Complement Factor I Deficiency

Complement factor I deficiency is a rare inherited loss of the serine protease that inactivates C3b and C4b. It causes uncontrolled alternative activation, low C3 and recurrent bacterial infection.

Pathophysiology. Factor I, with cofactors such as factor H, cleaves C3b and C4b. Without it, C3b accumulates, C3 convertase activity runs unchecked and plasma C3 and factor B are consumed.

Complete deficiency (homozygous or compound heterozygous CFI variants) gives infections in the first years. Heterozygous variants are linked to atypical haemolytic uraemic syndrome, C3 glomerulopathy and age related macular degeneration.

Some CFI variants lower the level of the protein (type I) and others leave a normal level with poor function (type II).

• Recurrent pyogenic infection from infancy: meningitis, pneumonia, otitis media and sepsis with meningococcus, pneumococcus and Haemophilus
• Skin infection and cellulitis
• Atypical haemolytic uraemic syndrome in some heterozygous carriers
• C3 glomerulopathy or immune complex glomerulonephritis
• Vasculitis or lupus like disease in a few
• Some are well and found through family testing

• C3 level: low; factor B: low; C4: normal.
• Total haemolytic complement (CH50) and alternative activation assay (AH50): low because C3 is consumed.
• Factor I level and function: absent or very low in complete deficiency; reduced in heterozygous carriers.
• Genetic testing of CFI, with CFH, MCP (CD46), C3, CFB and THBD panel testing, and family testing.
• Haemolytic uraemic syndrome workup when suspected: full blood count, film, haptoglobin, LDH, creatinine, ADAMTS13 activity.
• Renal workup: urinalysis, urine protein-to-creatinine ratio, biopsy with C3 immunofluorescence.
• Immunoglobulins and specific antibody responses.

Differential diagnosis.

• Factor H deficiency
• C3 deficiency and C3 nephritic factor associated glomerulopathy
• Antibody deficiency and splenic hypofunction
• Terminal complement component deficiencies
• Thrombotic thrombocytopenic purpura and Shiga toxin associated haemolytic uraemic syndrome
• Systemic lupus erythematosus

• Vaccination: pneumococcal conjugate vaccine, then pneumococcal polysaccharide vaccine at least 8 weeks later; meningococcal ACWY conjugate vaccine (2 doses at least 8 weeks apart, then a booster every 5 years) and meningococcal B vaccine (a course of 2 or 3 doses, with boosters every 5 years); Haemophilus influenzae type b vaccine; yearly inactivated influenza vaccine.
• Antibiotic prophylaxis from diagnosis: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily), often continued through childhood and longer after invasive infection.
• 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.
• Atypical haemolytic uraemic syndrome: eculizumab 900 mg intravenously weekly for 4 doses, then 1200 mg at week 5, then 1200 mg every 2 weeks in adults (children dosed by weight), with meningococcal vaccination at least 2 weeks earlier when time allows and antibiotic prophylaxis for the whole period. Bridge with plasma exchange (1 to 1.5 plasma volumes daily) if the inhibitor is not yet available.
• C3 glomerulopathy or immune complex disease: control blood pressure and proteinuria with an ACE inhibitor (ramipril 2.5 mg orally daily, increased to 10 mg daily, with potassium and creatinine checked after 1 to 2 weeks) or an angiotensin receptor blocker; mycophenolate mofetil 1 g orally twice daily with prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg), tapered, for progressive disease.
• Plasma infusion: fresh frozen plasma 10 to 15 mL/kg intravenously has been used as a short term source of factor I, with limited and brief benefit, so it is not routine.
• Immunoglobulin replacement only for coexisting antibody failure.

Special groups.

• Infants: highest risk of fatal infection, so keep a low threshold for admission.
• Families: genetic counselling; test siblings, since autosomal recessive inheritance gives each a 1 in 4 risk.

Monitoring. Review every 3 to 6 months in childhood. C3 and factor B levels, urinalysis, urine protein-to-creatinine ratio and creatinine every 6 months. On eculizumab: platelets, haemoglobin, LDH and creatinine monthly.

Referral and escalation. Refer to immunology and nephrology. Emergency for fever with illness, haemolysis with thrombocytopenia, or rapidly rising creatinine.