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Is tuberculosis to be regarded from the ætiological standpoint as an acute disease of childhood?
IS TUBERCULOSIS TO BE REGARDED FROM THE JETIOLOGICAL STANDPOINT AS AN ACUTE DISEASE OF CHILDHOOD? By Dr. Kr. F.
ANDVORD
(Christiania).
!\{y reason for attempting to ascertain at which period in life infection with tuberculosis, taken as a whole, occurs, is that I am convinced it is of supreme importance in combating tuberculosis to shed as much light as possible on this problem. While I shall attempt to be as strictly objective as possible, it is inevitable that this paper should reflect the point of view from which I see this problem. Let me at once, in order to avoid-any misconception, point out that the following tables and conclusions refer almost exclusively to populations in which tuberculosis has existed for g,enerations, and, secondly, that I have confined myself to the main outhnes, and only to the salient features of the course and occurrence of tuberculosis. My chief object in this paper is to correlate certain characteristic features of the mortality and morbidity of tuberculosis with
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the question of the age at which tuberculosis occurs, and to compare the results with recent epidemiological findings. I propose presenting my subject to a certain extent graphically, as this method is most illustrative and least tedious. But as I shall deviate from conventional graphic methods I must explain my system. Instead of the usual curves, showing rates per thousand, I have put actual, not relative, figures into a frame which I shall call a " population frame" as this will enable me, without difficulty, directly to compare one age period with another. 7
98
TUBERCLE
[December. 1921
Chart I shows such a. .. frame U holding a. hypothetical town or country population (stationary, i.e., without emigrants) of 200,000 persons, 53,000 of whom are under 15 years and 147,000 are adults. These respective figures are calculated from the tables of the Statistical Office for Christiania. for the year 1895, and, as the chart shows, the number of persons living within the" frame" diminishes gradually frOIn one age period to another with the curve of the total mortality. It is this decline of the population on which we must particularly focus attention when we wish to appreciate the significance of calculations expressed in fractions of a thousand. Thus, while 10 per thousand in the first year of life in the above population is equivalent to 50 persons, 10 per thousa.nd in the age period between 60 and 70 is equivalent only to 16-17 persons. Into such a " frame," i.e.• superimposed directly on the living population, I now propose to insert actual values, and I shall assume,. as a common factor, a tuberculosis mortality of three per thousand which ca,~ well be regarded as a suitable average value.
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n.-The monthly curve of tuberculosis, in this cese about 3 per thou.and (about 600 out of the 200,000 indivldua18ln the" population frame "],
In Chart· II we thus get a. total impression showing the relation between the population as a. whole and the mortality curve of tuberculosis which includes the 600 deaths which are equivalent to three per thousand and 150 of which we assume to occur 'before the fifteenth year, while 450 occur after this age. As, however. the details are insufficiently prominent on this scale, I have represented the same .curve on a. larger scale in Chart III. This shows the two highest waves, the greatest of which corresponds to the first two years of life, while the lesser. secondary waVe reaches its maximum between the ages 30 and 40. This second maximutn can, however, occur ten years earlier or ten to fifteen years later. Between these two highest levels there is an absolute minimum level at which the tuberculosis mortality coincides roughly with the tenth year. I would draw special attention to the' characteristic nature of this curve and its disclosure of the high mortality during the first three or four years of
December, Hl21]
TUDERCULOSIS : ACUTE DisEASE OF CIULDUOOD?
99
life, when, notably in the first year, it is at least twice as great as in any other later age ·period. Note G. Hedren's investigations in 1\1l2. Let us now get a clear conception of the clinical characteristics of tuberculosis during these first years oC life. Professor Medin insists that tuberculosis in infancy runs, as a rule, a course exactly like that of an acute infectious disease, and that it therefore often occurs in children's hospitals in purely epidemic forms. Professor Harbitz, in his work .. 'I'nberkulosens ' Former og Lokalisationer i Spoodbarnsalderen" comes to practically the same conclusion from the pathological point of view. He writes : .. At this age the disease runs a very rapid course, and with a marked tendency to generalisation-somewhat like inoculation tuberculosis in animals i in virgin soil infection is rapid and easy, and -t h e capacity shown by the bacilli for reproduction and extensive distribntion is enormous." It is this most characteristic tuberculosis of infancy-which I So
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Chart lII.-The morlalHy curve of tuberculosis, S per thousand, 2OO,lX:O Individua.ls600 dea.ths .
have reproduced in the most heavily shaded section of Chart III. .I t clearly shows how the disease at the close of the fourth ' to the fifth age period completes' a characteristic, sharply defined and very important phase. It now changes its form, passing into the more latent stage of scrofulatuberculosis with its comparatively small mortality due chiefly to meningitis and miliary -tuberculosis, This section, which corresponds to the middle of my curve, is after the age period 10 to 15 gradually replaced by more or .less chronic pulmonary tuberculosis which henceforth is the dominant cause of death. For the sake of comparison, two other mortality curves may be of interest. Cha.rt IVA shows the mortality curves of tuberculosis in Prussia Cor 188B and 1913. This shows the same high mortality in the first and second years; it has on the whole fallen considera.bly, not least in the latest age periods. Thus, in '1918, we find the greatest number of deaths
100
[December, 1921
TUBEUCLE
among adults about the age of 30, whereas in 1888 it was about 60 Chart V. which refers to Stockholm, shows.tbe same ptomincnt features, but in this ease the decline of mortality in the age period, 15 to 40, is
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strikingly small, whereas this decline in the first years of life is consider.. able. We shall come back to this point presently.
December, 1921]
TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
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Before I leave this particular subject, let me point out how misleading a curve may be when it represents a fraction of a thousand, at any rate when this method is applied to a disease, such as tuberculosis, which follows mankind from cradle to grave. In Chart IVn we find the same mortality curves calculated in fractions of a. thousand (Cornet) as those just shown for Prussia. Note, however, in this case the figures are absolute. One could hardly gather from these per thousand curves that, as IS really the case, more persons die from tuberculosis in the first and second years of life than in any subsequent age period. When one reflects that, even on a per thousand scale, the tuberculosis mortality in the first and second years usually reaches values greater than in any subsequent period, and when one at the same time remembers how much more often tuberculosis is overlooked in infancy than later in life, then first does the true significance of the enormous tuberculosis mortality in infancy become patent. $(J(;b
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There is yet another point concerning the tuberculosis mortality on which, in this connection, I would focus attention. It is the remarkable constancy which the mortality from pulmonary tuberculosis shows from year to year among populations of a comparatively stationary character. This mortality may, of course, gradually rise or fall from one decade to another, but such changes are brought about by, as a rule, comparatively minute oscillations. At first, when the disease is comparatively recent and both adults and children are a~tacked by acute, primary infections, the mortality may naturally be very Irregular: but as 800n as the disease has become endemic, the mortality becomes remarkably constant, not only taken as a whole, but also in the different age periods. This regularity, amounting almost to a law of nature, must, it seems to me, depend on a more fundamental cause than a more or less accidental infection, and it seems to point to the pulmonary tuberculosis of adult
102
[December, 1921
TUBERCLE
life. being a, secondary process only, the fruits, let us say, of an earlier sowing. To illustrate this point which seems to me to have been inadequately noticed, I have recorded in Chart VI the actual number of deaths from pulmonary tuberculosis in Upsala in the years 1894 to 1917, and in Chart VII-from one of my earlier publications-I have recorded, the deaths from pulmonary tuberculosis in Trondbjem in the years 1883 to 1891, in the three decades between the ages 20 to 50. In both cases we OHART VI.-NUMBER OF DEATHS FROM PULMONARY TUBERCULOSIS IN UPSALA IN 1894 TO 1917.
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44 39 45 51 45 39 51 46 44 50 45 51
1906 1907 1908 1909 1910 1911 1912 1913 1914 1915 1916 1917
34 67 42 45
48 53 53 56 63 45 44 44
As we see, they were seldom under 44 and just as seldom over 53. Average 48. OHART VII.-NuMB11lR OF DEATHS FROM PULMONARY TURERCULOSIS IN TRONDH.JEIII IN THE PERIOD 1883·1891 INCLUSIVE, AT THE VARIOUS AGE PERIODS.
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see.the same regularity, even in the shorter periods, manifested in a most striking fashion. p The fact .is well worth notice that variations from one year to another amounting to ever one-third per tlwusand are exceptional, To judge by the mortality curve the disease would seem to develop from stage to stage through the different age periods almost like an inoculation tuberculosis which runs a more or less chronic course, Let us now turn to the tuberculosis 71Wrbiditywhich during the past decades has been closelystudied clinically, pathologically, by v, Pirquet's tests and, not least, by the so-called mass examinations.
December, 1921]
TUBERCULOSIS: ACU'fE DISEASE OF CHILDHOOD?
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Confining ourselves to the last named, the most thorough of which come from Sweden (Neander and others) and from Finland (Tennberg, Dreijer and others), we find as their chief lesson that a.more or less welldefined pulmonary tuberculosis can be clinically demonstrated in not a few individuals, the proportion varying from about 0' 5 to 9 per cent; of the - population in different countries and _districts. ,,As ,a rule, the, greatest number of actual cases are to be found about the age of 30, the figures ranging.from 2 per cent. to 10-12 per cent. , I, should, therefore, be on the safe side when I estimate the clinically demonstrable morbidity from pulmonary tuberculosis at an average of 2'5 per cent. of. the population, with a maximum of,at least 5 per cent. for the age of 30. Adapting this calculation to my" population frame," we should find among my 200,000, persons .at least 5,000 living with manifest, clinically demonstrable pulmonary tuberculosis. (See Chart VIII.) [»
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CHART VIlI.-The tuberculosis morbidity in 1Io population of 200,000 with .. tuberculosis death rate of S per thousand.": (a) The lowest curve [shaded in) includes about 5,000 individull.1l1 (25 per cent.) with pulmonary tuberculosis demonstrated clinically by mass examinations. (b) The next lowest curve includes about 1l,OCO adults with manifest and virulent hberculosis demonstrated" by· pathological' investigations (Bang-Harbitz). '. (e) The area, indicated thus,;; (~~ includes about 2,000 children (a.bout 5'5 per cent.] with clinically definite glandular tuberculosis: traced upwards tbis area merges into the lighter and , more benign forms ::;. (d) The curve farthest to the left - • - - - is .. hypothetical" and is based on the researches of Pollack and Bergman. -2 (e) The uppermost curve (fine line) includes the perfectly ~enign glandular infeetiDn which gradually becomes obsolete and avirulent.
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In. p~ssing, it may. be ~o~ed :hat Dr,eijer, in the course of his investigations III the Rantasalml district of Finland, found the greatest absolute number .of persons suffering from demonstrable pulmonary tuberculosis at the early age of .10 to 15, and be, suggested that this fact, might be explained on the assumption that the disease was on the increase in the district investigated. If we now turn to pathological research, and continue to confine our-
104
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[December, 1921
selves to adult life, we find two interesting works in Scandinavia froIU which we can draw certain conclusions. One of these is by Professor Bang of Copenhagen, and dates from 1901. I" The Coincidence of Tuberculosis with Various Other Diseases Illustrated by 6,000 Necropsies."} The other is by Professor Harbitz in 1905. Professor Bang found that II undoubtedly recent, definitely macroscopic" tuberculosis could be demonstrated as an accidental finding in 8! per cent. of persons who had died from accidents or other diseases. And Professor Harbitz found among 1,300 necropsies co macroscopic, virulent and progressive tuberculosis as an accidental discovery" in about 7 t per cent. As both the curves thus obtained deal with practically the same population, about 8 per cent., with a maximum of about 13 per cent. at theage of 17 to 18, and as they in other respects coincide remarkably well, L have fused the two curves into one in Chart VIn for the sake of clearness. To judge by these investigations, my hypothetical population of 200,000 should include at least 11,000 persons with virulent manifest tuberculosis in a more or less latent form. In conjunction with these most interesting pathological investigations, I would observe that the tuberculosis mortality in the same period both in Copenhagen and Christiania was practically the same, being about 3'5 per thousand, i.e., about the same as that assumed in my "population frame." Further, both these investigators conclude, quite independently or each other, that as many as 13 per cent. in the age period 17 to 18i.e., at least 400 individuals-are infected seriously with tuberculosis. And I would draw special attention to the conclusion that this number, 400, tallies remarkably closely with the number of consumptives, about 425, who, in the age period under consideration, we know will die of thedisease. For I have assumed that of the total of 600 tuberculosis deaths (three per thousand) 150 occur before, and 450 occur after the age of 15. From this point of view, therefore, there should be no difficulty in assuming that a large proportion of our consumptives are recruited by re-auto-infection from these cases of manifest and, so it would seem, progressive disease of a serious character. It is the frequency and significance of these virulent processes which several writers, including Hart, appear to overlook. He, in fa.ct, concentrates attention only on the small, more or less obsolete foci, and argues-quite rightly-that "these foci can hardly be regarded as the sources of the more massive endogenous reinfections which, it must be assumed, occur if-as he denies-most cases of phthisis are due to infection in childhood. To avoid misunderstanding, let me make it perfectly clear that this manifest, macroscopic and virulent tuberculosis has nothing to do with the numerous cases of usually inactive and more or less obsolete forms of tuberculosis to which I shall come back later. If we now turn to the years of childhood, and particularly to the later years of childhood, and attempt to estimate the morbidity from tuber: eulosis in this age period, we are confronted with difficulties because the disease is fairly polymorphous and ill-defined. On the one side there is the pure scrofulo-tuberculosis with all its different shades, among which glandular tuberculosis, when definitely recognisable, is one of the most
December, 1921]
TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
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common and characteristic manifestations. On the other side, we have pulmonary disease, habitus phtltisicus and other clinical symptoms referable to Grancher's "pre.tuberculous stage." To deal first with the frequency of pulmonars] tuberculosis at this ' age, we cannot, from the clinical standpoint and on the evidence of mass examinations, put this higher than 1 per cent. of the population at the age of 10. (See Chart VIII.) Next we come to glandular tuberculosis, the frequency of which varies not a little according to different authorities. Naturally it is difficult to decide, and it is often a matter of opinion whether a disease of the lymphatic glands is undoubtedly tuberculous or not. Estimates vary from 2 to 20-30 per cent. (note Fr6lich's interesting investigations in Christiania). But if we confine ourselves to the definitely demonstrable tuberculosis of the glands, the estimates range from about 5 to 7 per cent. and seldom exceed 10 to 12 per cent. Of the 15,000 , school children .. carefully examined" in 1908 in Stockholm, 11 to 12 per cent. were found to suffer from this condition. To [udge by the above, it would not be excessive if I fitted into my .. population frame" pure glandular tuberculosis estimated at 51 per cent, and the clinicaUy manifest tuberculosis-all forms included-at 8 to 10 per cent., with a maximum of 12 to 13 per cent., at the age of' 10. (See Chart VIII.) But in addition to these 8 to'10 per cent. with manifest, unquestionable tu?erculosis of a serious character as a rule, we must at this age--'-late chJJdhood-also take into account a not inconsiderable number of slight forms of scrofulo-tuberculosis in which the clinical diagnosis is difficult and uncertain. This group marks the transition from definite scrofulotuberculosis on the one hand; to the perfectly benign infection which I now come to at last. This perfectly benign and 'usually perfectly latent glandular infection begins largely, as is well known, in infancy and ,the majority of a' population is often infected before the completion of the 'first decade. ' This. infection can, as a rule, be demonstrated during life by v. Pirquet's test and, in contradistinction to the clinically manifest glandular tuberculosis, this condition .has gradually begun to be obsolete and inactive from as' early as the middle of ,the first decade. It has also, in my opinion, the ability to confer immunity ev~n though this may perhaps be only relative. In Chart VIII I have showed this benign infection to 'exist in about' 70 per cent. of persons at the age of 15 ; this seems to me a fair intermediate estimate, the figures of other writers varying from 30 to 95-100 per cent. While it has been fairly easy to form an estimate of the tuberculosis morbidity back to the fourth and. fifth years, greater difficulty has been experienced with regard to this morbidity in early infancy. Important light was thrown on this subject in 1911 by Pollack's interesting' investigations into the fate of children living in tuberculous surroundings. It would seem tbat the reaction of the child to tuberculous iufection differs profoundly according as it occurs before'or after the fifth year. 11e found that children infected during the first years of life showed, as a rule, signs of clinically manifeet tuberculosis, usually of a serious character. Onthe other hand, the children, who could be assumed to have been infected 'later
106
TUBEROLE
[December, 1921
in life, showed no clinical symptom, infection being indicated only by a positive v. Pirquet test. It should be noted in passing that Pollack could arrive at no definite conclusion with regard to adult life as he had not followed the fate of the children concerned beyond the fifteenth year. Great and renewed interest attach to these remarkable observations by Pollack in the light of a recent (1919) important and very thorough work by Bergman, .. The Exposure of Children to Tuberculous Infect jon." He has not only confirmed Pollack's findings, but has, also greatly -enhanead their significance. With searching thoroughness Bergman has investigated as many as 233 tuberculous families, including 1,004 children, and he has followed everyone of these children from. birth onwards, and in many cases (at least. a third) he has traced them jar: up into adult, life. His conclusions with regard to the significance of tuberculous infection in childhood are briefly these: Everyone of the persons who had died of tuberculosis in childhood or adult life, and nine-tenths of those who were still alive but suffered from clinically demonstrable tuberculosis had been -exposed, to infection within the first four years of life. On the other hand, not, a single death from tuberculosis could be found among those whose exposure to, tuberculous infection had been deferred till aftel: the fourth year. Further, not one case, of clinically demonstrable tuberculosia in any form could be found among those whose exposure to infection had been deferred till after the seventh year of life. Of 6ga persons.who, in thefirst year of life, had lived in tuberculous surroundings, 277 or 40 per cent. had either died, of tuberculosis or showed persistence of the disease in a. clinically demonstrable form. These most instructive observations by Pollack and Bergman. undoubtedly will have a far-reaching influence on our prophylactic measures against tuberculosis, for they show, with transcendent clearness, what a. 'sinister influence on the, child for all the rest of its life exposure to serious infection within the first four or five years may have: far different is its lot, if such exposure is deferred to a later period in life. These observations tell us plainly, in so many words, that the primary. infection of cases of clinically manifest, usually fatal tuberculosis, at any rate in Ute majority oj cases, is traceable to the first years of life. If, now, I take. this majority to be 90 per cent., then 540 of my GOO bypothetical oases of fatal tuberculosis have received their primary infec'tion during their. three or four first years of life, and in Chart VIII I have indicated these cases in the dotted line farthest to the left. This shows the presumptive morbidiuj during the first period of childhood. These 540 represent, as we see, only about 13 per cent. .of the age periods under review, and barely two-thirdsot the cases which, from the pathological standpoint, can be regarded as being infected in the same age period. The remaining 10. per cent., i.e. 60 out of the 600 fatal cases of tuberculosis, would cover; in my opinion, the sporadic cases of primary 'infection which .undoubtedlyoccur throughout the whole of life, perhaps late in life oftener than at other ages. On the strength of these different .investigations into the morbidity of tuberculosis, we may-assume that, as an average mean 6 to 7 percent of ihe population harbours a manifest, virulent, undoubtedly active tubercu_
December, HJ21]
TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
107
losis i n a more or less latent jorm-a condit ion which ill a great proportion .oj cases is clinically demonstrable . Thus, from this point of view, there
is nothing to prevent our putting the average duration of the disease from infection to death at 15 to 20 years. These investigations with regard to mortality and morbidity, the significance of exposure to infection during childhood, &c., cannot be seen in true perspective till we compare them with the knowledge recently gained by clinical and pa.thological research with regard to the latency and duration of the disease. Even though the clinical evidence and history of a case cannot, of course, be as clear and straightCorward as desirable, most writers are agreed that, in 20 to 50 per cent., the primary infection can be referred back to childhood, and in this connection I would draw special attention to Arvid Wallgren's and 'I'illisch's well-known investigations. At any rate it must be permissible also from the clinical point of view, in many cases to assume the existence of a period of many years' latency between childhood and the outbreak of the disease later in life. In this connection it is of great interest to draw attention to' the fact that the chief physician for Leprosy ill Norway, Dr. Lie at Bergen, even several years ago has arrived at similar results regarding leprosy. In his work" Statistisches tiber Lepra," tArehi» fur Dermai. 1t1ld Syphilis-Band ex, 1911), he writes; page 780: "As shown in the above statistics, the greatest number or cases break out in the decennial period from 15 to 25 years of age. From this cannot be concluded that these persons have caught the infection in this same period. In the majority of cases the infection has taken place many years ago; how long, can in most cases not be easily ascertained. In my opinion a. latency of ten years is no exception, on the contrary, seems to be the rule." And on page 783 he writes, founding his opinion on the above mentione-l statistics and on series of epidemiologically carefully examined cases of leprosy, that in almost one half of the cases the infection .. had taken place before the age of 15 to 25 years. And if this is the case there is nothing particularly striking about the fact that lit leper more rarely carries the infection to his conjugal partner than to his children, as has been shown above." "We have, however, in my judgment, obtained a clear view in this matter only since Harbitz in 1917 published bis investigations into II The Relation of Glandular to Pulmonary- Tuberculosis." He fonnd that in not less than 18 per cent. of a series of necropsies on adult cases of pulmonary tuberculosis, it was possible to demonstrate and follow the continuity of the disease from ' the lymphatic tuberculosis of childhood to the pulmonary. tuberculosis of adult life; he argued that it was possible for the virulence of these old foci of disease to remain unchanged for a long period. Owing to these new and important observations .we are DO longer II up in the air," but are working on a. secure foundation when we assume that a direct connection between the various stages of tuberculosis can be established through more or less latent forms of the disease. These and earl ier observations make it, in my upinion, mucb more natural to believe in an endogenous auto-infection than ' in an exogenous re-infection. See also recent investigations by de 10. Camp, Roepke and Leschke.
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TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
There is yet another most important observation which also seems to indicate that most cases of pulmonary tuberculosis in adult -life represent late processes. I refer to the not rare instances in recent times of measures against tuberculosis reducing both the mortality and morbidity first. and to the greatest extent, in childhood. Only by slow degrees is the tuberculosis mortality in adult life influenced by prophylactic measures. Thus, in the provincial towns in Denmark in the period 1886 to 1910, the decline in the tuberculosis mortality was at least twice as great in the age o to 15, as it was between 15 to 55. A somewhat similar observation has also been made in Norway by the chief physician for tuberculosis, Dr. Heitmann, see Chart IX, and according to Lindhagen's account the same state of affairs has been observed in Stockholm.
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CHART X.-The morbidity returns for Kronoby IFinla.nd) in 1Il09 (the uppermost) and in 1919 (the lowest) converted from Dr. Tenn berg to my "population frame" of 200,000 individua.ls. After ten years of dlepensary work a fall from 6'!l per cent. to 2'8 per cent. (only pulmona.ry tuberculosis).
Most striking observations in this connection have recently been made by Tennberg in Kronoby (Finland) with regard to morbidity. In HJ09 this well-known tuberculosis specialist carried out a wholesale examination of the population in this district where, in the same year, he organised a system of dispensaries. In 1919, i.e., ten years later, he undertook a similar wholesale survey, after his colleague, T. Dreijer, had for the past aeven years conducted the dispensaries with singular energy and skill. and had impressed on the population the value of his campaign, To make the results of these investigations clear, I have depicted them graphically, fittiJlg Tennberg's figures into my "population Irame.' In Chart X we find the morbidity curves shown so as to compare directlv with the whole of the living population, and in Chnrt XI the scale fa enlarged so BS to bring out more clearly the differences between the curves.
110
TUBERCLE
[December, 1921
In the course of these ten years we find that the total number of caSes of pulmonary tuberculosis has dwindled to a. third of what it was, and here. indeed, we have an encouraging proof of what a systematically planned campaign againsttuberculosia can achieve. We find that it is during the first decade that the decline is most rapid, the number of cases of pulmonary tuberculosis in this age period in 1919 being not evena quarter of what it was in 1909; according to my figures the decline is from 112 to 25. In the, second decade the difference is not quite so marked but is still considerable, the number being reduced to less than a. third; it is reduced to a' half in the age period 20, to 30. In the two decades 30 to 50 the decline is hardly perceptible, but in the later age periods there is again a. considerable declinein the morbidity.
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Here we can read in Nature's book with all clearness that it is chiefly in the early years of childhood that we may expect to find 'any direct, effect from tuberculosis prophylaxis. On the other hand, it would seem as if the disease in ad uIt life can be influenced only little by little, and indirectly in this way that year by year fewer and fewer infected persons reach: the older age periods. With regard to the higher ages, from 1>5 to 60 onwards, matters may perhaps be different as it is conceivable' that susceptibility to infection has again become greater, and prophylaxis can prove more directly effective at this stage: It is important always to remember that hygienic and economic factors can by themselves prevent or promote the outbreak and manifestation 'of tuberculosis. Finally, to make a control test of the whole matter, it would be or interest to reverse my calculations and try to find out how the morbiditv
December,1921]
111
TUBEUCULOSIS: ACUTE DISEASE OF CHILDHOOD?
curve would appear if practically all the fatal cases of tuberculosis say, 90 per cent.-i.e., in my scheme 540 cases-had begun in the first three or four years of life. In Chart Xl I I have drawn such a curve, fitting it into my "population frame," and, as it sbows, I have taken a hypothetical morbidity which begins with 540 severely infected infants-a number that gradually dwindles with the tuberculosis mortality throughout life. If I now, as in Chart XIII, which shows these curves on a larger scale, compare the above hypothetical curve with those familiar to us from the findings of pathology and mass examinations, &c., we' are confronted by a striking similarity in many respects. Both the height and the course of these curves are similar, my hypothetical curve running sometimes a JOOO
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CHART
little under, sometimes over the Bang-Harbitz curve. Both curves deal with the same 7" to 8 per cent. of the population, and there are several other points of similarity t.o which I would call attention; Some I have already touched on. Possibly the 13 per cent. at the age of 10 is too high, but, acc?rding to what I hav~ said e~rl.ier, this figure should represent; WIth fair accuracy, the definitely clinically demonstrable tuberculosis of late childhood, all forms included, and when we assume that the total mortality from tuberculosis is three per thousand. We now come to the age period ,15-20 ; ·a~ this most important stage of transition from glandular tuberculosis to disease of the other organs we find that both curves attain practically the same height, i.e., they reach 12 to 13 per cent. with about 400 persons, Thus, we see how, judged by the evidence of pathological investigations, these 400 persons
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TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
113
may be assumed to suffer from a manifest and virulent tuberculosis; while, on the other hand, the same 400 persons are predestined, according to my calculation, sooner or later to die of tuberculosis. The same conformity of the curves continues to be striking at the age of 40, when they both go up to 7 per cent., which corresponds to about 200 persons in the respective age groups. In a population of 200,000 with a hypothetical tuberculosis mortality of 3 per 1,000, we thus find 2,682 persons belonging to the age period of 40, of whom 200 may be taken to be suffering from manifest pulmonary tuberculosis as judged by the clinical and the pathological standard. We also see that these 200 correspond very closely to 90 per cent. of that number which, after this age period, die of tuberculosis. Beside the above-mentioned similarities, there is also a slight difference which may possibly be of profound significance. I refer here to the somewhat inexplicable secondary rise of the morbidity about the Sixties which we find both in the Bang-Harbitz curve and also, partly, in the curve of pulmonary tuberculosis obtained by clinical, mass or wholesale exa.minations. It is conceivable that, as already mentioned, we have here. t~ do with primary infections of comparatively recent ?ate, ~nd tha~ It IS principally this age period to which we must trace infections which do not occur in childhood. There is yet another consideration which, though of an indirect character, may be cited in support of the view that most cases of phthisis developed the first phase of their disease in the first years of life. I refer to .the fact that. the" number of children, yearly born in surroundings seriously contamillated with tuberculosis, seems to bear a. definite relation to the number of the tuberculous patients who yearly die of the disease. We ar~ h~re confronted with a certain type of vicious circle. It IS difficult to conceive of the century-old theory as to the heredity of tuberculosis being so firmly established, but for the fact that the disease was somehow or other found to be so intimately tied to the family and home. As in the overwhelming majority of cases the disease is not congenital, we have no alternative explanation to this state of affairs other than that which refers the time of infection in the majority of cases to childhood and the home. In Chart XIV I have given a graphic presentation of the morbidity from tuberculosis, as I view it, in a district where the disease is definitely endemic. In this chart the crosses (X) indicate the time of primary infection which is taken to occur principally in childhood, and it is assumed that the younger the child, the more severe the infection. A certain number of primary infections (10 to 15 per cent.) are assumed to occur during adult life, notably about the sixties, and are also marked with a. cross. The uihole of the lower .portion of this morbidity curve includes the manifest, virulent and more progressive forms, and represents about 7 per cent. of the population; they are, to a certain extent,. clinically demonstrable either in the form of pulmonary disease (the darkest area) or in the form of scrofulo-tuberculous processes (the dark area in the period of late childhood) ; the remaining, somewhat lighter area represents 8
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TUDERCULOSIS: ACUTE DISEASE OF CHILDIIOOD?
115
the clinically more or less latent, but still virulent and serious forms of the disease. All the rest and the" upper portion of the curve (about 60 per cent.) includes. on the other hand, the great mass of usually quite benign infections which gradually become obsolete and avirulent and which, in my opinion, confer a certain, though perhaps only relative, immunity. Between these two components of the morbidity, the virulent and usually progressive processes on the one hand, and the slight and usually perfectly benign processes on the other, there may be assumed to be a comparatively narrow intermediate belt . I! we now view the subject as a whole, taking into account the characteristic course of the disease, its latency and , not least, the almost paradoxical state of affairs observed with regard to exposure to infection and prophylaxis in childhood as compared with adult life; and when we fuse these observations with our otber clinical and statistical findings, we cannot. in my opinion, come to any other conclusion than that most of our consumptives-let us say 80 to 00 per cent.-must already have contracted their first infection in childhood, and that the subsequent occurrence and manifestation oj the disease later in life must depend principally upon endogenous, re-auio-infections. Through these inquiries we also arrive nearly at the same conclusions, which I pronounced as early as 1895 in my work, .. Inquiries on the Frequency of Tuberculosis in Norway." In my conclusions, page 36, I wrote as follows: .. Dearing in mind the latent period, there are compelling reasons why we should fix as the time of infection the infantile years for the great majority of the tuberculous diseases , and the foetal period only for an inconsiderable number of cases." But, as I said in my introduction, these conclusions refer ' almost exclusively to populations in whick tuberculosis has raged for generations. For I do not doubt that in many of our more isolated districts with a scattered population, and where the disease has been comparatively lately introduced, its behaviour is of ·quite another character, and we shall certainly find far many more cases of acute and active primary infections among both adults and adolescents. These are my views; they may, of course, not coincide with others'; but it is at all events of the greatest importance at ·the earliest possible date to secure.the complete solution of this problem, for great issues are involved. To my mind the most effective prophylaxis would be the protection by every possible means of children. notably those in the first three or four years of life, from the more severe infections, either by removing the source of infection from the children's neighbourhood, or, if possible, by the isolation of the children. Secondly, we must seek further knowledge as to the immunity which I believe glandular infection is able to .confer, paying special attention to the relation of this problem to bovine tuberculosis and the more benign forms of pulmonary tuberculosis. On these lines it is possible that we might find some sort of va.ccine of practical benefit. Thirdly, it is essential that we obtain .more accurate knowledge as to the stages which precede pulmonary tuberculosis, particularly in late childhood and adolescence, so that we may know how to diagnose and treat the disease before it has manifested itself as full-blown pulmonary
116
TUBERCLE
[December, 1921
tuberculosis. For my own part I regard it as at least as important to attempt to minimize or remove predisposing causes, and thus possibly to prevent re-auto-infection, as it is to attempt to protect the individual from the danger of infection by his surroundings. Fourthly, and lastly, it is of importance that, as in the past, we train our consumptives to be as careful as possible with their expectoration particularly in relation to young children, but also, of course, in relatio~ to adults. In addition to the excellent bibliography appended to Bergman's work I would add the following references, of more recent date, bearing on th~ subject under discussion. IIARBITZ. "Tuberkulosens Former og Lokalisationer i Speedbamealderen," NOT8k Magazin for Laqevidenekoben, 1913, No.!. Idem. .. Om Lymfeglandeltuberkulosen og Dens Sammenbmng med Lunge_ tuberkulosen," Videnskabsselskabets'skrf, 1916, No. H. LINDA GEN. "Stockbolms Tuberkulosmortll.litet under de sena.ste Decennierne," Hygiea, Bd. 80, 1918. Idem. "Undersokelser over Livsvarigheten av 'l'reringssyke i Norge," !:Versk Magazin for Lagevidenskaben, 1906. No.4. DIREK10K KJ./ER. II Livs- og Dodstabeller for det Norske Folk efter Erfa.ringer fro. Tiaaret," 1882.1891. SCHEPPELEIiN. II Meddelelser fro. Kystbospitalet paa Re(snoos 1875·1890." VEJE. II Studier over Barnetuherkulosen i Danmark, 1915," Doktora.vba.ndling Kjobenbavn. ' CONSTANTIN TENNBERG. "ResultaLet av etL 10.Arigt ArbeLa fur Tuberkulosens Beksmpande i Kronoby Socken," Einska Liikaresiillskapets HalldlingaT Bd, lxi, September-October, 1919. ' DRElJER'. II Lung- og Korteltuberkulosens Forekomst i Rantasalmi Socken," Helsingfors, 1911. v. KHlEMER. .. Tuberkulos Infektion och Tuberkul~s Sjukdom bland Be(olkningen i en Osterbottnisk Kustsccken," llelsingfors, 1915. THERMAN. II Lungtuberkulosen has Arbetarbefolkningen i Kymmene, Kuersan., korskis och i Voikka Brukssamhallen," Helsingfors, 1917. GRANCHER. It Prophlaxie de la Tuberculose," Paris, 1918. HART. "Betraehtungen iiber die Entstehung der Tuberkulosen Lungeuspitaen, phthise," Zeitsch. f. Tub.• Bd, xxiii und Bd. xxiv. LESCHKE. II Die Tuberkulose im Krieg," Jliimh. med. Wochenschr.,1915. No.11. Ds LA. CAMP. II Die klinische Diagnose der Vergrosserung Entratborakaler Lympbdrusen," Med. Klin.• 1906, No.!. HEDRbl, G. II Pabbologisebe Anatomie und Infektionsweise der Tuberkulose des Kindes, besonders der Sli.uglinge," Zeitschr./. Hygiene u. Injektionskrank. heite», Bd. lsxiil, H. 2. BERGMAN, EMA.NUEL. "Barns uteiittande (or tuberkulos smitta... Akademisk avhandling, Upsala, 1918. ANDvoRD, K. F. "Studier over Tuberkulosens forekomst i Norge," NOTSk Magazin for Lagevidenskaben, No. 12. 1895.
ANDVORD
(Christiania).
!\{y reason for attempting to ascertain at which period in life infection with tuberculosis, taken as a whole, occurs, is that I am convinced it is of supreme importance in combating tuberculosis to shed as much light as possible on this problem. While I shall attempt to be as strictly objective as possible, it is inevitable that this paper should reflect the point of view from which I see this problem. Let me at once, in order to avoid-any misconception, point out that the following tables and conclusions refer almost exclusively to populations in which tuberculosis has existed for g,enerations, and, secondly, that I have confined myself to the main outhnes, and only to the salient features of the course and occurrence of tuberculosis. My chief object in this paper is to correlate certain characteristic features of the mortality and morbidity of tuberculosis with
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the question of the age at which tuberculosis occurs, and to compare the results with recent epidemiological findings. I propose presenting my subject to a certain extent graphically, as this method is most illustrative and least tedious. But as I shall deviate from conventional graphic methods I must explain my system. Instead of the usual curves, showing rates per thousand, I have put actual, not relative, figures into a frame which I shall call a " population frame" as this will enable me, without difficulty, directly to compare one age period with another. 7
98
TUBERCLE
[December. 1921
Chart I shows such a. .. frame U holding a. hypothetical town or country population (stationary, i.e., without emigrants) of 200,000 persons, 53,000 of whom are under 15 years and 147,000 are adults. These respective figures are calculated from the tables of the Statistical Office for Christiania. for the year 1895, and, as the chart shows, the number of persons living within the" frame" diminishes gradually frOIn one age period to another with the curve of the total mortality. It is this decline of the population on which we must particularly focus attention when we wish to appreciate the significance of calculations expressed in fractions of a thousand. Thus, while 10 per thousand in the first year of life in the above population is equivalent to 50 persons, 10 per thousa.nd in the age period between 60 and 70 is equivalent only to 16-17 persons. Into such a " frame," i.e.• superimposed directly on the living population, I now propose to insert actual values, and I shall assume,. as a common factor, a tuberculosis mortality of three per thousand which ca,~ well be regarded as a suitable average value.
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n.-The monthly curve of tuberculosis, in this cese about 3 per thou.and (about 600 out of the 200,000 indivldua18ln the" population frame "],
In Chart· II we thus get a. total impression showing the relation between the population as a. whole and the mortality curve of tuberculosis which includes the 600 deaths which are equivalent to three per thousand and 150 of which we assume to occur 'before the fifteenth year, while 450 occur after this age. As, however. the details are insufficiently prominent on this scale, I have represented the same .curve on a. larger scale in Chart III. This shows the two highest waves, the greatest of which corresponds to the first two years of life, while the lesser. secondary waVe reaches its maximum between the ages 30 and 40. This second maximutn can, however, occur ten years earlier or ten to fifteen years later. Between these two highest levels there is an absolute minimum level at which the tuberculosis mortality coincides roughly with the tenth year. I would draw special attention to the' characteristic nature of this curve and its disclosure of the high mortality during the first three or four years of
December, Hl21]
TUDERCULOSIS : ACUTE DisEASE OF CIULDUOOD?
99
life, when, notably in the first year, it is at least twice as great as in any other later age ·period. Note G. Hedren's investigations in 1\1l2. Let us now get a clear conception of the clinical characteristics of tuberculosis during these first years oC life. Professor Medin insists that tuberculosis in infancy runs, as a rule, a course exactly like that of an acute infectious disease, and that it therefore often occurs in children's hospitals in purely epidemic forms. Professor Harbitz, in his work .. 'I'nberkulosens ' Former og Lokalisationer i Spoodbarnsalderen" comes to practically the same conclusion from the pathological point of view. He writes : .. At this age the disease runs a very rapid course, and with a marked tendency to generalisation-somewhat like inoculation tuberculosis in animals i in virgin soil infection is rapid and easy, and -t h e capacity shown by the bacilli for reproduction and extensive distribntion is enormous." It is this most characteristic tuberculosis of infancy-which I So
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have reproduced in the most heavily shaded section of Chart III. .I t clearly shows how the disease at the close of the fourth ' to the fifth age period completes' a characteristic, sharply defined and very important phase. It now changes its form, passing into the more latent stage of scrofulatuberculosis with its comparatively small mortality due chiefly to meningitis and miliary -tuberculosis, This section, which corresponds to the middle of my curve, is after the age period 10 to 15 gradually replaced by more or .less chronic pulmonary tuberculosis which henceforth is the dominant cause of death. For the sake of comparison, two other mortality curves may be of interest. Cha.rt IVA shows the mortality curves of tuberculosis in Prussia Cor 188B and 1913. This shows the same high mortality in the first and second years; it has on the whole fallen considera.bly, not least in the latest age periods. Thus, in '1918, we find the greatest number of deaths
100
[December, 1921
TUBEUCLE
among adults about the age of 30, whereas in 1888 it was about 60 Chart V. which refers to Stockholm, shows.tbe same ptomincnt features, but in this ease the decline of mortality in the age period, 15 to 40, is
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strikingly small, whereas this decline in the first years of life is consider.. able. We shall come back to this point presently.
December, 1921]
TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
101
Before I leave this particular subject, let me point out how misleading a curve may be when it represents a fraction of a thousand, at any rate when this method is applied to a disease, such as tuberculosis, which follows mankind from cradle to grave. In Chart IVn we find the same mortality curves calculated in fractions of a. thousand (Cornet) as those just shown for Prussia. Note, however, in this case the figures are absolute. One could hardly gather from these per thousand curves that, as IS really the case, more persons die from tuberculosis in the first and second years of life than in any subsequent age period. When one reflects that, even on a per thousand scale, the tuberculosis mortality in the first and second years usually reaches values greater than in any subsequent period, and when one at the same time remembers how much more often tuberculosis is overlooked in infancy than later in life, then first does the true significance of the enormous tuberculosis mortality in infancy become patent. $(J(;b
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There is yet another point concerning the tuberculosis mortality on which, in this connection, I would focus attention. It is the remarkable constancy which the mortality from pulmonary tuberculosis shows from year to year among populations of a comparatively stationary character. This mortality may, of course, gradually rise or fall from one decade to another, but such changes are brought about by, as a rule, comparatively minute oscillations. At first, when the disease is comparatively recent and both adults and children are a~tacked by acute, primary infections, the mortality may naturally be very Irregular: but as 800n as the disease has become endemic, the mortality becomes remarkably constant, not only taken as a whole, but also in the different age periods. This regularity, amounting almost to a law of nature, must, it seems to me, depend on a more fundamental cause than a more or less accidental infection, and it seems to point to the pulmonary tuberculosis of adult
102
[December, 1921
TUBERCLE
life. being a, secondary process only, the fruits, let us say, of an earlier sowing. To illustrate this point which seems to me to have been inadequately noticed, I have recorded in Chart VI the actual number of deaths from pulmonary tuberculosis in Upsala in the years 1894 to 1917, and in Chart VII-from one of my earlier publications-I have recorded, the deaths from pulmonary tuberculosis in Trondbjem in the years 1883 to 1891, in the three decades between the ages 20 to 50. In both cases we OHART VI.-NUMBER OF DEATHS FROM PULMONARY TUBERCULOSIS IN UPSALA IN 1894 TO 1917.
Yea.r
Number
Year
Number
1894 1895 1896 1897 1898 1899 1900 1901 1902 1903 1904 1905
44 39 45 51 45 39 51 46 44 50 45 51
1906 1907 1908 1909 1910 1911 1912 1913 1914 1915 1916 1917
34 67 42 45
48 53 53 56 63 45 44 44
As we see, they were seldom under 44 and just as seldom over 53. Average 48. OHART VII.-NuMB11lR OF DEATHS FROM PULMONARY TURERCULOSIS IN TRONDH.JEIII IN THE PERIOD 1883·1891 INCLUSIVE, AT THE VARIOUS AGE PERIODS.
Year
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30-!l0
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1883 1884 1885 1886 1887 1888 1889 1890 1891
20 20 29
18 14 21 16 14 10 17 19 14
15 16 15 14 15 10 13 14 14
16
15
22
27 27 27 28 24
Average
24
see.the same regularity, even in the shorter periods, manifested in a most striking fashion. p The fact .is well worth notice that variations from one year to another amounting to ever one-third per tlwusand are exceptional, To judge by the mortality curve the disease would seem to develop from stage to stage through the different age periods almost like an inoculation tuberculosis which runs a more or less chronic course, Let us now turn to the tuberculosis 71Wrbiditywhich during the past decades has been closelystudied clinically, pathologically, by v, Pirquet's tests and, not least, by the so-called mass examinations.
December, 1921]
TUBERCULOSIS: ACU'fE DISEASE OF CHILDHOOD?
100
Confining ourselves to the last named, the most thorough of which come from Sweden (Neander and others) and from Finland (Tennberg, Dreijer and others), we find as their chief lesson that a.more or less welldefined pulmonary tuberculosis can be clinically demonstrated in not a few individuals, the proportion varying from about 0' 5 to 9 per cent; of the - population in different countries and _districts. ,,As ,a rule, the, greatest number of actual cases are to be found about the age of 30, the figures ranging.from 2 per cent. to 10-12 per cent. , I, should, therefore, be on the safe side when I estimate the clinically demonstrable morbidity from pulmonary tuberculosis at an average of 2'5 per cent. of. the population, with a maximum of,at least 5 per cent. for the age of 30. Adapting this calculation to my" population frame," we should find among my 200,000, persons .at least 5,000 living with manifest, clinically demonstrable pulmonary tuberculosis. (See Chart VIII.) [»
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CHART VIlI.-The tuberculosis morbidity in 1Io population of 200,000 with .. tuberculosis death rate of S per thousand.": (a) The lowest curve [shaded in) includes about 5,000 individull.1l1 (25 per cent.) with pulmonary tuberculosis demonstrated clinically by mass examinations. (b) The next lowest curve includes about 1l,OCO adults with manifest and virulent hberculosis demonstrated" by· pathological' investigations (Bang-Harbitz). '. (e) The area, indicated thus,;; (~~ includes about 2,000 children (a.bout 5'5 per cent.] with clinically definite glandular tuberculosis: traced upwards tbis area merges into the lighter and , more benign forms ::;. (d) The curve farthest to the left - • - - - is .. hypothetical" and is based on the researches of Pollack and Bergman. -2 (e) The uppermost curve (fine line) includes the perfectly ~enign glandular infeetiDn which gradually becomes obsolete and avirulent.
=
In. p~ssing, it may. be ~o~ed :hat Dr,eijer, in the course of his investigations III the Rantasalml district of Finland, found the greatest absolute number .of persons suffering from demonstrable pulmonary tuberculosis at the early age of .10 to 15, and be, suggested that this fact, might be explained on the assumption that the disease was on the increase in the district investigated. If we now turn to pathological research, and continue to confine our-
104
TUBERCLE
[December, 1921
selves to adult life, we find two interesting works in Scandinavia froIU which we can draw certain conclusions. One of these is by Professor Bang of Copenhagen, and dates from 1901. I" The Coincidence of Tuberculosis with Various Other Diseases Illustrated by 6,000 Necropsies."} The other is by Professor Harbitz in 1905. Professor Bang found that II undoubtedly recent, definitely macroscopic" tuberculosis could be demonstrated as an accidental finding in 8! per cent. of persons who had died from accidents or other diseases. And Professor Harbitz found among 1,300 necropsies co macroscopic, virulent and progressive tuberculosis as an accidental discovery" in about 7 t per cent. As both the curves thus obtained deal with practically the same population, about 8 per cent., with a maximum of about 13 per cent. at theage of 17 to 18, and as they in other respects coincide remarkably well, L have fused the two curves into one in Chart VIn for the sake of clearness. To judge by these investigations, my hypothetical population of 200,000 should include at least 11,000 persons with virulent manifest tuberculosis in a more or less latent form. In conjunction with these most interesting pathological investigations, I would observe that the tuberculosis mortality in the same period both in Copenhagen and Christiania was practically the same, being about 3'5 per thousand, i.e., about the same as that assumed in my "population frame." Further, both these investigators conclude, quite independently or each other, that as many as 13 per cent. in the age period 17 to 18i.e., at least 400 individuals-are infected seriously with tuberculosis. And I would draw special attention to the conclusion that this number, 400, tallies remarkably closely with the number of consumptives, about 425, who, in the age period under consideration, we know will die of thedisease. For I have assumed that of the total of 600 tuberculosis deaths (three per thousand) 150 occur before, and 450 occur after the age of 15. From this point of view, therefore, there should be no difficulty in assuming that a large proportion of our consumptives are recruited by re-auto-infection from these cases of manifest and, so it would seem, progressive disease of a serious character. It is the frequency and significance of these virulent processes which several writers, including Hart, appear to overlook. He, in fa.ct, concentrates attention only on the small, more or less obsolete foci, and argues-quite rightly-that "these foci can hardly be regarded as the sources of the more massive endogenous reinfections which, it must be assumed, occur if-as he denies-most cases of phthisis are due to infection in childhood. To avoid misunderstanding, let me make it perfectly clear that this manifest, macroscopic and virulent tuberculosis has nothing to do with the numerous cases of usually inactive and more or less obsolete forms of tuberculosis to which I shall come back later. If we now turn to the years of childhood, and particularly to the later years of childhood, and attempt to estimate the morbidity from tuber: eulosis in this age period, we are confronted with difficulties because the disease is fairly polymorphous and ill-defined. On the one side there is the pure scrofulo-tuberculosis with all its different shades, among which glandular tuberculosis, when definitely recognisable, is one of the most
December, 1921]
TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
105
common and characteristic manifestations. On the other side, we have pulmonary disease, habitus phtltisicus and other clinical symptoms referable to Grancher's "pre.tuberculous stage." To deal first with the frequency of pulmonars] tuberculosis at this ' age, we cannot, from the clinical standpoint and on the evidence of mass examinations, put this higher than 1 per cent. of the population at the age of 10. (See Chart VIII.) Next we come to glandular tuberculosis, the frequency of which varies not a little according to different authorities. Naturally it is difficult to decide, and it is often a matter of opinion whether a disease of the lymphatic glands is undoubtedly tuberculous or not. Estimates vary from 2 to 20-30 per cent. (note Fr6lich's interesting investigations in Christiania). But if we confine ourselves to the definitely demonstrable tuberculosis of the glands, the estimates range from about 5 to 7 per cent. and seldom exceed 10 to 12 per cent. Of the 15,000 , school children .. carefully examined" in 1908 in Stockholm, 11 to 12 per cent. were found to suffer from this condition. To [udge by the above, it would not be excessive if I fitted into my .. population frame" pure glandular tuberculosis estimated at 51 per cent, and the clinicaUy manifest tuberculosis-all forms included-at 8 to 10 per cent., with a maximum of 12 to 13 per cent., at the age of' 10. (See Chart VIII.) But in addition to these 8 to'10 per cent. with manifest, unquestionable tu?erculosis of a serious character as a rule, we must at this age--'-late chJJdhood-also take into account a not inconsiderable number of slight forms of scrofulo-tuberculosis in which the clinical diagnosis is difficult and uncertain. This group marks the transition from definite scrofulotuberculosis on the one hand; to the perfectly benign infection which I now come to at last. This perfectly benign and 'usually perfectly latent glandular infection begins largely, as is well known, in infancy and ,the majority of a' population is often infected before the completion of the 'first decade. ' This. infection can, as a rule, be demonstrated during life by v. Pirquet's test and, in contradistinction to the clinically manifest glandular tuberculosis, this condition .has gradually begun to be obsolete and inactive from as' early as the middle of ,the first decade. It has also, in my opinion, the ability to confer immunity ev~n though this may perhaps be only relative. In Chart VIII I have showed this benign infection to 'exist in about' 70 per cent. of persons at the age of 15 ; this seems to me a fair intermediate estimate, the figures of other writers varying from 30 to 95-100 per cent. While it has been fairly easy to form an estimate of the tuberculosis morbidity back to the fourth and. fifth years, greater difficulty has been experienced with regard to this morbidity in early infancy. Important light was thrown on this subject in 1911 by Pollack's interesting' investigations into the fate of children living in tuberculous surroundings. It would seem tbat the reaction of the child to tuberculous iufection differs profoundly according as it occurs before'or after the fifth year. 11e found that children infected during the first years of life showed, as a rule, signs of clinically manifeet tuberculosis, usually of a serious character. Onthe other hand, the children, who could be assumed to have been infected 'later
106
TUBEROLE
[December, 1921
in life, showed no clinical symptom, infection being indicated only by a positive v. Pirquet test. It should be noted in passing that Pollack could arrive at no definite conclusion with regard to adult life as he had not followed the fate of the children concerned beyond the fifteenth year. Great and renewed interest attach to these remarkable observations by Pollack in the light of a recent (1919) important and very thorough work by Bergman, .. The Exposure of Children to Tuberculous Infect jon." He has not only confirmed Pollack's findings, but has, also greatly -enhanead their significance. With searching thoroughness Bergman has investigated as many as 233 tuberculous families, including 1,004 children, and he has followed everyone of these children from. birth onwards, and in many cases (at least. a third) he has traced them jar: up into adult, life. His conclusions with regard to the significance of tuberculous infection in childhood are briefly these: Everyone of the persons who had died of tuberculosis in childhood or adult life, and nine-tenths of those who were still alive but suffered from clinically demonstrable tuberculosis had been -exposed, to infection within the first four years of life. On the other hand, not, a single death from tuberculosis could be found among those whose exposure to, tuberculous infection had been deferred till aftel: the fourth year. Further, not one case, of clinically demonstrable tuberculosia in any form could be found among those whose exposure to infection had been deferred till after the seventh year of life. Of 6ga persons.who, in thefirst year of life, had lived in tuberculous surroundings, 277 or 40 per cent. had either died, of tuberculosis or showed persistence of the disease in a. clinically demonstrable form. These most instructive observations by Pollack and Bergman. undoubtedly will have a far-reaching influence on our prophylactic measures against tuberculosis, for they show, with transcendent clearness, what a. 'sinister influence on the, child for all the rest of its life exposure to serious infection within the first four or five years may have: far different is its lot, if such exposure is deferred to a later period in life. These observations tell us plainly, in so many words, that the primary. infection of cases of clinically manifest, usually fatal tuberculosis, at any rate in Ute majority oj cases, is traceable to the first years of life. If, now, I take. this majority to be 90 per cent., then 540 of my GOO bypothetical oases of fatal tuberculosis have received their primary infec'tion during their. three or four first years of life, and in Chart VIII I have indicated these cases in the dotted line farthest to the left. This shows the presumptive morbidiuj during the first period of childhood. These 540 represent, as we see, only about 13 per cent. .of the age periods under review, and barely two-thirdsot the cases which, from the pathological standpoint, can be regarded as being infected in the same age period. The remaining 10. per cent., i.e. 60 out of the 600 fatal cases of tuberculosis, would cover; in my opinion, the sporadic cases of primary 'infection which .undoubtedlyoccur throughout the whole of life, perhaps late in life oftener than at other ages. On the strength of these different .investigations into the morbidity of tuberculosis, we may-assume that, as an average mean 6 to 7 percent of ihe population harbours a manifest, virulent, undoubtedly active tubercu_
December, HJ21]
TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
107
losis i n a more or less latent jorm-a condit ion which ill a great proportion .oj cases is clinically demonstrable . Thus, from this point of view, there
is nothing to prevent our putting the average duration of the disease from infection to death at 15 to 20 years. These investigations with regard to mortality and morbidity, the significance of exposure to infection during childhood, &c., cannot be seen in true perspective till we compare them with the knowledge recently gained by clinical and pa.thological research with regard to the latency and duration of the disease. Even though the clinical evidence and history of a case cannot, of course, be as clear and straightCorward as desirable, most writers are agreed that, in 20 to 50 per cent., the primary infection can be referred back to childhood, and in this connection I would draw special attention to Arvid Wallgren's and 'I'illisch's well-known investigations. At any rate it must be permissible also from the clinical point of view, in many cases to assume the existence of a period of many years' latency between childhood and the outbreak of the disease later in life. In this connection it is of great interest to draw attention to' the fact that the chief physician for Leprosy ill Norway, Dr. Lie at Bergen, even several years ago has arrived at similar results regarding leprosy. In his work" Statistisches tiber Lepra," tArehi» fur Dermai. 1t1ld Syphilis-Band ex, 1911), he writes; page 780: "As shown in the above statistics, the greatest number or cases break out in the decennial period from 15 to 25 years of age. From this cannot be concluded that these persons have caught the infection in this same period. In the majority of cases the infection has taken place many years ago; how long, can in most cases not be easily ascertained. In my opinion a. latency of ten years is no exception, on the contrary, seems to be the rule." And on page 783 he writes, founding his opinion on the above mentione-l statistics and on series of epidemiologically carefully examined cases of leprosy, that in almost one half of the cases the infection .. had taken place before the age of 15 to 25 years. And if this is the case there is nothing particularly striking about the fact that lit leper more rarely carries the infection to his conjugal partner than to his children, as has been shown above." "We have, however, in my judgment, obtained a clear view in this matter only since Harbitz in 1917 published bis investigations into II The Relation of Glandular to Pulmonary- Tuberculosis." He fonnd that in not less than 18 per cent. of a series of necropsies on adult cases of pulmonary tuberculosis, it was possible to demonstrate and follow the continuity of the disease from ' the lymphatic tuberculosis of childhood to the pulmonary. tuberculosis of adult life; he argued that it was possible for the virulence of these old foci of disease to remain unchanged for a long period. Owing to these new and important observations .we are DO longer II up in the air," but are working on a. secure foundation when we assume that a direct connection between the various stages of tuberculosis can be established through more or less latent forms of the disease. These and earl ier observations make it, in my upinion, mucb more natural to believe in an endogenous auto-infection than ' in an exogenous re-infection. See also recent investigations by de 10. Camp, Roepke and Leschke.
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109
TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
There is yet another most important observation which also seems to indicate that most cases of pulmonary tuberculosis in adult -life represent late processes. I refer to the not rare instances in recent times of measures against tuberculosis reducing both the mortality and morbidity first. and to the greatest extent, in childhood. Only by slow degrees is the tuberculosis mortality in adult life influenced by prophylactic measures. Thus, in the provincial towns in Denmark in the period 1886 to 1910, the decline in the tuberculosis mortality was at least twice as great in the age o to 15, as it was between 15 to 55. A somewhat similar observation has also been made in Norway by the chief physician for tuberculosis, Dr. Heitmann, see Chart IX, and according to Lindhagen's account the same state of affairs has been observed in Stockholm.
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Most striking observations in this connection have recently been made by Tennberg in Kronoby (Finland) with regard to morbidity. In HJ09 this well-known tuberculosis specialist carried out a wholesale examination of the population in this district where, in the same year, he organised a system of dispensaries. In 1919, i.e., ten years later, he undertook a similar wholesale survey, after his colleague, T. Dreijer, had for the past aeven years conducted the dispensaries with singular energy and skill. and had impressed on the population the value of his campaign, To make the results of these investigations clear, I have depicted them graphically, fittiJlg Tennberg's figures into my "population Irame.' In Chart X we find the morbidity curves shown so as to compare directlv with the whole of the living population, and in Chnrt XI the scale fa enlarged so BS to bring out more clearly the differences between the curves.
110
TUBERCLE
[December, 1921
In the course of these ten years we find that the total number of caSes of pulmonary tuberculosis has dwindled to a. third of what it was, and here. indeed, we have an encouraging proof of what a systematically planned campaign againsttuberculosia can achieve. We find that it is during the first decade that the decline is most rapid, the number of cases of pulmonary tuberculosis in this age period in 1919 being not evena quarter of what it was in 1909; according to my figures the decline is from 112 to 25. In the, second decade the difference is not quite so marked but is still considerable, the number being reduced to less than a. third; it is reduced to a' half in the age period 20, to 30. In the two decades 30 to 50 the decline is hardly perceptible, but in the later age periods there is again a. considerable declinein the morbidity.
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Here we can read in Nature's book with all clearness that it is chiefly in the early years of childhood that we may expect to find 'any direct, effect from tuberculosis prophylaxis. On the other hand, it would seem as if the disease in ad uIt life can be influenced only little by little, and indirectly in this way that year by year fewer and fewer infected persons reach: the older age periods. With regard to the higher ages, from 1>5 to 60 onwards, matters may perhaps be different as it is conceivable' that susceptibility to infection has again become greater, and prophylaxis can prove more directly effective at this stage: It is important always to remember that hygienic and economic factors can by themselves prevent or promote the outbreak and manifestation 'of tuberculosis. Finally, to make a control test of the whole matter, it would be or interest to reverse my calculations and try to find out how the morbiditv
December,1921]
111
TUBEUCULOSIS: ACUTE DISEASE OF CHILDHOOD?
curve would appear if practically all the fatal cases of tuberculosis say, 90 per cent.-i.e., in my scheme 540 cases-had begun in the first three or four years of life. In Chart Xl I I have drawn such a curve, fitting it into my "population frame," and, as it sbows, I have taken a hypothetical morbidity which begins with 540 severely infected infants-a number that gradually dwindles with the tuberculosis mortality throughout life. If I now, as in Chart XIII, which shows these curves on a larger scale, compare the above hypothetical curve with those familiar to us from the findings of pathology and mass examinations, &c., we' are confronted by a striking similarity in many respects. Both the height and the course of these curves are similar, my hypothetical curve running sometimes a JOOO
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CHART
little under, sometimes over the Bang-Harbitz curve. Both curves deal with the same 7" to 8 per cent. of the population, and there are several other points of similarity t.o which I would call attention; Some I have already touched on. Possibly the 13 per cent. at the age of 10 is too high, but, acc?rding to what I hav~ said e~rl.ier, this figure should represent; WIth fair accuracy, the definitely clinically demonstrable tuberculosis of late childhood, all forms included, and when we assume that the total mortality from tuberculosis is three per thousand. We now come to the age period ,15-20 ; ·a~ this most important stage of transition from glandular tuberculosis to disease of the other organs we find that both curves attain practically the same height, i.e., they reach 12 to 13 per cent. with about 400 persons, Thus, we see how, judged by the evidence of pathological investigations, these 400 persons
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TUBERCULOSIS: ACUTE DISEASE OF CHILDHOOD?
113
may be assumed to suffer from a manifest and virulent tuberculosis; while, on the other hand, the same 400 persons are predestined, according to my calculation, sooner or later to die of tuberculosis. The same conformity of the curves continues to be striking at the age of 40, when they both go up to 7 per cent., which corresponds to about 200 persons in the respective age groups. In a population of 200,000 with a hypothetical tuberculosis mortality of 3 per 1,000, we thus find 2,682 persons belonging to the age period of 40, of whom 200 may be taken to be suffering from manifest pulmonary tuberculosis as judged by the clinical and the pathological standard. We also see that these 200 correspond very closely to 90 per cent. of that number which, after this age period, die of tuberculosis. Beside the above-mentioned similarities, there is also a slight difference which may possibly be of profound significance. I refer here to the somewhat inexplicable secondary rise of the morbidity about the Sixties which we find both in the Bang-Harbitz curve and also, partly, in the curve of pulmonary tuberculosis obtained by clinical, mass or wholesale exa.minations. It is conceivable that, as already mentioned, we have here. t~ do with primary infections of comparatively recent ?ate, ~nd tha~ It IS principally this age period to which we must trace infections which do not occur in childhood. There is yet another consideration which, though of an indirect character, may be cited in support of the view that most cases of phthisis developed the first phase of their disease in the first years of life. I refer to .the fact that. the" number of children, yearly born in surroundings seriously contamillated with tuberculosis, seems to bear a. definite relation to the number of the tuberculous patients who yearly die of the disease. We ar~ h~re confronted with a certain type of vicious circle. It IS difficult to conceive of the century-old theory as to the heredity of tuberculosis being so firmly established, but for the fact that the disease was somehow or other found to be so intimately tied to the family and home. As in the overwhelming majority of cases the disease is not congenital, we have no alternative explanation to this state of affairs other than that which refers the time of infection in the majority of cases to childhood and the home. In Chart XIV I have given a graphic presentation of the morbidity from tuberculosis, as I view it, in a district where the disease is definitely endemic. In this chart the crosses (X) indicate the time of primary infection which is taken to occur principally in childhood, and it is assumed that the younger the child, the more severe the infection. A certain number of primary infections (10 to 15 per cent.) are assumed to occur during adult life, notably about the sixties, and are also marked with a. cross. The uihole of the lower .portion of this morbidity curve includes the manifest, virulent and more progressive forms, and represents about 7 per cent. of the population; they are, to a certain extent,. clinically demonstrable either in the form of pulmonary disease (the darkest area) or in the form of scrofulo-tuberculous processes (the dark area in the period of late childhood) ; the remaining, somewhat lighter area represents 8
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XIV.-The morbidity from tuberculosis (graphically represented). 200.000 individuals, 3 per thousand totall morta.lity from tuberculosis. x x x x x indicate ., primary infections." See text.
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TUDERCULOSIS: ACUTE DISEASE OF CHILDIIOOD?
115
the clinically more or less latent, but still virulent and serious forms of the disease. All the rest and the" upper portion of the curve (about 60 per cent.) includes. on the other hand, the great mass of usually quite benign infections which gradually become obsolete and avirulent and which, in my opinion, confer a certain, though perhaps only relative, immunity. Between these two components of the morbidity, the virulent and usually progressive processes on the one hand, and the slight and usually perfectly benign processes on the other, there may be assumed to be a comparatively narrow intermediate belt . I! we now view the subject as a whole, taking into account the characteristic course of the disease, its latency and , not least, the almost paradoxical state of affairs observed with regard to exposure to infection and prophylaxis in childhood as compared with adult life; and when we fuse these observations with our otber clinical and statistical findings, we cannot. in my opinion, come to any other conclusion than that most of our consumptives-let us say 80 to 00 per cent.-must already have contracted their first infection in childhood, and that the subsequent occurrence and manifestation oj the disease later in life must depend principally upon endogenous, re-auio-infections. Through these inquiries we also arrive nearly at the same conclusions, which I pronounced as early as 1895 in my work, .. Inquiries on the Frequency of Tuberculosis in Norway." In my conclusions, page 36, I wrote as follows: .. Dearing in mind the latent period, there are compelling reasons why we should fix as the time of infection the infantile years for the great majority of the tuberculous diseases , and the foetal period only for an inconsiderable number of cases." But, as I said in my introduction, these conclusions refer ' almost exclusively to populations in whick tuberculosis has raged for generations. For I do not doubt that in many of our more isolated districts with a scattered population, and where the disease has been comparatively lately introduced, its behaviour is of ·quite another character, and we shall certainly find far many more cases of acute and active primary infections among both adults and adolescents. These are my views; they may, of course, not coincide with others'; but it is at all events of the greatest importance at ·the earliest possible date to secure.the complete solution of this problem, for great issues are involved. To my mind the most effective prophylaxis would be the protection by every possible means of children. notably those in the first three or four years of life, from the more severe infections, either by removing the source of infection from the children's neighbourhood, or, if possible, by the isolation of the children. Secondly, we must seek further knowledge as to the immunity which I believe glandular infection is able to .confer, paying special attention to the relation of this problem to bovine tuberculosis and the more benign forms of pulmonary tuberculosis. On these lines it is possible that we might find some sort of va.ccine of practical benefit. Thirdly, it is essential that we obtain .more accurate knowledge as to the stages which precede pulmonary tuberculosis, particularly in late childhood and adolescence, so that we may know how to diagnose and treat the disease before it has manifested itself as full-blown pulmonary
116
TUBERCLE
[December, 1921
tuberculosis. For my own part I regard it as at least as important to attempt to minimize or remove predisposing causes, and thus possibly to prevent re-auto-infection, as it is to attempt to protect the individual from the danger of infection by his surroundings. Fourthly, and lastly, it is of importance that, as in the past, we train our consumptives to be as careful as possible with their expectoration particularly in relation to young children, but also, of course, in relatio~ to adults. In addition to the excellent bibliography appended to Bergman's work I would add the following references, of more recent date, bearing on th~ subject under discussion. IIARBITZ. "Tuberkulosens Former og Lokalisationer i Speedbamealderen," NOT8k Magazin for Laqevidenekoben, 1913, No.!. Idem. .. Om Lymfeglandeltuberkulosen og Dens Sammenbmng med Lunge_ tuberkulosen," Videnskabsselskabets'skrf, 1916, No. H. LINDA GEN. "Stockbolms Tuberkulosmortll.litet under de sena.ste Decennierne," Hygiea, Bd. 80, 1918. Idem. "Undersokelser over Livsvarigheten av 'l'reringssyke i Norge," !:Versk Magazin for Lagevidenskaben, 1906. No.4. DIREK10K KJ./ER. II Livs- og Dodstabeller for det Norske Folk efter Erfa.ringer fro. Tiaaret," 1882.1891. SCHEPPELEIiN. II Meddelelser fro. Kystbospitalet paa Re(snoos 1875·1890." VEJE. II Studier over Barnetuherkulosen i Danmark, 1915," Doktora.vba.ndling Kjobenbavn. ' CONSTANTIN TENNBERG. "ResultaLet av etL 10.Arigt ArbeLa fur Tuberkulosens Beksmpande i Kronoby Socken," Einska Liikaresiillskapets HalldlingaT Bd, lxi, September-October, 1919. ' DRElJER'. II Lung- og Korteltuberkulosens Forekomst i Rantasalmi Socken," Helsingfors, 1911. v. KHlEMER. .. Tuberkulos Infektion och Tuberkul~s Sjukdom bland Be(olkningen i en Osterbottnisk Kustsccken," llelsingfors, 1915. THERMAN. II Lungtuberkulosen has Arbetarbefolkningen i Kymmene, Kuersan., korskis och i Voikka Brukssamhallen," Helsingfors, 1917. GRANCHER. It Prophlaxie de la Tuberculose," Paris, 1918. HART. "Betraehtungen iiber die Entstehung der Tuberkulosen Lungeuspitaen, phthise," Zeitsch. f. Tub.• Bd, xxiii und Bd. xxiv. LESCHKE. II Die Tuberkulose im Krieg," Jliimh. med. Wochenschr.,1915. No.11. Ds LA. CAMP. II Die klinische Diagnose der Vergrosserung Entratborakaler Lympbdrusen," Med. Klin.• 1906, No.!. HEDRbl, G. II Pabbologisebe Anatomie und Infektionsweise der Tuberkulose des Kindes, besonders der Sli.uglinge," Zeitschr./. Hygiene u. Injektionskrank. heite», Bd. lsxiil, H. 2. BERGMAN, EMA.NUEL. "Barns uteiittande (or tuberkulos smitta... Akademisk avhandling, Upsala, 1918. ANDvoRD, K. F. "Studier over Tuberkulosens forekomst i Norge," NOTSk Magazin for Lagevidenskaben, No. 12. 1895.