Abstract
Prevalence of complement deficiencies (CDs) is markedly higher in Slovenian primary immunodeficiency (PID) registry in comparison to other national and international PID registries. The purposes of our study were to confirm CD and define complete and partial CD in registered patients in Slovenia, to evaluate frequency of clinical manifestations, and to assess the risk for characteristic infections separately for subjects with complete and partial CD. CD was confirmed with genetic analyses in patients with C2 deficiency, C8 deficiency, and hereditary angioedema or with repeated functional complement studies and measurement of complement components in other CD. Results of genetic studies (homozygous subjects vs. heterozygous carriers) and complement functional studies were analyzed to define complete (complement below the level of heterozygous carriers) and partial CD (complement above the level of homozygous patients). Presence of characteristic infections was assessed separately for complete and partial CD. Genetic analyses confirmed markedly higher prevalence of CD in Slovenian PID registry (26% of all PID) than in other national and international PID registries (0.5-6% of all PID). Complement functional studies and complement component concentrations reliably distinguished between homozygous and heterozygous CD carriers. Subjects with partial CD had higher risk for characteristic infections than previously reported. Results of our study imply under-recognition of CD worldwide. Complement functional studies and complement component concentrations reliably predicted risk for characteristic infections in patients with complete or partial CD. Vaccination against encapsulated bacteria should be advocated also for subjects with partial CD and not limited to complete CD.
Highlights
Complement is a cascade of soluble proteins and membrane expressed receptors and regulators, playing a key role in host homeostasis, inflammation, and defense against pathogens
28/44 patients with complement deficiencies (CDs) were evaluated for the clinical manifestations because data were not available for the 16 diagnosed before 1995
Functional complement tests can be temporary reduced in subjects without CD because of complement consumption or improper transport; only patients with persistently reduced functional complement tests were included in the Slovenian primary immunodeficiency (PID) registry, which increases reliability of epidemiologic PID data
Summary
Complement is a cascade of soluble proteins and membrane expressed receptors and regulators, playing a key role in host homeostasis, inflammation, and defense against pathogens. It is well recognized that homozygous mutations in complement component C1–C9 genes severely reduce complement activity and lead to recurrent infections with encapsulated bacteria and autoimmune phenomena [2, 3]. Heterozygous mutations in complement component C1–C9 genes partially reduce complement activity that only exceptionally leads to clinical manifestations [5]. The correlation between homozygous and heterozygous states, complement activity and clinical manifestations in a large cohort has not been studied yet. Published data are limited to small case series and 1 multicenter study evaluating clinical manifestations in 77 patients with CD (excluding HAE, MBL deficiency, and CD carriers) from 18 cities across Europe [6]. CD was genetically confirmed in only 25% of included patients and the study did not evaluate the correlation between complement activity and clinical manifestations. Prevalence of complement deficiencies (CDs) is markedly higher in Slovenian primary immunodeficiency (PID) registry in comparison to other national and international PID registries
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