Basics
Description
- Complement is a major component of the innate immune system.
- Consists of plasma and membrane proteins which mediate 3 pathways of cascading enzyme reactions
- Pathway activation leads to inflammatory and immune responses.
- Deficiencies can arise in any of the proteins, leading to loss of activity of the deficient protein as well as loss of function of proteins that follow in the cascade.
- Inherited deficiencies of the complement components may predispose individuals to infections and autoimmunity.
- Secondary/acquired deficiencies are much more common than inherited deficiencies and are most often caused by increased consumption by immune complexes.
Clinical manifestations of complement deficienciesView LargeClinical manifestations of complement deficienciesDeficiencyClinical manifestationsC1q,r,s, C2Systemic lupus erythematosus (SLE), bacterial infectionsC4SLE, autoimmune disordersC3Severe infections with encapsulated bacteria (i.e., Haemophilus influenzae), glomerulonephritis, immune complex diseaseFactor H, ISecondary C3 deficiency, atypical hemolytic uremic syndromeProperdinMales with neisserial and sinopulmonary infectionsFactor DNeisserial infectionsMBL, MASPInfections with encapsulated bacteria, SLE, rheumatoid arthritisC5, 6, 7, 8, 9Disseminated neisserial infectionsDAF, CD59Paroxysmal nocturnal hemoglobinuriaC1 inhibitorHereditary angioedema (HAE)
Epidemiology
- Complement deficiency accounts for approximately 2% of all primary immune deficiencies.
- Homozygous C2 deficiency 1 in 10,000
- Borderline C4 in 1-3% of Caucasian population
- C9 deficiency almost always found in people of Japanese descent
- C6 deficiency more common in African Americans
- Alternative pathway deficiencies (properdin, factor D) are rare.
Risk Factors
Genetics
- Properdin deficiency is X-linked.
- Most other complement deficiencies are autosomal recessive.
- C1 inhibitor deficiency is autosomal dominant.
- Heterozygotes are usually phenotypically normal.
Pathophysiology
- Classic complement pathway is activated when IgM or IgG antibodies bind to antigen.
- Lectin pathway is activated when a lectin such as mannose-binding lectin (MBL) binds to antigen.
- Alternative pathway does not need antibody or lectins to be activated.
- Main goal of all 3 pathways is to deposit C3b fragments on the target antigen to mark the target for immune response.
Etiology
- Primary complement deficiencies are hereditary.
- Acquired deficiencies: accelerated consumption by immune complexes (most common), decreased hepatic production (less common), or loss through the urine (rare)
Diagnosis
History
Indications for evaluating complement system:
- Recurrent pyogenic infections in patients with normal white blood cell count and immunoglobulin levels
- Recurrent neisserial infections (meningitis, sepsis, gonococcal arthritis) at any age
- Multiple family members who have had neisserial infections
- SLE, especially familial lupus: Evaluate for C2 deficiency.
- Recurrent angioedema without urticaria: Evaluate for C1 inhibitor deficiency (HAE).
Physical Exam
- Depends on which component is deficient
- Assess for signs and symptoms of autoimmunity (i.e., SLE) and also of bacterial infections and sequelae.
- Failure to thrive
- Recurrent angioedema without urticaria for HAE
Diagnostic Tests & Interpretation
Diagnostic Procedures/Other
- Initial lab tests
- Total hemolytic complement (CH50): Screens for homozygous deficiencies in the classical pathway. All 9 components (C1-C9) required for normal CH50
- Complement activity is thermolabile and reduced quickly at room temperature. Low levels often due to improper specimen handling
- Complete deficiency of any component gives undetectable CH50 level.
- Heterozygotes may have normal CH50.
- AH50
- To assess integrity of alternate pathway
- Individual component testing
- Based on clinical history
- C4, C1 esterase inhibitor level and function may be used to evaluate for HAE
Differential Diagnosis
- Antibody (humoral) deficiency syndromes
- Secondary complement deficiencies
Alert
- Most common cause of low complement levels is improper specimen handling.
- Secondary deficiency may be caused by consumption of complement components.
Treatment
Medication
- There are no specific treatments for most complement deficiencies.
- Aggressive diagnosis and treatment of infections with antibiotics
- HAE prophylaxis and treatment for C1 inhibitor deficiency
Additional Treatment
General Measures
- Consider prophylactic antibiotics to prevent recurrent infections.
- Vaccination with Streptococcus pneumoniae and Neisseria meningitidis conjugate vaccines as well as Haemophilus influenzae for patients and household contacts
- Can receive other routine vaccines (including live viral vaccines) safely
- Wear medical identification tag identifying condition.
- Plasma infusions impractical over lifetime and risk of development of antibody against missing component
Issues for Referral
- Should be followed by immunologist
- Monitor for autoimmune disease and refer to rheumatologist for autoimmunity management.
- Genetic counseling for family members
Ongoing Care
Complications
- Severe infections and sequelae including death
- Immune complex disease
- Autoimmunity
Additional Reading
- Bonilla FA, Geha RS. Primary immunodeficiency diseases. J Allergy Clin Immunol. 2003;111:S571-S581. [View Abstract]
- Frank MM. Complement deficiencies. Pediatr Clin North Am. 2000;47(6):1339-1354. [View Abstract]
- Frank M. Complement disorders and hereditary angioedema. J Allergy Clin Immunol. 2010;125(2) (Suppl. 2):S262-S271. [View Abstract]
- Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344(14):1058-1066. [View Abstract]
- Walport MJ. Complement. Second of two parts. N Engl J Med. 2001;344(15):1140-1144. [View Abstract]
Codes
ICD09
- 279.8 Other specified disorders involving the immune mechanism
ICD10
- D84.1 Defects in the complement system
SNOMED
- 234593008 Classical complement pathway abnormality (disorder)
- 234594002 Complement 1q deficiency (disorder)
- 234599007 Complement 2 deficiency (disorder)
- 234603007 Complement 3 deficiency (disorder)
- 234617003 Complement 9 deficiency (disorder)
- 234597009 Complement 1r deficiency (disorder)
- 234609006 Complement 5 deficiency (disorder)
- 234611002 Complement 6 deficiency (disorder)
- 234600005 Complement 4 deficiency (disorder)
- 234612009 Complement 7 deficiency (disorder)
- 234598004 Complement 1s deficiency (disorder)
FAQ
- Q: When should I evaluate for a complement deficiency?
- A: Any child with recurrent sinopulmonary infections or >1 episode of a neisserial infection.