Reply letter to “Fatal meningococcemia due to Neisseria meningitidis serogroup Y in a vaccinated child receiving eculizumab”

This article refers to:

Fatal meningococcemia due to Neisseria meningitidis serogroup Y in a vaccinated child receiving eculizumab

We want to thank Polat et al¹ for their important commentary and case report describing a meningococcal conjugate (MenACWY-D) vaccinated 11-year-old boy with fatal meningococcemia due to Neisseria meningitidis serogroup Y occurring while he was on treatment with the humanized monoclonal antibody, eculizumab. The child was also receiving oral penicillin prophylaxis and the serogroup Y isolate showed intermediate penicillin susceptibility. Eculizumab binds C5 and inhibits the terminal complement pathway. It is used in complement mediated thrombotic microangiopathies such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome,² and now for other conditions. Patients on eculizumab treatment are a population of concern at high risk for meningococcal disease. The incidence of meningococcal disease in individuals receiving eculizumab is >300/100,000.³

Current US Advisory Committee on Immunization Practices (ACIP) guidelines recommend that all patients who will receive eculizumab should be vaccinated prior to starting treatment with both ACWY conjugate and MenB vaccines.^4,5 Although developed for MenB disease prevention, MenB vaccines are directed at outer membrane proteins, not the capsule, and these proteins can be shared by meningococci expressing different capsular serogroups and by nongroupable strains. Antibiotic chemoprophylaxis with oral penicillin has also been recommended based on risk factors. However, cases such as the one described by Polat et al. and similar cases reported by others^3,6,8 are particularly alarming since despite current prevention recommendations, the patients still died from meningococcal disease.

Vaccine-induced protection either with ACWY conjugate and MenB vaccines is incomplete in patients treated with eculizumab,^3,6,7 due to eculizumab's inhibition of both complement mediated bactericidal activity and also complement mediated opsonic functions.⁷ While this case was caused by serogroup Y, nongroupable strains of N. meningitidis cause a majority of reported cases of meningococcal disease in patients on eculizumab.³ Antibiotic prophylaxis with oral penicillin is also recommended, but rates of resistance to penicillin among meningococcal isolates are rising,⁶ and effectiveness of this strategy for meningococcal disease prevention has not been established. In a CDC analysis of 14 isolates from meningococcal cases in patients on eculizumab in the US, ten isolates were susceptible to penicillin, three had intermediate susceptibility and one isolate was resistant.³ Several other recent case reports document meningococcal infections with penicillin-intermediate or penicillin-resistant strains in patients on eculizumab.^{6, 8} These factors contribute to a very high risk of meningococcal disease in patients on eculizumab despite vaccination and penicillin prophylaxis.

Clinical trials are underway looking at alternative complement pathway inhibitors such as the small molecule factor D inhibitor ACH-4471, which may lower the risk of acquiring invasive meningococcal disease.⁷ For patients on eculizumab, heightened patient and family awareness of the risks of meningococcal disease and the symptoms (fever, chills, headache and myalgias – rash may occur only late in the course), early care seeking, vaccination of close contacts to reduce meningococcal transmission and the home administration of ceftriaxone or other effective antibiotic agents at first signs of symptoms are approaches. The US FDA requires a Risk Evaluation and Mitigation Strategy (http://www.solirisrems.com/) to educate health care providers and patients about the risk for and early signs of possible meningococcal infection and the need for immediate medical evaluation of signs and symptoms consistent with possible meningococcal infection.³ Given the very high risk of meningococcal disease, antibiotic prophylaxis regimens other than oral penicillin such as weekly ceftriaxone (or an oral macrolide if beta-lactam allergic) for the entire duration of eculizumab treatment is also a consideration. Monoclonal antibodies are a burgeoning treatment option for a variety of conditions, and new agents are being developed and introduced into the market at an unprecedented pace.⁹ Balancing the benefits of these important treatment advances with the infectious risks will continue to be a significant challenge.