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Resistance to tuberculosis in early infancy
RESISTANCE TO TUBERCULOSIS IN EARLY INFANCY. By ARVID \VALLGREN, M.D. (Stockholm). I.-EXPERIMENTAL 'EVIDENCE.
IN Hl1S [1] I published two series of investigations into the reaction Qf rabbits of various ages to infection with tuberculosis. In the first series there were eight rabbits, two each being aged 12, 9, 7 and 2 months. With a view to studying the course of So benign, chronic infection, I inoculated bacilli of the human type, the glycerine-bouillon culture being .5 weeks old. The dosage, determined in each case by the weight of each animal, was for each kilo body weight, 3 mg. bacilli injected subcutaneously. According to Findel's [2J calculation, 1 mg. of tubercle bacilli contains about 35 millions, whereas Selter (3] multiplies this figure by three. One of the 9-months old rabbits died after four months, and the remainder were killed at the same time. The results are shown in the following table:TABLIl:
1.
2,770 2,700
8'3 8'0
3 3
0'231 0'229
0'141 0'127
Caseous foci Milia.ry tubercles
r 3 t 4
2.575
7'7
3 2
O'HIO 0'24()
0,118
III
7 I 5
2,170 1,900
3
0'163 0'171
0'112 0'089
IV
2 '( 8
7
1,100 1,660
2 2
0'2~5
0'231 0·236
Scattered tubercles Tubercles as big as a. pea Focus size of a. pea. Scattered miliary tubercles No tuberculosis
I
II
12 ( 1
( 2
o
( G I
2,5GO
7'7
2
0'299
0'117
"
"
I These figures Indicate in milligrams the excess of weight of the infected popliteal glands over the non-Infected I':laods of the opposite poplitea.l space,
The first palpable reaction at the site of inoculation was detected after three weeks in the two oldest groups, and after two weeks in the two youngest groups. Thus, though the absolute amount of the inoculated virus was less for the younger animals, they reacted sooner at the site of injection. If the incubation period be defined as the interval between inoculation and ~he appearance of the first signs of ~ reac.tio~ at the site of injection, then It would seem that the length of this period IS not determined only by the amount of the virus, but also by the age of the animal. In the two 31
[.\u~u,t, 1921
TVb&JlCLE
)'oun~~,L Rroupg
tho local reaction dnelo(1cd sooner And ,,~u mora ICt-UO thnn in tho older groups. In some of these, tho local rCA{:llon went on to liqucfnclion, Tho neighbouring gll\nds
nr
T.uIU II. All-
l':umbcr
Onr
n
11
8
month'
mooth.t
month.
6 montb.
IDOnth.
!l
~
1
~
G
4
l-S , 3~ 2 IIlODth. D)Ooth. lDoolhA
1
.
3
I
!DOO'' . 8
M)' object was to give a fatal dose and. by determining the period of IUl1ivnlllftcr infection in each case. to obtain direct evidence of eaeh animal's resiatance. It has been shown that. a.s a rule. an adult rabbil dies three to four months nrter subcutaneous inoculation ",ith 10 lUg. of tubercle bacilli of tho bovine type. Accordingly, each animal 'WU cinn 3 mg. bllCilli per kilo body \\'f:iSh&. All were st\"cn subcutaneoull injt"Ctionl on the anma dllY God from tho saruo culture, 1"i\,o (1111 belonging to tho )"onngc&L agc) died soon after inoculation. l'fobt\bl}' owing to coecidioais. Thil exilted also in tbo ."maining three of tho .)'.otl~ge", Gf:O group, and in five or tho older rabbits it lnll)' bate been & delJlltt41log influence, affecting tho course or tho tuberculosis. AmoD~ tho )'oungcd Ani!II111. Who lurvivc,} till puberty or later, it was noti~ tJlal U1ero WAS mVlU'illbl)' A IUllrked defieiency of normal dovelopment.
August, 1921J
TUBERCULOSIS IN EARLY INFANCY
483
They were feeble, in poor condition, and their muscles were flabby. Possibly this condition is analogous to that described by Pollak [4J whose
zoo
+
+ ISO
+
. +
.'fo
+ +
50
IYz
3/4
Z
ZYz
4
37Z
Agf' in montn3 at the timt! DIAGRAM
6
6
or- inoC'u/at:,on.
"overl2.
I.
?bser~ati~ns, unconfirmed by other workers, showed that early tuberculous
infection
III
man delays normal development of the body.
484
TUBERCLE
[August, 1921
In this series, as distinct from the first, I could establish no definite relation between the reaction at the site of inoculation and in the neighbouring lymphatic glands on the one hand, and the a.ge ?f the animal on the other. In all but one case there was a reaction at the site of inoculation after two weeks. This focus was always large and caseous, and sometimes liquefaction was demonstrable in the centre. The uniformity of this reaction was presumably due to the amount of the virus being in excess of the animals' powers of resistance. As all the lymphatic glands were more or less diseased, none was available as a standard for comparison to show in figures the exact degree of reaction. With regard to the distribution of the disease, only the lungs and kidneys showed tuberculous changes in every case. All the animals, except those that died within a week of inoculation, developed pulmonary tuberculosis which was undoubtedly the immediate cause of death. The distribution of the pulmonary disease was remarkably uniform; there was miliary tuberculosis, with more or less confluent, caseous tubercles. This miliary disease in the lungs and the general involvement of the lymphatics and kidneys undoubtedly pointed to infection by the blood-stream. The lungs being invariably invaded, I could not, as in my first series, take the presence or absence of pulmonary tuberculosis as a criterion by which to estimate the prognosis. This had, therefore, to be gauged by the length of survival of each animal after inoculation. The following diagram shows that, though the inoculation invariably proved fatal, there were considerable differences in the duration of the disease. Only those animals are included which died of tuberculosis, arid a + is put against each animal whose disease was complicated by some non-tuberculous infection. As the diagram shows, the duration of life varied, but not considerably within the same age group. It will be noted that animals 2t to 4 months old, i.e., approaching puberty, lived the shortest timewhile the younger and older groups lived longer. This difference was assuredly too great to be a coincidence, and it would seem that, under the conditions present, these investigations do not show that young animals are less resistant to tuberculosis than older animals, but rather the contrary. It would also appear that the amount of lymphoid tissue present does not affect the course of infection, for, as Hellman [5J has shown, rabbits approaching or at puberty possess the greatest quantity of lymphoid tissue. But it is just at this age, as my investigations prove, that the rabbit is least resistant to tuberculosis. It may, however, be argued that, in my experiments, the dose of virus was so great that the lymphoid tissue was paralysed. The bacilli presumably reached the blood-stream soon after infection owing to the inability of the regional lymphatic glands to arrest their progress, as was the case in the youngest animals of my first series. Even if lymphoid tissue, as commonly supposed, is of importance in producing immunizing substances against a virus, this function would not seem to be very prominent once the virus has passed through this tissue. he involvement of superficial glands, other than those adjoining the SIte.of inoculation, point to the participation of the former in the reaction to 1OfectlOo. At any rate it may be said that resistance against
rr:
August, 1921]
TUBERCULOSIS IN EARLY INFANCY
485
tuberculosis does not exclusively depend on the amount of lymphoid tissue in the body. 200
1l'
359
150
+-
+
50
0/4
i
2
3
~t tn£> DU.GRAM rr,
Age /n montn3
4
12
over-ZY.
time of' "f1ocu/ation.
The following is an account of a series of control investigations and of their bearing on resistance to tuberculosis in early infancy. My second
[August, 1921
TUBERCLE
series of investigations being most remarkab.le! .viewed in the .light of modern theories as to the comparative susceptibility of young animals to tuberculosis, I decided to make my third series resemble the second as much as possible. The 26 rabbits used were classified as follows : TABLE
III.
Age in months:
Over 24
12
4
3
Number :
2
3
6
4
5
6
\
2
Highest weight
...
3,200
2,070
1,700
570
800
340
Lowest weight
...
3,100
2,020
1,500
430
700
240
Unfortunately I could not secure newborn rabbits suitable for my purpose, nor were all 26 of the same breed. Two of the youngest rabbits died within a week; there was no reaction to the inoculation, and the cause of death could not be discovered. One of the 2-months-old rabbits developed coccidiosis, and another pneumonia. The other animals showed, after death, no disease other than tuberculosis. The rabbit to die first as a result of tuberculosis was one of the oldest; it died on the 32nd day, of miliary tuberculosis of ' the lungs. The rabbit which lived longest after inoculation (a year) was one of the youngest. Among the rest, survival after inoculation lasted from 76 days (in the 4-months-old group) to 158 days (in the 2-months and 3-weeksold group). Further details are given in the following diagram, which show that the differences in the length of life after inoculation among rabbits in the youngest and oldest groups were considerable. In the remaining age groups the duration of life was more uniform. There was little difference in the duration of life in the 2-months and 3-months-old rabbits, but there were marked differences between the 12-months and 4months-old rabbits. The shortest-lived were the oldest rabbits. Another group which succumbed early was the 4-months-old, i.e., the group approaching puberty. Then came the 3-months-old group in the order of early death. On the whole, the rabbits proving most resistant to infection were the 2-months and 12-months-old, and some of the youngest animals. Neither in this series could I find any evidence to prove that young animals (3-weeks-old rabbits) are less resistant to tuberculosis than their elders. On the contrary, these investigations, like those of my first and second series, would rather suggest that some of the youngest animals exhibited greater resistance than the animals approaching puberty. It is probable that in other animals also the age just before and during puberty is associated with less resistance to tuberculosis than younger ages. It should be noted that 12-months-old rabbits reacted quite differently in my first and second series.
August, 1921]
TUBERCULOSIS IN EARLY INFANCY
487
n.-CLINICAL EVIDENCE.
If my experimental evidence is applicable to man, it would sug-gest that infants are not, as usually supposed, more susceptible to tuberculosis than older human beings. But clinicians and pathologists teach that manifest tuberculosis in infancy is rapidly fataL In the clinical evidence for this view, there is one important link missing: the amount of the ingested virus is unknown. Only approximately can this amount be gauged. But even such an approximate estimate seems to indicate that it is not merely the infant's age that determines the course of the disease. Thus there is Bound evidence for believing that the amount of virus passing to an infant from its consumptive mother is considerably greater than that from other consumptives in the family or outside it, and also greater than that to which older children are exposed. The newborn child is in much more intimate contact with the mother than older children, the process of infection being continuous in the first case, intermittent in the second. The resulting differences in the character of the disease are shown by the following observations. Ustvedt [6J found that of 480 children in tuberculous families, 39'7 per cent. had died in families in which the mother was ill, 19'7 per cent. in which the father was ill, and 16'1 per cent. in which a brother or sister was ill. Bergman [7J has pointed out that in those families in which both parents were ill, the tuberculosis mortality among the children was more than twice as great as it was in families infected by others than the parents. Tennberg [8] showed that of 52 children with both parents tuberculous, 17'3 per cent. were tuberculous, whereas of ~l4 children whose fathers only were tuberculous, 7'4 per cent. had contracted tuberculosis. Of the 169 children whose mothers only were tuberculous, 13 '6 per cent. had developed tuberculosis. Pollak [9J finds that infants exposed to intection from severe cases of phthisis usually develop fatal tuberculosis, whereas the infant which survives infection will be found to have been infected by a comparatively well patient. In other words, in advanced 'Cases of phthisis the sputum is loaded with bacilli, and the patient being 'Confined to the house or bed, has exceptional facilities for conveying massive infection. There are exceptions, but as a rule the 'm ore advanced the disease the greater is the number of bacilli. Evidence, such as the above, 'Could be multiplied easily, and it all points to the amount of ingested virus being of great importance in determining the course of tuberculosis in infancy. Yet such dogmatic statements as the following keep cropping 'Up: (( If infection occurs within the first year of life, the disease usually runs an unfavourable course, and natural immunity to tuberculosis in'Creases during the years after the first." Or it is declared that If the significance of the first exposure to infection is largely determined by the age at which infection occurs ." So established has this teaching become, that its challenge by experimen~ has hard~y be~n contemplated. I can only find two investigations bearing on this point, and they are not illuminating. In 1910 Paul ROmer [10] inoculated fourteen 2-week-old lambs and four full-grown sheep with intravenous injections of tubercle bacilli, the dose of which was graduated according to the weight of each animal. He found no
488
'IUDERCLE
[August, 192)
differences in the results D.9 noted in animals of different ages. In 1016 SeIter and Burgers [Ill exposed 36 rabbits of various ages to. i~rcction by lnhalation of different quantities of human tubercle bacilli ; they could not evidently show any relation between the age of the animals and their reaction to infection. No doubt manifest, clinically demonstrable tuberculosis in infancy runs a rapidly fatal course in practically every case, but it is not proven that. every tuberculous infection in infan~~ takes such n. course. A cle~r distinction should be made between clinically demonstrable tuberculosis and infection betrayed only by 0. tuberculin reaction. \Vhile the diagnosis of tuberculosis in infancy depended on clinically demonstrable signs, this disease, as pointed out by Hahn [12J, was regarded as rare, and was detected only in an advanced stage, when the infant was cachectic. lIence the tendency to regard tuberculosis in infancy as a wasting disease, and to suspect its presence only when an infa.nt was debilitated. And as this is the terminal stage of the disease, it is not strange that it should have been regarded as invariably fatal. The impression has slowly grown that tuberculosis, notably glandular tuberculosis, may run a benign course, but not till the advent of tuberculin diagnosis, von Pirquet's test in particular, was it possible to demonstrate infection at II much earlier stage and when the child still looks perfectly well. The Xvrays, also, have disclosed forms of tuberculosis undemonstrable by older tests. Hence the conclusion that the rapidly fatal cases of tuberculosis in infancy constitute only a fraction of all the cases infected at this age. It is 0. check on the pessimism of the old school to follow the career of children who, in infancy, gave a positive von Pirquet reaction. Permin [13] has shown that of 15 children found to be infected within the first year of life, G had died, while the remainder, examined at ages ranging from 1 to 7 years, were not only alive but well, with the exception of one with signs of scrofula. There are also the well known observations of Schloss [14], whose account of a. small tuberculosis epidemic in a. hospital for children in 1917 referred to 14 children infected b)' a tuberculous nurse. All developed a positive tuberculin reaction. and 4 constitutionally weak children succumbed to tuberculosis. But the rest remained well, a.lthough all of them during the following winter developed signs of tuberculosis of the bronchial glands which subsequently passed off. Schloss concluded that the prognosis is certainly not bad provided infection is not too massive, and a normal infant lives under hygienic conditions. He added: .. of least importance, contrary to the experience oj others, is the child's age. Bernard and Debre [15] found that of 30 infants exposed to infection by their sputum-positive mothers for 2 to 13 months, only 12 had succumbed to tuberculosis during a maximum observation period of 2 years. These and similar observations discredit the old view that infection in infancy is necessarily of bad omen. Even massive infection is not necessarily fatal, for of six children infected in the first year and still alive at the end .of the third year, Permin found that five had been exposed to massive infection. He concluded tha.t, even with mnssi\'& doses of virus, infection need not inevitably lead to actual disease. If we compare these observations with those of Calmette, \VestenhOler, De~'cke.
August, 1921]
TUBERCULOSIS IN EARLY INFANCY
489
Romer and Cummins [19], as to individuals (belonging to races hitherto tubercle-free) who develop rapidly fatal tuberculosis when they settle in tubercle-positive communities, we may well ask if there is any great difference in resistance to infection as between infants and adults. It should be borne in mind that, as a rule, the infection to which an adult is exposed is far less massive, both absolutely and relatively, than that to which the infant of a consumptive mother is exposed. Even when infection of an infant leads to manifest disease, the resistance shown may be considerably greater than was once thought possible. Among 171 infants dying of tuberculosis, Sehlbach [16J found in two 5·month and in one 7-month old infant, definite signs of localization of the disease. Geipel [17] has even demonstrated calcification in a tuberculous focus in infants aged 6 and 8 months respectively. In 1911, Bardt [18] recorded a case of tuberculosis of the bronchial glands in a child of 18 months, the disease having been diagnosed first when he was only 4 months old. Lederer [20J had also reported three cases of tuberculosis diagnosed in infancy, with survival for a year or more. Similar cases have been recorded by Engel and Schick [21J. Frolich [22J has followed up the case of a child exposed from birth to infection by a nurse. When 9 months old, fretfulness and loss of weight occurred, and three months later there was general debility, with lichen sorofulosorum and signs of tuberculosis of the bronchial glands. A very bad prognosiS was given, but two years later he heard that the child had recovered. I do not, however, argue that infection in infancy may not lead to disease in adult life; investigations I have published elsewhere (23) suggest that early infection may be of sinister importance in adult life If my observations in rabbits are applicable to man, why should the tuberculosis of early infancy so seldom be benign? The source of infection in the tuberculosis of infancy is usually demonstrable and can in most cases be traced to a member of the family. 'rhus the absolute amount of the ingested virus must be great, and relative to the weight of the infant it must be enormous. The older the infant becomes, the less does the quantity of the virus become relative to its weight. Again, the younger the infant, the more intimate is its contact with a consumptive mother. Finally," an adult exposed to massive infection usually enjoys the benefit of previous infection with comparatively small doses, and is therefore relatively immune (note the reverse conditions in the observa.. tions of Calmette, Westenhdfer and others), whereas the infant enjoys no preparatory immunisation before exposure to massive infection by the mother. 'I'he first infection being massive, the body is flooded with virus, the protective mechanism is inadequate, and the blood-stream carries multiple infection to various organs. Thus the clinical evidence as to the gravity of tuberculosis in infancy does not necessarily indicate that the organism's resistance in infancy is less than in childhood or adult life. This problem is rather of theoretical than practical interest, and its solution is not likely to affect practical measures in the tuberculosis. campaign. But it may throw light on aspects of the disease which have hitherto been obscure. We may ultimately concentrate on the prevention of massive infection only, ignoring slight infection. How this is to be effected, whether by removal of the infant from the infected home [24].
490
TUBERCLE
[August, 1921
by segregation of sources of infection, or by prophylactic inoculation with minute doses of tubercle bacilli, it is too early to decide. Forsok rorande ympningstuberkulosens forlopp hos kanin i olika aldrar," Upsala Lakarfor. Forhandl" 1918, Bd. xxiii. [2] Zeitsehr.], Hygiene, 1907, Bd.lvii. [3] Centralbl. f. Bakt., 1916, Bd. lxxviii. [4J Brauers Beitriige zur Klinik de" Tuberkulose, 1911, Bd, xix, {5J Akadem. Aohandl., Upsala, 1914. [6] Norsk Magazin for Laeqeoidenskaben, 1916, Bd. Ixxvii, [7] Akadem, Avandl., Upsala, 1918. [81 Akadem: Avandl., Helsingfors, 1913. (9J Brauers Beitriiqe, Bd. xlx. . [10] Ibid., Bd. xvii. [11] Centralbl. f. Bakt., 1916, Bd. lxxviii, [12] Monatschr. f. Kinderheilk., Bd . x, 1912. (13) Hospitalstidende, 1911t [14] Jahr.], Kinderheilk., 1917, Bd.Txxxv, [15J Bull. Z·Acad. de Med., October 5, 1920. [16] }fiinch. med. Wochenschr., 1908, Bd, lv, {l7J Zeitschr. f. Hygiene. 1906. Bd. liii. {I8J Ref. Mtmatsch», f. Kinderheilk., 1911, Bd. x, f19] "Racial Differences in Susceptibility to Tuberculosis," Brit. Journ, of Tuberculosis, 1920, vol. xiv. {20] Monatschr, f. KillderheiZk., 1914. Bd. xii. [21] Ref. Pollak, Brauers Beitriige, Bd. xix. [22J Norsk Magazi1i for Laegevidenskaben, 1918, Bd. lsxix, {23] Brauers Beiiriuje, 1915, Bd. xxxiv. {24J See BERNARD and DEBRE, Bull. l' Acad. de M~d., October 5. 1920. [1]
U
THE CLIMATIC AND SUNLIGHT THEATl\IENT OF SURGICAL TUBERCULOSIS. By Dr. O. BERNHARD. St. Moritz. HISTORICAL. DURING the past three decades there has been a revolution in the treatment of surgical tuberculosis, and the radical, operative treatment of the surgeon has largely given place to climate-therapy and orthopredic measures. With regard to the two climatic extremes, the maritime and the high altitude, I propose to confine myself to the latter. As a medical "Student, spending my holidays at my home in Samaden (Oberengadin 1,750 metres above the sea) in 1880, I was struck by the remarkable 'Cures effected by a small colony of consumptive Italian visitors, and while I almost daily watched the surgical work of my honoured teacher Professor .Koch er , in Bern, I came to wonder whether operations on surgical tuberculosis might not be superseded by climatic-dietetic treat. ment, supplemented when necessary by orthopredic and other conservative
IN Hl1S [1] I published two series of investigations into the reaction Qf rabbits of various ages to infection with tuberculosis. In the first series there were eight rabbits, two each being aged 12, 9, 7 and 2 months. With a view to studying the course of So benign, chronic infection, I inoculated bacilli of the human type, the glycerine-bouillon culture being .5 weeks old. The dosage, determined in each case by the weight of each animal, was for each kilo body weight, 3 mg. bacilli injected subcutaneously. According to Findel's [2J calculation, 1 mg. of tubercle bacilli contains about 35 millions, whereas Selter (3] multiplies this figure by three. One of the 9-months old rabbits died after four months, and the remainder were killed at the same time. The results are shown in the following table:TABLIl:
1.
2,770 2,700
8'3 8'0
3 3
0'231 0'229
0'141 0'127
Caseous foci Milia.ry tubercles
r 3 t 4
2.575
7'7
3 2
O'HIO 0'24()
0,118
III
7 I 5
2,170 1,900
3
0'163 0'171
0'112 0'089
IV
2 '( 8
7
1,100 1,660
2 2
0'2~5
0'231 0·236
Scattered tubercles Tubercles as big as a. pea Focus size of a. pea. Scattered miliary tubercles No tuberculosis
I
II
12 ( 1
( 2
o
( G I
2,5GO
7'7
2
0'299
0'117
"
"
I These figures Indicate in milligrams the excess of weight of the infected popliteal glands over the non-Infected I':laods of the opposite poplitea.l space,
The first palpable reaction at the site of inoculation was detected after three weeks in the two oldest groups, and after two weeks in the two youngest groups. Thus, though the absolute amount of the inoculated virus was less for the younger animals, they reacted sooner at the site of injection. If the incubation period be defined as the interval between inoculation and ~he appearance of the first signs of ~ reac.tio~ at the site of injection, then It would seem that the length of this period IS not determined only by the amount of the virus, but also by the age of the animal. In the two 31
[.\u~u,t, 1921
TVb&JlCLE
)'oun~~,L Rroupg
tho local reaction dnelo(1cd sooner And ,,~u mora ICt-UO thnn in tho older groups. In some of these, tho local rCA{:llon went on to liqucfnclion, Tho neighbouring gll\nds
nr
T.uIU II. All-
l':umbcr
Onr
n
11
8
month'
mooth.t
month.
6 montb.
IDOnth.
!l
~
1
~
G
4
l-S , 3~ 2 IIlODth. D)Ooth. lDoolhA
1
.
3
I
!DOO'' . 8
M)' object was to give a fatal dose and. by determining the period of IUl1ivnlllftcr infection in each case. to obtain direct evidence of eaeh animal's resiatance. It has been shown that. a.s a rule. an adult rabbil dies three to four months nrter subcutaneous inoculation ",ith 10 lUg. of tubercle bacilli of tho bovine type. Accordingly, each animal 'WU cinn 3 mg. bllCilli per kilo body \\'f:iSh&. All were st\"cn subcutaneoull injt"Ctionl on the anma dllY God from tho saruo culture, 1"i\,o (1111 belonging to tho )"onngc&L agc) died soon after inoculation. l'fobt\bl}' owing to coecidioais. Thil exilted also in tbo ."maining three of tho .)'.otl~ge", Gf:O group, and in five or tho older rabbits it lnll)' bate been & delJlltt41log influence, affecting tho course or tho tuberculosis. AmoD~ tho )'oungcd Ani!II111. Who lurvivc,} till puberty or later, it was noti~ tJlal U1ero WAS mVlU'illbl)' A IUllrked defieiency of normal dovelopment.
August, 1921J
TUBERCULOSIS IN EARLY INFANCY
483
They were feeble, in poor condition, and their muscles were flabby. Possibly this condition is analogous to that described by Pollak [4J whose
zoo
+
+ ISO
+
. +
.'fo
+ +
50
IYz
3/4
Z
ZYz
4
37Z
Agf' in montn3 at the timt! DIAGRAM
6
6
or- inoC'u/at:,on.
"overl2.
I.
?bser~ati~ns, unconfirmed by other workers, showed that early tuberculous
infection
III
man delays normal development of the body.
484
TUBERCLE
[August, 1921
In this series, as distinct from the first, I could establish no definite relation between the reaction at the site of inoculation and in the neighbouring lymphatic glands on the one hand, and the a.ge ?f the animal on the other. In all but one case there was a reaction at the site of inoculation after two weeks. This focus was always large and caseous, and sometimes liquefaction was demonstrable in the centre. The uniformity of this reaction was presumably due to the amount of the virus being in excess of the animals' powers of resistance. As all the lymphatic glands were more or less diseased, none was available as a standard for comparison to show in figures the exact degree of reaction. With regard to the distribution of the disease, only the lungs and kidneys showed tuberculous changes in every case. All the animals, except those that died within a week of inoculation, developed pulmonary tuberculosis which was undoubtedly the immediate cause of death. The distribution of the pulmonary disease was remarkably uniform; there was miliary tuberculosis, with more or less confluent, caseous tubercles. This miliary disease in the lungs and the general involvement of the lymphatics and kidneys undoubtedly pointed to infection by the blood-stream. The lungs being invariably invaded, I could not, as in my first series, take the presence or absence of pulmonary tuberculosis as a criterion by which to estimate the prognosis. This had, therefore, to be gauged by the length of survival of each animal after inoculation. The following diagram shows that, though the inoculation invariably proved fatal, there were considerable differences in the duration of the disease. Only those animals are included which died of tuberculosis, arid a + is put against each animal whose disease was complicated by some non-tuberculous infection. As the diagram shows, the duration of life varied, but not considerably within the same age group. It will be noted that animals 2t to 4 months old, i.e., approaching puberty, lived the shortest timewhile the younger and older groups lived longer. This difference was assuredly too great to be a coincidence, and it would seem that, under the conditions present, these investigations do not show that young animals are less resistant to tuberculosis than older animals, but rather the contrary. It would also appear that the amount of lymphoid tissue present does not affect the course of infection, for, as Hellman [5J has shown, rabbits approaching or at puberty possess the greatest quantity of lymphoid tissue. But it is just at this age, as my investigations prove, that the rabbit is least resistant to tuberculosis. It may, however, be argued that, in my experiments, the dose of virus was so great that the lymphoid tissue was paralysed. The bacilli presumably reached the blood-stream soon after infection owing to the inability of the regional lymphatic glands to arrest their progress, as was the case in the youngest animals of my first series. Even if lymphoid tissue, as commonly supposed, is of importance in producing immunizing substances against a virus, this function would not seem to be very prominent once the virus has passed through this tissue. he involvement of superficial glands, other than those adjoining the SIte.of inoculation, point to the participation of the former in the reaction to 1OfectlOo. At any rate it may be said that resistance against
rr:
August, 1921]
TUBERCULOSIS IN EARLY INFANCY
485
tuberculosis does not exclusively depend on the amount of lymphoid tissue in the body. 200
1l'
359
150
+-
+
50
0/4
i
2
3
~t tn£> DU.GRAM rr,
Age /n montn3
4
12
over-ZY.
time of' "f1ocu/ation.
The following is an account of a series of control investigations and of their bearing on resistance to tuberculosis in early infancy. My second
[August, 1921
TUBERCLE
series of investigations being most remarkab.le! .viewed in the .light of modern theories as to the comparative susceptibility of young animals to tuberculosis, I decided to make my third series resemble the second as much as possible. The 26 rabbits used were classified as follows : TABLE
III.
Age in months:
Over 24
12
4
3
Number :
2
3
6
4
5
6
\
2
Highest weight
...
3,200
2,070
1,700
570
800
340
Lowest weight
...
3,100
2,020
1,500
430
700
240
Unfortunately I could not secure newborn rabbits suitable for my purpose, nor were all 26 of the same breed. Two of the youngest rabbits died within a week; there was no reaction to the inoculation, and the cause of death could not be discovered. One of the 2-months-old rabbits developed coccidiosis, and another pneumonia. The other animals showed, after death, no disease other than tuberculosis. The rabbit to die first as a result of tuberculosis was one of the oldest; it died on the 32nd day, of miliary tuberculosis of ' the lungs. The rabbit which lived longest after inoculation (a year) was one of the youngest. Among the rest, survival after inoculation lasted from 76 days (in the 4-months-old group) to 158 days (in the 2-months and 3-weeksold group). Further details are given in the following diagram, which show that the differences in the length of life after inoculation among rabbits in the youngest and oldest groups were considerable. In the remaining age groups the duration of life was more uniform. There was little difference in the duration of life in the 2-months and 3-months-old rabbits, but there were marked differences between the 12-months and 4months-old rabbits. The shortest-lived were the oldest rabbits. Another group which succumbed early was the 4-months-old, i.e., the group approaching puberty. Then came the 3-months-old group in the order of early death. On the whole, the rabbits proving most resistant to infection were the 2-months and 12-months-old, and some of the youngest animals. Neither in this series could I find any evidence to prove that young animals (3-weeks-old rabbits) are less resistant to tuberculosis than their elders. On the contrary, these investigations, like those of my first and second series, would rather suggest that some of the youngest animals exhibited greater resistance than the animals approaching puberty. It is probable that in other animals also the age just before and during puberty is associated with less resistance to tuberculosis than younger ages. It should be noted that 12-months-old rabbits reacted quite differently in my first and second series.
August, 1921]
TUBERCULOSIS IN EARLY INFANCY
487
n.-CLINICAL EVIDENCE.
If my experimental evidence is applicable to man, it would sug-gest that infants are not, as usually supposed, more susceptible to tuberculosis than older human beings. But clinicians and pathologists teach that manifest tuberculosis in infancy is rapidly fataL In the clinical evidence for this view, there is one important link missing: the amount of the ingested virus is unknown. Only approximately can this amount be gauged. But even such an approximate estimate seems to indicate that it is not merely the infant's age that determines the course of the disease. Thus there is Bound evidence for believing that the amount of virus passing to an infant from its consumptive mother is considerably greater than that from other consumptives in the family or outside it, and also greater than that to which older children are exposed. The newborn child is in much more intimate contact with the mother than older children, the process of infection being continuous in the first case, intermittent in the second. The resulting differences in the character of the disease are shown by the following observations. Ustvedt [6J found that of 480 children in tuberculous families, 39'7 per cent. had died in families in which the mother was ill, 19'7 per cent. in which the father was ill, and 16'1 per cent. in which a brother or sister was ill. Bergman [7J has pointed out that in those families in which both parents were ill, the tuberculosis mortality among the children was more than twice as great as it was in families infected by others than the parents. Tennberg [8] showed that of 52 children with both parents tuberculous, 17'3 per cent. were tuberculous, whereas of ~l4 children whose fathers only were tuberculous, 7'4 per cent. had contracted tuberculosis. Of the 169 children whose mothers only were tuberculous, 13 '6 per cent. had developed tuberculosis. Pollak [9J finds that infants exposed to intection from severe cases of phthisis usually develop fatal tuberculosis, whereas the infant which survives infection will be found to have been infected by a comparatively well patient. In other words, in advanced 'Cases of phthisis the sputum is loaded with bacilli, and the patient being 'Confined to the house or bed, has exceptional facilities for conveying massive infection. There are exceptions, but as a rule the 'm ore advanced the disease the greater is the number of bacilli. Evidence, such as the above, 'Could be multiplied easily, and it all points to the amount of ingested virus being of great importance in determining the course of tuberculosis in infancy. Yet such dogmatic statements as the following keep cropping 'Up: (( If infection occurs within the first year of life, the disease usually runs an unfavourable course, and natural immunity to tuberculosis in'Creases during the years after the first." Or it is declared that If the significance of the first exposure to infection is largely determined by the age at which infection occurs ." So established has this teaching become, that its challenge by experimen~ has hard~y be~n contemplated. I can only find two investigations bearing on this point, and they are not illuminating. In 1910 Paul ROmer [10] inoculated fourteen 2-week-old lambs and four full-grown sheep with intravenous injections of tubercle bacilli, the dose of which was graduated according to the weight of each animal. He found no
488
'IUDERCLE
[August, 192)
differences in the results D.9 noted in animals of different ages. In 1016 SeIter and Burgers [Ill exposed 36 rabbits of various ages to. i~rcction by lnhalation of different quantities of human tubercle bacilli ; they could not evidently show any relation between the age of the animals and their reaction to infection. No doubt manifest, clinically demonstrable tuberculosis in infancy runs a rapidly fatal course in practically every case, but it is not proven that. every tuberculous infection in infan~~ takes such n. course. A cle~r distinction should be made between clinically demonstrable tuberculosis and infection betrayed only by 0. tuberculin reaction. \Vhile the diagnosis of tuberculosis in infancy depended on clinically demonstrable signs, this disease, as pointed out by Hahn [12J, was regarded as rare, and was detected only in an advanced stage, when the infant was cachectic. lIence the tendency to regard tuberculosis in infancy as a wasting disease, and to suspect its presence only when an infa.nt was debilitated. And as this is the terminal stage of the disease, it is not strange that it should have been regarded as invariably fatal. The impression has slowly grown that tuberculosis, notably glandular tuberculosis, may run a benign course, but not till the advent of tuberculin diagnosis, von Pirquet's test in particular, was it possible to demonstrate infection at II much earlier stage and when the child still looks perfectly well. The Xvrays, also, have disclosed forms of tuberculosis undemonstrable by older tests. Hence the conclusion that the rapidly fatal cases of tuberculosis in infancy constitute only a fraction of all the cases infected at this age. It is 0. check on the pessimism of the old school to follow the career of children who, in infancy, gave a positive von Pirquet reaction. Permin [13] has shown that of 15 children found to be infected within the first year of life, G had died, while the remainder, examined at ages ranging from 1 to 7 years, were not only alive but well, with the exception of one with signs of scrofula. There are also the well known observations of Schloss [14], whose account of a. small tuberculosis epidemic in a. hospital for children in 1917 referred to 14 children infected b)' a tuberculous nurse. All developed a positive tuberculin reaction. and 4 constitutionally weak children succumbed to tuberculosis. But the rest remained well, a.lthough all of them during the following winter developed signs of tuberculosis of the bronchial glands which subsequently passed off. Schloss concluded that the prognosis is certainly not bad provided infection is not too massive, and a normal infant lives under hygienic conditions. He added: .. of least importance, contrary to the experience oj others, is the child's age. Bernard and Debre [15] found that of 30 infants exposed to infection by their sputum-positive mothers for 2 to 13 months, only 12 had succumbed to tuberculosis during a maximum observation period of 2 years. These and similar observations discredit the old view that infection in infancy is necessarily of bad omen. Even massive infection is not necessarily fatal, for of six children infected in the first year and still alive at the end .of the third year, Permin found that five had been exposed to massive infection. He concluded tha.t, even with mnssi\'& doses of virus, infection need not inevitably lead to actual disease. If we compare these observations with those of Calmette, \VestenhOler, De~'cke.
August, 1921]
TUBERCULOSIS IN EARLY INFANCY
489
Romer and Cummins [19], as to individuals (belonging to races hitherto tubercle-free) who develop rapidly fatal tuberculosis when they settle in tubercle-positive communities, we may well ask if there is any great difference in resistance to infection as between infants and adults. It should be borne in mind that, as a rule, the infection to which an adult is exposed is far less massive, both absolutely and relatively, than that to which the infant of a consumptive mother is exposed. Even when infection of an infant leads to manifest disease, the resistance shown may be considerably greater than was once thought possible. Among 171 infants dying of tuberculosis, Sehlbach [16J found in two 5·month and in one 7-month old infant, definite signs of localization of the disease. Geipel [17] has even demonstrated calcification in a tuberculous focus in infants aged 6 and 8 months respectively. In 1911, Bardt [18] recorded a case of tuberculosis of the bronchial glands in a child of 18 months, the disease having been diagnosed first when he was only 4 months old. Lederer [20J had also reported three cases of tuberculosis diagnosed in infancy, with survival for a year or more. Similar cases have been recorded by Engel and Schick [21J. Frolich [22J has followed up the case of a child exposed from birth to infection by a nurse. When 9 months old, fretfulness and loss of weight occurred, and three months later there was general debility, with lichen sorofulosorum and signs of tuberculosis of the bronchial glands. A very bad prognosiS was given, but two years later he heard that the child had recovered. I do not, however, argue that infection in infancy may not lead to disease in adult life; investigations I have published elsewhere (23) suggest that early infection may be of sinister importance in adult life If my observations in rabbits are applicable to man, why should the tuberculosis of early infancy so seldom be benign? The source of infection in the tuberculosis of infancy is usually demonstrable and can in most cases be traced to a member of the family. 'rhus the absolute amount of the ingested virus must be great, and relative to the weight of the infant it must be enormous. The older the infant becomes, the less does the quantity of the virus become relative to its weight. Again, the younger the infant, the more intimate is its contact with a consumptive mother. Finally," an adult exposed to massive infection usually enjoys the benefit of previous infection with comparatively small doses, and is therefore relatively immune (note the reverse conditions in the observa.. tions of Calmette, Westenhdfer and others), whereas the infant enjoys no preparatory immunisation before exposure to massive infection by the mother. 'I'he first infection being massive, the body is flooded with virus, the protective mechanism is inadequate, and the blood-stream carries multiple infection to various organs. Thus the clinical evidence as to the gravity of tuberculosis in infancy does not necessarily indicate that the organism's resistance in infancy is less than in childhood or adult life. This problem is rather of theoretical than practical interest, and its solution is not likely to affect practical measures in the tuberculosis. campaign. But it may throw light on aspects of the disease which have hitherto been obscure. We may ultimately concentrate on the prevention of massive infection only, ignoring slight infection. How this is to be effected, whether by removal of the infant from the infected home [24].
490
TUBERCLE
[August, 1921
by segregation of sources of infection, or by prophylactic inoculation with minute doses of tubercle bacilli, it is too early to decide. Forsok rorande ympningstuberkulosens forlopp hos kanin i olika aldrar," Upsala Lakarfor. Forhandl" 1918, Bd. xxiii. [2] Zeitsehr.], Hygiene, 1907, Bd.lvii. [3] Centralbl. f. Bakt., 1916, Bd. lxxviii. [4J Brauers Beitriige zur Klinik de" Tuberkulose, 1911, Bd, xix, {5J Akadem. Aohandl., Upsala, 1914. [6] Norsk Magazin for Laeqeoidenskaben, 1916, Bd. Ixxvii, [7] Akadem, Avandl., Upsala, 1918. [81 Akadem: Avandl., Helsingfors, 1913. (9J Brauers Beitriiqe, Bd. xlx. . [10] Ibid., Bd. xvii. [11] Centralbl. f. Bakt., 1916, Bd. lxxviii, [12] Monatschr. f. Kinderheilk., Bd . x, 1912. (13) Hospitalstidende, 1911t [14] Jahr.], Kinderheilk., 1917, Bd.Txxxv, [15J Bull. Z·Acad. de Med., October 5, 1920. [16] }fiinch. med. Wochenschr., 1908, Bd, lv, {l7J Zeitschr. f. Hygiene. 1906. Bd. liii. {I8J Ref. Mtmatsch», f. Kinderheilk., 1911, Bd. x, f19] "Racial Differences in Susceptibility to Tuberculosis," Brit. Journ, of Tuberculosis, 1920, vol. xiv. {20] Monatschr, f. KillderheiZk., 1914. Bd. xii. [21] Ref. Pollak, Brauers Beitriige, Bd. xix. [22J Norsk Magazi1i for Laegevidenskaben, 1918, Bd. lsxix, {23] Brauers Beiiriuje, 1915, Bd. xxxiv. {24J See BERNARD and DEBRE, Bull. l' Acad. de M~d., October 5. 1920. [1]
U
THE CLIMATIC AND SUNLIGHT THEATl\IENT OF SURGICAL TUBERCULOSIS. By Dr. O. BERNHARD. St. Moritz. HISTORICAL. DURING the past three decades there has been a revolution in the treatment of surgical tuberculosis, and the radical, operative treatment of the surgeon has largely given place to climate-therapy and orthopredic measures. With regard to the two climatic extremes, the maritime and the high altitude, I propose to confine myself to the latter. As a medical "Student, spending my holidays at my home in Samaden (Oberengadin 1,750 metres above the sea) in 1880, I was struck by the remarkable 'Cures effected by a small colony of consumptive Italian visitors, and while I almost daily watched the surgical work of my honoured teacher Professor .Koch er , in Bern, I came to wonder whether operations on surgical tuberculosis might not be superseded by climatic-dietetic treat. ment, supplemented when necessary by orthopredic and other conservative