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Post-eculizumab meningococcaemia in vaccinated patients

Open ArchivePublished:July 20, 2017DOI:https://doi.org/10.1016/j.cmi.2017.07.011
      A 25-year-old male was admitted for evaluation of fatigue, and was found to have severe anaemia with a haemoglobin level of 6.4 gr%, MCV 118 fL, 116 000 reticulocytes/μL (7%), 1800×109/L neutrophils and thrombocytopaenia of 37×109/L. Biochemical parameters were compatible with haemolysis as elevated LDH (1314 U/L) and low haptoglobin (2 mg/dL). Bone marrow biopsy revealed hypocellular bone marrow (15%), leading to a diagnosis of aplastic anaemia dominated by a paroxysmal nocturnal haemoglobinuria (PNH) clone in 60% of neutrophils. As no matched donors were identified for allogeneic stem cell transplantation (SCT), the patient was vaccinated with a conjugated vaccine against Neisseria meningitidis (Nimenrix, GSK), designed to prevent invasive meningococcal disease (IMD) by serogroups A,C,W135 and Y, followed 2 weeks later by initiation of PNH treatment with the complement inhibitor eculizumab (Soliris, Alexion).
      Four days after the first eculizumab dose, the patient was admitted with a 40°C fever and rigors in the absence of nuchal rigidity or evidence of focal infection, and treatment with empirical intravenous ceftriaxone and ampicillin was started. Twenty-four hours later, Neisseria meningitidis serogroup Y growth was noted in blood cultures. The patient completed 5 days of intravenous ceftriaxone, followed by a 7-day treatment with oral ciprofloxacin. The patient did not have any risk factors for meningococcal infection but was living with his parents and 12 siblings, all were screened for meningococcal pharyngeal carriage and found to be negative. To date, the patient has been treated with repeated blood transfusions and has declined allogeneic SCT. Eculizumab treatment has not yet been renewed.
      Neisseria meningitidis is a cause of bacterial meningitis, sepsis, pneumonia, and localized infections. Approximately 10% of the population feature pharyngeal Neisseria meningitidis carrier state. Populations at risk for invasive meningococcal diseases (IMD) include splenectomized patients, crowded household contacts, smokers, and individuals suffering from complement deficiency or antecedent viral infection. Eculizumab, a humanized monoclonal antibody used for treatment of PNH, has been reported to predispose to infection with encapsulated bacterial strains including Neisseria meningitidis. Thus, meningococcal vaccination has been recommended at least 2 weeks prior to initiation of eculizumab treatment [
      • Hillmen P.
      • Muus P.
      • Röth A.
      • Elebute M.O.
      • Risitano A.M.
      • Schrezenmeier H.
      • et al.
      Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria.
      ], but because of enhanced haemolysis observed in patients already treated with eculizumab and then vaccinated against serogroup B meningococcal infection, it is recommended to vaccinate this group of patients within a week of eculizumab infusion. Nevertheless, 63 cases of IMD following prior vaccination were reported by the manufacturer, including eight cases fully described in the medical literature [
      • Vicente D.
      • Esnal O.
      • Pérez-Trallero E.
      Fatal Neisseria meningitidis serogroup X sepsis in immunocompromised patients in Spain. Virulence of clinical isolates.
      ,
      • Struijk G.H.
      • Bouts A.H.
      • Rijkers G.T.
      • Kuin E.A.
      • ten Berge I.J.
      • Bemelman F.J.
      Meningococcal sepsis complicating eculizumab treatment despite prior vaccination.
      ,
      • Cullinan N.
      • Gorman K.M.
      • Riordan M.
      • Waldron M.
      • Goodship T.H.
      • Awan A.
      Case report: Benefits and challenges of long-term eculizumab in atypical hemolytic uremic syndrome.
      ,

      Parikh SR, Lucidarme J, Bingham C, Warwicker P, Goodship T, Ramsay ME et al. First report of meningococcal B vaccine failure in a young adult on long-term eculizumab. 20th International Pathogenic Neisseria Conference, 4th–9th September 2016. Manchester, United Kingdom. http://www.ipnc2016.org/IPNC2016AbstractBook.pdf. Page 54.

      ,
      • Hernando Real S.
      • Vega Castaño S.
      • Pajares García R.
      Meningococcemia in vaccinated patient under treatment with eculizumab.
      ] (including two events in the same patient [
      • Hernando Real S.
      • Vega Castaño S.
      • Pajares García R.
      Meningococcemia in vaccinated patient under treatment with eculizumab.
      ]) (Table S1, online supplementary data). Of these, the presented case is the second described following the use of a conjugated meningococcal vaccine.
      Invasive disease is associated with a 10–40% fatality rate. Thus, prevention by population-based vaccination is considered a major strategy in the battle against this pathogen. Meningococcal vaccine preparations include a quadrivalent polysaccharide A,C,W-135,Y meningococcal vaccine, conjugated vaccines to A,C,W-135,Y, and a hybrid vaccine that confers immunity to C and Y meningococcal serogroups in addition to Haemophilus influenza type b. Recently, two recombinant preparations that protect against serogroup B were introduced. Although the quadrivalent polysaccharide and conjugated vaccines protect against the same serogroups, major differences in immunogenicity have been noted between these preparations. Conjugation is believed to activate T cells and induce immune memory, therefore conferring a longer protection and a reduced carriage rate.
      In four of the nine described cases, meningococcal sepsis was caused by a serogroup against which the patients were not vaccinated [
      • Hillmen P.
      • Muus P.
      • Röth A.
      • Elebute M.O.
      • Risitano A.M.
      • Schrezenmeier H.
      • et al.
      Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria.
      ,
      • Vicente D.
      • Esnal O.
      • Pérez-Trallero E.
      Fatal Neisseria meningitidis serogroup X sepsis in immunocompromised patients in Spain. Virulence of clinical isolates.
      ,
      • Hernando Real S.
      • Vega Castaño S.
      • Pajares García R.
      Meningococcemia in vaccinated patient under treatment with eculizumab.
      ].
      In one of the five cases in which the vaccine did match the serogroup of invading bacteria, the non-conjugated polysaccharide vaccine was used, which is less immunogenic than the conjugated vaccine currently in use. Additionally, this patient was heavily immune suppressed and failed to mount a proper humoral response [
      • Struijk G.H.
      • Bouts A.H.
      • Rijkers G.T.
      • Kuin E.A.
      • ten Berge I.J.
      • Bemelman F.J.
      Meningococcal sepsis complicating eculizumab treatment despite prior vaccination.
      ]. Another patient was vaccinated with a conjugated vaccine, but featured suboptimal antibody titres [
      • Cullinan N.
      • Gorman K.M.
      • Riordan M.
      • Waldron M.
      • Goodship T.H.
      • Awan A.
      Case report: Benefits and challenges of long-term eculizumab in atypical hemolytic uremic syndrome.
      ], thus it is useful to measure serological response to meningococcal vaccine, and repeat vaccination every 3 years as suggested by Alashkar et al.
      Importantly, decreased susceptibility to penicillin reported ranging from 18% in 2010 in the USA to 55.7% in Tunisia, and the emergence of penicillin-resistant meningococcal strains, will render the common practice of administrating prophylactic penicillin treatment ineffective in an increasing number of cases. Of note, two of the nine described cases developed infection with a non-susceptible strains [
      • Cullinan N.
      • Gorman K.M.
      • Riordan M.
      • Waldron M.
      • Goodship T.H.
      • Awan A.
      Case report: Benefits and challenges of long-term eculizumab in atypical hemolytic uremic syndrome.
      ,

      Parikh SR, Lucidarme J, Bingham C, Warwicker P, Goodship T, Ramsay ME et al. First report of meningococcal B vaccine failure in a young adult on long-term eculizumab. 20th International Pathogenic Neisseria Conference, 4th–9th September 2016. Manchester, United Kingdom. http://www.ipnc2016.org/IPNC2016AbstractBook.pdf. Page 54.

      ]. As conjugated meningococcal vaccines have been shown to reduce pharyngeal meningococcal carriage, we suggest a modified strategy that includes vaccination of close household contacts of eculizumab treatment candidates, coupled with routine surveillance aimed at identification of a Neisseria meningitidis carrier state among these contacts. Those found to be carriers of Neisseria meningitidis should be offered a targeted, susceptibility-based antibiotic course, in addition to the routine but increasingly ineffective penicillin prophylactic treatment. An alternative approach is providing patients with oral 750 mg ciprofloxacin, coupled with comprehensive explanation to use it when symptoms compatible with meningococcal infection occur, while seeking immediate medical evaluation.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:
      TABLE S1. Cases of IMD following prior vaccination, as described in the medical literature (including two events in the same patient)

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