Complement Deficiency

Complement deficiency is a category of primary immunodeficiency disease. The complement system comprises a complex group of proteins that play a role in host defense and inflammation. These proteins act as a cascade with three parallel pathways, each activated by different stimuli: the classical pathway (CP), alternative pathway (AP), and lectin pathway (LP). These three pathways converge on a terminal pathway (TP). Deficiency in any of the proteins involved in these pathways, including complement components (eg, complement component 3 [C3]) and factors (eg, factor B), may lead to recurrent infections or inappropriate immune responses. Laboratory testing for complement deficiency includes primary testing to determine which pathway is affected, followed by secondary testing to identify the deficient component or factor and reach a definitive diagnosis.

Quick Answers for Clinicians

When should complement deficiency be suspected?

Complement deficiency is marked by recurrent bacterial infections, particularly respiratory infections with encapsulated organisms, or by systemic autoimmune disease that resembles systemic lupus erythematosus (SLE). Atypical hemolytic uremic syndrome (aHUS) is observed with several complement system defects. Recurrent Neisseria meningitis may also occur in patients with a terminal pathway complement deficiency. Laboratory testing for complement deficiency is recommended for patients with normal humoral immunity and recurrent bacterial infections with or without autoimmunity, as well as for patients with aHUS or recurrent Neisseria infections. See the Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children and Immunodeficiency Evaluation for Chronic Infections in Infants and Children testing algorithms for more information on testing for recurrent infections.

Which complement tests are useful in the evaluation of systemic lupus erythematosus?

Complement consumption often occurs in active systemic lupus erythematosus (SLE), which leads to low concentrations of classical pathway complement proteins, particularly complement component 3 (C3) and C4. Complement testing, including total complement testing and testing for the C3 and C4 components, may therefore be useful to support a diagnosis of SLE. Complement tests are also recommended every 3-6 months to monitor disease activity in patients with SLE. Decreased C3 and C4 concentrations may also be associated with glomerulonephritis in SLE. For more information, see the ARUP Consult Systemic Lupus Erythematosus topic.

What is the role of complement testing in hereditary angioedema?

The complement component 1 (C1) esterase inhibitor protein is deficient in hereditary angioedema, which leads to complement defects. Laboratory testing for hereditary angioedema includes testing for C1 esterase and C4 concentrations. For more information, see the ARUP Consult Hereditary Angioedema topic.

Laboratory Testing

Primary Testing

Initial evaluation for suspected complement deficiency is used to identify the affected pathway and should include testing for CP and TP activity (using the CH50 assay for total hemolytic complement) and AP activity (using the AH50 assay for alternative pathway hemolytic activity). The initial evaluation may also include testing for LP function (using a mannose binding lectin [MBL] test), depending on the clinical circumstance.

Secondary Testing

Results from the initial evaluation guide secondary testing to identify the deficient component or factor. Complement deficiency may present similarly to complement consumption (eg, due to autoimmune disease); complement consumption can be distinguished by the simultaneous reduction in multiple complement component concentrations. Secondary tests may include tests to directly measure protein concentrations or to assess protein function. Genetic testing may be useful if a hereditary deficiency of a particular component or regulatory factor is suspected.

Primary and Secondary Testing for Complement Deficiency^a
Primary Testing			Defect Implicated	Secondary Testing
CH50	AH50	MBL	Defect Implicated	Secondary Testing
Low or absent	Normal	Normal	CP defect or complement consumption^b	Complement concentrations or functional testing: C1, C2, C4
Normal	Low or absent	Normal	AP or regulatory factor deficiency	Properdin concentration or functional testing Factor levels: B, D
Low or absent	Low or absent	Normal	TP defect, regulatory factor deficiency, or complement consumption^b	Complement component concentrations or functional testing: C3, C5, C6, C7, C8, C9 Factor levels: H, I
Normal	Normal	Low	LP defect	LP components
^aRefer to the Complement Deficiency Testing algorithm for visual representation of suggested testing sequence. ^bSimultaneous reduction in concentrations of multiple components (eg, C3 and C4) suggests a disorder of complement consumption. Source: Bonilla, 2015