Overview (N Engl J Med 2001;344:1058, N Engl J Med 2001;344:1140)
• Divided into 3 pathways: Classical, mannose-binding lectin, and alternative
• Functions of complement: Defense against infection (opsonization, chemotaxis, lysis), interface between innate and adaptive immunity, clearance of waste
• Complement works as predetermined cascade pattern, all pathways activate C3
Hereditary Angioneurotic Edema (Pediatrics 2011;128:1173, J Allergy Clin
Immunol 2008;121:S398)
• Definition: Recurrent self-limited episodes of tissue swelling affecting the skin, upper respiratory and GI tracts
• Type 1 (85%) w/ ↓ amount and activity of C1-inhibitor (C1-INH) in serum
• Type 2 (15%) w/ normal amount, but functional impairment of C1-INH
• Type 3 w/ normal level and fxn of C1-INH; associated w/ mutation in coagulation factor XII protease
• Pathophysiology: Autosomal dominant, >200 mutations of C1-INH gene identified
• C1 activates classical complement pathway; C1-INH prevents spont activation
• Epidemiology: Usually presents in 1st or 2nd decade of life; 1:10,000 to 1:150,000
• 25% of pts have no family history and are presumed new mutations
• Clinical manifestations:
• 50% have attacks ≤5 times/yr; 30% have attacks >12 times/yr
• Patients generally feel prodrome 1–2 hr before onset
• Recurrent edema lasting up to 1 wk after stress or traumatic events
• Edema tends to be nonpainful, nonpitting; subcutis (face, trunk, genitals, extremities) and submucosal (intestines, larynx), laryngeal swelling can be life-threatening
• Intestinal swelling → significant abdominal pain, vomiting, diarrhea; sx can be similar to appendicitis/other causes of acute abdomen
• Diagnostic studies:
• ↓ C1-INH and ↓ levels of C4 (↑ C1 levels result in↑ cleavage of C4 from pathway)
• Nml complement levels and C1 inhib levels reached from 2–3 yo, infant eval uncertain
• Management:
• Not a histamine release so typical agents (anti-histamines, epi, steroids) will not help
• Acute attacks: Hydration, pain relief, plasma derived C1-INH or ecallantide (kallikrein inhibitor) or icatibant (bradykinin B2 receptor antagonist); 2nd-line agents: FFP and solvent detergent-treated plasma
• Short-term ppx (before high-risk procedure): C1-INH (off-label); or danazol (androgen) +/− C1-INH, icatibant, or ecallantide; or FFP
• Long-term ppx: (If attacks >1/mo); danazol or antifibrinolytic agent (tranexamic acid)
• New therapies: Nano-filtered C1-INH concentrate (FDA approved for long-term prophy), recombinant human C1-INH (under FDA review for acute attacks)
• Complications: Critical airway management
• ACE inhibitors, OCP (estrogen), dental work can bring on an episode
• Higher incidence of autoimmune disease, no higher incidence of atopy
Other Complement Deficiencies (Mol Immunol 2011;48:1643)
• C1q def; sepsis, meningitis, pneumonia; S. pneumoniae, N. meningitidis; SLE-like syndrome
• C2 def; sepsis, meningitis, pneumonia; S. pneumoniae, N. meningitidis, S. aureus; rheumatic disease, CV disease
• C5, C6, C7, C8, C9 def; meningococcal meningitis
• CD59, CD55 def: Thrombosis, hematopoietic cytopenia