C8 Deficiency

C8 deficiency is a rare autosomal recessive terminal complement deficiency that causes recurrent systemic Neisseria infection. It exists in two forms, from variants in C8A and C8G (alpha gamma subunit) or C8B (beta subunit).

Pathophysiology. C8 binds the C5b67 complex and inserts into the membrane, starting pore formation. C9 then amplifies the pore. Without C8, the complex cannot lyse Neisseria.

Disease may start in childhood or adulthood, and meningococcal episodes are often recurrent and caused by uncommon serogroups.

Frequencies differ by population, and genetic testing should cover all three C8 genes.

• Recurrent meningococcal meningitis or septicaemia
• Disseminated gonococcal infection
• Occasional lupus like disease
• Some are well and found on family testing

• Total haemolytic complement (CH50) and alternative activation assay (AH50): both absent or very low.
• C8 level and function: absent or very low; hybrid haemolytic assays identify the missing subunit.
• Genetic testing of C8A, C8B and C8G, with family testing.
• Immunoglobulins and specific antibody responses to exclude antibody deficiency.
• Microbiology and serogroup identification during infection.
• Retest after recovery from acute infection.

Differential diagnosis.

• C5, C6, C7 and C9 deficiency
• Properdin deficiency
• Acquired terminal complement inhibition (eculizumab, ravulizumab)
• Factor H and factor I deficiency
• Antibody deficiency and splenic hypofunction
• Systemic lupus erythematosus with complement consumption

• Vaccination:
  • Meningococcal ACWY conjugate vaccine, 2 doses at least 8 weeks apart, then a booster every 5 years.
  • Meningococcal B vaccine, a course of 2 or 3 doses depending on the product, with boosters every 5 years.
  • Pneumococcal conjugate vaccine, then pneumococcal polysaccharide vaccine at least 8 weeks later.
  • Haemophilus influenzae type b vaccine and yearly inactivated influenza vaccine.
  • Vaccine protection is incomplete, so continue prophylaxis and fever precautions.
• Antibiotic prophylaxis: long term phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily), especially after a first episode of invasive disease.
• Acute fever or illness: this is possible meningococcal disease. 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. Give the family an emergency card.
• Contacts of an invasive case: ciprofloxacin as a single oral dose of 500 mg in adults (children 5 to 12 years 250 mg; 1 month to 4 years 30 mg/kg, maximum 125 mg), or rifampicin 600 mg twice daily for 2 days in adults.
• Lupus like disease, if it occurs: hydroxychloroquine 200 to 400 mg orally daily, not over 5 mg/kg of actual body weight daily, and prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg), tapered.
• Fresh frozen plasma is not used routinely.

Special groups.

• Relatives: test siblings, since each has a 1 in 4 risk of being affected.
• Adolescents: confirm boosters and the emergency plan at transition to adult care.

Monitoring. Clinical review every 6 to 12 months. Vaccine booster record every 5 years. Confirm adherence to prophylaxis.

Referral and escalation. Refer to immunology after any second episode of meningococcal disease, an uncommon serogroup, or disseminated gonococcal infection. Emergency for fever with rash, headache, vomiting or drowsiness.