Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort

Abstract

Background: Terminal complement pathway deficiencies often present with severe and recurrent infections. There is a lack of good-quality data on these rare conditions. This study investigated the clinical outcome and genetic variation in a large UK multi-center cohort with primary and secondary terminal complement deficiencies.

Methods: Clinicians from seven UK centers provided anonymised demographic, clinical, and laboratory data on patients with terminal complement deficiencies, which were collated and analysed.

Results: Forty patients, median age 19 (range 3-62) years, were identified with terminal complement deficiencies. Ten (62%) of 16 patients with low serum C5 concentrations had underlying pathogenic CFH or CFI gene variants. Two-thirds were from consanguineous Asian families, and 80% had an affected family member. The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections. Nine (22%) were treated in intensive care for meningococcal septicaemia. Two patients had died, one from intercurrent COVID-19. Twenty-one (52%) were asymptomatic and diagnosed based on family history. All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics.

Discussion: The genetic etiology and clinical course of patients with primary and secondary terminal complement deficiency are variable. Patients with low antigenic C5 concentrations require genetic testing, as the low level may reflect consumption secondary to regulatory defects in the pathway. Screening of siblings is important. Only half of the patients develop septicaemia, but all should have a clear management plan.

Keywords: Factor H; Factor I; Genetics; Meningococcal infection; Terminal complement pathway.

Fig. 1

Distribution of primary and secondary terminal complement component deficiencies

Fig. 2

Meningococcal infection by serotype. The relative percentages of each serotypes associated with invasive meningococcal disease in England between 1999 and 2019 are quoted in brackets in the legend [13]