C9 Deficiency

C9 deficiency is an autosomal recessive deficiency of the last component of the membrane attack complex. It carries a milder risk of Neisseria infection than loss of C5 to C8, and many affected people are well.

Pathophysiology. C9 polymerises into the ring that completes the pore of the membrane attack complex. Without C9, the C5b-8 complex still forms and lyses bacteria slowly, so killing is reduced but not absent.

It is much more frequent in Japan, where roughly 1 in 1,000 people are homozygous, than in other populations.

The risk of meningococcal disease is raised but lower than in other terminal deficiencies, and episodes are less often recurrent.

• Meningococcal meningitis or septicaemia, usually non-recurrent and less severe
• Disseminated gonococcal infection
• Many affected people have no infection
• Rarely other bacterial infection

• Total haemolytic complement (CH50): reduced to roughly one third of normal, not absent.
• Alternative activation assay (AH50): reduced or normal.
• C9 level: absent or very low by immunoassay, with normal C3 and C4.
• Genetic testing of C9, with family testing.
• Immunoglobulins and specific antibody responses to exclude antibody deficiency.
• Microbiology and serogroup identification during infection.

Differential diagnosis.

• C5, C6, C7 and C8 deficiency
• Properdin deficiency
• Acquired terminal complement inhibition (eculizumab, ravulizumab)
• Factor H and factor I deficiency
• Antibody deficiency and splenic hypofunction
• Subtotal deficiencies of other terminal components

• Asymptomatic homozygotes: vaccination and an emergency plan are needed, but continuous antibiotic prophylaxis is a decision made individually.
• 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.
• Antibiotic prophylaxis after an invasive episode: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily).
• 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.
• 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.
• Counselling: a result of C9 deficiency in an otherwise healthy person does not require lifelong treatment.

Special groups.

• Relatives: test siblings, since each has a 1 in 4 risk of being affected.
• Patients from populations where the deficiency is frequent: be aware that C9 deficiency may be found incidentally on testing.

Monitoring. Clinical review yearly. Vaccine booster record every 5 years.

Referral and escalation. Refer to immunology after any meningococcal or disseminated gonococcal infection. Emergency for fever with rash, headache, vomiting or drowsiness.