SOME CONCEPTIONS OF EPIDEMICS IN

Vol. 103. No 2

AMERICAN JOURNAL OF EPIDEMIOLOGY

Copyright © 1976 by The Johns Hopkins University School of Hygiene and Public Health

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SOME CONCEPTIONS OF EPIDEMICS IN GENERAL1

All through history there have occurred from time to time great outbreaks of disease which have been notable for their high prevalence, often for great mortality, for widespread, and frequently for novel or unusual clinical characteristics. The word which has been used to describe such outbreaks, the designation "epidemic," is in itself sufficient evidence that they have been matters of great and general concern, events of a kind which men would not be satisfied merely to describe, but which they would also try to explain. It would require a great deal of time to review the various theories of epidemics which have been put forward; and, as regards the older theories, this would be unprofitable, for the natural philosophy of the past permitted men to hold theories of epidemics which are not tenable to us. Perhaps the most fundamental difference between the older theories and those which we may now entertain is that in the past it was reasonable to believe that epidemics originated de novo; it could be thought that the disease prevailing in an epidemic bore no constant or necessary relation to the diseases which had previously existed. Nowadays, as regards epidemics of specific infectious diseases we can hold no such view. If we accept a disease as a specific infection then our conceptions of biology require us to believe that the specific microorganism concerned is the lineal descendant of progenitors not necessarily identical, but at least generally similar, which have existed for an indefinite time. Regarding more modern views it seems

to be a fact that the development of bacteriology which so greatly extended our fundamental knowledge of infectious diseases, had, for a while, the effect of checking interest in the phenomena and causes of epidemics as such. It seems to have been taken for granted for some years after the beginning of bacteriology, that the prevalence of an infectious disease was strictly proportionate to the chance of contact with the specific microorganism, and to have been assumed that epidemics were principally due to circumstances especially favoring the mechanical distribution of the infective agent. Or, if the disease were unusual, the epidemic was rather lightly attributed to fresh importation from some other country. However, as bacteriology, protozoology and immunology have developed, and as the movements and changing character of epidemic diseases have been more closely studied in the new light which they have shed, conceptions of epidemiology have greatly broadened. It has been increasingly recognized that in the rise and fall of infectious diseases variables other than rate of exposure are concerned. Year by year evidence has accumulated pointing to variability in the properties of specific microorganisms. In particular cases the evidence has frequently been inconclusive; but in the aggregate, it has materially modified the older views of rigid fixity in specific properties. At the same time, there has been increasing recognition of variations in susceptibility to specific infections, variations related to prior infection without disease, and to inherent differences between individuals of the same species and 1 This paper, published now for the first time, was the same specific history. presented as the first of two Cutter Lectures at Harvard University on February 2, 1928. With these broader conceptions of the The Journal regrets that reprints of this article are not available. factors in infection there has been, in 141

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nisms, and in general about the nature of infection and resistance Can these facts be fitted into any general theory of the laws governing epidemics? I may say that I do not think so, if by a "law of epidemics" we mean a law which is simple enough for mathematical expression, and is at the same time broad enough to apply to all epidemics. So far as I am aware, Brownlee is the only one who has undertaken in recent years to formulate such a general law. His theory is that the rise and decline of epidemics is due principally to corresponding increase and decrease of the infective power of the specific microorganism; but while there are many facts which support this explanation of particular epidemics, there are few students of the subject who have accepted it as a general law. For my part, I believe we have no reason to suppose that any such simple law applies to all epidemics. But it does seem to me possible to bring into view the different variables which may be concerned in deterAt present, then, we have a great mass of mining the course of epidemics, to indicate facts relating more or less directly to epi- in a general way how these may interact; demics. From experience we have records and to call attention to the present gaps in of many natural epidemics, in man and in our knowledge and imperfections in our the lower animals. These records not only means of observation. show the distributions of numerous epiAny discussion of the subject must necdemics in time and their extension in essarily begin with some definition of an space, but also give fairly detailed accounts epidemic. In common usage an "epidemic" of the particular circumstances under implies a prevalence of disease which is which they have occurred—circumstances somewhat unusual, but we cannot specify of climate, of weather, of social organiza- any particular rate of prevalence which tion in the countries affected, and of the constitutes an epidemic. Thus, 100 cases of presence or absence of unusual conditions poliomyelitis occurring in a large city which might be supposed to favor or hinder within three or four months would be the spread of infection. They also include called an epidemic if this were an unusual descriptions of the clinical differences, if number of cases of that disease, whereas any, between the diseases as they occur in 100 cases of measles or diphtheria occurepidemics and the same diseases as they ring in the same period of time would not occur in ordinary times. From the experi- be called an epidemic, simply because an mental studies which have been pursued equal or greater number is usual. Again, since the beginnings of bacteriology, we the major waves of measles, which recur have another great mass of facts about the every few years, are called epidemics; but life history of numerous specific microorga- this term is not usually applied to the


recent years, a distinct revival of interest in and study of the nature and causes of epidemics. The studies especially directed to this end have been of two kinds. First, statistical studies of natural epidemics have been made especially by Ross, Brownlee and Greenwood, in England, and earlier by Farr, comparing the actual rise and fall of disease with the theoretical distributions deduced from various hypotheses. Still more recently, there has been a great development in experimental studies of spontaneous or induced epidemics of certain natural infections in laboratory animals, by Flexner, Amoss, Webster and Pritchett in this country, by Topley and Greenwood and their associates in England, and by Neufeld and others, in Germany. These have led in turn to more exact studies by the same observers, notably Webster and Pritchett, in which carefully controlled experimental methods have been applied to studies of the influence of dosage, microbial virulence and host susceptibility in experimental animals.

SOME CONCEPTIONS OF EPIDEMICS IN GENERAL

sideration most of the important diseases of man, including such diseases as yellow fever and malaria, since their parasites require the human host for completion of their life-cycles.2 Now the continued existence of an obligate parasite requires an unbroken series of transfers from host to host, hence we are dealing with a reaction between host and parasite which is continuous; and, being continuous this reaction must be constantly tending to establish an equilibrium. This equilibrium will be stable when each generation of infected hosts is succeeded by an equal number in the next "generation." It is not necessary, however, that this stable equilibrium should be maintained, for the reaction may be progressing to a lower limit of extermination, or an upper limit of universal and continuous infection, or it may be oscillating around a mean level which may have a trend either upward or downward or horizontally. It is not necessary that the infections which keep up this reaction should always result in disease. Any part of them may be subclinical, and the ratio of clinical to subclinical infections, which certainly varies in different specific infections, may vary also in the same infection at different times, so that the equilibrium with respect to infection may be quite different from equilibrium with respect to disease. The factors concerned in keeping up this equilibrium and in bringing about the changes from one level of prevalence to another are: 1) A specific microorganism capable of producing the infection and the disease. As this organism is present not singly, but in numbers, we may refer to it as a microbial population. 2) A host population (man being usually the host to which we refer) containing 1

With respect to yellow fever, knowledge subsequently acquired has, of course, shown this view to be incorrect (Editor).


annual seasonal increase in occurrence of diphtheria. As the distinctions which are thus made are somewhat vague and are not altogether consistent, it seems necessary, for purposes of general discussion, to define an epidemic more broadly. The definition which I would suggest is any temporary increase in the prevalence of an infectious disease of such extent and course as to indicate a definite change in the balance of forces controlling the occurrence of the disease in the population. Fluctuations in rate of prevalence which are "epidemics" in this sense are not rare occurrences which may be attributed to unusual combinations of circumstances. They are, on the contrary, quite characteristic of many infectious diseases. In certain diseases such as typhoid fever, the diarrheal diseases of infants, pneumonia, and others, the fluctuations are fairly regular in their range and bear a well defined relation to the seasonal cycle, so that the peak of prevalence recurs at about the same months in each year, and does not vary much in height from year to year. In other diseases, such as measles and scarlet fever, the fluctuations are characteristically of wider range and at longer intervals, following a periodicity which appears to be somewhat irregular. Where the entire course of a disease is made up of such oscillations, we may consider these as a continuous series of epidemics, the period of each one extending from the point which marks the beginning of an upward trend to the point which marks the lowest level in the subsequent decline. From this point, I think the discussion may well be limited to such of the specific infectious diseases as are caused by microorganisms which are obligate parasites of the host in question. This throws out of the discussion such diseases as bubonic plague in man, since plague is primarily a disease of rodents, and human infections are not in any way essential to the life of the specific microorganism. However, it leaves for con-

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disease to infection (or of infection to inoculation) is changing in a given population, we cannot prove that this is due to a change in the properties of the specific microorganism unless we can at the same time prove that susceptibility has remained constant. On the side of the host population, the variable which is difficult to determine is susceptibility. With respect to certain diseases, such as measles, smallpox and yellow fever, experience shows that susceptibility to infection is approximately coextensive with susceptibility to the disease, and that, except in those who have been specifically immunized, a high susceptibility to these infections is well nigh universal, so that the mass-susceptibility of the population is determined by the ratio between two sharply differentiated groups, one made up of individuals who are highly susceptible and the other of those who are highly resistant as the result of previous specific immunization. By a careful census both of these groups may be enumerated with some approximation to accuracy, affording an index of mass-resistance. For instance, if we know that 50 per cent of one population and 25 per cent of another have previously had measles, we may conclude, with reasonable safety, that the average resistance of the first population is twice that of the second. However, we have equally good reason to believe that with respect to many other diseases susceptibility varies in a much more complex way, so that if it were possible to measure the susceptibility of all individuals and classify them accordingly, they would fall not into two but into many classes according to their different degrees and kinds of susceptibility. We find in our experience of human diseases evidence enough that such individual and racial differences in susceptibility actually exist; and we are often able to show that certain classes of people—certain racial or age-groups, or people with a


susceptible individuals in sufficient numbers to keep up the infection. 3) Such conditions of environment as are necessary for bringing the specific microorganism into potentially effective contact with infectible hosts. Each of these factors is subject to many and complex variations, which we can recognize as possibilities, and which we may demonstrate as realities, but which we can measure only imperfectly under natu ral conditions with our present means of observation. The microbial population may vary in numbers, due either to a change in the mean number of organisms per infected host or to a change in the number of infected hosts or to both causes. Our nearest approach to a measure of such changes, is afforded by observing the change in numbers of infected individuals in the population, including indistinct cases and "carriers." This is often difficult and may be impossible, and at best affords only a rough index, since we can seldom estimate changes in the number of bacteria per host. The microorganism may also quite possibly vary in specific properties, notably in infectivity and pathogenicity. The theoretical measure of infectivity is the frequency of infection resulting from inoculation of a given number of microorganisms into groups of hosts of the same average or mass susceptibility; but this is a measure which can be applied directly only under experimental conditions. The index of pathogenicity is the ratio of clinical to subclinical reactions resulting from infection under uniform conditions of dosage in hosts of the same average of susceptibility. This is theoretically determinable where means are available for recognition of subclinical and passive infections, as in diphtheria and cerebrospinal meningitis; but even in such cases the observations actually made are seldom sufficiently exact or extensive to measure the variations which may take place. Moreover, if we find that the ratio of


If the several variables which have been

mentioned were entirely independent of each other, i.e., if a change in one did not affect the other, the whole course of an epidemic might be determined by the changes in a single factor, all the others remaining constant. In this case, however, the variation must be temporary in its effect or must be reversed, so that it would operate first to increase and then to diminish prevalence of the disease, since an epidemic implies not only a rise but a subsequent decline in morbidity. It is not likely that the variables are in fact ever entirely independent of each other in nature, but special cases may be cited in which it is allowable to infer that the course of a particular epidemic may be governed principally by variation in one factor alone. For example, it seems fairly certain that the incidence of typhoid fever in most of the large cities of this country is held down to its present low level chiefly by restriction of the opportunities for transfer of the typhoid bacillus from person to person rather than by resistance of the population or enfeeblement of the specific microorganism. Therefore, any circumstance which temporarily increases the rate of transference of the typhoid bacillus from existing sources to the surrounding population may, by itself, give rise to an epidemic of typhoid fever, since increase in the number of persons exposed will cause an increase in the disease, and a decline will follow when the special and temporary increase in exposure ceases. This appears to be essentially what happens when a water supply or a milk supply which is distributed to a considerable number of people is accidentally contaminated with typhoid bacilli. The effect of such contamination obviously is to bring a larger number of people into contact with the typhoid bacillus through eating or drinking the contaminated medium. If the infections are not sufficiently numerous to materially reduce the mass-susceptibility of the popu-


certain kind of history—are more susceptible than others, but we can hardly hope to measure variations in individual susceptibility at all exactly except under controlled experimental conditions which we cannot expect to set up for the human subject. Conditions affecting the frequency of contact between the specific microorganism and the host population are obviously subject to manifold variations, related to changes of one kind and another in the habits or environment of the population. Where we know the means by which a particular infection is spread we may often conclude with some certainty that a particular known change in habit or environment will tend to increase or decrease the opportunities for transfer of the specific infective agent (crowding, pollution of water) and we find abundant evidence that increased exposure is associated in nature with increased incidence of infection; but we have no very exact quantitative idea of the increase in prevalence of an infection which will probably result from a given increase in the frequency and extent of exposure. As Topley has stated it, "dosage" or "exposure" under natural conditions "can only be expressed as the probability that any one individual in the population at risk will, within a given time, receive a given number of the specific microorganisms." And this implies even more complex ideas of the probable frequency of doses of different size, and of repeated inoculations at varying intervals. Under conditions of natural exposure the factor of dosage must always be more or less indeterminate. We may hope to study the effect of varying dosage in an exact quantitative way only under experimental conditions where inoculation is done artificially, and it remains to be seen whether such studies—necessarily confined for the most part to lower animals—will yield laws of general application with respect to the relation between dosage and infection.

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in the number of infections in a later time interval. In the absence of any counterbalancing force this increase in the numbers infected in successive time-intervals would continue in a geometric progression, until the entire population had been infected. The other general relation, which tends automatically to check such progressive increase in rate of prevalence, results from the fact that infection usually establishes, in the host, some degree of specific immunity to subsequent infection. This immunity may be of high or low degree; and it may be durable or transient, but there are few, if any, known exceptions to the general rule that recovery from an infection carries with it some degree of specific immunity. Consequently, as the number of infected individuals in a population is increased the number of susceptibles available for infection in succeeding time periods is correspondingly diminished by immunizations or by deaths or both. If all other factors remained constant, the interplay between these two opposing but mutually dependent forces, one tending to progressively increase the prevalence of infection and the other to progressively diminish it, would tend to bring about just the kind of result that we see in an epidemic, namely, first a rise and then a decline in prevalence of the disease To illustrate this effect, let us take a hypothetical case, simplified as much as possible. Suppose we have an initial population of, say, 100 people, all equally and highly susceptible to a specific infection, say that of measles. Now suppose we introduce into that group a single individual suffering from the disease in its communicable stage, and that the following conditions obtain—all being more or less the kind of conditions which we have reason to believe do obtain in measles. 1) That an infected individual is infective to others for a brief period (not exceeding the time-periods used in describing the epidemic). 2) That the infection is spread directly


lation, and if the secondary cases resulting from the primary increase in number of foci of infection are relatively few, the whole course of such an epidemic may be governed by the extent and duration of the increased exposure brought about by contamination of the common medium. In the simplest case, where the mass exposure is limited to a single day, the distribution in the time of the primary cases will represent merely the distribution of incubation periods. There are other instances in which variation in some other single factor might be concerned. For example, it is well known that the number of persons harboring penumococci greatly exceeds the number suffering from pneumonia; hence, we may infer that the occurrence of this disease is limited not by the rarity of exposure to the specific microorganism, but rather by host resistance or by low pathogenicity of the pneumococcus. Therefore, an epidemic of pneumonia might conceivably result from a temporary lowering of mass-resistance as for instance, by excessive fatigue, or by unfavorable weather conditions. The above examples are cited merely to illustrate the possibility that variation in a single factor may possibly govern the whole course of an epidemic. These, however, are special cases, for it is certain that the variables concerned in the equilibrium of infectious diseases are not really independent, but are intimately related to each other. Their inter-relation doubtless differs in different diseases, but there are two which are quite general. One is the relation between the number of infected individuals in a given community and the exposure of the rest of the population. Thus, other things being equal, the number of exposures in the population would bear a direct ratio to the number of infected individuals present. Hence, any increase in the number of the latter, no matter what its primary cause, tends to increase the total exposures in the community, and other conditions being equal, this causes a further increase

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GENERATIONS of EPIDEMIC w FIGURE 1 Epidemic curve, starting with one case added to a population of 100 susceptibles, and assuming that each individual has contact with two others during the infectious period of the disease, and number of remaining susceptibles at each time period *

the original 100 would remain uninfected and susceptible.' This illustration is given merely to show in a simple case the kind of effect which progressive mass-immunization may have toward checking the course of an infection which otherwise would tend to spread in a geometric ratio; and especially to illustrate the principle that an epidemic may be brought to an end for lack of susceptible material while a considerable residue of susceptibles remain uninfected. Of course, this residue bears no fixed relation to the • Figure 1 has been drawn as it is supposed Frost may have intended, using the equation given in footnote 3 (Editor) ' This exposition would seem to suggest that Frost used the equation Ct+i = 2 x C, x S,/100 in calculating the number of new cases Ct+i in each generation, where C, is the number in the preceding generation and S, the number of susceptibles Carrying the calculations out, however, this would have left only 12 susceptibles unattacked at the end The correct equation is C,+( - [1 - (1 - p) c '] x S,,p being the contact rate (.02), and this leaves 22 susceptibles unattacked, as Frost stated Clearly, therefore, he used the correct equation which avoids overestimating Ct+i when C, is large. In this lecture he evidently wished to avoid all but the simplest calculations, and may have developed the correct equation in the second lecture.


from infected individuals to others by a certain kind of contact and in no other way. 3) That any susceptible individual in the group, after such contact in a given time period will develop the infection in the next time period. 4) That during and after this period of infectivity, the infected individual is wholly immune. 5) That each infected individual, during his period of infectivity, comes into contact with a definite number (in this instance, two) of others, who if not previously immunized in this epidemic, will develop the infection in the next time interval. 6) That all conditions affecting the course of the epidemic remain constant, except the progressive immunization of the population resulting from the epidemic. In accordance with the above assumptions, the first individual infected would come into contact with two others, who would develop as "new cases" in the next time period. Each of these would then establish two contacts among his 100 companions, of whom two are now immune, leaving 98 susceptible. The chance that a contact will be one of the susceptibles rather than one of the immunes is therefore 98/100; and resulting infections are 2 x 2 x .98 ( = 3.92, which is considered as 4). Similarly, each of these, moving in a company now containing 94 susceptibles and six immunes would come into contact with two others, giving rise to 2 x 4 x .94 new cases ( = 7 and a fraction = 7) which would develop as new cases in the next period. In the same manner each successive term may be computed, from the one preceding, with the result shown in figure 1, in which it is seen that the progressive increase in number infected is more and more checked by the fact that an increasing proportion of the contacts fall upon persons who have been specifically immunized, so that the epidemic would terminate in the 11th time period or generation. It would die out for lack of susceptible hosts to carry on the succession, notwithstanding that 22 out of

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many other considerations) the fact- that epidemics frequently decline after the disease has attacked only a small proportion of the population. With the highest respect to Brownlee's opinions, which were based on careful study, I am obliged to think that he has underrated the probable extent and influence of mass-immunization. To fully appreciate this effect it needs to be borne in mind that to check an epidemic and bring the rate of prevalence temporarily below the level of equilibrium it is by no means necessary that all the susceptibles in the population must have been infected. They need only be reduced below a certain critical ratio, which varies in accordance with other conditions. Moreover, a considerable proportion of individuals, even though not specifically immunized, may have a natural immunity to certain infections, so that those initially susceptible may constitute only a fraction of the total population. Also, what is of great importance, the prevalence of immunizing infection in an epidemic may be much greater than is shown by the incidence of clinically recognizable cases of the disease, so that we cannot always take the prevalence of a disease as any measure of the extent of the resultant immunization. Of such immunization by subclinical infection, there is direct evidence in epidemics of diphtheria, and quite convincing though somewhat indirect evidence in epidemics of poliomyelitis. Experimental studies of epidemic infections in mice by Webster, and by Topley and his associates, have also given evidence to the same effect. Therefore, the effect of an epidemic, as regards massimmunization, may be far greater than would appear from the observed ratio of morbidity to population. One does not need to argue that mass-immunization is always and necessarily the sole factor concerned in the decline of epidemics—I think there is evidence to the contrary—but it is a factor which is very generally operative in some degree; it must necessarily operate in the direction of decline; and, for the rea-


total. If the contact rate had been four or five in the example given, all the susceptibles would have been infected. On the other hand, if the population had been larger, and the contact rate smaller—such that 10 infected persons established 12 contacts instead of 20, then the percentage left uninfected would have been much larger—it would in fact be more than 50 per cent. Obviously, the assumptions on which these calculations were made might be modified in any number of ways, to correspond to different combinations of circumstances which we may reasonably suppose occur in different diseases. Thus, we might suppose that the supply of susceptibles is continuously replenished, as by immigration, births, and lapses of immunity; we might suppose infectivity to be prolonged in some or all of the cases; we might assume in the population different grades of initial susceptibility, requiring different kinds or repetitions of contacts to establish infection. And the results would be correspondingly different. The illustration which is given is not intended, then, to express any particular theory of the exact way in which epidemics actually do develop. It is intended only to illustrate the interplay between two opposing forces which we know are quite generally operative; and to show how they tend to balance each other. I believe that all the writers of recent years who have discussed the forces controlling epidemics have recognized the progressive immunization of a population as a factor in bringing about the decline of epidemics, but there seem to be differences of opinion as to whether or not such immunization by itself is usually competent to account for the decline. Brownlee, especially, seemed to doubt this, and thought it necessary to suppose that the decline of epidemics was generally attributable in large part to a progressive loss of infective power by the specific microorganism. In support of this view he cites (along with


disease be due to an increase in exposure rate, a lowering of host resistance, or enhanced activity of the specific infective agent, we need not suppose that it must necessarily be any great change. If the equilibrium of infection is nicely balanced, a very slight change in any of the factors may suffice to initiate an upward swing. The resultant primary increase in the number of infected persons, even though it might be slight, would then tend to establish a further progressive increase; and this, in turn, would result in a compensatory mass-immunization, which would tend not only to check the increase, but eventually to depress the rate of infection below the level of equilibrium, thus preparing the way for a subsequent upward swing by way of re-adjustment. Probably a general explanation of epidemics is to be found in some such sequence 01 events as this, oscillations above and below the axis of equilibrium being kept up by occasional and perhaps slight changes in any one or more of the variables which enter into the reaction. And all this might readily happen over and over, without any essential change in the properties of the specific infective microorganism itself. Granted that we cannot actually analyze the causes of ordinary recurrent epidemic waves, I think we can at least see the possibility that they may be the result of comparatively slight changes in circumstances affecting exposure and host susceptibility to an infective agent of fairly constant properties. However, such an explanation does not seem to be applicable to the origin of such great widespreading epidemics or pandemics as have been seen in the history of influenza, Asiatic cholera, cerebrospinal meningitis, poliomyelitis and diphtheria. Here the fact which confronts us is that a disease which has previously been confined to certain geographic limits suddenly passes beyond them, as cholera repeatedly did in the last century; or that a disease like diphtheria or poliomyelitis, which is


sons stated, it may be a factor of much greater importance than would at first appear. But even if we can thus reasonably account for the decline of epidemics, this leaves unanswered the question of their origin. What is the cause of the initial increase in prevalence of a disease, which constitutes the beginning of an epidemic? Here, I think the variations which occur more or less regularly year after year, in the prevalence of many endemic diseases, must perhaps be distinguished from the occasional and extraordinary outbreaks which constitute epidemics in the older historic sense. The regularly recurrent seasonal epidemics of such diseases as typhoid fever, infantile diarrhea, malaria, pneumonia, diphtheria, etc., are clearly related in some way to changes in the seasonal cycle. We cannot say generally what the effect of season as such may be in starting an epidemic except that it must be either to increase the infectivity of the specific microorganism, to lower the resistance of the population, or to increase the rate of contact or exposure. In certain particular cases we may well believe that the first influence is an increase in the rate of transfer of the specific agent from infected individuals to others. This seems to afford an adequate explanation of the inception of seasonal epidemics of certain insect-borne diseases such as malaria, yellow fever and plague (in rats). Again, the closer contact which presumably results from the opening of schools in the autumn and from the tendency of people to stay more indoors in cold weather has often been suggested as the explanation of the increased autumn and winter prevalence of diphtheria, pneumonia and other diseases, though I doubt that the explanation is adequate. It is equally possible, and perhaps equally probable that there may be seasonal changes in susceptibility to infection. However, whether the primary impulse to an increased prevalence of an endemic

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in susceptibility; and I do not know of any argument in favor of this doctrine except that we are unable to directly disprove its hypothesis. It is, moreover, difficult to conceive of a cosmic influence passing from country to country, progressively breaking down the barriers of resistance in such a way as to account for the observed distributions of epidemics in time and space. It is, of course, readily conceivable that a virus which lowered resistance to the disease in question might spread in this way. But a lowering of resistance brought about in this way would be attributable really to one of the microbial factors concerned. It would not represent a primary change in the host. It seems much more probable that epidemics of this class owe their origin to a change in the properties of the specific virus itself, which somehow acquires greater power to establish infection, or greater power to produce disease or both. True, it has not been clearly established that such changes in virulence are actually associated with the development of epidemics. On the contrary, epidemic and endemic strains have usually been found to be identical. Nevertheless, we have sufficient proof that pathogenic microorganisms have a degree of variability—different in different organisms, so such an assumption in explanation of this kind of epidemic is not altogether groundless. Moreover, the facts which we know about these epidemics, that they frequently develop, first as localized outbreaks here and there, then as greater outbreaks; their progressive spread; the severity of clinical types—all these are just the result which we would expect to follow from an increased virulence of the specific organism. Finally, if we reject this explanation, we leave no other that has equally good support from present knowledge. In conclusion it seems to me that, considering all kinds of epidemics, the regularly recurrent waves of endemic preva-


already geographically widespread, suddenly becomes more prevalent; or that a disease like epidemic influenza or lethargic encephalitis emerges from obscurity. Here we have too, the definite picture of progressive spread from one area to another —often irregular, but evident as a wide extension in space. Often, too, the disease, as it occurs in such an epidemic, has distinctive clinical features, especially an increased malignity; if it is an endemic disease it may disregard its usual seasonal limitations; and, as has happened in diphtheria, poliomyelitis and other diseases, it may for years maintain a general level of prevalence much higher than it previously had. Such a profound change in the manifestations of a disease indicates a corresponding change in the balance of the factors which have previously kept it at a quite different level of equilibrium. If our conceptions of infection are fundamentally sound this change must have been either a great increase in the opportunities for transfer of the specific infective agent from host to host, a general lowering of host resistance to the infection, an increase in the specific disease-producing powers of the microorganism, or some combination of these. As to the first of these possibilities we can seldom if ever point to any particular condition of human intercourse or of weather which would account for such an increase in opportunities for spread of the particular disease in question, without correspondingly increasing the opportunities for spread of various others. As to the second possibility, that the primary factor in the origin of such an epidemic is a general lowering of host resistance, this is essentially a return to the ancient doctrine of an "epidemic constitution." The fact is that we are unable to point to any particular change in environment which might be supposed to bring about any such great and general increase


in certain cases, quite important variations in the properties of specific microorganisms. The known differences between different diseases as regards variability of the specific microorganism, its period of survival in the individual host, the ratio of subclinical to clinical infections, the character and distribution of natural host resistance, the degree and durability of acquired immunity, and the kind of conditions necessary for conveyance from host to host—all these are sufficient to account for the widest differences in periodicity and range of epidemics in different diseases; and we can hardly expect to discover any simple and general law which will take account of all these variables.


lence, local outbreaks, and the rarer widespreading epidemics of history, we may reasonably believe that they are governed to some extent by the general law that infection tends to increase progressively, due to multiplication of foci; and that it is progressively checked by the resultant decrease in susceptibles. due to specific immunizations and deaths in the host population. But I do not think we need suppose that these are the sole forces, or that they are necessarily the principal ones, or that they are of the same relative importance in all diseases, or in all times and places. On the contrary, I think we are obliged to recognize as possible and probable influences, changes in the habits affecting rates of exposure, perhaps seasonal and other variations in host susceptibility, and,

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