Mendelian susceptibility to mycobacterial diseases: An overview

INTRODUCTION — The conditions grouped together under Mendelian susceptibility to mycobacterial diseases (MSMD; MIM #209950) are caused by genetic defects affecting the interactions of mononuclear phagocytes and T helper cells around the synthesis and response to interferon (IFN) gamma, often referred to as the T helper cell type 1 (Th1) pathway [1]. These diseases were recognized through severe adverse effects related to the administration of Bacillus Calmette-Guérin (BCG), the live-attenuated tuberculosis vaccine, in the first days of life. In countries in which BCG is not given, the clinical and infectious manifestations of MSMD may differ, as infections are dominated by environmental mycobacteria but also dimorphic yeasts and bacteria. In addition, anticytokine autoantibodies that block IFN-gamma, the critical mediator of this pathway, mimic the genetic disorders and should be considered in the differential for MSMD.

Infectious agents in patients with MSMD tend to be weakly virulent environmental organisms including mycobacteria (the nontuberculous mycobacteria [NTM], BCG, occasionally Mycobacterium tuberculosis); bacteria (salmonellae, some Burkholderia, Listeria); fungi, especially the dimorphic molds (Histoplasma, Blastomyces, Coccidioides, cryptococci); and the intracellular parasite Leishmania. In addition, herpes virus family infections are more common and can be severe, including herpes simplex virus (HSV) type 1 and 2, cytomegalovirus (CMV), and Epstein-Barr virus (EBV), which can cause EBV+ neoplasms (table 1). Thus, while the name of this group of diseases was coined from susceptibility to mycobacterial infections, these conditions really involve susceptibility to the broader group of intracellular infections of macrophages, including bacteria, fungi, and viruses.

This topic reviews the pathogenesis, typical presentation, diagnosis, and general management. Specific diseases are reviewed separated. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

PATHOGENESIS — The ability of macrophages to kill intracellular pathogens depends heavily upon the functional integrity of their interaction with T cells, which is mediated by both cell surface markers and soluble cytokines. Interferon (IFN) gamma is a pleiotropic cytokine, produced predominantly by T helper cell type 1 (Th1) cells, that is essential for elimination of the numerous infectious organisms (bacterial, parasitic, and mycobacterial) that target and reside in the intracellular niche [2-8]. This same set of pathways is also critical in the control of certain viral infections, especially those of the herpes family. (See "Pathogenesis of nontuberculous mycobacterial infections".)

When macrophages are infected with mycobacteria or other intracellular pathogens, they produce the cytokines interleukin (IL) 12 (a heterodimer of IL-12 p40 plus IL-12 p35) [9], which stimulates T cells and natural killer (NK) cells via its cell surface heterodimeric receptor (IL-12Rb1 plus IL-12Rb2) and IL-23 (a heterodimer of IL-12 p40 plus IL-23 p19). In response to stimulation with IL-12 and IL-23, activated T cells and NK cells produce IFN-gamma (figure 1). IFN-gamma binds to its cell surface heterodimeric receptor (IFNGR1 and IFNGR2), leading to receptor dimerization. The Janus kinases, JAK1 and JAK2, are tyrosine kinases constitutively associated with the intracellular IFNGR1 and IFNGR2 chains, respectively. With receptor occupation, JAK1 and JAK2 transphosphorylate each other, leading to phosphorylation of the intracellular portion of IFNGR1. This phosphorylated site recruits and facilitates the phosphorylation of signal transducer and activator of transcription (STAT) 1, making pSTAT1. pSTAT1 homodimerizes and then translocates to the nucleus, where it binds to promoters of IFN-gamma-regulated genes (figure 2) [10,11].

IFN-gamma activation leads to the production of tumor necrosis factor (TNF) alpha, further upregulation of IL-12 production, and production of superoxide through the NADPH oxidase, among other properties. The specific effector mechanism by which IFN-gamma promotes mycobacterial killing remains unknown. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Activation of NADPH oxidase'.)

Many genes are impacted by the IL-12/IFN-gamma pathway and regulate it in turn. MSMD typically refers to defects in IFNGR1, IFNGR2, IL-12 receptor beta 1 (IL12RB1), IL-12 receptor beta 2 (IL12RB2), IL-12 p40 (IL12B), STAT1, tyrosine kinase 2 (TYK2), IFN regulatory factor 8 (IRF8), the zinc-finger transcription factor GATA2 (GATA2), IFN-stimulated gene 15 (ISG15), IKBKG (which encodes the NFKB essential modulator [NEMO]), NFKBIA, RORgamma/RORgammaT (RORC), and signal peptide peptidase-like 2A (SPPL2A) [12]. Each specific defect is discussed in detail separately. The genetic defect is unidentified in approximately half of patients with disseminated nontuberculous mycobacterial (NTM) disease. Anticytokine autoantibodies to IFN-gamma account for some of the cases in which MSMD defects are not found. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

PRESENTATION AND CLINICAL FEATURES — Patients with MSMD typically present with severe Bacillus Calmette-Guérin (BCG; a live-attenuated strain of Mycobacterium bovis used in a vaccine to prevent tuberculosis and other mycobacterial infections), environmental nontuberculous mycobacterial (NTM), or other infections (table 1) [13]. As BCG vaccination is given in the first days of life, patients tend to present in early childhood, weeks to months after vaccination, but the times can vary.

Clinical features of disseminated NTM infection are nonspecific and may include fever, weight loss, diarrhea, generalized lymphadenopathy, generalized cutaneous lesions, diffuse abdominal tenderness, hepatosplenomegaly, and ascites. Symptoms and signs reflect the major sites of involvement (eg, bone marrow, lymphoreticular system, gastrointestinal tract, lungs). Partial defects, such as that caused by the autosomal-dominant (AD) partial interferon (IFN) gamma receptor 1 (ADIFNGR1) deficiency, often present with more limited disease such as NTM osteomyelitis and often later in childhood or even adulthood. Skin lesions are common in patients with disseminated infection. The clinical manifestations of disseminated disease are discussed in detail separately. (See "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children", section on 'Clinical features'.)

Most cases of disseminated BCG infection present within weeks to months of immunization. Clinical manifestations are similar to those for environmental NTM infection, with a few exceptions. The lymph nodes draining the site of inoculation may fistulize to skin and surrounding tissues. Diffuse disseminated disease with extensive liver, gut, and bloodstream involvement; meningitis; brain abscesses; and osteomyelitis may occur. (See "Prevention of tuberculosis: BCG immunization and nutritional supplementation", section on 'Safety and adverse effects'.)

The mode of presentation and the particular mycobacterial strain depend upon geographic location and whether BCG vaccine was administered [14]:

●In countries that administer BCG vaccine, the clinical presentation is usually infection with the vaccine strain. Many labs have difficulty distinguishing BCG from tuberculosis (TB) in routine testing, so the diagnosis of disseminated TB in an infant or child who was BCG vaccinated should always include MSMD in the differential.

●In countries where the first encounter with mycobacteria is via environmental exposure, infection with a wide variety of NTM occurs, such as Mycobacterium avium complex, Mycobacterium fortuitum, Mycobacterium chelonae, or Mycobacterium kansasii.

Disease severity and age of onset depend upon the part of the IFN-gamma pathway affected and the degree of the genetic defect (partial or complete) (table 2). Patients with complete defects typically present in early childhood with disseminated disease [14], whereas those with partial or less severe defects in IFNGR1, IRF8, or IL12RB1 may present in adolescence or adulthood with milder recurrent infections. Patients who live in highly M. tuberculosis (TB) endemic parts of the world may present with disseminated TB [1]. MSMD defects rarely if ever present as isolated or recurrent lung disease, especially in adulthood.

Certain clinical features suggest particular defects. Examples include:

●NTM osteomyelitis in patients with AD partial IFN-gamma receptor deficiencies (see "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'Autosomal dominant partial IFNGR1 deficiency')

●Increased susceptibility to severe viral infections, including cytomegalovirus (CMV), respiratory syncytial virus (RSV), varicella-zoster virus (VZV), and parainfluenza virus, in patients with autosomal-recessive (AR) signal transducer and activator of transcription 1 (STAT1) deficiency (see "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'STAT1 defects')

●Mucocutaneous candidiasis in patients with STAT1 gain-of-function (GOF) pathogenic variants, interleukin 12 receptor beta 1 (IL12RB1) deficiency, and those with AD NFKBIA mutations (see "Chronic mucocutaneous candidiasis", section on 'Signal transducer and activator of transcription (STAT1) dysfunction')

●Infection with dimorphic fungi in patients with STAT1 GOF pathogenic variants, IFN-gamma receptor deficiencies, and IL-12RB1 deficiency

●Ectodermal dysplasia, as well as inflammatory bowel disease, with IKBKG and NFKBIA pathogenic variants

●Absolute circulating monocytopenia, natural killer (NK) cell cytopenia, B cell lymphopenia, myelodysplasia, myeloid malignancies, pulmonary alveolar proteinosis, or disseminated warts in patients with GATA2 deficiency (see "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)')

GENERAL APPROACH TO DIAGNOSIS — An underlying genetic cause should be sought in all children and adults with recurrent or disseminated nontuberculous mycobacterial (NTM) infection or disseminated Bacillus Calmette-Guérin (BCG) infection. The more common pediatric condition of isolated cervical or thoracic NTM lymphadenopathy has not been genetically characterized, although rarely these cases have had autosomal-dominant (AD) partial interferon (IFN) gamma receptor 1 deficiency (ADIFNGR1). Young children presenting with isolated cervical NTM adenitis are typically not screened for MSMD unless the infections are difficult to treat or recur. For those with disseminated disease, proper treatment of MSMD hinges upon identification of the underlying molecular defect, the specific organism causing the infection, and the extent of disease [15].

Identification of the pathogenic mycobacteria — Definitive determination of the specific infecting mycobacteria is important for choosing treatment and for determining epidemiology. There are over 150 different mycobacterial species. Methods currently in use include culture, direct molecular identification, and proteomic detection. In disseminated disease, NTM frequently can be grown from mycobacterial blood cultures (these need to be ordered separately from routine blood cultures). For more isolated disease, such as NTM osteomyelitis, culture of the infected tissue is typically required to make the diagnosis. If histopathology demonstrates acid-fast bacilli (AFB) and mycobacterial cultures are not performed or are negative, then direct polymerase chain reaction (PCR) on tissue samples may allow determination of the NTM species. When the suspicion differential is between BCG and M. tuberculosis, molecular typing is required to distinguish them [16]. Molecular drug-resistance testing can be done molecularly, but antibiotic susceptibility testing still requires growth in culture. Diagnostic testing for NTM infection is discussed in greater detail separately. (See "Microbiology of nontuberculous mycobacteria" and "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children", section on 'Diagnosis' and "Nontuberculous mycobacterial lymphadenitis in children", section on 'Diagnosis' and "Nontuberculous mycobacterial skin and soft tissue infections in children", section on 'Diagnosis'.)

Immunologic testing — Cytokine secretion and response and cell-surface or intracellular molecule detection by flow cytometry have been used as research tests but suffer from poor standardization and difficulty in transporting live cells to specialty labs for testing. In addition, functional tests to interrogate pathways are not definitive, and no functional tests are available to exclude all forms of MSMD [17]. Since the purpose of the functional tests is to guide the exploration of defects in specific genes, it is now easier, faster, more reliable, and much less expensive to move right to molecular testing (gene panels or whole exome or genome; in the case of panels, it is imperative to know which genes are included) (see 'Identification of the molecular defect' below). With molecular tests in hand, there will still be variants of uncertain significance (VUS) that will need functional confirmation, which can be done with commercial or research labs, but will be focused on select pathways. The findings expected for each known defect are shown in the table (table 2). Surface expression of IFNGR1 (CD119) can be determined by flow cytometry, but it not widely available. Absence suggests recessive IFNGR1 deficiency, while excess IFNGR1 display on the cell surface suggests the dominant partial form of deficiency, ADIFNGR1. (See "Flow cytometry for the diagnosis of inborn errors of immunity".)

Identification of the molecular defect — Genetic testing is the only definitive way to identify genetic diseases, and the molecular diagnosis affects treatment decisions, such as IFN-gamma therapy or hematopoietic cell transplantation (HCT), and prognosis [18]. Candidate genes can be screened individually in panels by whole-exome sequencing (WES) or by whole-genome sequencing (WGS). Particular attention is necessary when a defect in the IKBKG gene is suspected, as the IKBKG gene encoding NEMO has pseudogenes that make genomic sequencing difficult to interpret. Thus, sequencing of complementary DNA (cDNA), derived from spliced IKBKG mRNA, is required to make a reliable diagnosis of IKBKG mutation. GATA-binding protein 2 (GATA2) deficiency can be caused by intronic pathogenic variants that are missed on WES. (See "Laboratory evaluation of the immune system", section on 'Advanced genomic studies for all forms of IEIs'.)

The purified protein derivative [PPD] test and the IFN-gamma release assay (IGRA; diagnostic tests for M. tuberculosis infection) may be difficult in patients with MSMD. In general, NTM do not provoke a positive IGRA, which depends on the antigens ESAT6 and CFP10 in M. tuberculosis but not in BCG (note that M. kansasii, M. marinum and M. szulgai can also give positive IGRA assay results). Defects in the IFN-gamma/interleukin (IL) 12 pathway may give variable results depending on the specific organism and the specific defect. It is important to be aware that anti-IFN-gamma autoantibodies cause an indeterminate IGRA since the antibody blocks detection of IFN-gamma in the positive control tube [19].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis in patients with disseminated nontuberculous mycobacterial (NTM) or BCG infections includes the following:

●T cell immunodeficiencies, such as severe combined immunodeficiency (SCID) or combined immunodeficiency syndromes are particularly associated with disseminated BCG infections but much less with NTM. Patients with SCID typically have very low naïve T cells and impaired proliferative responses to mitogens such as phytohemagglutinin (PHA), typically present in early infancy, and have a broad susceptibility to infection. These children should be identified on newborn T cell receptor excision circle (TREC) screening. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Diagnosis' and "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects' and "Combined immunodeficiencies: An overview".)

●Hairy cell leukemia has a high incidence of disseminated NTM, much more than other lymphoid malignancies. This disease has an adult onset, distinct from MSMD defects. (See "Clinical features and diagnosis of hairy cell leukemia".)

●Autoantibodies to interferon (IFN) gamma cause disseminated NTM infections. Most reported patients are from Southeast Asia and have adult-onset disease [20-24]. Some patients with these autoantibodies to IFN-gamma present with other opportunistic infections (eg, Cryptococcus neoformans, Histoplasma capsulatum, and Talaromyces [Penicillium] marneffei), salmonellosis, or severe varicella-zoster virus (VZV) infection, with or without NTM infections [22]. No familial clustering has been reported. In patients with late-onset disseminated mycobacterial infection, anti-IFN-gamma antibodies with neutralizing activity should be sought. Options for treatment in these patients include targeted anti-B cell therapy [25,26]. These patients will invariably have an indeterminate IFN-gamma release assay due to the presence of neutralizing anti-IFN-gamma autoantibodies, which block the signal in the positive control tube [19].

●Secondary immunodeficiency due to immune-suppressing medications. Tumor necrosis factor (TNF) alpha blockers, Janus kinase (JAK) inhibitors, and interleukin (IL) 12/23 blockers increase susceptibility to mycobacterial infection [27,28].

GENERAL APPROACH TO TREATMENT — Aggressive treatment with antimycobacterial antibiotics remains the most important management for patients with these disorders [29,30]. Cytokine replacement therapy with interferon (IFN) gamma is an additional treatment option in patients with defects that preserve the IFN-gamma receptor, but it should be used with expert consultation.

The antibiotics used for NTM infections in patients with MSMD are the same as those used for other patients, but treatment intensity and duration in patients with MSMD are greater since the burden of disease is typically higher and the immune contribution is lower [31]. The duration of treatment is based upon clinical response, radiologic improvement, and microbiologic cure. Patients should be maintained on secondary antibiotic prophylaxis once the infection is successfully cleared, typically with daily azithromycin. Treatment of NTM infections is discussed in greater detail separately. (See "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children".)

Most MSMD, other than complete IFN-gamma receptor defects and complete (autosomal-recessive [AR]) signal transducer and activator of transcription 1 (STAT1) defects, are responsive, at least to some degree, to IFN-gamma therapy [1]. IFN-gamma therapy is typically added for defects with residual response to IFN-gamma therapy (such as autosomal-dominant [AD] partial IFN-gamma receptor 1 [ADIFNGR1] deficiency) when response to antibiotic management is unsuccessful at clearing or ameliorating infection after several months of adherent therapy. Patients with interleukin (IL) 12 receptor beta 1 (IL-12RB1) defects may respond to IFN-gamma therapy but may develop hyperinflammation, such as a hemophagocytic lymphohistiocytosis (HLH) like response, so close monitoring is necessary when IFN-gamma therapy is used. Depression has also been reported with IFN-gamma therapy. Patients are typically started on the same doses of IFN-gamma as are used for chronic granulomatous disease (CGD), but doses several times higher may be needed for IFN-gamma-resistant defects such as ADIFNGR1 deficiency. Dosing is adjusted based upon the patient's response to therapy and such factors as fever, inflammation, and fatigue. IFN-gamma is not usually continued as secondary prophylaxis. IFN-alpha therapy has also been used for treatment of disseminated NTM in ARIFNGR1 deficiency [32]. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects" and "Chronic granulomatous disease: Treatment and prognosis", section on 'Immunomodulatory therapy with interferon-gamma'.)

Hematopoietic cell transplantation (HCT) has been successful in many forms of MSMD (ARIFNGR1, ADIFNGR1, ARSTAT1, ADSTAT1 gain of function [GOF], ARIL12RB1, and GATA2 deficiency) [33-36]. HCT for primary immunodeficiencies is discussed in greater detail separately. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

PROGNOSIS — Most nontuberculous mycobacterial (NTM) infections in patients with MSMD initially respond to prolonged and intensive antimycobacterial therapy (with or without cytokine therapy). However, mycobacterial infections may recur or become antibiotic resistant, and there is increased susceptibility to certain other bacterial, fungal, and viral infections. Survival in the severe genetic deficiencies often requires hematopoietic cell transplantation (HCT). Outcomes for interleukin (IL) 12 receptor beta 1 (IL-12RB1) deficiency are quite variable, with some patients dying of infection in early childhood, whereas others have minimal infection susceptibility. The overall premature mortality is approximately 30 percent for IL12RB1 deficiency in one international survey [37]. Those with partial defects, such as autosomal-dominant (AD) partial interferon (IFN) gamma receptor 1 (ADIFNGR1) deficiency, typically live well into adulthood but benefit from antimycobacterial prophylaxis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

●Pathogenesis and genetics – Host defense against intracellular pathogens including mycobacteria, Salmonella, certain fungi, and viruses depends upon the functional integrity of the interferon (IFN) gamma/interleukin (IL) 12 pathway. Genetic defects in the IFN-gamma/IL-12 pathway result in conditions grouped together as Mendelian susceptibility to mycobacterial diseases (MSMD), including defects in IFN-gamma receptor 1 (IFNGR1), IFN-gamma receptor 2 (IFNGR2), IL-12 receptor beta 1 (IL12RB1), IL-12 receptor beta 2 (IL12RB2), IL-12 p40, signal transducer and activator of transcription (STAT) 1, IFN regulatory factor 8 (IRF8), GATA-binding protein 2 (GATA2), nuclear factor of kappa light chain gene enhancer in B cells inhibitor alpha (NFKBIA), IFN-stimulated gene 15 (ISG15), nuclear factor kappa B essential modulator (NEMO or IKBKG), gp91phox, signal peptide peptidase-like 2A (SPPL2A), and ROR-gamma c. (See 'Introduction' above and 'Pathogenesis' above.)

●Clinical features – Patients with MSMD typically present with severe Bacillus Calmette-Guérin (BCG; a live-attenuated strain of Mycobacterium bovis encountered in countries that use it as a vaccine to prevent tuberculosis) or environmental nontuberculous mycobacterial (NTM) infection (table 1). Patients are also susceptible to infection with other intracellular pathogens, such as extraintestinal nontyphoid Salmonella. Clinical features of disseminated NTM infection are nonspecific and may include fever, weight loss, diarrhea, generalized lymphadenopathy, generalized cutaneous lesions, diffuse abdominal tenderness, hepatosplenomegaly, and ascites. Clinical manifestations of disseminated BCG infection are similar to those for environmental NTM infection. However, with BCG infection, the lymph nodes draining the site of inoculation may fistulize to skin and surrounding tissues. Diffuse disseminated disease with extensive liver, gut, bloodstream, meningeal, brain, and bone infection may occur. (See 'Presentation and clinical features' above and "Prevention of tuberculosis: BCG immunization and nutritional supplementation", section on 'Safety and adverse effects'.)

●Diagnosis – Firm diagnosis of a genetic disease is only established by genetic sequencing. Immunologic testing can be useful to guide gene sequencing or when variants of uncertain significance (VUS) are detected. Immunologic testing such as cell surface receptor expression and intracellular signaling (eg, lack of STAT1 phosphorylation in response to IFN-gamma or lack of STAT4 phosphorylation in response to IL-12) can be performed by flow cytometry or immunoblotting. . (See 'General approach to diagnosis' above.)

●Differential diagnosis – The differential diagnosis in patients with disseminated NTM infections includes anti-IFN-gamma autoantibodies. The differential diagnosis for disseminated BCG includes severe T cell immunodeficiencies such as severe combined immunodeficiency (SCID), and rarely chronic granulomatous disease (CGD). (See 'Differential diagnosis' above.)

●Treatment – Aggressive treatment with antimycobacterial antibiotics is required management of patients with these disorders. Cytokine therapy with IFN-gamma is an additional treatment option for most defects. However, it has limited efficacy among patients with autosomal-recessive (AR) complete defects of IFNGR1 and IFNGR2 since unexpressed receptors cannot respond to IFN-gamma. (See 'General approach to treatment' above.)

Hematopoietic cell transplantation (HCT) is an increasingly successful option for many defects, including IFNGR1, IFNGR2, GATA2, IKBKG (NEMO), cytochrome b-245 beta chain (CYBB; gp91phox), IL12RB1, and STAT1. Experience is limited but developing with the other defects. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, and Gulbu Uzel, MD, who contributed as Section Editor and author, respectively, to earlier versions of this topic review.