IRF8 Deficiency

IRF8 deficiency is a rare disorder of myeloid and dendritic cell development. Autosomal recessive variants cause a severe form with absent monocytes and dendritic cells, while autosomal dominant variants cause a milder form with loss of one dendritic cell subset and mycobacterial disease.

Pathophysiology. IRF8 is a transcription factor that drives monocyte and dendritic cell lineages. Without it, IL-12 production and interferon gamma signalling against mycobacteria are weak, and a myeloid expansion with neutrophilia occurs in the recessive form.

The recessive form (for example T80A) presents in infancy with severe infection and early death. The dominant form (for example K108E) starts in childhood with mycobacterial infection.

Both forms are very rare.

• Recessive form: severe BCG disease, candidiasis, Cryptosporidium infection, chronic diarrhoea, failure to thrive, recurrent respiratory infection
• Recessive form: neutrophilia, with absent monocytes, and often lymphoid abnormalities
• Dominant form: BCG disease and other non-tuberculous mycobacterial infection in childhood, without the severe infections of the recessive form
• Salmonella and tuberculosis in some
• Lymphadenitis and osteomyelitis from mycobacteria
• Myeloproliferation in the recessive form

• Full blood count and flow cytometry: absent monocytes and CD11c-positive, CD1c-positive and plasmacytoid dendritic cells in the recessive form; selective loss of CD1c-positive dendritic cells in the dominant form.
• IL-12 production and IFN-gamma response tests in whole blood after stimulation with BCG plus interferon gamma or IL-12.
• Genetic testing of IRF8, with parental testing.
• Mycobacterial cultures from blood, nodes, bone and tissue, with species and susceptibility testing.
• HIV test, immunoglobulins, lymphocyte subsets, and neutrophil oxidative burst test.
• Imaging for bone and lymph node involvement.

Differential diagnosis.

• Mendelian susceptibility to mycobacterial disease of other genes (IFNGR1, IFNGR2, IL12RB1, STAT1)
• GATA2 deficiency
• Chronic granulomatous disease
• Severe combined immunodeficiency
• Severe congenital neutropenia
• HIV infection

• Recessive form: haematopoietic stem cell transplantation as early as possible, since the disease is usually fatal without it. Supportive care until then.
• BCG disease or non-tuberculous mycobacterial infection: combination therapy for at least 12 months and often longer. 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, because 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.
• Safety monitoring: liver enzymes monthly at first, visual acuity and colour vision monthly on ethambutol, and review of drug interactions with rifampicin.
• Interferon gamma 1b adjunct: 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. Its benefit is uncertain in the recessive form.
• Secondary prophylaxis after treatment: azithromycin 10 mg/kg orally three times weekly in children (maximum 500 mg), 500 mg in adults, after ECG shows QTc under 450 ms.
• Pneumocystis and fungal prophylaxis when lymphoid or myeloid function is low: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week; fluconazole 3 to 6 mg/kg daily (maximum 400 mg).
• Cryptosporidium: boiled or filtered water, and nitazoxanide 500 mg orally twice daily for 3 to 14 days (aged 12 years and over; younger children by weight).
• Vaccines: no BCG or other live vaccines.

Special groups.

• Infants in families with a known variant: avoid BCG vaccination until the diagnosis is excluded, with early cord blood or blood testing.

Monitoring. Full blood count monthly while unwell. Mycobacterial cultures monthly during treatment. Liver enzymes and visual function monthly during treatment. Growth and weight at each visit.

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