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. 2021 Oct 5;111(10):998-1005.
doi: 10.7196/SAMJ.2021.v111i10.15341.

Mendelian susceptibility to mycobacterial disease in tuberculosis-hyperendemic South Africa

H M Cornelissen  1 , B Glanzmann, A Van Coller, C Engelbrecht, D R Abraham, K Reddy, M Möller, C Kinnear, R H Glashoff, M Esser
Affiliations

Mendelian susceptibility to mycobacterial disease in tuberculosis-hyperendemic South Africa

H M Cornelissen et al. S Afr Med J. .

Abstract

Background: Severe infections in the absence of secondary immunodeficiency can alert clinicians to single-gene inborn errors of immunity/primary immunodeficiency disorders (PIDDs). Mendelian susceptibility to mycobacterial disease (MSMD) is characterised by selective susceptibility to mycobacterial infections due to inborn errors in the interleukin 12-interferon gamma pathway. The South African (SA) burden of hyperendemic tuberculosis (TB) infection provides an interesting context for the study of MSMD.

Objectives: To evaluate whether severe, persistent, unusual or recurrent (SPUR) definitions of TB can be applied in the context of MSMD in SA.

Methods: This study is a retrospective review of an SA PIDD cohort. Patients aged 0 - 15 years with SPUR TB infections, assessed between 2013 and 2018, were identified using a proposed algorithm. HIV infection or other secondary causes for immunodeficiency were excluded. Basic investigations, then focused immunophenotyping and next-generation sequencing, were performed.

Results: A total of 20 patients with a clinical diagnosis of MSMD were identified. A further two, forming part of a family cohort, had pathogenic variants but remain asymptomatic. Infection with Mycobacterium tuberculosis complex predominated (64%), while 27% had BCG infection or non-tuberculous mycobacteria (NTM) infection. Molecular analysis revealed pathogenic variants in 41% of patients with SPUR mycobacterial infection, mainly in those with BCG/NTM infection.

Conclusions: In the SA paediatric population, SPUR TB infections, particularly BCG/NTM, in the absence of secondary immunodeficiency, can alert to possible MSMD. The molecular diagnosis is pivotal, guiding disease classification and influencing clinical approach and management. The diagnosis is complex and requires a multidisciplinary approach with close collaboration between clinical immunologists, bioinformaticians, immunologists, clinical geneticists and genetic counsellors.

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