appeared to be a relative degree of protection for the highly tubercularized. If we accept these figures at their face value we must conclude then either that tuberculosis offers some degree of protection against acute influenzal infection, or, that the tuberculous of Framingham have been so well trained in sanitation and personal hygiene, as a result of the Framingham demonstration, that they have been able to protect themselves against the grip. In the latter case we must look upon the result as a successful demonstration of the principles of preventive medicine. Certainly this did play a part, to the extent at least that individuals knowing themselves to be infected with tuberculosis, and knowing themselves to be in the presence of a pandemic, became more wary of crowd contact, and in case they did become ill, they undoubtedly went to bed at the earliest opportunity.
If, on the other hand, this is a true demonstration of relative immunity in a chronically infected individual, the explanation must be sought elsewhere. Does a chronic respiratory infection confer a relative degree of immunity to an acute respiratory disease? Do the germs already on the premises exert, so to speak, “squatters’ rights?” Are we observing an example of non-specific immunity due to local preceding infection? Still another factor may play an important role, the factor of race stock. The excess of tuberculosis in negroes, for instance, over that in whites, is in some localities double or treble, while various observers, as Frost, Brewer, and Fränkel and Dublin, report that the influenza incidence and mortality among negroes was decidedly less than that among the whites. Winslow and Rogers found that in Connecticut the proportion of influenza-pneumonia deaths is lower than would be expected among persons of native Irish, English and German stock, and higher than was to be expected among Russian, Austrian, Canadian and Polish stock, while it was enormously high among the Italian. Italians are notably insusceptible to tuberculosis, while the Irish are much more prone to infection with the disease. For example, in Framingham, where the tuberculosis incidence rate for the entire population was 2.16 per cent., the rate in the Italian race stock was 0.58 per cent., and in the Irish, 4.80 per cent. In Framingham there was about four times as much influenza among the Italians as among the Irish. Is this apparent insusceptibility of certain race stocks an inherent condition, or is it dependent chiefly on differences in living conditions and in age prevalence in the different races? Probably it is chiefly the former. Frost, for instance, found that among the negroes the incidence of influenza was lower even though the living conditions were much poorer than those among the whites.
Armstrong’s survey has also thrown some light on the effect of the influenza on previously tubercularized individuals. In a survey of 700 individuals who had had the acute disease there were ten arrested cases of tuberculosis, or 1.4 per cent. All these had been known to be arrested cases previous to the epidemic, and in none of them did the disease appear to have been actively and permanently lighted up. Some had manifested a slight activity, but all seemed to be on the way to a rearrest of the disease. On the other hand, thirteen cases, or 2 per cent. of the 700, were found to have active tuberculosis which had hitherto been undiagnosed, and an additional eight cases, with indefinite broncho-pulmonary signs, were designated as incipient tuberculosis cases. This is to be contrasted with an incidence of active tuberculosis in the pre-epidemic examination of approximately one per cent. These figures would indicate an increase in tuberculosis incidence. How may this be explained? The accuracy of these results will depend on how the 700 cases were selected. If, for example, individuals who feared tuberculosis because of known exposure, requested examination, the results might be influenced by their inclusion.
It has long been known that individuals with measles will not react to tuberculin tests, even though they have been positive before developing the measles, and though they will become positive again after recovery. The same may be said of vaccination. Individuals vaccinated against smallpox, who have measles, and are during their illness revaccinated, will not show an immediate reaction. The test will remain entirely negative, while after recovery, the immediate reaction may be obtained. Normally, it will appear in 95 per cent. of cases, while among those with measles the phenomenon remains absent in 90 per cent. The same phenomenon is present in certain other acute illnesses, particularly scarlet fever. It has been variously explained. von Pirquet, who was the first to observe it in measles, believed that the acute disease created a temporary inability to produce antibodies, and therefore designated the condition by the name “anergie.” The same phenomenon of anergie has been found recently to hold in the case of influenza. Debré and Jacquet, Lereboullet, Bloomfield and Mateer, as well as Berliner and Schiffer, have brought forth abundant evidence to this effect, following the 1918 pandemic. It has also been shown by Cayrel and others that there is a diminution of typhoid agglutinins in the serum of influenza patients vaccinated against typhoid. The agglutinin titer again increases after recovery. It is true that the agglutinin titer is not a measure of immunity, but it is frequently used as such and serves to give us some information on the subject. If, then, influenza is an anergic disease, a “maladie anergisante,” we have a theoretical explanation of the increase in severity of tuberculosis following the acute infection. We have long observed that tuberculosis frequently follows measles. We have recently been thoroughly convinced that influenza lessens resistance to secondary infection with streptococcus, pneumococcus, and other respiratory tract organisms. Shall the tubercle bacillus be added to this list? During the 1918 epidemic we saw men in the army camps who passed through an attack of influenza-pneumonia and died within a few weeks from tuberculous pneumonia or miliary tuberculosis. These men had previously been so free from signs of their tuberculosis, as to be accepted for military service as healthy individuals. The number of these cases was small, to be sure, but sufficiently large to convince us that there do exist instances in which tuberculosis is tremendously fired by an intercurrent influenza.
If we may judge merely by the balance of evidence and risk any conclusions from such conflicting testimony, we may sum up as follows:
1. Great variation in the interaction of tuberculosis and influenza must be expected, because of the many stages at which the tuberculous may be attacked, because of the altered mode of living of known consumptives, and because of the protected life of most of them.
2. Phthisical patients as a group, may be relatively insusceptible to influenza infection. This may be due to the tuberculous process itself or to some extrinsic, but nearly related cause.
3. But many individuals with pulmonary tuberculosis do get influenza.
4. And the disease, having been contracted, in many cases hastens the fatal termination of the tuberculous process.
5. It may be that this phthisical exacerbation occurs more frequently in individuals with latent tuberculosis, individuals who are not at the time mobilizing their protective antibodies.
Other infectious diseases.—We have found diversity of opinion regarding the relationship between influenza and tuberculosis, and yet the latter, being as a rule very chronic and presenting very definite signs which may easily be followed, should theoretically be a disease in which the results of study would be quite definite. When it comes to a study of other maladies we find the same difference of opinion frequently present.
It has been the experience of many that during influenza epidemics other acute specific infectious diseases appear to diminish, both in number of cases and in extent. At Camp Sevier, for example, two measles wards had been quite constantly full of patients up to the time of the fall influenza epidemic, while during the time of the epidemic one ward appeared sufficient to hold all cases of measles. In the stress of the epidemic this difference was probably more apparent than real, and certainly is not to be taken as of statistical value.
Vaughan and Palmer report for all troops in the United States that, “Without exaggeration it may be said that for the time being at least, influenza and pneumonia suppressed other infectious diseases. Typhoid fever increased to a barely noticeable degree. The death rate from this disease was somewhat higher, but the total number is so small as to barely warrant comment, and not to justify any definite conclusion. Scarlet fever and malaria were both lower than during the summer. In fact, there was but one scarlet fever outbreak of any importance and that occurred at Camp Hancock. Within two weeks over 300 cases were reported and this marks the largest scarlet fever epidemic that occurred in the camps in this country at any time. Meningitis increased although it did not reach the prevalence of the previous winter. The weekly incidence curve for all troops in this country suggests that meningitis was in some instances a sequel to influenza. The greatest meningitis incidence corresponds with the influenza peak. Diphtheria showed no material increase. Deaths from tuberculosis were higher in the autumn than in the two previous periods, the death rate rising from 18 per 100,000 during the summer to 46 in the autumn. The rate for the previous winter was 15.”
In 1889 Abbott was unable to find satisfactory evidence of a connection between influenza and other epidemic diseases, although as he mentions, such connection had often been affirmed. Instances in support of each position were to be found in the literature of the time.
P. Friedrich, after an exhaustive study of the literature, following the 1889 pandemic, concluded that there was no relationship whatever between the incidence of influenza and other acute infections. Wutzdorff reached the same view after studying the various diseases during the influenza recrudescences and recurrences. Finally, Ripperger concluded likewise.
It may be remarked that following 1918 there have been several articles written concerning the relationship between influenza and certain other diseases. These are difficult to correlate and in most instances so many additional factors play a part that the conclusions drawn are perhaps not entirely well grounded. Sylvestri found that in his experience malaria patients escaped the influenza during the pandemic. He believes that it was the malaria rather than the quinine which was responsible for the apparent immunity. On the contrary others have observed, if anything, an increase in malarial patients.
Fränkel and Dublin found that during the pandemic period deaths from whooping cough increased. The difficulty of differentiating between whooping cough and influenza as a cause of death is apparent.
It seems quite certain that deaths from organic diseases of the heart increase during and following influenza epidemics and are due probably to the inability of the weakened patients to resist the added burden. Fränkel and Dublin found an increase in deaths from this cause. This was also observed to be true in Spain and other localities.
Jordan has compared the curves of influenza with those of acute coryza among school children of Chicago and finds that the period of highest incidence of colds in October, 1918, occurred in the second week of school and that it preceded the corresponding period of influenza by seven weeks. There were three peaks in the curve for colds and only two in that for influenza. The period of highest incidence of colds follows the first peak of the influenza curve by one week, while during the week of greatest prevalence of influenza there is a sharp fall of the number of cases of colds. The third peak for colds occurred one week after the height of the influenza curve. As a rule the colds curve runs at a higher level than that for influenza. A striking fact is that the portion of the curve for influenza contained within the period November 23d to December 7th, is almost the exact opposite of the corresponding portion in the curve for colds. How much of this is due to the factor of diagnosis is difficult to say.
Encephalitis lethargica.—It is not within the scope of our report to discuss in detail this disease. Its apparent relationship with influenza, in point of time, if not otherwise, calls for special mention. In 1712 a disease followed a pandemic of influenza, occurring particularly in Germany, where it was known under the name of “Tübingen Sleeping Sickness.” In the spring of 1890, according to Netter, a disease of similar character called “Nona” was distributed especially in Northern Italy and Hungary and scattered more or less diffusely over a large part of Europe. Preceding the last influenza pandemic the disease was first reported in Vienna in the winter of 1916–17. Cases were seen in Paris in February and March, 1918, and the first official report of the disease in England seems to have been on January 26, 1918. In the spring of 1918 there were 168 officially reported cases in England with 37 deaths. The disease seems to have disappeared there in June, 1918, and reappeared in the autumn of the same year. The first cases in the United States were reported by Pothier at Camp Lee, Va. Following the great influenza pandemic cases of lethargic encephalitis have appeared in all parts of the world. It has been present in England, France, Belgium, Switzerland, Austria, Greece, Italy, and other countries of Europe, South America, Mexico, the United States, Australia, Queensland, New South Wales, and Algiers. There was an increase of encephalitis lethargica concomitant with the increase of influenza in the early months of 1920. Thus, in Switzerland 440 cases were reported during February, 1920. The 1920 epidemic of influenza in that country had almost ceased by the middle of March, while that of lethargic encephalitis had greatly decreased. One hundred and forty-one cases of the latter disease appeared in the canton of Zürich alone.
Is epidemic encephalitis a disease sui generis or is it a form of influenza?
The consensus of opinion has been that it is a separate disease. There is, however, no way of telling how close is the relationship to the influenza itself. If lethargic encephalitis is a sequel to influenza, is it caused by the same germ? Flexner points out that in 1916, when the first cases of encephalitis appeared or at least were recognized in Austria, the epidemic of influenza had not yet appeared. In England, France and the United States the epidemics of the two diseases were more or less coincidental. He believes that little weight can be given the supposed coincidence of influenza and the “sleeping sickness” of 1712, and that it is highly improbable that the semi-mysterious affection, “nona,” which dates from 1890 was definitely a sequel of influenza. He concludes that the outbreak of encephalitis either antedated the pandemic of influenza of 1918, or that the two diseases more or less overlapped; that is, although probably quite by accident, they prevailed concurrently. He prefers for the time being at least to regard them as independent diseases.
Crookshank believes that encephalitis lethargica is a distinct disease, but that it occurs frequently as an antecedent of or coincident with influenza, together with increase in the existence of poliomyelitis and certain other diseases.
Nevertheless the association in point of time and place between influenza and lethargic encephalitis cannot be lightly overlooked. As we have seen, Flexner’s criticism that encephalitis antedated the influenza is not valid, because the latter was present in 1916. We must await fuller evidence on this subject.