C6 Deficiency

C6 deficiency is an autosomal recessive deficiency of a terminal complement component that causes recurrent Neisseria infection. It is among the commoner terminal deficiencies in some populations.

Pathophysiology. C6 binds C5b and allows the complex to bind C7, so it is needed to build the membrane attack complex that lyses Neisseria. Without it, Neisseria survive in the bloodstream. Some people have subtotal deficiency, in which a low but detectable level is present with an impaired function.

Carrier frequency is high in some groups, including parts of southern Africa, but frequencies differ by population.

Onset is usually in childhood or adolescence, and recurrence is typical if prophylaxis and vaccination are not in place.

• Meningococcal meningitis or septicaemia, often recurrent, with uncommon serogroups
• Disseminated gonococcal infection
• Neisseria infection in a family with several affected members
• Rare other bacterial infection
• Some affected people are well and found through family testing

• Total haemolytic complement (CH50) and alternative activation assay (AH50): both absent or very low.
• C6 level: absent or very low in total deficiency; low with poor function in subtotal deficiency. C3 and C4 are normal.
• Genetic testing of C6, with family testing.
• Immunoglobulins and specific antibody responses to exclude antibody deficiency.
• Microbiology and serogroup identification during infection.
• Retest after recovery from acute infection when the first result is unclear.

Differential diagnosis.

• C5, C7, C8 and C9 deficiency
• Properdin deficiency
• Acquired terminal complement inhibition (eculizumab, ravulizumab)
• Factor H and factor I deficiency
• Antibody deficiency and splenic hypofunction
• Other complement deficiencies (C3, C2, C1q)

• 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.
• Fresh frozen plasma is not used routinely.

Special groups.

• Relatives: test siblings and other family members, since many carriers are well and affected relatives may be unrecognised.
• Adolescents: confirm vaccination boosters and 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.