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How Prevent Childhood Infection From Becoming Active Tuberculosis Later in Life
Abstract of address delivered before the Tuberculosis Institute for Nurses, University of Minnesota, Minneapolis, June 14-19, 1926. Published in Northwest Medicine, December 1926.
* * *
The Bearing of Von Pirquet’s and Römer’s Work on our New Conception of Tuberculosis
The use of tuberculin in diagnosis dates back to the first tuberculin era in 1890-91. The early method of using the test, however, was by subcutaneous injection, which was not suitable for wholesale testing. It was a great advance when von Pirquet in 1906-71,2 reported the fact that tuberculin could be used as a local skin test; because, as he had found, the skin of those who have been infected by tubercle bacilli is rendered hypersensitive to the bacillus and its products.
The testing of large groups of people revealed a fact wholly unexpected, that children who were apparently in all respects healthy were sensitized to tuberculin. Not only some children but nearly all children, as shown by Hamburger,3 in Table I, reacted by the time they had attained the age of fifteen years. The accuracy of Table I is supported by the statistics from Harbitz,4 shown in Table II. This surprising prevalence of tubercle infection furnished new problems for solution; for while these children showed infection and were sensitive to tuberculin, they were not ill of tuberculosis. It will be interesting to note to what degree both total and massive infection will be reduced by the intelligent application of present known methods of preventing the spread of bacilli.
Table I
Percentage of children reacting to tuberculin according to age period.
Test repeated when negative (Vienna)
46 children in the 2nd year of whom 4 or 9 per cent reacted
56 children in the 3rd year of whom 11 or 20 per cent reacted 75 children in the 4th year of whom 24 or 32 per cent reacted 50 children in the 5th year of whom 26 or 52 per cent reacted 63 children in the 6th year of whom 32 or 51 per cent reacted 46 children in the 7th year of whom 28 or 61 per cent reacted 30 children in the 8th year of whom 22 or 73 per cent reacted 35 children in the 9th year of whom 25 or 71 per cent reacted 26 children in the 10th year of whom 22 or 85 per cent reacted 29 children in the 11th year of whom 27 or 93 per cent reacted 19 children in the 12th year of whom 18 or 95 per cent reacted 17 children in the 13th year of whom 16 or 94 per cent reacted 17 children in the 14th year of whom 16 or 94 per cent reacted (509 total children, 271 total reactions) |
Much experimentation was then carried out to determine the meaning of the tuberculin reaction, and it was found that the formation of tubercle, in other words, infection, is essential to the establishment of the conditions which produce the tuberculin reaction. This means that all children who react to tuberculin when applied to the skin have been previously infected with bacilli. The natural corollary to this is that infection does not mean disease; there is a difference between tuberculous infection and tuberculous disease. This fact is basic to our understanding of not only clinical tuberculosis but the prevention of tuberculosis also.
Table II
Percentage of children showing tuberculosis infection in postmortem examination
Age | No. of those examined | Free from tuberculosis | Infected with tuberculosis | Died of tuberculosis | Latent tuberculosis | Latent tubercle bacilli | ||
1st year:
1st quarter 2nd quarter 3rd quarter 4th quarter |
82
55 36 28 201 |
76
46 20 19 161 |
%
80 |
6
9 16 9 40 |
%
20 |
4
4 10 6 24 |
1
2 3 |
2
5 5 1 13 |
2 years
3 years 4 years 5 years 6 years 7 years 8 years 9 years 10 years 11 years 12 years 13 years 14 years 15 years
|
65
26 18 16 12 13 20 9 11 14 13 13 13 40 484 |
48
18 12 7 2 7 7 3 3 1 4 4 1 8 286 |
74
69 67 44 20 54 35 33 27 7 31 31 8 20 59 |
17
8 6 9 10 6 13 6 8 13 9 9 12 32 198 |
26
31 33 56 80 46 65 67 73 93 69 69 92 80 41 |
14
4 5 8 8 3 6 3 4 7 6 4 4 19 119 |
1
1 1 … 1 … 6 2 4 4 3 5 8 13 52 |
2
3 … 1 1 2 1 1 … 2 … … … … 27 |
484 | 198 |
The interpretation of the meaning of the tuberculin test and the significance of the immunity created by previous infection was studied most carefully by Römer.5,6 In his phenomenal studies he clarified the nature of the acquired resistance to tuberculosis and greatly advanced our knowledge of the relationship of early infection to clinical disease. He showed that a primary infection often prevented bacilli, which were later injected subcutaneously, from becoming implanted.
It is Römer’s work especially which established the conception that the chronic form of adult tuberculosis is probably due to metastatic infection from foci which resulted from childhood infection; and further that the chronic nature of the adult type of the disease is a result of the immunity gained by the implantation of bacilli which resulted in tubercle formation in early life.
Koch7 had observed in some of his very early experiments that primary subcutaneous infection is not accompanied by inflammatory reaction at the site of inoculation, but that such an inoculation in an animal already tuberculous is accompanied by inflammation and sloughing at the point of injection. He further stated that the bacilli in the nontuberculous animal escaped freely from the seat of inoculation and even found their way to the regional lymph glands and into the general bloodstream, while in the tuberculous animal the bacilli were hindered in their passage through the tissues. Something held them at the point of inoculation, and there was even an attempt at ridding the animal of them through a sloughing process. Regional lymph glands took little part in the defense and the bloodstream was only attained by the bacilli at a late period. Krause8 has shown that the difference in time of bacilli gaining access. to the blood stream is three to four days in the nontuberculous animal, and three to four weeks in the tuberculous.
This observation of Koch was the first recognition of the property of producing a specific inflammatory reaction which is granted to the body cells by a primary infection, the first observation of allergy, which is now recognized as an essential factor in the body’s specific protective mechanism against bacilli.
Fig. 1, a, and b, is a schematic representation of the difference in action of the body in the presence of primary and secondary inoculation of tubercle bacilli. In a, the inoculation of bacilli occurs for the first time and the bacilli readily pass through the tissues to the neighboring lymph glands; while in b, the inoculation occurs in tissues which, because of previous infection, have acquired the specific immunity reaction known as allergy, through which a defensive opposition is at once presented to the invading bacilli, hindering their passage to such an extent that only a few are able, and this only tardily, to pass beyond the point of inoculation and gain access to the neighboring lymph glands and the general circulation.
Fig. 1. a and b illustrate schematically the difference in behavior of tissues towards invading bacilli. In a, specific defense has not been established by previous infection. The bacilli pass through the lymphatic channels to the lymph glands quickly. In b, specific defense has been established by previous infection. Bacilli are held in check immediately under the skin at the point of injection. The tissues between the point of injection and the gland, as well as the gland itself, remain free from infection for a considerable time.
Sources Of Infection
Whence comes this all but universal infection? This question cannot be answered too dogmatically. We assume that the bacilli which produce human infection are either of human or bovine origin, but personally I do not believe the last word has been said as to the relative frequency of the two sources.
In discussing this question in Clinical Tuberculosis9 I quote statistics as shown in Table III from Park and Krumwiede,10 who analyzed 1,038 carefully studied cases of tuberculosis, and showed that prior to eleven years of age about 75 per cent of cases of tuberculosis were caused by human bacilli and 25 per cent by bovine, and after sixteen years 98.69 per cent were due to human and only 1.31 per cent to bovine bacilli. Also Table IV presents an analysis of 1400 cases studied by the Imperial German Board of Health, showing the number of cases of particular types of the disease with the strain of bacillus responsible for each, in which the percentages in childhood and adult life are compared.
Table III–from Park and Krumwiede
Age Period | Per cent of
Human Tuberculosis |
Per cent of Bovine Tuberculosis |
0- 5 years
6-11 years 16 years and over |
73.50
75.00 98.69 |
26.500
25.000 1.31 |
Table IV–from the Imperial German Board of Health
Total no. investigated cases | Types | Per Cent of all Cases Due to Bovine Type | |||
Human | Bovine | In adults | In children | ||
Tuberculosis of the lungs | 811 | 807 | 5 | 0.66 | 0 |
Tuberculosis of the bones and joints | 99 | 95 | 5 | 6.66 | 4.3 |
Meningeal tuberculosis | 33 | 30 | 3 | 0 | 10.34 |
Generalized tuberculosis | 178 | 147 | 33 | 2.5 | 23.18 |
Tuberculosis of the cervical glands | 167 | 120 | 47 | 5.8 | 40.7 |
Tuberculosis of the mesenteric glands | 112 | 78 | 35 | 12.0 | 51.0 |
Totals: | 1400 | 1277 | 128 |
When Koch11 at the London Congress in 1901 declared that human and bovine tuberculosis were different and that there was no danger to human beings from infected cattle, he called attention to the very important but previously hardly suspected fact that human bacilli differ from bovine bacilli. He was wrong in stating that there was no danger to human beings from bovine bacilli. In fact, there is no way of telling how great this danger is. He was correct in his statement that the bacilli differ.
What seems to me to be the most important fact bearing on the question of transmissibility of bovine bacilli to the human race is that, while we recover bovine bacilli from a considerable number of such childhood forms of tuberculosis as that of the miliary and general tuberculosis, we rarely find them in the adult forms, particularly tuberculosis of the lungs. We must assume either that little bovine infection occurs in those who develop clinical tuberculosis in adult life or that the bovine bacilli which are taken into the body during childhood gradually adapt themselves to the human soil, and are transmitted to human bacilli.12 This assumption seems perfectly reasonable and in accordance with the powers of adaptation to different media which is shown by bacilli in laboratory cultures.
Therefore, we must recognize bovine bacilli as potentially able to produce a considerable but an unknown percentage of clinical tuberculosis during both childhood and adult life. An adequate program of prevention of tuberculosis must recognize childhood as a time when infection occurs very generally and institute protective measures against contact with persons suffering from open tuberculosis and against the use of raw milk from dairy cattle infected with tuberculosis. It is best to use only milk from tuberculin-tested cattle, but where this cannot be had pasteurized milk may be used.
The danger of infection is the greater the more intimate the contact. This danger manifests itself in a greater proportion of early infections in children who associate intimately with open tuberculosis, as will be seen by comparing the percentage columns in Table V from Fishberg13; and also in infections produced by larger numbers of bacilli, both of which conditions increase the likelihood of the child at once or later developing an active clinical tuberculosis.
Table V–(Fishberg)
Percentage Giving Positive Reaction
Age | Children of tuberculous parents | Children of non-tuberculous parents | ||
No. of cases | Per Cent | No. of cases | Per Cent | |
Under 1 year
1 to 2 years 3 to 4 years 5 to 6 years 7 to 10 years 11 to 14 years 14 years |
33
49 90 95 244 181 37 |
15.15
55.10 68.88 65.26 71.31 74.58 83.79 |
56
39 80 106 173 134 20 |
10.07
33.33 41.25 50.00 64.74 69.40 75.00 |
Total: | 729 | 608 |
Results Of Early Childhood Infection
When a child first becomes infected with tubercle bacilli, a very important chain of events ensues. The bacilli become enmeshed in the body cells which proliferate and attempt by mechanical means to surround them and wall them off, the same as they would in case of other particles of foreign material.
This purely mechanical action, however, does not last long for both bacilli and body cells are living, and vital action comes into play. The bacilli attempt to make conditions congenial to them and favorable for their growth and multiplication. The cells, on the other hand, attempt to destroy the invading bacilli. In order to do this they develop an entirely new property which they had not possessed until they came in contact with bacilli and bacillary products. This is the property of minimizing the activity of, preventing the spread of, and destroying bacilli.
This property constitutes the mechanism of immunity. It is not constant but increases each time that an infection or spread of infection is overcome. It increases as clinical tuberculosis advances, even though the patient may eventually succumb to the disease. This is evident from the fact that, while a few bacilli will infect an individual who has not previously been infected, a patient with advanced tuberculosis will cast off millions of bacilli from the ulcerated surfaces in the lungs which will pass over the bronchial surfaces without implantation occurring. It decreases during certain infections, such as measles and influenza and also under various stresses of life.
The nature of this immunity is still somewhat obscure. The fact that not only the cells surrounding the tubercle but all cells of the body develop specific immunizing properties shows that the products of the bacillus which stimulate this property gain access to the cells through the circulation.
Of possible properties conferred upon the cells which belong to the immunizing response two stand out very prominently. First of these is the property of producing substances which destroy the bacilli. This is evident from the fact observed particularly after inoculating a tuberculous animal intraperitoneally with bacilli. In a very few minutes the bacilli are degenerated and only a few of them are to be found, suggesting that a destructive action has occurred. The second property is that of reacting with an inflammatory process wherever bacilli are found imbedded in the tissues.
Evidence of the development of a specific immunizing mechanism is shown in the decrease in percentage of mortality and increase in chronicity which follows the advances in age periods, as illustrated in Tables VI and VII from Hamburger.14
Table VI–(Hamburger)
Mortality of Tuberculosis by Age Periods
I | II | III | IV | V | VI | |||
1 Year | 2 years | 3-4 years | 5-6 years | 7-10 years | 11-14 years | |||
0-3 mos. | 4-6 mos. | 7-12 mos. | ||||||
Number of cases | 4 | 49
13 |
32 | 74 | 102 | 38 | 41 | 31 |
Fatal cases | 4 | 44
13 |
27 | 51 | 69 | 23 | 28 | 16 |
% of fatality | 100% | 90-100% | 80% | 70% | 67% | 60% | 68% | 50% |
Table VII–(Hamburger)
Frequency of Healed Tuberculosis by Age Periods
1 year | 2 years | 3-4 years | 5-6 years | 7-10 years | 11-14 years | |
Total number of cases | 49 | 74 | 102 | 38 | 41 | 31 |
Number with signs of healing | 0 | 0 | 7 | 4 | 7 | 10 |
Percentage showing healing | 0 | 0 | 7 | 10 | 17 | 33 |
Chronicity begins to show markedly in the late years of childhood and after the age of fifteen nearly all clinical tuberculosis is of the chronic type.
It is now generally believed that nearly all clinical tuberculosis met in the adult years of life is due to metastatic implantation from childhood infections. While infections from without are not wholly denied, yet it is difficult to persuade oneself that an allergic reaction which will prevent bacilli from entering the bronchial mucous membrane of a patient with advanced tuberculosis would be unable to ward off bacilli coming in contact with the tissues via the air passages. And it seems almost inconceivable for bacilli to gain access to the lung through other portals of entry, such as the intestinal tract, in the presence of allergy. Infection could take place with comparative ease, however, at times when allergy is temporarily in abeyance.
The important results of childhood infection, then, are two: (1) the development of a specific immunizing mechanism; ( 2) the establishment of areas of infection, from which bacilli escape to form metastases which may result in future clinical tuberculosis.
How Prevent Clinical Tuberculosis
The younger the child when infection occurs the less its chance of overcoming it. Therefore, it is especially desirable to shield children from infection during infancy and early childhood.
All else being equal, infections with large numbers of bacilli are more difficult to overcome than infections with few. Therefore, it is essential to shield children from intimate association with those suffering from open tuberculosis and also protect them from the use of infected milk.
When infection has once occurred, the possibility of activation with metastasis should be borne in mind. The picture which represents these early spreads of infection should be familiar to all who have care of children. From the time of the primary focus to the development of definite symptoms the chances are that several or many small foci of infection are overcome. If the metastasis is not caused by too many bacilli, or if too many foci do not develop at one time, there is little or no danger; a heightening of immunity only results. But, on the other hand, if a large focus or several foci become established, then clinical symptoms may appear. Whenever tuberculosis is so marked as to make its presence known by symptoms, the individual needs special care if he is to overcome it.
References Cited:
-
- v. Pirquet: “Diagnostische Verwertung der Allergie.” Wien. klin. Wochenschr. 1907. Nr. 41. S. 1271.
- v. Pirquet: “Der diagnostische Wert der kutanen Tuberkulinreaktion bei der Tuberkulose des Kindesalters auf Grund von 100 Sektionen.” Wien. klin. Wochenschr. 1907. Nr. 28. S. 1369-1374 und Wien. med. Wochenschr. 1907. Nr. 28.
- Hamburger: Kindertuberkulose, Leipzig and Wien., 1910.
- Harbitz: “Untersuchungen über die Tuberkulose im Kindesalter. 1. Die Haufigkeit. 2. Die Formen der Tuberkulose. 3. Angeborene Tuberkulose (Vom pathologischanatomischen Institut zu Kristiania).” Norsk Magazin for Lægevidenshapen, No. 1, pp. 1-36, 1913.
- Römer, Paul H. and Joseph, Karl : “Die Tuberkulose Reinfection.” Bauer’s Beit. zur Klin. der Tuberk. Bd. XVII, 1910, S. 287.
- Römer, Paul H.: “Tuberkulose-Immunitat, Phthiseogenese und praktische Schwindsuchtbekämpfung.” Bauer’s Beit. zur Klin. der Tuberk., Bd. XVII, 1910, S. 383.
- Koch, R.: “Fortsetzung der Mitteilungen über ein Heilmittel gegen Tuberkulose.” Deutsche med. Wochenschrift, 1891, Nr. 3.
- Krause, Allen K.: “Human Resistance to Tuberculosis at Various Ages of Life.” Am. Rev. of Tuberc. 1925. Vol. XI., p. 303.
- Pottenger, F. M.: Clinical Tuberculosis. C. V. Mosby Co., St. Louis, 2d edition, 1922, p. 58.
- Park and Krumwiede: “The Relative Importance of the Bovine and Human Types of Tubercle Bacillin in the Different Forms of Tuberculosis.” Jour. Med. Res., Dec. 1911.
- Koch, R.: “Die Bekämpfung der Tuberkulose unter Berücksichtigung der Erfahrungen, welche bei der erfolgreichen Bekämpfung anderer Infektionskrankheiten gemacht sind.” Report British Congress on Tuberculosis, London, 1901; also Deutsche med. Wochenschrift, 1901.
- Pottenger, F. M.: Clinical Tuberculosis. C. V. Mosby Co., St. Louis., 2d edition, 1922, p. 65.
- Fishberg, Morris: “The Cutaneous Tuberculin Test in Children.” Arch. Ped., Jan. 1925.
- Hamburger: Kind. Tuberk. Leipzig & Wien. 1910.