Complement Deficiency Workup
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Direct answer
Recurrent meningococcal disease with otherwise normal immunity points to the terminal complement pathway (C5–C9), where deficiency raises the lifetime risk of Neisseria invasion by up to thousands-fold, and the screening tool is a CH50 that comes back essentially zero rather than merely low. Combining CH50 with AH50 maps the lesion: both absent means terminal-component deficiency, CH50 absent with AH50 intact means classical pathway (C1q, C1r/s, C2, C4), AH50 absent with CH50 normal means alternative pathway (properdin, factor D, factor B). Early classical-component deficiencies instead produce SLE-like disease — the second face of complement deficiency every NEET-PG Medicine candidate must recognise.
What you must remember
- CH50 assays classical plus terminal pathway function; it is near-zero in any component deficiency of that route and merely reduced with consumption (SLE, immune-complex disease, cryoglobulinaemia).
- AH50 assays the alternative pathway; the CH50/AH50 pair localises the deficient arm.
- Both near-zero: terminal pathway C5–C9; CH50 zero with AH50 normal: classical pathway; AH50 zero with CH50 normal: alternative pathway.
- Terminal C5–C9 deficiency: recurrent meningococcal meningitis or meningococcaemia, often with milder-than-expected first episodes; properdin deficiency is X-linked with the same phenotype.
- Early classical deficiency (C1q, C1r/s, C4, C2): SLE-like illness with photosensitive rash and low complement; C1q deficiency carries the highest SLE risk, C2 deficiency is the commonest classical deficiency in Caucasian populations.
- C3 deficiency: severe recurrent pyogenic infections with encapsulated bacteria, immune-complex disease.
- Factor H, factor I or CD46 deficiency: complement-mediated thrombotic microangiopathy (atypical haemolytic uraemic syndrome).
- C1-inhibitor deficiency: hereditary angioedema — the exam's bridge protein.
- Management of late-component deficiency: meningococcal ACWY plus MenB vaccination, pneumococcal and Hib immunisation, an antibiotics-at-first-symptoms plan, and family counselling with screening.
- Mannose-binding lectin deficiency: mostly minor childhood infection susceptibility, largely clinically silent in adults.
How to work through a typical case
A 19-year-old college student is admitted with his second episode of meningococcal meningitis in three years; immunoglobulins, HIV serology, full blood count and metabolic screen are normal, and he has no splenectomy history.
Step one: recognise the pattern — recurrent invasive Neisseria disease with otherwise intact immunity is the terminal-complement phenotype until excluded. Step two: order the functional screen first, CH50; a result near zero in a well patient indicates a component deficiency, whereas a moderately low value in an ill, immune-complex-loaded patient suggests consumption. Step three: localise with AH50 — his AH50 also near-zero places the defect in the shared terminal pathway (C5–C9), and specific assays for individual components confirm, C9 deficiency being notably prevalent in Japanese populations. Step four: manage immediately and concretely — quadrivalent ACWY and MenB vaccination (infection can still occur despite vaccination, so counsel fast access to antibiotics), pneumococcal and Hib cover, a written "fever means emergency" plan, and avoidance where practical of dormitory crowding during outbreaks. Step five: extend to the family — screen siblings with CH50 given the autosomal recessive inheritance, and counsel on cascade testing before high-risk settings such as military recruitment or Hajj travel. Step six: contrast the other face aloud for completeness — had this patient presented with photosensitive rash, arthritis and low C3/C4, the working diagnosis would be lupus from early classical deficiency, and the CH50 would still be near zero but the clinical route entirely different.
Where students slip
First, ordering C3 and C4 alone and declaring the workup complete — functional CH50 is the deficiency screen; antigen levels only map selected components. Second, confusing "low CH50 in active SLE" (consumption, rises with treatment) with "absent CH50 in a well patient" (deficiency, permanent). Third, forgetting the SLE-like face of early classical deficiency when a stem pairs photosensitivity with absent CH50. Fourth, missing properdin as the X-linked alternative to autosomal recessive terminal defects in a family history of affected males. Finally, offering vaccination as fully protective — terminal-deficiency patients still contract meningococcal disease, so the emergency-antibiotic plan is part of the answer, not an optional extra.
Frequently asked questions
Which screening test detects classical complement pathway deficiency?
CH50 — a near-zero result in an otherwise well patient indicates deficiency somewhere in the classical or terminal pathway, unlike the moderate reduction of consumption.
How do CH50 and AH50 together localise a complement deficiency?
Both absent points to the shared terminal pathway (C5–C9); absent CH50 with normal AH50 indicates classical pathway deficiency; absent AH50 with normal CH50 indicates alternative pathway deficiency.
Which infections dominate terminal complement deficiency?
Recurrent Neisseria meningitidis meningitis and meningococcaemia, with lifetime risk increased up to thousands-fold; gonococcal infection is also increased.
Which complement deficiencies produce an SLE-like syndrome?
Early classical pathway defects — C1q (highest risk), C1r/s, C4 and C2 — presenting with photosensitive rash, immunopathology and characteristically absent CH50.
How are patients with terminal complement deficiency managed?
Meningococcal ACWY and B, pneumococcal and Haemophilus vaccinations, a rapid-access antibiotic plan for fever, counselling that vaccination is imperfect, and family screening by CH50.