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

The complement system is an important component of innate immune defence against invading bacteria, particularly encapsulated meningococci and pneumococci. Terminal complement deficiencies are inherited as autosomal recessive traits and their prevalence varies, depending on consanguinity and family size [1]. The terminal complement pathway is made up of five components (C5–C9). They combine to form the pore-forming membrane attack complex (MAC) that disrupts membranes and lyse bacteria [2].

Deficiencies in terminal complement components impair immunity, particularly against meningococci [3]. Patients have a 7,000 to 10,000-fold higher risk of invasive meningococcal disease, and half have recurrent infections [4, 5]. Less prevalent meningococcal strains with lower virulence often cause invasive meningococcal infections in these patients [4, 6].

Good-quality data on this topic are sparse, with only a few published case reports or series [6‐11]. The aim of this study was to characterise the clinical and laboratory features of a large UK cohort of patients with primary and secondary terminal complement deficiencies, to understand more fully the morbidity and mortality, thus providing information to guide future management decisions.

This is the largest retrospective, multicenter, cohort study of patients with terminal complement deficiencies. There are several lessons to be learned from the study.

Two-thirds of patients were from a consanguineous Asian family and 80% had an affected family member, highlighting the importance of testing siblings of index cases. The only patient to die as a direct complication of his complement deficiency (factor I) was a 4-month-old who succumbed to fulminant pneumococcal meningitis. The infant had three older siblings who were regularly being followed by the clinical immunology service. However, the immunology team was not made aware of the mother’s pregnancy nor the child’s birth. This tragic case illustrates the importance of ensuring early screening and a clear management plan for infants born to families with immune deficiency. A previous UK study screened 824 patients who had previously suffered from meningococcal sepsis for primary complement deficiency and found only one case [14]. Unlike their series, many of our cohorts had consanguineous parents and other affected siblings, highlighting the importance of taking a thorough family history in patients with meningococcal disease (especially with less common serotypes) or unusual or recurrent infections.

DNA was sent for genetic sequencing in the majority of patients, particularly those with low serum C5 concentrations. Ten (62%) of 16 patients with low C5 antigenemia had CFH or CFI pathogenic gene variants with normal C5 genetics, consistent with a diagnosis of secondary consumptive C5 deficiency due to a primary defect in the regulatory complement component. We recommend that all patients with a suspected complement deficiency should have confirmatory genetic testing. Complement factors H and I regulate the formation of C3 and C5 convertase enzymes and cause excessive consumption [15]. In contrast, to complete deficiencies of complement factors suffered by patients in our cohort, haplo-insufficiencies of these regulatory factors are often associated with normal serum protein levels and overactivity of the complement pathway, leading to atypical haemolytic uremic syndrome or other vasculopathies [16, 17]. In addition, those patients treated with anti-C5 biologics such as eculizumab or ravulizumab also have a higher risk of meningococcaemia [18]. No C9 deficient patients were detected in this series, in keeping with the absence of this immune deficiency in the UK and other European Primary Immunodeficiency registries [19]. In contrast, C9 deficiency has been documented in some Japanese patients with terminal complement deficiency [20].

This is one of the first studies to document the proportion of family members with terminal complement deficiency who are asymptomatic. Fifty-two percent of patients (median age of 17 (range 3–46) years) had no prior history of bacterial sepsis. Asymptomatic adults cannot be excluded based on the absence of clinical disease and their complement pathway should be tested. It is also important to be aware that the median age of first meningococcal infection in these patients was 9 (range 1–25) years, while in the UK, the incidence of meningococcal infections is highest in infants under one year old [21]. In keeping with our findings, Platonov et al. previously found that the mean age of first meningococcal infection in their cohort of terminal complement deficient patients was 15 years old [22]. Thus, there should be a higher index of suspicion of complement defects in patients presenting later in childhood or beyond.

Patients with defects in terminal complement deficiencies typically suffer from meningococcal sepsis as was the case with nearly half of the patients in this cohort [23]. The relatively low mortality per episode of meningococcal disease in patients with terminal complement deficiencies has been demonstrated previously, hypothesised as due to lower endotoxin release from the bacterial surface in the absence of a complete terminal complement pathway [22]. Deep-seated non-meningococcal infections are also common, occurring in one-third of patients, and include bacterial meningitis, osteomyelitis/septic arthritis, sinopulmonary infection, and soft-tissue infections.

Conjugate meningococcal B and ACYW and pneumococcal and Haemophilus influenzae type B vaccines should be given to all patients with complement deficiencies, with subsequent monitoring of antibody titres. Prophylactic antibiotics are recommended, particularly in patients with recurrent meningococcal infections or those at higher risk of endemic or occupational exposure [24]. The use of prophylactic antibiotics should be balanced against the potential development of resistance. Patients also need education, including an emergency plan in the event of infection and travel. Some patients have emergency antibiotics at home and MedicAlert or similar bracelets. The effectiveness of these measures in preventing disease is not possible to determine from the present study. This study found no association between either rate of infection or admission to intensive and receiving antibiotic prophylaxis but did not formally assess adherence. Twenty-two percent of patients admitted not to take their antibiotic prophylaxis, but there were no obvious predictive demographic or clinical correlates. Adherence and factors influencing it are generic issues that would be possibly better addressed in studies of adherence to medications given for more common conditions, e.g., asthma, hypertension, and HIV.

In summary, this study highlights the complexities of terminal complement deficiencies. Meningococcal infection over 5 years of age and with less common serotypes (e.g. E, Y) or recurrent meningococcal infection should prompt further investigation of terminal pathway defects, particularly where there is a family history of unusual or deep-seated bacterial infections or consanguinity. The importance of genetic testing for possible factor H and I deficiency in patients with low antigenic C5 levels is also emphasised. Further studies investigating the prevalence of terminal complement deficiencies and the impact of antibiotic prophylaxis and vaccination on outcome are required. The use of international databases may enable long-term follow-up of these patients.