Fulminant meningococcal sepsis due to non-groupable Neisseria meningitidis in a patient receiving eculizumab

Here, we report a case of fulminant meningococcal sepsis due to a csw-deficient, unencapsulated strain of N. meningitidis. N. meningitidis can cause a wide spectrum of clinical disease, including meningitis and fulminant sepsis, and more atypical disease, such as pneumonia, septic arthritis, pericarditis, conjunctivitis, epiglottitis, sinusitis, urethritis and proctitis.2 Meningococcaemia can present with non-specific symptoms, such as loss of appetite, nausea, vomiting and, occasionally, as in our patient, diarrhoea.2

Invasive meningococcal disease (IMD) is usually caused by encapsulated strains of serogroups A, B, C, W, X and Y.2 The polysaccharide capsule is a major virulence factor which enables evasion of opsonisation and complement-mediated killing, and forms the target proteins for serogrouping by agglutination, and for serogroup A, C, W and Y meningococcal vaccines.2

Eculizumab is a recombinant, humanised monoclonal antibody approved for use in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome, which specifically binds to and inhibits cleavage of complement protein C5, blocking formation of C5 convertase and its cleavage to C5a and C5b.3 This prevents the generation of C5bC9, the terminal membrane attack complex, an important defence mechanism against encapsulated bacteria such as N. meningitidis.3 Patients receiving eculizumab have about 1000–2000 times greater likelihood of IMD than the general population, and are recommended to have meningococcal vaccination before initiating treatment.2,3 Long term prophylaxis with penicillin is also recommended.3 Although our patient had been prescribed penicillin V potassium prophylaxis, in retrospect, he acknowledged poor compliance, and, subsequently, daily instead of twice-daily prophylaxis was used. Local epidemiological data have observed a rising prevalence of N. meningitidis with reduced susceptibility to penicillin, although the clinical significance of this remains uncertain for patients taking prophylaxis.

Our patient had not previously received the meningococcal B vaccine, due to concerns of an increased risk of haemolysis or low haemoglobin observed in patients treated with eculizumab who were vaccinated with the recombinant multicomponent meningococcal B vaccine (Bexsero, Novartis/GlaxoSmithKline).4 A safety alert in Canada noted that the risk was highest when predicted systemic levels of eculizumab were low, recommending that vaccination should occur when the underlying complement-mediated disease (paroxysmal nocturnal haemoglobinuria or atypical haemolytic uraemic syndrome) is stable and within one week of eculizumab infusion, when concentrations of the drug are still high.4

Non-groupable N. meningitidis strains have been previously isolated from clinical samples, with late complement deficiency being a major predisposing factor. These unencapsulated isolates are not covered by meningococcal vaccines targeting the polysaccharide capsule, but rarely cause invasive disease.5 However, in a recent series of 16 patients who developed IMD on eculizumab, despite prior meningococcal vaccination, 11 cases were due to non-groupable isolates.5 Our case adds to this case series and provides observational data supporting expert recommendations that these patients receive indefinite chemoprophylaxis to prevent breakthrough IMD.3

Additional information: Whole genome sequencing data of the isolates have been uploaded to the National Center for Biotechnology Information Sequence Read Archive under BioProject accession PRJNA400326.

Box – Diagrammatic representation of the capsule genetic (cps) locus from the meningococcus W strain M10208 (GenBank accession no. CP009422.1) (top), compared with the cps locus from the patient’s isolate*

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LPS = lipopolysaccharide. * Arrows represent genes oriented in the forward or reverse direction in each of the genomes. Grey blocks indicate corresponding genomic regions > 99% nucleotide identity. No csw gene was present in the patient’s meningococcal isolate genome.