Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic and thrombotic condition. Patients can experience severe anemia due to intravascular hemolysis, thrombotic events, renal impairment and pulmonary hypertension. Symptomatic patients are treated with complement inhibitors either in clinical trials or with eculizumab the only licensed treatment in the UK. Due to the mechanism of action of eculizumab, it increases susceptibility to Neisseria infection, including Neisseria meningitidis. To reduce this risk of infection, worldwide practice is for patients to be vaccinated at least 2 weeks prior to receiving eculizumab (serogroups A, C, Y, W 135 and B). It was noted within the PNH National Service at Leeds (UK) that a small number of patients deteriorated with enhanced intravascular hemolysis and thrombosis during the period between vaccination and eculizumab, leading to a review of practice.
We report five of 121 patients with events in the intervening 2 weeks between vaccination and commencement of eculizumab from 2002-2012:
A 44 year female presented with hemolysis and hemoglobinuria, with a granulocyte PNH clone of 99.4%. She was transfusion dependent and on anticoagulation. She consented to the PNH pilot eculizumab study, undergoing meningococcal vaccination as per protocol. Twenty two days later, she suffered an ischemic stroke with left hemiplegia and permanent weakness, resulting in exclusion from the study. Two years later she received eculizumab in the TRIUMPH study.
A 37 year male presented with hemoglobinuria and fatigue with a granulocyte PNH clone of 99.58%. He had significant hemolysis, managed initially with warfarin and blood transfusions. He consented to start eculizumab and received meningococcal vaccination. 4 days later he presented with a symptomatic right hepatic vein thrombosis, promptly commenced eculizumab.
A 29 year male, with abdominal pain and hemoglobinuria for 3 years developed a stroke and portal vein thrombosis leading to a diagnosis of PNH, with a granulocyte PNH clone of 84.99%. He commenced anticoagulation. Four months after the stroke he received meningococcal vaccination in preparation for scheduled commencement with eculizumab. He experienced a left central retinal vein thrombosis 15 days after its administration prior to starting eculizumab.
A 47 year old male, was diagnosed with haemolytic PNH but only had mild symptoms and anaemia. Twenty four years later, he developed increasing hemolysis and symptoms; granulocyte PNH clone of 96.45%. Eculizumab was planned and he received meningococcal vaccination, but presented ten days later with acute renal failure secondary to massive intravascular haemolysis, necessitating emergency eculizumab therapy.
A 35 year female, with a granulocyte PNH clone of 99.87%. Although she had active intravascular hemolysis, eculizumab was declined, and anticoagulation commenced. Four years later she consented to start eculizumab, receiving meningococcal vaccination. She was admitted 24 hours later with a stroke and commenced eculizumab the same day, but has persistent neurological impairment to date.
See Table 1
The close time proximity of these serious events to the patients' vaccinations raised concern that the complement system was being activated by administration of the vaccine, precipitating complications of PNH. It is also concerning that 4 of the 5 patients experienced thrombotic events despite therapeutic anticoagulation, confirming that anticoagulation only partially mitigates the risk of thrombosis in patients with PNH. The decision was taken to administer the vaccination immediately after the first dose of eculizumab, with therapeutic doses of antibiotic (ciprofloxacin 500mg bd) for the first 14 days post vaccination, followed by long term meningococcal prophylaxis (penicillin V or erythromycin 500mg bd) whilst receiving a complement inhibitor.
Since this change in practice in 2012 we have commenced eculizumab therapy in 211 patients with no similar complications as described. Thus the change in practice appears to reduce the occurrence of these severe complications associated with vaccinations prior to initiating anti-complement therapy. Whilst it is possible these events could have been caused by the underlying condition of PNH, we would advise colleagues to also adopt a change in practice to reduce potentially significant complications.
Arnold:Alexion Pharmaceuticals: Honoraria. Kelly:Alexion: Honoraria. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Pike:Apellis: Research Funding. Riley:Alexion: Honoraria. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees. Hillmen:Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding.
Asterisk with author names denotes non-ASH members.