Although many studies have investigated Mendelian susceptibility to mycobacterial disease (MSMD) worldwide, there is no report of the long-term clinical management and prognosis for MSMD in China.
This is a cohort study from January 2000 to June 2018. Three hundred and twenty-four patients with bacillus Calmette-Guérin (BCG) infection were diagnosed during this period, and those with MSMD diagnosed by genetic and functional experiments were enrolled in the study. The clinical and genetic characteristics and management of these MSMD patients were summarized.
Thirty patients diagnosed with MSMD were followed up. The age at the follow-up end point ranged from 5 to 173 months. Among the patients, IL12RB1 mutations were identified in 22, IFNGR1 mutations in 5, STAT1 mutations in 2, and IFNGR2 mutation in 1. The medium age at onset was 3 months. BCG infection involved multiple organs, including regional infection (8/30; 26.7%) or distant or disseminated infection (22/30; 73.3%). Ten percent (30/324) of patients with BCG infection had a confirmed MSMD diagnosis. Protein expression of IL12RB1 or IFNGR1 was decreased in all patients with IL12RB1 or IFNGR1 mutation, respectively, as indicated by flow cytometry. In addition, 77.8% of patients received rhIFN-γ treatment, which can improve the prognosis of patients with IL12RB1 deficiency. Two patients received stem cell transplantation. Twenty-five patients remained alive at the time of publication.
MSMD is an important cause of BCG infection. Flow cytometric detection of IL12RB1 and IFNGR1 expression is very useful for rapid MSMD diagnosis. rhIFN-γ therapy is effective in patients with MSMD, particularly improving prognosis in those with IL12RB1 deficiency.
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Casanova JL, Abel L. Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol. 2002;20:581–620. https://doi.org/10.1146/annurev.immunol.20.081501.125851.
MacLennan C, Fieschi C, Lammas DA, Picard C, Dorman SE, Sanal O, et al. Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans. J Infect Dis. 2004;190(10):1755–7. https://doi.org/10.1086/425021.
Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J, et al. Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol. 2006;18(6):347–61. https://doi.org/10.1016/j.smim.2006.07.010.
Bustamante J, Arias AA, Vogt G, Picard C, Galicia LB, Prando C, et al. Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nat Immunol. 2011;12(3):213–21. https://doi.org/10.1038/ni.1992.
Bogunovic D, Byun M, Durfee LA, Abhyankar A, Sanal O, Mansouri D, et al. Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science. 2012;337(6102):1684–8. https://doi.org/10.1126/science.1224026.
Hambleton S, Salem S, Bustamante J, Bigley V, Boisson-Dupuis S, Azevedo J, et al. IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med. 2011;365(2):127–38. https://doi.org/10.1056/NEJMoa1100066.
Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramirez-Alejo N, Kilic SS, et al. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med. 2015;212(10):1641–62. https://doi.org/10.1084/jem.20140280.
Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, et al. Immunodeficiencies. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science. 2015;349(6248):606–13. https://doi.org/10.1126/science.aaa4282.
Eletto D, Burns SO, Angulo I, Plagnol V, Gilmour KC, Henriquez F, et al. Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection. Nat Commun. 2016;7:13992. https://doi.org/10.1038/ncomms13992.
Kong XF, Martinez-Barricarte R, Kennedy J, Mele F, Lazarov T, Deenick EK, et al. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat Immunol. 2018;19(9):973–85. https://doi.org/10.1038/s41590-018-0178-z.
Rosain J, Kong XF, Martinez-Barricarte R, Oleaga-Quintas C, Ramirez-Alejo N, Markle J, et al. Mendelian susceptibility to mycobacterial disease: 2014-2018 update. Immunol Cell Biol. 2019;97(4):360–7. https://doi.org/10.1111/imcb.12210.
Global tuberculosis report 2018. https://www.who.int/tb/publications/global_report/en/. 2018. Accessed 8 Jan 2019.
He GX, Zhao YL, Jiang GL, Liu YH, Xia H, Wang SF, et al. Prevalence of tuberculosis drug resistance in 10 provinces of China. BMC Infect Dis. 2008;8:166. https://doi.org/10.1186/1471-2334-8-166.
Lee PP. Disseminated bacillus Calmette-Guerin and susceptibility to mycobacterial infections-implications on bacillus Calmette-Guerin vaccinations. Ann Acad Med Singap. 2015;44(8):297–301.
Zhou Q, Hui X, Ying W, Hou J, Wang W, Liu D, et al. A cohort of 169 chronic granulomatous disease patients exposed to BCG vaccination: a retrospective study from a single Center in Shanghai, China (2004-2017). J Clin Immunol. 2018;38(3):260–72. https://doi.org/10.1007/s10875-018-0486-y.
Kourime M, Akpalu EN, Ouair H, Jeddane L, Benhsaien I, Ailal F, et al. BCGitis/BCGosis in children: diagnosis, classification and exploration. Arch Pediatr. 2016;23(7):754–9. https://doi.org/10.1016/j.arcped.2016.04.003.
Ying W, Sun J, Liu D, Hui X, Yu Y, Wang J, et al. Clinical characteristics and immunogenetics of BCGosis/BCGitis in Chinese children: a 6 year follow-up study. PLoS One. 2014;9(4):e94485. https://doi.org/10.1371/journal.pone.0094485.
Hesseling AC, Rabie H, Marais BJ, Manders M, Lips M, Schaaf HS, et al. Bacille Calmette-Guerin vaccine-induced disease in HIV-infected and HIV-uninfected children. Clin Infect Dis. 2006;42(4):548–58. https://doi.org/10.1086/499953.
Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, et al. International Union of Immunological Societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Clin Immunol. 2018;38(1):96–128. https://doi.org/10.1007/s10875-017-0464-9.
Sakai T, Matsuoka M, Aoki M, Nosaka K, Mitsuya H. Missense mutation of the interleukin-12 receptor beta1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection. Blood. 2001;97(9):2688–94.
de Beaucoudrey L, Samarina A, Bustamante J, Cobat A, Boisson-Dupuis S, Feinberg J, et al. Revisiting human IL-12Rbeta1 deficiency: a survey of 141 patients from 30 countries. Medicine. 2010;89(6):381–402. https://doi.org/10.1097/MD.0b013e3181fdd832.
Cleary AM, Tu W, Enright A, Giffon T, Dewaal-Malefyt R, Gutierrez K, et al. Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor beta 1 deficiency. J Immunol. 2003;170(1):597–603.
Lichtenauer-Kaligis EG, de Boer T, Verreck FA, van Voorden S, Hoeve MA, van de Vosse E, et al. Severe Mycobacterium bovis BCG infections in a large series of novel IL-12 receptor beta1 deficient patients and evidence for the existence of partial IL-12 receptor beta1 deficiency. Eur J Immunol. 2003;33(1):59–69. https://doi.org/10.1002/immu.200390008.
Alinejad Dizaj M, Mortaz E, Mahdaviani SA, Mansouri D, Mehrian P, Verhard EM, et al. Susceptibility to mycobacterial disease due to mutations in IL-12Rbeta1 in three Iranian patients. Immunogenetics. 2018;70(6):373–9. https://doi.org/10.1007/s00251-017-1041-3.
Fieschi C, Dupuis S, Catherinot E, Feinberg J, Bustamante J, Breiman A, et al. Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications. J Exp Med. 2003;197(4):527–35.
Tesi B, Sieni E, Neves C, Romano F, Cetica V, Cordeiro AI, et al. Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-gamma receptor deficiency. J Allergy Clin Immunol. 2015;135(6):1638–41. https://doi.org/10.1016/j.jaci.2014.11.030.
Wang Q, Xia W, Zhao D. Interferon-gamma receptor 1 deficiency in a 19-month-old child: case report and literature review. Zhonghua er ke za zhi. 2014;52(5):387–91.
Lee WI, Huang JL, Lin TY, Hsueh C, Wong AM, Hsieh MY, et al. Chinese patients with defective IL-12/23-interferon-gamma circuit in Taiwan: partial dominant interferon-gamma receptor 1 mutation presenting as cutaneous granuloma and IL-12 receptor beta1 mutation as pneumatocele. J Clin Immunol. 2009;29(2):238–45. https://doi.org/10.1007/s10875-008-9253-9.
Hoshina T, Takada H, Sasaki-Mihara Y, Kusuhara K, Ohshima K, Okada S, et al. Clinical and host genetic characteristics of Mendelian susceptibility to mycobacterial diseases in Japan. J Clin Immunol. 2011;31(3):309–14. https://doi.org/10.1007/s10875-010-9498-y.
van de Vosse E, van Dissel JT. IFN-gammaR1 defects: mutation update and description of the IFNGR1 variation database. Hum Mutat. 2017;38(10):1286–96. https://doi.org/10.1002/humu.23302.
Ouederni M, Sanal O, Ikinciogullari A, Tezcan I, Dogu F, Sologuren I, et al. Clinical features of candidiasis in patients with inherited interleukin 12 receptor beta1 deficiency. Clin Infect Dis. 2014;58(2):204–13. https://doi.org/10.1093/cid/cit722.
de Vor IC, van der Meulen PM, Bekker V, Verhard EM, Breuning MH, Harnisch E, et al. Deletion of the entire interferon-gamma receptor 1 gene causing complete deficiency in three related patients. J Clin Immunol. 2016;36(3):195–203. https://doi.org/10.1007/s10875-016-0244-y.
Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin Immunol. 2014;26(6):454–70. https://doi.org/10.1016/j.smim.2014.09.008.
Wu UI, Holland SM. Host susceptibility to non-tuberculous mycobacterial infections. Lancet Infect Dis. 2015;15(8):968–80. https://doi.org/10.1016/s1473-3099(15)00089-4.
Bax HI, Freeman AF, Anderson VL, Vesterhus P, Laerum D, Pittaluga S, et al. B-cell lymphoma in a patient with complete interferon gamma receptor 1 deficiency. J Clin Immunol. 2013;33(6):1062–6. https://doi.org/10.1007/s10875-013-9907-0.
Esteve-Solé A, Sologuren I, Martínez-Saavedra MT, Deyà-Martínez À, Oleaga-Quintas C, Martinez-Barricarte R, et al. Laboratory evaluation of the IFN-γ circuit for the molecular diagnosis of Mendelian susceptibility to mycobacterial disease. Crit Rev Clin Lab Sci. 2018;55(3):184–204. https://doi.org/10.1080/10408363.2018.1444580.
Many thanks to the patients and their parents who were involved in this study.
This study was supported by the National Natural Science Foundation of China (81172877, 81373221, 81471482) and Children’s Hospital of Fudan University Funding (EK1125180110, EK112520180202).
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Ying, W., Liu, D., Dong, X. et al. Current Status of the Management of Mendelian Susceptibility to Mycobacterial Disease in Mainland China. J Clin Immunol 39, 600–610 (2019). https://doi.org/10.1007/s10875-019-00672-x
- Mycobacterium infection
- interleukin-12 receptor beta 1 subunit