Pathogenesis of tuberculosis in young children and the formation of an antigen-specific immune response: history lessons rethought
AbstractThe review examines the pathogenesis of tuberculosis in young children. Particular attention is paid to the development of tuberculosis in children of this age in the pre-antibacterial era, since the disease developed naturally – without the influence of vaccination and chemotherapy.
Thus, much attention is paid to the analysis of the tragedy that occurred at the beginning of 1930 in the German city of Lübeck, when 251 newborn children, as a result of a tragic mistake, were administered a virulent strain of Mycobacterium tuberculosis (MBT) three times per os instead of the BCG vaccine. As a result, they developed tuberculosis and 77 (30.7 %) children died. Posthumously, 72 of them underwent a pathological-anatomical study and bacteriological culture of the material, which confirmed the presence of virulent MBT, and the picture of the development of the tuberculosis process until the moment of death was described, since the children died at different times after the administration of MBT, the last one died on the 313th day.
The data obtained from autopsy have not yet been evaluated and fully characterized. Major contributions to the assessment of these events were made by P. Donald et al., who examined the documents describing these events. It is important to note that after this, the surviving children did not develop tuberculosis for 12 years, while they were monitored. Of the surviving children, 90 % had positive reactions to the tuberculin skin test, which could have been a reaction to both the introduction of virulent mycobacteria and, probably, the vaccine strain of BCG. Due to the low specificity of tuberculin tests, it was not possible to determine this reliably.
Only now it has been possible to obtain skin tests based on the MBT-specific proteins ESAT6 and CFP10, which make it possible to differentiate these conditions with almost 100 % specificity. Data from Russian scientists obtained during the period before the advent of anti-tuberculosis drugs are also presented.
The review also provides modern views on the development of tuberculosis in children, starting from intrauterine development, the moment of birth, based on an analysis of the immune mechanisms of the development of tuberculosis, which is especially important to consider when creating new vaccines against tuberculosis in children in different age groups.
Keywords:tuberculosis; pathogenesis; tuberculosis infection
For citation: Kudlay D.A. Pathogenesis of tuberculosis in young children and the formation of an antigen-specific immune response: history lessons rethought. Immunologiya. 2024; 45 (3): 278–89. DOI: https://doi.org/10.33029/1816-2134-2024-45-3-278-289 (in Russian)
Funding. The study had no sponsor support.
Conflict of interests. The author declares no conflict of interests.
References
1. World Health Organization. Global tuberculosis report 2022. World Health Organization, 2022. URL: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022
2. Clinical guidelines «Tuberculosis in adults» (2024-2025-2026) (05.15.2024) (Approved by the Ministry of Health of the Russian Federation). Moscow. 2024, 167 p. URL: https://cr.minzdrav.gov.ru/recomend/16_3 (in Russian)
3. Clinical guidelines «Tuberculosis in children» (05.31.2022) (Approved by the Ministry of Health of the Russian Federation). Moscow. 2022, 111 p. https://cr.minzdrav.gov.ru/recomend/507_2 (in Russian)
4. Clinical guidelines «Latent tuberculosis infection in children» (Approved by the Working group of the specialized commission on phthisiopediatrics of the Ministry of Health of the Russian Federation). Moscow. 2024, 76 p. URL: https://roftb.ru/netcat_files/userfiles/KR%20LTI%20u%20detey.pdf (in Russian)
5. Borodulina E.A., Kudlay D.A., Kuznetsova A.N., Doktorova N.P., Borodulin B.E., Kalashnikova E.V. Possibilities of the Enzyme-Linked Immunospot Assay (ELISPOT) method in carrying out anti-tuberculosis measures in patients with HIV infection. Immunologiya. 2021; 42 (5): 536–44. DOI: https://doi.org/10.33029/0206-4952-2021-42-5-536-544 (in Russian)
6. Borodulina E.A., Kudlay D.A., Kuznetsova A.N., Gladunova E.P, Kalashnikova E.V. The use of the ELISPOT technological platform in the diagnosis of tuberculosis infection in patients with HIV infection. Immunologiya. 2021; 42 (4): 395–402. DOI: https://doi.org/10.33029/0206-4952-2021-42-4-395-402 (in Russian)
7. Poddubnaya L.V., Shilova E.P., Kudlay D.A., Doktorova N.P. Immunodiagnostic tests in the assessment of specific sensitization to M. tuberculosis in children under the current epidemiological situation. Tuberculosis and Lung Diseases. 2021; 99 (11): 47–54. DOI: http://doi.org/10.21292/2075-1230-2021-99-11-47-54 (in Russian)
8. Kudlay D.A., Doktorova N.P. ESAT-6 and CFP-10 antigens as a biotechnology molecule substrate. applications in medicine. Russian Journal of Infection and Immunity [Infektsiya i immunitet]. 2022; 12 (3): 439–49. DOI: http://doi.org/10.15789/2220-7619-EAC-1763 (in Russian)
9. Morozova T.I., Doktorova N.P. Latent tuberculosis infection in risk groups of the adult population of the Saratov Region. Meditsinskiy Sovet. 2023; 17 (4): 92–100. DOI: http://doi.org/10.21518/ms2023-054 (in Russian)
10. Shovkun L.A., Aksenova V.A., Kudlay D.A., Sarychev A.M. The role of immunological tests in the diagnosis of tuberculosis infection in children with juvenile idiopathic arthritis (JIA). Eur Resp Journal, Supplement. 2018; 52 (S62): PA2733. DOI: http://doi.org/10.1183/13993003.congress-2018.PA2733
11. WHO consolidated guidelines on tuberculosis. Module 2: screening – systematic screening for tuberculosis disease. Geneva: World Health Organization; 2021. URL: https://www.who.int/publications/i/item/9789240022676
12. Kisel A.A. Tuberculosis in children. Kharkiv, 1922: 16. (in Russian)
13. Model L.M., Sidelnikova E.F. To characterize the manifestations of tuberculosis in children. Tuberculosis issues. 1925; (1): 40–5. (in Russian)
14. Markuzon V.D. Clinic of pulmonary tuberculosis in children and adolescents. Practical guide for doctors. In D.I. Shifmana ed. Moscow: Medgiz, 1934. 400 p. (in Russian)
15. Medovikov P.S. Tuberculosis in childhood. Leningrad: Practical medicine, 1926. 252 p. (in Russian)
16. Moegling A. Die «Epidemiologie» der Lübecker Säuglingstuberkulose. In: Moegling A., Schümann P., Kleinschmidt H., et al., eds. Die Säuglingstuberkulose in Lübeck. Berlin, Springer Verlag, 1935.
17. Donald P., Kaufmann S., Thee S., Mandalakas A.M., Lange C. Pathogenesis of tuberculosis: the 1930 Lübeck disaster revisited. Eur. Respir. Rev. 2022; 31: 220046. DOI: http://doi.org/10.1183/16000617.0046-2022
18. Hunter R.L. The Pathogenesis of Tuberculosis – The Koch Phenomenon Reinstated. Patogens. 2020; 9 (10): 813. DOI: http://doi.org/10.3390/pathogens9100813
19. Lange L. Die Tuberkuloses chutzimpfungen in Lübeck. Klin Wchnschr. 1930; 24: 1105–8. DOI: http://doi.org/10.1007/BF01737577
20. Friedberger E. Betrachtungen über die Misserfolge der Calmette–Impfung mit BCG in Lübeck. Deutsche med Wochschr. 1930; 56: 1300–03. DOI: http://doi.org/10.1055/s-0028-1125847
21. Jänasch H., Remé G. Röntgenbefunde im Bereich des Thorax bei der Lübecker Säuglingstuberkulose. Berlin, Heidelberg, Springer. 1935; pp. 326–65.
22. Kleinschmidt H. Untersuchungen der als Neugeborene tuberkuloseinfizierten Lübecker Kinder im Alter von 12 Jahren. Beitr z Klinik d Tuberk u spez Tuberk-Forsch. 1943; 99: 291–335. DOI: http://doi.org/10.1007/BF02139863
23. De Assis A. The oral application of BCG. Bibl Tuberc. 1957; 13: 105–130.
24. Klotz M. Über Kindertuberkulose. Teil II. Die Lehren der Lübecker Säuglingstuberkulose von 1930. 2nd ed. Germany, Neue Deutsche Klinik, 1934; pp. 224–47.
25. Kudlay D.A. Hybrid proteins CFP10 and ESAT6. A path from developing a molecule to population screening for TB infection. Immunologiya. 2021; 42 (2): 166–74. DOI: https://doi.org/10.33029/0206-4952-2021-42-2-166-174 (in Russian)
26. Tran D., Patel K., Ashfaq A., et al. Disseminated Miliary and Intestinal Tuberculosis Mimicking Inflammatory Bowel Disease. Cureus. 2023; 15 (12): e50002. DOI: http://doi.org/10.7759/cureus.5000
27. Vargas Rodríguez A.E., Godinez Vidal A.R., Alcántara Gordillo R., et al. A Case Report and Literature Review of Intestinal Perforation Due to Tuberculosis. Cureus. 2023; 15 (8): e43241. DOI: http://doi.org/10.7759/cureus.43241
28. Rich A.R. The different types of tubercle bacillus and their relation to tuberculosis in man and in lower animals. In: Rich A.R., ed. The Pathogenesis of Tuberculosis. New York, Charles C. Thomas, 1952; pp. 28–79.
29. Grosset J. Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary. Antimicrob. Agents Chemother. 2003; 47: 833–6. DOI: http://doi.org/10.1128/AAC.47.3.833-836.2003
30. Kagramanov A.I. Early dissemination of tuberculosis bacilli in the child’s body. In the book: Tuberculosis in young children. In Z.A. Lebedeva, A.E. Rabukhina ed. Moscow: Medgiz. 1947: 18–28. (in Russian)
31. Jenkins H.E. Global burden of childhood tuberculosis. Pneumonia 2016; 8: 24. DOI: http://doi.org/10.1186/s41479-016-0018-6
32. Wallgren A. The time-table of tuberculosis. Tubercle. 1948; 29: 245–51. DOI: http://doi.org/10.1016/S0041-3879(48)80033-4
33. Lincoln E.M. Course and prognosis of tuberculosis in children. Am. J. Med. 1950; 9: 623–32. DOI: http://doi.org/10.1016/0002-9343(50)90212-9
34. Behr M.A., Edelstein P.H., Ramakrishnan L. Revisiting the timetable of tuberculosis. BMJ. 2018; 362: k2738. DOI: http://doi.org/10.1136/bmj.k2738
35. Yakhnis B.L. Initial forms of tuberculosis in children (on the issue of the clinic of the anteallergic period). Tuberculosis problems. 1947; (4): 40–7. (in Russian)
36. Sorkina E.Z. Primary tuberculosis infection in children. Moscow: Medgiz, 1960. 160 р. (in Russian)
37. Martinez L., Cords O., Horsburgh C.R., et al. The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis. Lancet. 2020; 395: 973–84. DOI: http://doi.org/10.1016/S0140-6736(20)30166-5
38. Seddon J.A., Shingadia D. Epidemiology and disease burden of tuberculosis in children: a global perspective Infection and Drug Resistance. 2014; (7): 153–65. DOI: http://doi.org/10.2147/IDR.S45090
39. Seddon J.A., Chiang S.S., Esmail H., Coussens A.K. The Wonder Years: What Can Primary School Children Teach Us About Immunity to Mycobacterium tuberculosis? Front Immunol. 2018; 9: 2946. DOI: http://doi.org/10.3389/fimmu.2018.02946
40. Coppola M., Villar-Hernández R., van Meijgaarden K.E., Latorre I., Muriel Moreno B., Garcia-Garcia E., et al. Cell-Mediated Immune Responses to in vivo-Expressed and Stage-Specific Mycobacterium tuberculosis Antigens in Latent and Active Tuberculosis Across Different Age Groups. Front Immunol. 2020; 11: 103. DOI: http://doi.org/10.3389/fimmu.2020.00103
41. Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol. 2007; 7: 379–90. DOI: http://doi.org/10.1038/nri2075
42. Robinson D.P., Klein S.L. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm. Behav. 2012; 62: 263–71. DOI: http://doi.org/10.1016/j.yhbeh.2012.02.023
43. Teilmann S.C., Clement C.A., Thorup J., Byskov A.G., Christensen S.T. Expression and localization of the progesterone receptor in mouse and human reproductive organs. J. Endocrinol. 2006; 191: 525–35. DOI: http://doi.org/10.1677/joe.1.06565
44. Jones L.A., Kreem S., Shweash M., Paul A., Alexander J., Roberts C.W. Differential modulation of TLR3- and TLR4-mediated dendritic cell maturation and function by progesterone. J Immunol. 2010; 185: 4525–34. DOI: http://doi.org/10.4049/jimmunol.0901155
45. Menzies F.M., Henriquez F.L, Alexander J., Roberts C.W. Selective inhibition and augmentation of alternative macrophage activation by progesterone. Immunology. 2011; 134: 281–91. DOI: http://doi.org/10.1111/j.1365-2567.2011.03488.x
46. Klein S.L., Flanagan K.L. Sex differences in immune responses. Nat Rev Immunol. 2016; 16: 626–38. DOI: http://doi.org/10.1038/nri.2016.90
47. Lee J.H., Ulrich B., Cho J., Park J., Kim C.H. Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol. 2011; 187: 1778–87. DOI: http://doi.org/10.4049/jimmunol.1003919
48. Simon A.K., Hollander G.A., McMichael A. Evolution of the immune system in humans from infancy to old age. Proc Biol Sci. 2015; 282: 20143085. DOI: http://doi.org/10.1098/rspb.2014.3085
49. Marais B.J., Gie R.P., Schaaf H.S., et al. The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis. 2004; 8 (3): 278–85. PMID: 15139465.
50. Schaaf H.S., Gie R.P., Kennedy M., Beyers N., Hesseling P.B., Donald P.R. Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 30-month follow-up. Pediatrics. 2002; 109 (5): 765–71. DOI: http://doi.org/10.1542/peds.109.5.765
51. Kollmann T.R., Levy O., Montgomery R.R., Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity. 2012; 37: 771–83. DOI: http://doi.org/10.1016/j.immuni.2012.10.014
52. Guilmot A., Hermann E., Braud V.M., Carlier Y., Truyens C. Natural killer cell responses to infections in early life. J Innate Immun. 2011; 3: 280–8. DOI: http://doi.org/10.1159/000323934
53. Manser A.R., Uhrberg M. Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance. Cancer Immunol Immunother. 2016; 65: 417–26. DOI: http://doi.org/10.1007/s00262-015-1750-0
54. Georgountzou A., Papadopoulos N.G. Postnatal innate immune development: from birth to adulthood. Front Immunol. 2017; 8: 957. DOI: http://doi.org/10.3389/fimmu.2017.00957
55. Kollmann T.R., Crabtree J., Rein-Weston A., Blimkie D., Thommai F., Wang X.Y., et al. Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol. 2009; 183: 7150–60. DOI: http://doi.org/10.4049/jimmunol.0901481
56. Jenkins H.E., Yuen C.M., Rodriguez C.A., Nathavitharana R.R., McLaughlin M.M., Donald P., et al. Mortality in children diagnosed with tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2017; 17: 285–95. DOI: http://doi.org/10.1016/S1473-3099(16)30474-1
57. Yakub R.M. Data on mortality from tuberculosis per 10,000 population of Moscow in 1926/1927. Tuberculosis issues. 1931; (3-4): 386–7. (in Russian)
58. Trunz B.B., Fine P., Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet. 2006; 367: 1173–80. DOI: http://doi.org/10.1016/S0140-6736(06)68507-3
59. Dockrell H.M., Smith S.G. What Have We Learnt about BCG Vaccination in the Last 20 Years? Front. Immunol. 2017; 8: 1134. DOI: http://doi.org/10.3389/fimmu.2017.01134