C3 Deficiency

Primary C3 deficiency is a rare autosomal recessive complement deficiency that causes severe, recurrent pyogenic infection from infancy and immune complex disease. C3 is the central component of all complement activation.

Pathophysiology. C3 is the hub of classical, lectin and alternative activation. Without C3, opsonisation and killing of encapsulated bacteria fail, and immune complexes are not cleared, so they deposit in kidney and skin.

Infections begin in the first months or years and can be fatal. Glomerulonephritis and lupus like disease occur in some.

Low C3 may also be secondary: factor H or factor I deficiency lowers C3 through uncontrolled consumption.

• Recurrent invasive infection: pneumonia, meningitis, sepsis and otitis media with Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis
• Recurrent sinopulmonary infection from infancy
• Immune complex glomerulonephritis (membranoproliferative pattern)
• Lupus like disease, vasculitis and arthritis
• Skin infection and cellulitis
• Little fever or inflammatory response in some

• Total haemolytic complement (CH50) and alternative activation haemolytic assay (AH50): both absent or very low.
• C3 level: undetectable (primary deficiency), with normal C4 and factors B, H and I.
• Genetic testing of C3, with family testing.
• Exclusion of secondary C3 depletion: factor H, factor I and C3 nephritic factor testing; low C3 with normal C3 gene suggests consumption.
• Immunoglobulins, lymphocyte subsets and specific antibody responses (to exclude antibody deficiency).
• Renal assessment: urinalysis, creatinine, urine protein-to-creatinine ratio, renal biopsy for glomerulonephritis.
• Microbiology: cultures during infection.

Differential diagnosis.

• Factor H and factor I deficiency (secondary C3 consumption)
• C3 nephritic factor associated glomerulonephritis
• Antibody deficiency
• Splenic hypofunction
• IRAK4 and MyD88 deficiency
• Other complement deficiencies (C1q, C2, C4, terminal components)

• Prophylaxis from diagnosis through childhood and often for life: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily). Add co-trimoxazole or amoxicillin by culture history under specialist direction.
• Acute fever or illness: this is sepsis until proven otherwise. After blood cultures, give ceftriaxone 2 g intravenously once daily (children 50 to 80 mg/kg, maximum 2 g) without waiting for results, and admit.
• Vaccination: pneumococcal conjugate vaccine, then pneumococcal polysaccharide vaccine at least 8 weeks later, meningococcal ACWY and B vaccines, Haemophilus influenzae type b vaccine, and yearly inactivated influenza vaccine. Responses may be weak, so continue antibiotic prophylaxis after vaccination.
• Immunoglobulin replacement is not helpful unless antibody failure coexists: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks or subcutaneous immunoglobulin 100 to 150 mg/kg weekly in that case.
• Immune complex disease: prednisolone 0.5 to 1 mg/kg orally daily (maximum 60 mg) for flares, tapered; hydroxychloroquine 200 to 400 mg daily, not over 5 mg/kg of actual body weight daily, with eye screening; mycophenolate mofetil 1 g orally twice daily for glomerulonephritis.
• Plasma infusion: fresh frozen plasma 10 mL/kg intravenously has been used as a short term source of C3 during severe infection, but its effect is brief.
• Haematopoietic stem cell transplantation is not established, since C3 is made mainly in the liver.

Special groups.

• Infants: highest risk of fatal infection, so keep a low threshold for admission.
• Families: genetic counselling, since each pregnancy has a 1 in 4 risk.

Monitoring. Review every 3 to 6 months in childhood. Urinalysis, creatinine and urine protein-to-creatinine ratio every 6 months. Pneumococcal and meningococcal titres every 3 to 5 years.

Referral and escalation. Refer to paediatric or adult immunology and nephrology. Emergency for fever with illness, meningism, or sepsis.