Immunology and AllergyTier 2Disease (DEADMAN)

Complement deficiencies

Description

Inherited deficiencies of complement pathway components - rare, but produce characteristic, predictable patterns of susceptibility depending on which component is missing

Individually rare; C2 deficiency is the most common inherited complement deficiency overall

Complement has three activation pathways (classical, alternative, lectin) converging on a shared terminal pathway (C5-C9, the membrane attack complex)
Early classical pathway deficiencies (C1q, C2, C4) - strongly associated with SLE-like autoimmune disease (impaired clearance of immune complexes and apoptotic debris)
Terminal pathway deficiencies (C5-C9) - markedly increased susceptibility to recurrent Neisseria infections (meningococcal, gonococcal) - the membrane attack complex is specifically important for lysing these organisms
C1 esterase inhibitor deficiency - not an infection susceptibility syndrome, but causes hereditary angioedema via unregulated bradykinin generation

CH50 (classical pathway functional assay) and AH50 (alternative pathway functional assay) screen for deficiencies - a low result with individual component assays localises the specific defect
Recurrent meningococcal infection, especially with unusual serogroups or at an atypical age, should prompt complement pathway testing

Vaccination (meningococcal, pneumococcal) is particularly important in terminal pathway deficiency given the infection risk
C1 esterase inhibitor deficiency (hereditary angioedema) - managed with C1-INH concentrate, icatibant (bradykinin receptor antagonist), or prophylactic agents - not antihistamines/adrenaline, which target histamine-mediated (not bradykinin-mediated) swelling

SLE (early classical pathway deficiency), recurrent Neisserial infection (terminal pathway deficiency), hereditary angioedema (C1-INH deficiency)

Early recognition of terminal pathway deficiency and appropriate vaccination substantially reduces the risk of life-threatening meningococcal disease

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