Current Status of the Management of Mendelian Susceptibility to Mycobacterial Disease in Mainland China
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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.
KeywordsMycobacterium infection immunodeficiency IFN-gamma interleukin-12 receptor beta 1 subunit therapy
Many thanks to the patients and their parents who were involved in this study.
Dr. Ying participated in study design, collected data, performed data analyses, drafted the manuscript, and incorporated revisions, and takes responsibility for the manuscript as a whole.
Prof Wang and Prof Sun conceptualized and designed the study, supervised data collection, and reviewed and revised the manuscript.
Dr. Liu and Dr. Dong support technical and material experiment and performed the statistical analysis.
Dr. Wang, Dr. Hou, Dr. Yao, Dr. Hui, Dr. Zhou, and Dr. Sun collected data and reviewed and revised the manuscript.
All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 1.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.Google Scholar
- 12.Global tuberculosis report 2018. https://www.who.int/tb/publications/global_report/en/. 2018. Accessed 8 Jan 2019.
- 14.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.Google Scholar
- 15.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.Google Scholar
- 16.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.
- 19.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.Google Scholar
- 20.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.Google Scholar
- 22.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.Google Scholar
- 23.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.Google Scholar
- 25.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.Google Scholar
- 27.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.Google Scholar
- 28.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.Google Scholar
- 36.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.Google Scholar