Mendelian Susceptibility to Mycobacterial Disease

Mendelian susceptibility to mycobacterial disease (MSMD) is a group of inborn errors of the IL-12 and interferon gamma axis. Affected people develop severe disease from weakly virulent mycobacteria, such as BCG and environmental non-tuberculous species, and from Salmonella.

Pathophysiology. Macrophages and dendritic cells make IL-12, which stimulates T and NK cells to make interferon gamma, which in turn activates macrophage killing. Variants in IFNGR1, IFNGR2, STAT1 (dominant negative), IL12B, IL12RB1, IRF8, ISG15, TYK2, NEMO, RORC and CYBB disrupt this axis.

A genetic cause is not found in every patient. Disease usually starts in childhood, with some late onset cases.

Severity ranges from localised lymphadenitis to fatal disseminated disease.

• Disseminated BCG disease after vaccination: fever, lymphadenitis, hepatosplenomegaly, osteomyelitis
• Environmental non-tuberculous mycobacterial infection, and tuberculosis
• Recurrent non-typhoidal Salmonella infection
• Histoplasmosis and other endemic fungal disease
• Chronic mucocutaneous candidiasis (IL-12Rbeta1 and IL-12p40 defects)
• Granulomatous inflammation with weight loss and anaemia
• Normal resistance to most common pathogens

• Exclude other causes first: HIV test, severe combined immunodeficiency screen (lymphocyte subsets, immunoglobulins), chronic granulomatous disease (neutrophil oxidative burst test), and anti-interferon-gamma autoantibodies in adults.
• Mycobacterial and Salmonella cultures from blood, nodes, bone and tissue, with species and susceptibility testing, and biopsy with acid fast staining.
• Functional tests of the axis: whole blood stimulation with BCG plus IL-12 or interferon gamma, measuring interferon gamma and IL-12p70.
• Flow cytometry: IFNGR1, IL-12Rbeta1 expression, and STAT1 phosphorylation after interferon gamma.
• Genetic testing with a gene panel for the axis (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IRF8, ISG15, TYK2, NEMO, CYBB).
• Imaging of bone, chest and abdomen.

Differential diagnosis.

• Chronic granulomatous disease
• Severe combined immunodeficiency
• GATA2 deficiency
• HIV infection
• Adult onset immunodeficiency with anti-interferon-gamma antibodies
• Tuberculosis in an immunocompetent host

• Combination treatment for at least 12 months and often longer, with a regimen tailored to the organism and its susceptibility.
  • BCG disease: isoniazid 5 mg/kg orally once daily (children 10 mg/kg; maximum 300 mg) with pyridoxine 10 mg daily, rifampicin 10 mg/kg once daily (children 15 mg/kg; maximum 600 mg) and ethambutol 15 mg/kg once daily. Pyrazinamide is not used, since BCG is intrinsically resistant.
  • Mycobacterium avium complex: clarithromycin 500 mg orally twice daily (children 7.5 mg/kg twice daily, maximum 500 mg), ethambutol and rifampicin, adding amikacin 15 mg/kg intravenously once daily for the first 2 to 3 months in severe disease.
  • Mycobacterium tuberculosis: isoniazid, rifampicin, pyrazinamide 25 mg/kg daily (maximum 2 g) and ethambutol for 2 months, then isoniazid and rifampicin for at least 7 to 10 months.
• Safety monitoring: liver enzymes monthly at first, visual acuity and colour vision monthly on ethambutol (stop for visual change), ECG for QTc under 450 ms on macrolides, hearing and creatinine on amikacin, and review of rifampicin drug interactions.
• Interferon gamma 1b: 50 microgram/m2 subcutaneously three times weekly (1.5 microgram/kg for body surface area 0.5 m2 or less), with paracetamol 15 mg/kg orally before doses for fever, as an adjunct for patients with some receptor function or other defects with normal responsiveness. It is not effective in complete interferon gamma receptor deficiency.
• Non-typhoidal Salmonella: ceftriaxone 2 g intravenously once daily (children 50 to 80 mg/kg, maximum 2 g) for 14 days, then ciprofloxacin 500 mg orally twice daily to complete 4 to 6 weeks; longer for osteomyelitis.
• Secondary prophylaxis for life: azithromycin 500 mg orally three times weekly in adults (children 10 mg/kg three times weekly, maximum 500 mg), after ECG shows QTc under 450 ms.
• Haematopoietic stem cell transplantation for complete deficiency, IRF8 deficiency, and refractory disease.
• Surgery: drainage of abscesses and excision of infected nodes or bone when medical treatment fails.
• Vaccines: no BCG or other live bacterial vaccines; give inactivated vaccines.

Special groups.

• Newborns in families with a known variant or a sibling with mycobacterial disease: defer BCG vaccination until the diagnosis is excluded.
• Patients in tuberculosis endemic regions: continue prophylaxis through the transmission period and screen household contacts.

Monitoring. Liver enzymes and full blood count monthly during treatment. Mycobacterial cultures monthly until negative. Visual function monthly on ethambutol. Growth, weight and fever history at each visit.

Referral and escalation. Refer to paediatric or adult immunology and infectious diseases. Urgent for sepsis, persistent fever, bone pain or disseminated disease.