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

Nicholas Brodszki,Elena Perez,Anete S Grumach,Jiri Litzman,Stephen Jolles,Kathleen E Sullivan,Ashley Frazer-Abel,Mikko R J Seppänen,Michael Kirschfink

doi:10.1007/s10875-020-00754-1

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.

Highlights

Most complement deficiencies have a combined estimated prevalence of 0.03% in the general population, meaning that they meet the criteria for rare diseases (< 0.05% in the EU and< 200,000 individuals in the USA [i.e., approximately < 0.06%]) [1]
Complement deficiencies collectively account for 5.2% of the primary immunodeficiencies (PIDs) reported in the European Society for Immunodeficiencies (ESID) Registry and may well be underestimated partly due to a lack of readily available laboratory testing [4, 5]
Patients with C3 deficiency are prone to severe infectious complications, e.g., pneumonia, meningitis, osteomyelitis or bacteremia caused by encapsulated bacteria, e.g., Haemophilus influenzae and Neisseria meningitidis

Summary

Introduction

Most complement deficiencies have a combined estimated prevalence of 0.03% in the general population, meaning that they meet the criteria for rare diseases Genetic variants in the CFH and CFI genes that lead to haploinsufficiency (i.e., ~50% reductions in the levels of FH and FI) have been associated with age-related macular degeneration (AMD) [44, 45] These variants underpin the complexity and range of clinical manifestations, relating to both the degree of impairment and the involvement of multiple complement pathways in the pathogenesis of AMD [1, 46, 47]. AHUS atypical hemolytic uremic syndrome, AMD agerelated macular degeneration, AD autosomal dominant, AR autosomal recessive, C1-INH C1 esterase inhibitor, C3G C3 glomerulopathy, CVID common variable immunodeficiency, DAF decay-accelerating factor, CFHR complement factor Hrelated protein, GoF gain of function, HAE hereditary angioedema, LAD leukocyte adhesion deficiency, LFA lymphocyte function-associated antigen 1, MASP mannose-associated serine protease, MBL mannose-binding lectin, MCP membrane cofactor protein, PNH paroxysmal nocturnal hemoglobinuria, RA rheumatoid arthritis, SLE systemic lupus erythematosus. The first protein in the classical pathway is C1, which comprises one C1q molecule, two C1r molecules and two C1s

Factor B Factor D MBL

Findings

Deficiency