Virulence Enhancement.
Before attempting to study the mechanism of origin of the 1918 pandemic it is highly essential that we devote some attention to a consideration of the processes by which the germs of infection, particularly the virus of influenza, may develop an increase in virulence. Followers of the theory of periodicity would base virulence enhancement primarily on some intrinsic property of the virus itself. We know from past experience and particularly from animal experiments that this is not the only manner by which virulence may be increased.
As far as we know there is no new infectious disease. Individuals who delve into the history of the past inform us of more and more diseases which were well known to the ancients. We are frequently amazed at the variety of diseases now known to be infectious that were very correctly described by the Hippocratic writers. The infectious diseases are with us always and live nearly always in man, the host. There are few exceptions. Very few of the contagious viruses can live for any long period of time outside of the human body. A few, such as the plague bacillus, may live on other hosts, but these are the exception. The remarkable feature is that for long periods of time the virus exists in the host in a quiescent state and only at intervals does it become highly invasive and thereby produces epidemics of greater or less extent. Under what conditions does the metamorphosis of the microorganisms occur?
Topley, in the Goulstonian lectures, discusses this subject. He says: “The first difficulty with which we were faced in forming any theory of the spread of bacterial infection, which should conform to the known facts of epidemiology, was to find some explanation of the perpetuation of the virus during interepidemic periods. The bacteriologic data which have accumulated, especially during the last twenty years, have shown that the causative agents of specific diseases are to be found in apparently normal persons who give no history of having been in contact with the disease in question, as well as in contact with actual cases of the disease. Moreover, the organisms in question have been shown, in certain cases, to persist for long periods of time in or upon the tissues of their hosts, and we must always remember that the difficulty of bacteriologic technic is likely to lead to a serious under-estimate. Clinical and epidemiologic investigations have yielded confirmatory evidence, and we are thus left with a conception of the virus of a given disease being distributed fairly widely throughout the world as an apparently harmless parasite on the human host, but taking on during epidemic periods a new and sinister role, only to relapse again into comparative quiescence as the epidemic subsides.”
He explains the rise of the epidemic wave as follows: “There are at least three possible explanations—an increase in the power of the parasite to produce disease, a decrease in the resistance of the host, and some attraction in the surrounding circumstances which favor the transference of parasites from case to case without any alteration of the pathogenicity of the one or in the resistance of the other. The third of these hypotheses may, I think, be disregarded. That alterations in environment may be the determining cause in initiating an outbreak of bacterial disease is probable enough; but they will almost certainly act through the variations which they bring about in the other two factors. The whole of bacteriologic knowledge is clearly against the occurrence of a considerable epidemic in which the pathogenicity of the parasite and the resistance of the host remain constant. Again, while we may well believe a lowered resistance of a certain number of the host-species to be an important factor in the initiation of the process, yet we cannot believe that it is the whole story. The widespread ravages of many epidemics would seem altogether to preclude such an explanation. We seem forced therefore to the conclusion that an increase in the pathogenicity of the specific parasite is an essential factor in the rise of epidemics, excluding from this category small sporadic outbreaks which may be due to the introduction of a fully virulent parasite by a healthy carrier in some other way.”
If a disease like measles is quiescent in a given community it must be that in that locality the hosts and parasites are existing in a state of biological equilibrium. They are living in a state somewhat akin to symbiosis. Such a condition could be attained either by a diminution of the invasive powers of the parasite, or by an increase in resistance of the host. Probably both elements are active; as the relative immunity of the host rises the infectivity or virulence of the parasite must rise to an equal extent to maintain the equilibrium. If this were true we would find that in those localities in which the disease is endemic and where the population is relatively resistant there is a normally more virulent virus in existence. A stranger coming into such a community would, in view of his lower resistance to the virus, be more susceptible of becoming actively infected. There would, however, be little danger of an epidemic spread because the number of susceptibles would, roughly, be limited to the number of strangers in the community. If, however, an individual from the community carrying the more virulent virus were to travel to another community where the greater proportion of the population was relatively less immune the field would be fertile for the beginning of an epidemic. Furthermore, there is the possibility of an outbreak in the first community if there should occur gross changes in its constitution; another infectious disease, a redistribution of the population with greater crowding, anything to change the balance between host and parasite.
Theobald Smith has described this possibility very clearly:
“During the elimination of the more virulent races of microorganisms, there goes on as well a gradual weeding out of the most susceptible hosts. In a state of nature in which medical science plays no part, there must occur a slight rise in the resistance of individuals, due to selection and perhaps acquired immunity, which meets the decline of virulence on the part of microbes until a certain norm or equilibrium between the two has been established. The equilibrium is different for every different species of microorganism, and is disturbed by any changes affecting the condition of the host or the means of transmission of the parasite. One result of the operation of this law is the low mortality of endemic as compared with epidemic diseases. Certain animal diseases while confined to the enzootic territory, cause only occasional, sporadic disease, but as soon as they are carried beyond this territory epizootics of high mortality may result. Climate in some cases enters as an important factor, but the most important, perhaps, is the slight elevation in virulence brought about by a more highly resistant host. The most susceptible animals are weeded out and the rest strengthened by non-fatal attacks. The virulence of the microbe rises slightly to maintain the equilibrium. In passing into a hitherto unmolested territory, the disease rises to the level of an epizootic until an equilibrium has been established.
“The same is true of human diseases, among which smallpox is a conspicuous example. The great pandemics of influenza, which seem to travel from east to west every one or two decades, soon give away to sporadic cases, and the careful work of many bacteriologists would indicate that the influenza bacilli found at present have fallen to the level of secondary invaders, and are parasites of the respiratory tract in many affections.”
Smith describes his hypothesis that the tendency of microbes in perfecting the parasitic habit is to act solely on the defensive. The aim of microorganisms, if we may speak of such, is to become able to live unharmed on the host. If they kill the host they have lost their home. The biologic tendency would be in this case for diseases which were once acute to become more and more chronic and indolent.
The extremely virulent parasite, which kills its host, will die with the host unless it has effected a means of exit before its death and escapes into a new host. For this reason Pasteur failed to exterminate the rabbits of Australia. He believed that with races of the bacillus of rabbit septicemia, which were very virulent, and which destroyed life very quickly, all that would be necessary was to start the disease among the rabbits of Australia and that it would tend to spread and would kill off all of the rabbits. But the parasite killed the animals before it had perfected for itself a means of escape from the body and thereupon died.
“From the biologic standpoint which I have endeavored to present, we may conceive of all highly pathogenic bacteria as incompletely adapted parasites, or parasites which have escaped from their customary environment into another in which they are struggling to adapt themselves, and to establish some equilibrium between themselves and their host. The less complete the adaptation, the more virulent the disease produced. The final outcome is a harmless parasitism or some well-established disease of little or no fatality, unless other parasites complicate the invasion. The logical inference to be drawn from the theory of a slowly progressive parasitism would be that in the long run mortality from infectious diseases would be greatly reduced through the operation of natural causes. But morbidity would not be diminished, possibly greatly increased by the wider and wider diffusion of these parasites, or potential disease producers. The few still highly mortal plagues would eventually settle down to sporadic infections or else disappear wholly because of adverse conditions to which they cannot adapt themselves.
“In this mutual adaptation of microorganism to host, there is, however, nothing to hinder a rise in virulence in place of the gradual decline if proper conditions exist. In fact, it is not very difficult to furnish adequate explanations for the recrudescence and activities of many diseases today, though the natural tendencies are toward a decline in virulence. In the more or less rapid changes in our environment due to industrial and social movements the natural equilibrium between host and parasite established for a given climate, locality, and race or nationality is often seriously disturbed and epidemics of hitherto sporadic diseases result.
“These illustrations indicate that so-called natural law does not stand in the way of our having highly virulent types of disease, if we are ignorant enough to cultivate them. The microorganism is sufficiently plastic to shape itself for an upward as well as a downward movement. Among the most formidable of the obstacles toward a steady decline of mortality is the continual movement of individuals and masses from one part of the world to another, whereby the partly adapted parasites become planted as it were into new soil and the original equilibrium destroyed. These various races of disease germs become widely disseminated by so-called germ carriers, and epidemics here and there light up their unseen paths.”
An example of increasing virulence from changing environmental conditions, is the experience in the United States Army camps in 1917 and 1918 with the streptococcus. This microorganism, which at first was but a secondary invader, particularly to measles, became so exalted in virulence that it soon became the cause of primary disease. This is likewise true of the various secondary invaders of the influenza epidemics. They become so highly virulent that they dominate the picture in the later stages. The organisms included in this group are particularly the streptococcus, the various pneumococci, and the meningococcus. Probably the tubercle bacillus should be added to this list.
It requires a certain amount of time for such organisms to attain increased virulence. The earliest cases in any epidemic are comparatively very mild. Thus Major Billings, epidemiologist at Camp Custer, says that for the first five days of the autumn influenza epidemic in that camp the cases admitted to the hospital were very mild in character and were recorded as simple bronchitis and pharyngitis, of no great severity, the majority soon recovering. Five days after the first case was admitted, however, the entire symptom complex seemed to change, and the cases admitted to the hospital from then on were a very different and much more severe type. Major Billings, after going over the records, feels that both types of cases were the same disease, the second being a more severe form. Woolley reports essentially the same condition from Camp Devens.
The same phenomena were found in 1889. During the 1889 epidemic Prudden examined by current bacteriologic methods seven cases of influenza and six cases of influenza-pneumonia. In them he found staphylococcus pyogenes aureus, streptococcus pyogenes, diplococcus pneumoniae, and in other cases he found a streptococcus. He concludes that the use of culture methods and media commonly employed has brought to light no living germ which there is reason to believe has anything to do with causing the disease. He emphasizes the probable importance of streptococcus pyogenes in particular in inducing the various complications.
At this point we should include for the sake of completeness reference to a recent theory propounded by Sahli explaining influenza epidemics, a theory to which we do not subscribe. He believes that the pneumococcus, the streptococcus, the influenza bacillus, and possibly other organisms, form a complex group, an obligate complex, a symbiosis, a higher unit, which infects the organism as a unit. It is all of these organisms acting together which produce the influenza. After infection has occurred one or the other member of the group may develop preferentially. In favor of this he says that in one of his cases the sputum was swarming with influenza bacilli on one day, and that the next day the sputum was a thick pure culture of the pneumococcus. He says that if an ultramicroscopic germ should yet be discovered this would not invalidate the theory, but would merely add another member to the group forming the obligate complex virus unit.
Meteorologic conditions.—Formerly attempts were made to demonstrate etiologic relationships between the occurrence of influenza and unusual conditions of the atmosphere. In most cases no relationship has been discovered. Nevertheless it is conceivable that the changes in the atmosphere, particularly seasonal variations, might influence the virulence of the organism. It has been found that nearly all of the many epidemics apparently originating in Russia took their origin there either in the late autumn or in the winter months. The spread of influenza appears to be uninfluenced by atmospheric conditions, but the severity of the disease is definitely increased in the winter months, and Leichtenstern believes that the development of a primary spread from its point of origin is also influenced by the season. Hirsch found that out of 175 correlated pandemics or epidemics, 50 occurred in the winter between December and February, 85 in the spring from March to May, 16 in the summer from June to August and 24 in the autumn.
The soil plays no part in the spread of the disease. It prevails on every soil or geologic formation; on the mountain top, in the low malarial swamps, in the tropics and within the arctic circle. Volcanic eruptions, fogs, electrical conditions, ozone, direction of the wind, have all been considered in previous epidemics and successively eliminated as etiologic factors.
It must be stated, however, that Teissier, who investigated the influenza in Russia in 1890 and has compared his conclusions at that time with the results of investigation of the recent visitation, believes that some particular cosmic conditions suddenly enhanced the virulence of an endemic etiologic microorganism—probably some ordinary germ—and that this opened the portals to secondary infections.
Secondary invaders.—We have considered a possible manner in which the virulence of the organism causing influenza may become enhanced. Whatever this organism may be, another and equally important virulence enhancement occurs in the opportunist group of the germs, so-called secondary invaders of influenza. As we have previously remarked, it is a characteristic of influenza outbreaks in all communities that the earliest cases are very mild. Secondary infection has not as yet obtained a foothold. After about a week the character of the illness changes, becoming distinctly more severe. Billings reported that at Camp Custer in the autumn of 1918 cases admitted to the hospital during the first five days were very mild in character and were reported as simply bronchitis or pharyngitis of no great severity, the majority soon recovering. After this time the entire symptom complex seemed to change and the cases admitted to the hospital were of a very different and more severe type.
Benjafield reports that in the Egyptian Expeditionary Force the epidemic commenced in May, 1918, and that the cases occurring during the earlier portion of the epidemic were mild in type and of short duration, only a very small proportion being complicated by bronchopneumonia. Wooley found at Camp Devens that the first cases were of a mild form and were usually diagnosed “naso-pharyngitis, acute catarrhal.” After a few days the disease became more severe and pneumonia cases developed.
Bezançon found that among the repatriated French soldiers from Switzerland those cases occurring in May and June had a much lower severity than in the later epidemic. Zinsser’s description of the mild, earlier epidemic in Chaumont has already been quoted.
The secondary invaders of pathogenic importance are the various forms of the streptococcus and pneumococcus, the meningococcus, the staphylococcus, and probably the tubercle bacillus and the influenza bacillus. In the last epidemic as in that of thirty years previously, the chief complications were bronchitis and pneumonia. Capps and Moody found these to be the chief complications in December, 1915. Also they found a high incidence of sinusitis. This has been a feature of the last epidemic. Wooley cites a good example of the damage done by these opportunist organisms when they are present. Among the troops stationed at Camp Devens in the fall of 1918 pneumonia following influenza was particularly prevalent in a battalion of negroes from the South. This battalion had, a short time previously, passed through an epidemic of pneumonia and Wooley believes that many of the blacks were harboring the pneumococci which were only awaiting a favorable opportunity to invade their hosts. The influenza furnished the required opportunity.
That the meningococcus should be classed in this group is certain. The author observed at Camp Sevier cases of epidemic meningitis occurring in various influenza wards scattered throughout the hospital, with no demonstrable relationship. Usually there was but one case in a ward and almost invariably meningitis occurred when convalescence was beginning. No epidemic occurred in any ward. Others have reported actual epidemics of meningitis following influenza. Moss found that a large proportion of his influenza cases had the meningococcus in the circulating blood, as demonstrated by culture. Fletcher cultivated meningococci from the lungs in all of eleven autopsies, and in all eleven cases the influenza bacillus was also present.
In considering the effect of influenza on the death rate in general, and in considering the relationship of influenza to other diseases in general, it is important to distinguish those diseases which are apparently unrelated and those diseases which occur as direct complications or sequelae. Bronchopneumonia, bronchitis, empyema, otitis media, frequently tonsillitis and sometimes erysipelas, occur as sequelae. Meningitis should frequently be included in this group.
Not only is there an increase in certain other diseases following influenza outbreaks, genetically related, as we have seen, but also some observers, particularly Crookshank, believe that previous to epidemic influenza prevalences there occurs an increase in the incidence of other entirely unrelated infectious diseases, such as poliomyelitis. This theory of simultaneous increase in invasiveness of many apparently unrelated germs is comparatively new and will probably receive deep consideration in the future. For the present the information on the subject is so limited that attempted conclusions would have no value.