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.

Quantitative multiplex profiling of the complement system to diagnose complement‐mediated diseases

“…Complement deficiencies are rare and have a combined genetic prevalence of 0.03% in the general population and comprise only 5% of all primary immunodeficienciesexcluding more frequently occurring C4A, C4B and MBL variants (estimated 11-22%, 30-45% and 5-10%, respectively). 14 The mode of inheritance is mostly autosomal recessive, with the exception of a few cases of autosomal dominant inheritance: CR1, C1S, C1-inhibitor (C1-INH), mannose-binding lectin (MBL), and properdin (X-linked). 12 For factor H, both recessive and dominant modes of inheritance have been reported depending on the type of disease.…”

“…Conventionally, the classical, lectin, or alternative pathway activity is tested using functional assays (CH50, LP50 and AH50, respectively), followed by single tests measuring individual proteins of the affected pathway to identify the impaired protein. 14,16 Unfortunately, this testing strategy has some major shortcomings. Functional assays may not always rule out certain deficiencies, 12 and for most complement proteins, no standardised tests are available.…”

“…The diversity in clinical symptoms necessitates laboratory testing to diagnose the complement deficiency. Conventionally, the classical, lectin, or alternative pathway activity is tested using functional assays (CH50, LP50 and AH50, respectively), followed by single tests measuring individual proteins of the affected pathway to identify the impaired protein 14,16 . Unfortunately, this testing strategy has some major shortcomings.…”

Characterising COVID-19 as a Viral Clotting Fever: A Mixed Methods Scoping Review

“…The complement pathway is part of the innate immune response and is divided into three pathways – the classical, alternative and lectin complement pathways. (Brodszki et al, 2020) provide a guideline for the complement deficiencies and their management and review the evidence on complement deficiencies and the regulation of complement. They note a thrombotic microangiopathy associated with dysregulation of the alternative complement pathway.…”

Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience

“…For the purpose of this study we have used European Society for Immunodeficiencies (ESID) working group definition for the categorization of SAID. ESID has defined “unclassified autoinflammatory diseases” to be characterized by recurrent fever (temperature >38°C) having occurred on at least six occasions with exclusion of other known infective/inflammatory autoimmune disorders and documented evidence of increased inflammatory markers [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)], age of onset under 40 years and predominantly but not exclusively with systemic symptoms ( 23 ). In the present study all patients who fulfilled ESID working group definition and had molecular confirmation of monogenic SAID were included.…”