European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management

Abstract

This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for ~5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disorders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning.

Keywords: Complement; alternative pathway; classical pathway; complement deficiencies; mannan-binding lectin.

Fig. 1

Complement system activation pathways. LPS lipopolysaccharide, MAC membrane attack complex, MASP mannose-binding lectin-associated serine protease, MBL mannose-binding lectin. *Examples of anaphylatoxins from the complement pathways

Fig. 2

Algorithm for complement testing. a Where to start investigating the possibility of primary immunodeficiency, e.g., infection with encapsulated organisms. b Where to start if a disease of complement dysregulation is suspected, such as complement-related kidney disease, e.g., aHUS. c If not all functions can be tested, do what is available and proceed to test all possibilities from unavailable pathways. d If multiple pathways are low, the deficiency likely lies in the shared terminal pathway. e Activation marker testing can also be helpful to determine if a component is low due to consumption. If it is a true deficiency then the cognate fragment would be low or absent with a normal activation marker level. f When testing for a disease of complement dysregulation, testing function as well as abundance can help give a more complete picture of the extent and location of the dysfunction. g Markers of activation to consider testing include: sC5b-9, C4a, C4d, C3a, C3d, iC3b, C5a, Bb, Ba and C3 convertase. It is not necessary to measure all markers but by measuring one in each pathway it is possible to better determine the site of the dysregulation. For all complement measurement, and activation markers in particular, proper specimen handling by assay type is key, including freezing at − 80°C within 2 h of collection. AH50, alternative pathway hemolytic activity; aHUS, atypical hemolytic uremic syndrome; AP, alternative pathway; C1-INH, C1 esterase inhibitor; CH50, complement hemolytic activity; CP, classical pathway; LP, lectin pathway; MASP, MBL-associated serine protease; MBL, mannose-binding lectin; PID, primary immunodeficiency. *The sample may have been improperly handled, or the patient has autoantibodies against complement components.