Mendelian susceptibility to mycobacterial disease in tuberculosis-hyperendemic South Africa

Abstract

Immunodeficiency, whether primary or secondary, results in the disruption of normal immune response and function. Typical presentations of immune deficiency are increased susceptibility to infection, usually in a specific class depending on the immune pathway or cell affected. [1,2] The phenotype is broad, and autoimmunity, immune dysregulation and increased risk for malignancy may also be hallmarks of the immunodeficiency. [2,3] In the absence of secondary immunodeficiency, severe infections in otherwise healthy children can alert clinicians to single-gene inborn errors of immunity or primary immunodeficiency disorders (PIDDs). [1,4] In tuberculosis (TB)-hyperendemic settings such as South Africa (SA), the risk for infection with TB cumulates with exposure, which provides an interesting context for the study of PIDD, in particular Mendelian susceptibility to mycobacterial disease (MSMD). [5][6][7][8] MSMD is molecularly characterised by errors in the interleukin 12 (IL-12) and interferon gamma (IFN-γ) pathway. [9] IFN-γ is a key cytokine in both innate and adaptive responses against viruses and intracellular bacteria, namely mycobacteria. [9][10][11] There is a dynamic balance between the host and the organism that determines the course of TB infection. [4,[12][13][14][15] The risk of progression to active disease is highest in infants aged <12 months and lowest in children aged 5 -10 years, the 'wonder years' . [6] Severe disease implies that there is either poor host control of the infection, i.e. dissemination, or a complex disease manifestation, often with severe sequelae such as TB empyema or pericarditis. [15] Non-severe disease implies that the host has managed to control the pathogen, resulting in contained disease. [15] Impaired response to IFN-γ is caused by mutations in the IFNGR1, IFNGR2, STAT1, CYBB, IRF8 and NEMO genes. [9,10] Deficient production of IFN-γ is associated with mutations in IL12B, IL12RB1, IL12RB2, TYK2, SPPL2a and ISG15. [9,10] MSMD is a PIDD characterised by selective predisposition to infections, typically with BCG or poorly pathogenic mycobacteria (e.g. Mycobacterium avium complex, M. kansasii, M. ghodii). [10,12] Individuals with MSMD are also predisposed to infection with M. tuberculosis complex (MTBC), Salmonella species, Listeria, Candida species, Toxoplasma species, and This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

A rare mutation causing autosomal dominant STAT1 deficiency in a South African multiplex kindred with disseminated BCG infection

“…In SSA where neonatal BCG vaccination is widely practised, disseminated BCG infection has been infrequently described, mainly in HIV-infected children [6,11]. In HIV-uninfected children, severe combined immunodeficiency, chronic granulomatous disease and MSMD have been reported to present with disseminated BCG infection in SSA [11][12][13]. However, the small number of patients in reports from SSA is currently insufficient to establish the most frequent IEI associated with disseminated BCG infection in this region [11][12][13].…”

“…In HIV-uninfected children, severe combined immunodeficiency, chronic granulomatous disease and MSMD have been reported to present with disseminated BCG infection in SSA [11][12][13]. However, the small number of patients in reports from SSA is currently insufficient to establish the most frequent IEI associated with disseminated BCG infection in this region [11][12][13]. Reasons for the scarcity of SSA reports primarily relate to limited laboratory capacity for diagnosing both BCG infection and IEI.…”

Challenges of Diagnosing Mendelian Susceptibility to Mycobacterial Diseases in South Africa

“…Since resistance to mycobacterial infection relies on an efficacious immune system and the immune response is largely determined by the host's genetic makeup, IEI cases that relate to mycobacterial infection are of particular concern in TB-endemic areas like South Africa. MSMD and other IEI cases associated with TB susceptibility could be more prevalent than believed but may be either under-or misdiagnosed [14,32].…”

“…Without an accurate molecular diagnosis, clinicians are not able to understand the disease phenotype well, resulting in a lack of precise treatment for patients and results in a high overall mortality rate in South Africans with IEI, ranging from 25 to 34.5% [20,30,31]. In cases with confirmed diagnoses, treatment regimens are able to be altered by, for instance, increasing clinical surveillance, extending treatment duration, as well as potential supplementation with IFN-γ, to name a few [32].…”

African Society for Immunodeficiency (Asid) Guidelines for Diagnosis and Management of Inborn Errors of Immunity in Africa: Core Concept, Development and Initial Results

“…To support early diagnosis of IEI with Mendelian Susceptibility to Mycobacterial Disease (MSMD), the team in South Africa investigated whether severe, persistent, unusual or recurrent (SPUR) de nitions of TB can be used as a surrogate marker for MSMD for considering IEI [14]. Using the SPUR criteria among a group of 22 patients with TB, a pathogenic mutation in one of MSMD genes, was identi ed in 36% of patients using NGS [15][16]. Thus endemic diseases pose a major challenge in identifying IEIs within the African setting.…”