Properdin Deficiency

Properdin deficiency is the only X-linked complement deficiency. It causes fulminant meningococcal disease, mostly in boys and men, with a higher mortality than other complement deficiencies.

Pathophysiology. Properdin (factor P) stabilises the alternative activation C3 convertase and so amplifies C3b deposition and activation of the terminal components on bacteria. Without it, the alternative route fails to kill Neisseria.

Variants in CFP on the X chromosome cause three types: type I (absent), type II (low) and type III (normal level with poor function). Female carriers have about half of normal levels and are usually well.

Meningococcal disease is typically caused by serogroups Y and W, may be the first presentation, and often presents in adolescence.

• Fulminant meningococcal septicaemia with purpura, shock and a high case fatality
• Meningococcal meningitis
• Family history of male relatives with meningococcal disease or sudden death
• Occasional pneumococcal infection
• Carrier females are usually well

• Alternative activation haemolytic assay (AH50): absent or very low.
• Total haemolytic complement (CH50): normal, which distinguishes this from terminal component deficiency.
• Properdin level: absent in type I, low in type II, and normal with poor function in type III.
• Genetic testing of CFP, with testing of mother and male relatives.
• Immunoglobulins and specific antibody responses to exclude antibody deficiency.
• Microbiology and serogroup identification during infection.
• Retest after recovery from acute infection.

Differential diagnosis.

• Terminal component deficiencies (C5 to C9)
• Factor D deficiency
• Factor H and factor I deficiency
• Acquired complement inhibition (eculizumab, ravulizumab)
• 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), started at diagnosis because the risk of fatal disease is high.
• 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; it may be considered in life threatening infection while antibiotics are given.

Special groups.

• Mothers and female relatives: carrier testing and genetic counselling; each son of a carrier has a 50% chance of being affected and each daughter a 50% chance of being a carrier.
• Male relatives of an affected patient: test early and start prevention before a first infection.

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

Referral and escalation. Refer to immunology and genetics. Emergency for fever with rash, headache, vomiting or drowsiness.