C5 Deficiency

C5 deficiency is a rare autosomal recessive deficiency of the first terminal complement component. It causes recurrent, often severe, infection with Neisseria species.

Pathophysiology. C5 is cleaved by the C5 convertase into C5a (an inflammatory mediator) and C5b, which starts assembly of the membrane attack complex (C5b to C9) that lyses Gram negative diplococci. Without C5, the membrane attack complex cannot form, so Neisseria are not killed, although opsonisation through C3b is intact.

The first meningococcal episode usually occurs in late childhood, adolescence or early adulthood. Disease is often caused by uncommon serogroups (Y, W, X or non-groupable) and tends to be recurrent but with lower mortality than in people with normal complement.

Disseminated gonococcal infection is also a feature. Lupus like disease and pneumococcal infection are less common.

• Meningococcal meningitis or septicaemia, often recurrent, in a child over 10 years or an adult
• Disseminated gonococcal infection: fever, migratory arthralgia, tenosynovitis, pustular rash
• Neisseria infection with an uncommon serogroup
• Occasional pneumococcal or Haemophilus infection
• Rarely lupus like disease or glomerulonephritis
• Family history of meningococcal disease or sudden death

• Total haemolytic complement (CH50): absent or very low.
• Alternative activation haemolytic assay (AH50): absent or very low (both assays are abnormal because they depend on the terminal components).
• C5 level: absent or very low by immunoassay or functional assay, with normal C3 and C4.
• Genetic testing of C5, with family testing.
• Immunoglobulins, lymphocyte subsets and specific antibody responses to exclude antibody deficiency.
• Microbiology: blood and CSF cultures, PCR, and serogroup identification.
• Test after recovery from acute infection, since complement is consumed in active disease and can give a falsely low result.

Differential diagnosis.

• Other terminal component deficiencies (C6, C7, C8 and C9)
• Properdin deficiency (X-linked) and factor D deficiency
• Acquired terminal complement inhibition from eculizumab or ravulizumab
• Factor H and factor I deficiency
• Antibody deficiency and splenic hypofunction
• C3 deficiency

• 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), offered particularly after a first meningococcal episode and for many patients for life.
• 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 and plan.
• 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.
• Gonococcal infection: safer sexual practice counselling, screening, and treatment of partners.
• Fresh frozen plasma is not used routinely.
• Haematopoietic stem cell transplantation is not used.

Special groups.

• Adolescents and young adults: the highest risk period, so confirm vaccination and boosters before leaving paediatric care.
• Families: test siblings, since each has a 1 in 4 risk of being affected.

Monitoring. Clinical review every 6 to 12 months. Vaccine booster record every 5 years. Check adherence to prophylaxis and that the emergency plan is current.

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