Interferon Gamma Receptor Deficiency

Interferon gamma receptor deficiency is a defect in IFNGR1 or IFNGR2 that stops cells responding to interferon gamma. It causes severe mycobacterial disease and is the most severe form of Mendelian susceptibility to mycobacterial disease.

Pathophysiology. Interferon gamma from T and NK cells activates macrophages to kill intracellular organisms. When the receptor is absent or non-functional, macrophages cannot respond, and mycobacteria, Salmonella and some viruses spread.

Complete autosomal recessive deficiency causes disease in infancy and is often fatal. Partial recessive and dominant negative deficiency are milder, with onset in later childhood and a typical multifocal osteomyelitis.

Serum interferon gamma is very high in complete deficiency.

• Disseminated BCG disease after vaccination
• Non-tuberculous mycobacterial infection: fever, weight loss, lymphadenopathy, hepatosplenomegaly
• Multifocal osteomyelitis (dominant form), with lytic bone lesions
• Tuberculosis, non-typhoidal Salmonella and histoplasmosis
• Severe viral infection (CMV, herpes simplex, parainfluenza) in complete deficiency
• Granulomatous inflammation in many organs
• Onset in the first years of life in complete deficiency

• IFNGR1 or IFNGR2 expression on monocytes or lymphocytes by flow cytometry: absent in complete recessive deficiency, normal or raised in partial and dominant forms.
• STAT1 phosphorylation after interferon gamma: absent or reduced.
• Serum interferon gamma level: raised in complete deficiency.
• Genetic testing of IFNGR1 and IFNGR2.
• Mycobacterial cultures from blood, marrow, nodes, bone and tissue, with species and susceptibility testing.
• Imaging: bone MRI or scintigraphy, and chest CT.
• HIV test, immunoglobulins, lymphocyte subsets.

Differential diagnosis.

• IL-12 receptor beta-1 deficiency and IL-12 p40 deficiency
• STAT1 dominant negative deficiency
• IRF8 deficiency and GATA2 deficiency
• Chronic granulomatous disease
• HIV infection
• Severe combined immunodeficiency

• Anti-mycobacterial treatment: combination therapy for at least 12 months and often lifelong. For BCG, 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. For Mycobacterium avium complex use clarithromycin 500 mg twice daily (children 7.5 mg/kg twice daily, maximum 500 mg), ethambutol and rifampicin, with amikacin 15 mg/kg intravenously once daily for the first 2 to 3 months in severe disease.
• Safety monitoring: liver enzymes monthly at first, visual acuity and colour vision monthly on ethambutol, ECG for QTc under 450 ms on macrolides, hearing and creatinine on amikacin.
• Complete deficiency: haematopoietic stem cell transplantation, as early as possible and ideally after infection is controlled. Graft failure is frequent, so transplant at a specialist centre. Interferon gamma does not work because the receptor is absent.
• Partial recessive and dominant forms: 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, together with antimicrobials. Doses up to 100 microgram/m2 are used only under specialist direction.
• Secondary prophylaxis for life in those not transplanted: 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.
• 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.
• Surgery: drainage or excision of abscesses and infected bone.
• Vaccines: no BCG or other live bacterial vaccines; inactivated vaccines are given.

Special groups.

• Infants of affected families: avoid BCG vaccination until the diagnosis is excluded by early testing.

Monitoring. Liver enzymes and full blood count monthly during treatment. Mycobacterial cultures monthly until negative. Bone imaging if pain recurs. Growth and weight at each visit.

Referral and escalation. Refer urgently to paediatric immunology, infectious diseases and a transplant centre. Emergency for sepsis, respiratory distress or disseminated disease.