Complement Factor H Deficiency

Complement factor H deficiency is an inherited loss of the main regulator of alternative activation. It causes uncontrolled C3 consumption, recurrent bacterial infection, atypical haemolytic uraemic syndrome and C3 glomerulopathy.

Pathophysiology. Factor H limits C3b activity in plasma and on host cells. Without it, C3 is continuously activated and depleted, leaving plasma C3 and factor B low, and complement is deposited on glomerular and endothelial surfaces.

Homozygous or compound heterozygous variants in CFH (autosomal recessive) usually cause complete deficiency with early onset. Heterozygous variants cause partial deficiency and are associated with atypical haemolytic uraemic syndrome in a setting of a trigger.

Anti-factor H autoantibodies cause a similar acquired picture.

• Recurrent bacterial infection from infancy: meningococcal, pneumococcal and Haemophilus disease
• Atypical haemolytic uraemic syndrome: microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury
• C3 glomerulopathy (dense deposit disease or C3 glomerulonephritis) with haematuria and proteinuria
• Membranoproliferative glomerulonephritis
• Drusen and macular degeneration in some
• Relapses triggered by infection, pregnancy, surgery or drugs

• C3 level: low; factor B: low; C4: normal.
• Total haemolytic complement (CH50) and alternative activation assay (AH50): low because C3 is consumed.
• Factor H level and function: absent or very low in homozygous deficiency; reduced in partial deficiency. Test for anti-factor H autoantibodies.
• Genetic testing of CFH, including the related gene cluster, with CFI, MCP (CD46), C3, CFB and THBD panel testing.
• Haemolytic uraemic syndrome workup: full blood count, blood film for fragmented red cells, haptoglobin, LDH, creatinine, ADAMTS13 activity (to exclude thrombotic thrombocytopenic purpura), and stool testing for Shiga toxin producing organisms.
• Renal workup: urinalysis, urine protein-to-creatinine ratio, and renal biopsy with immunofluorescence for C3 deposition.
• Immunoglobulins and specific antibody responses.

Differential diagnosis.

• Factor I deficiency
• C3 deficiency and C3 nephritic factor associated glomerulopathy
• Shiga toxin associated haemolytic uraemic syndrome
• Thrombotic thrombocytopenic purpura
• Post-infectious glomerulonephritis and lupus nephritis
• Antibody deficiency

• 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: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily) in recurrent infection or during complement inhibition.
• Acute fever or illness: this is possible sepsis. 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:
  • Start complement inhibition promptly: 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). Ravulizumab is an alternative with an 8-weekly maintenance dose set by weight.
  • Vaccinate against meningococcus at least 2 weeks before the first dose when time allows, and continue antibiotic prophylaxis for the whole period of treatment. If treatment cannot wait, give antibiotics at the same time as vaccination.
  • Bridge with plasma exchange (1 to 1.5 plasma volumes daily with fresh frozen plasma replacement) or, if exchange is not possible, plasma infusion 10 to 20 mL/kg daily, until the inhibitor is available.
• C3 glomerulopathy: 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; for progressive disease use mycophenolate mofetil 1 g orally twice daily with prednisolone, or a complement inhibitor such as the factor B inhibitor iptacopan 200 mg orally twice daily, under nephrology direction.
• Anti-factor H antibodies: plasma exchange with prednisolone 1 mg/kg daily (maximum 60 mg) and an immunosuppressant such as cyclophosphamide or mycophenolate mofetil.
• Kidney transplantation: recurrence is high in factor H deficiency, so give complement inhibition from the time of surgery.

Special groups.

• Pregnancy: relapse risk is raised, so plan joint care with nephrology and obstetrics.
• Children: weight based eculizumab dosing, and growth and renal function monitoring.

Monitoring. On eculizumab: platelets, haemoglobin, LDH, haptoglobin and creatinine weekly at first and then monthly. Urine protein-to-creatinine ratio and C3 level every 3 months. Meningococcal booster record every 5 years. Blood pressure at each visit.

Referral and escalation. Refer to nephrology and immunology. Emergency for haemolysis with thrombocytopenia and rising creatinine, or fever and illness while on complement inhibition.