IRAK4 Deficiency

IRAK4 deficiency is an autosomal recessive defect of Toll like receptor and IL-1 receptor signalling. Children develop invasive bacterial infections with weak inflammatory signs, and the risk falls after adolescence.

Pathophysiology. IRAK4 is a kinase that links MyD88 to downstream NF-kappa-B activation after Toll like receptors (except TLR3) and IL-1 family receptors are triggered. Without it, cells make little IL-6, TNF and other cytokines against bacteria, so fever and acute phase responses are blunted.

It is rare. First invasive infection usually occurs before the age of 2 years, and many deaths occur before 10 years.

Adaptive immunity is intact, so immunoglobulins, T cells and most vaccine responses are normal.

• Invasive pneumococcal disease: meningitis, sepsis, arthritis, pneumonia
• Staphylococcus aureus skin and deep abscesses, osteomyelitis
• Pseudomonas aeruginosa and other Gram negative infection
• Deep infection with little or no fever and a low CRP in the early hours
• Cutaneous cold abscesses and omphalitis in infancy
• Viral and fungal infections are usually not a problem
• Improvement in frequency of invasive infection after adolescence

• CRP and temperature can be misleadingly low during infection, so assess the child clinically.
• Blood count, immunoglobulins, lymphocyte subsets and specific antibody responses: usually normal; some have poor responses to polysaccharide vaccines.
• Functional TLR and IL-1 assay: absent IL-6 and TNF production by whole blood or monocytes after stimulation with TLR agonists and IL-1 beta.
• Genetic testing of IRAK4, with parental testing.
• IRAK4 protein expression by immunoblot or flow cytometry (may be present but non-functional).
• Microbiology: cultures, and imaging for deep infection.

Differential diagnosis.

• MyD88 deficiency
• NEMO deficiency and other NF-kappa-B defects
• Complement C3 deficiency and complement deficiencies (neisserial disease)
• Splenic hypofunction
• STAT3 loss-of-function (hyper IgE) syndrome
• Antibody deficiency (X-linked agammaglobulinaemia)

• Prophylactic antibiotics from diagnosis to at least late adolescence, since invasive risk is highest in early life: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily).
• Immunoglobulin replacement for recurrent invasive infection despite prophylaxis, or proven poor antibody function: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Early treatment of any suspected infection, because fever and CRP are unreliable: after blood cultures, ceftriaxone 2 g intravenously once daily (children 50 to 80 mg/kg, maximum 2 g), then adjust to cultures. Give an emergency letter to the family stating that a normal temperature and a low CRP do not exclude sepsis.
• Vaccination: all routine inactivated vaccines, including pneumococcal conjugate vaccine then pneumococcal polysaccharide vaccine at least 8 weeks later, Haemophilus influenzae type b vaccine, and meningococcal vaccines. Live vaccines (BCG, measles-mumps-rubella) are safe since cellular immunity is intact.
• Abscesses: drainage and culture directed antibiotics. Flucloxacillin 500 mg to 1 g orally four times daily for 7 days in adults for staphylococcal skin infection (children by weight).
• Haematopoietic stem cell transplantation is not used routinely because the risk falls with age.

Special groups.

• Infants under 2 years: highest risk, so keep a low threshold for admission and intravenous antibiotics.
• Adults: infections become rarer, but keep emergency antibiotic access and vaccination current.

Monitoring. Review every 3 to 6 months in childhood. Immunoglobulins and vaccine titres yearly. Trough IgG every 3 to 6 months if on replacement.

Referral and escalation. Refer to paediatric immunology. Emergency for any fever or unwell child with this diagnosis, regardless of CRP.