Paeds · allergy-and-immunology
Complement deficiencies
Also known as Complement component deficiency · Classical pathway deficiency · Alternative pathway deficiency · Terminal complement deficiency · Hereditary angioedema due to C1-inhibitor deficiency · Inborn errors of the complement system
A fellowship approach to complement deficiencies in children: recognise the three clinical fingerprints (recurrent invasive Neisseria, unexplained angioedema without urticaria, and childhood-onset lupus-like disease), screen with the total haemolytic complement CH50 and AP50 rather than a lone C3/C4, localise the block to a pathway, and then tailor prevention to the site of the defect — meningococcal vaccination and antibiotic prophylaxis for terminal-pathway loss, C1-inhibitor-directed therapy for hereditary angioedema, and specialist-led surveillance for the immune-complex phenotypes.
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Target exams
Red flags
- Two or more episodes of invasive meningococcal disease — search for a terminal complement (C5-C9) deficiency or properdin deficiency
- Recurrent angioedema without urticaria or itch, not responding to adrenaline, antihistamines or steroids — think hereditary angioedema due to C1-inhibitor deficiency
- Childhood-onset systemic lupus erythematosus or lupus-like disease, especially with low complement — check C1q, C2 and C4
- Recurrent sinopulmonary or pyogenic infection in an otherwise well child with a single unexplained low CH50
- A child about to start eculizumab or ravulizumab — they become functionally C5-deficient and need meningococcal vaccination and antibiotic prophylaxis before the first dose
- Family history of meningitis deaths, consanguinity, or known complement deficiency
- Atypical haemolytic uraemic syndrome or C3 glomerulopathy — consider factor H, factor I or membrane cofactor protein deficiency
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- General and Community Paediatrics
- Infectious Diseases, Immunology and Allergy
- Rheumatology
- Allergy and immunology - recognise, investigate and manage primary immunodeficiency and recurrent infection
- Immunology and allergy - hereditary angioedema and complement deficiency
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A previously well fifteen-year-old presents with his second episode of invasive meningococcal septicaemia in two years. He recovered fully each time and is entirely well between episodes. His C3 and C4 are normal, but his total haemolytic complement (CH50) is undetectable, and the AP50 is normal. Two doors open from that single result. Through one door sits a boy with a terminal complement component deficiency (C5, C6, C7, C8 or C9) who will live a normal life provided he receives meningococcal vaccination, standing antibiotic prophylaxis and a plan for immediate-access emergency antibiotics. Through the other sits a child in whom the low CH50 reflects sample handling or an acquired consumption — and who will be labelled with a chronic immunodeficiency and subjected to years of unnecessary intervention if the result is not repeated and the components quantified. Telling those two children apart — without dismissing the recurrent meningococcaemia as "unlucky" and without over-labelling the well child — is the whole skill of this topic. [9] [10]
CH50 is the screen, not C3/C4 alone · Otherwise-well recurrent Neisseria = terminal (C5–C9) block · Meningococcal vaccines ACWY + B plus penicillin prophylaxis for terminal loss · Properdin is the X-linked one (maternal male relatives) · Lupus in a child — check C1q, C2, C4 (classical pathway) · Eculizumab makes a patient functionally C5-deficient · Membrane attack complex = C5b–9 · Edema without urticaria, no response to adrenaline — hereditary angioedema (C1-INH) · Normal C3/C4 does NOT exclude complement deficiency · Treat the attack site: infection-defence blocks vs bradykinin angioedema vs immune-complex disease. [1] [8]
Overview & Definition
The complement system is a cascade of plasma and cell-surface proteins that, once activated, opsonise pathogens, recruit inflammatory cells, and directly lyse susceptible organisms through the membrane attack complex. Three activation pathways converge on the central component C3: the classical pathway (triggered by antigen–antibody complexes), the lectin pathway (triggered by microbial sugars binding mannose-binding lectin), and the alternative pathway (a continuously ticking surveillance loop). All three generate C3 convertases that cleave C3, and the downstream C5 convertase drives assembly of the terminal membrane attack complex C5b–9. [1] [2]
A complement deficiency is any inborn error or acquired loss that removes a component or a regulator of this cascade. The clinical consequence is not one syndrome but several, and which one a child develops is determined entirely by the site of the block. Loss of an early classical-pathway component impairs clearance of immune complexes and apoptotic debris and predisposes to lupus-like disease. Loss of C3 or an alternative-pathway component compromises opsonisation and produces severe, recurrent pyogenic and neisserial infection. Loss of a terminal component removes the lytic pathway and produces selective, isolated susceptibility to Neisseria. Loss of a regulator produces either uncontrolled bradykinin generation (hereditary angioedema) or uncontrolled C3 activation on the glomerulus (atypical haemolytic uraemic syndrome, C3 glomerulopathy). [3]
The headline distinction for a general paediatrician is that a normal C3 and C4 does not exclude a complement deficiency. The routine immunochemistry assays measure the intact protein concentration, and most component deficiencies leave C3 and C4 in the reference range. The correct screen is the functional haemolytic assay — CH50 for the classical and terminal pathway, AP50 for the alternative pathway — which tests the integrity of the whole cascade by measuring its capacity to lyse sensitised red cells. [1] [6]
References10ShowHide
- [1]Walport MJ. Complement. First of two parts. N Engl J Med, 2001.PMID 11287977
- [2]Walport MJ. Complement. Second of two parts. N Engl J Med, 2001.PMID 11297706
- [3]Botto M, Kirschfink M, Macor P, et al. Complement in human diseases: Lessons from complement deficiencies. Mol Immunol, 2009.PMID 19481265
- [4]Pekkarinen PT, Heikkilä N, Kisand K, et al. Dysregulation of adaptive immune responses in complement C3-deficient patients. Eur J Immunol, 2015.PMID 25446578
- [5]Bousfiha A, Moundir A, Tangye SG, et al. The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity. J Clin Immunol, 2022.PMID 36198931
- [6]Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract, 2019.PMID 30776527
- [7]Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med, 2008.PMID 18768946
- [8]Maurer M, Magerl M, Betschel S, Aberer W, Ansotegui IJ, Aygören-Pürsün E, et al. The international WAO/EAACI guideline for the management of hereditary angioedema - The 2021 revision and update. World Allergy Organ J, 2022.PMID 35497649
- [9]Rauscher CK, Fajt ML, Bryk J, et al. Clinical implications of C6 complement component deficiency. Allergy Asthma Proc, 2020.PMID 32867893
- [10]Ladhani SN, Campbell H, Lucidarme J, Ramsay ME, Borrow R, Parikh SR, et al. Invasive meningococcal disease in patients with complement deficiencies: a case series (2008-2017). BMC Infect Dis, 2019.PMID 31200658