Varicella‐zoster virus meningoencephalitis in a patient treated with ruxolitinib
Authors: Ophir Eyal, Maayan Flaschner, Arie Ben Yehuda, Deborah Rund
Journal: American Journal of Hematology (2017)

Ruxolitinib, a JAK1 + JAK2 inhibitor, is a novel agent for the treatment of myeloproliferative diseases.1 This agent has been associated with viral infections most notably herpetic.2, 3 We hereby describe a case of varicella zoster virus (VZV) meningoencephalitis associated with ruxolitinib treatment in an immunocompetent patient. The patient was diagnosed as having polycythemia vera (PV) at age 39. Previous treatments included aspirin, phlebotomies, hydroxyurea for 15 years (stopped due to refractoriness) and PEG-interferon. The latter was started over 6 years before her presentation and was given initially for less than 2 years. It was stopped due to achievement of longstanding myelosuppression. It was restarted briefly, but had been stopped over 27 months earlier following an episode of acute pleuropericarditis for which no infectious or autoimmune etiology was found. Post PV myelofibrosis was noted 3 years before her present presentation. Therefore, 2 years and 1 month earlier, treatment with ruxolitinib 20 mg twice daily was initiated with an excellent response. Her hematocrit normalized, obviating the need for phlebotomies, her intractable itching ceased, and there was regression of her marked splenomegaly which had reached below and to the right of the umbilicus. The patient had been in her usual state of health until 4 days prior to admission, when left upper quadrant (LUQ) abdominal pain developed, reminiscent of a previous episode which had been diagnosed as splenic infarction. She also reported the onset of bilateral frontal headache which was stable in its intensity, woke her from sleep, and was associated with mild phono-photophobia. On presentation she was fully conscious and in pain. Vital signs were normal except for a fever of 38°C. Physical examination was significant for focal LUQ tenderness and a faint vesicular rash in the distribution of the left T10 dermatome which consisted of reddening of the skin and a dozen small vesicles over an area 20 cm in length. Blood tests including electrolytes, renal and liver function tests and C-reactive protein were within normal limits; blood count was significant for mild lymphopenia (0.7 × 109 cells/L). Computerized tomography (CT) of the abdomen with oral and intravenous (IV) contrast showed no source of fever and a spleen with a span of 11 cm without signs of infarction. CT of the head revealed minimal generalized parenchymal atrophy of the brain, mild leukomalacia, and no evidence of hemorrhage, mass, abnormal enhancement, or edema. A lumber puncture was performed. Examination of the CSF showed 10/μL polymorphonuclear cells, 140/μL red blood cells, 160/μL lymphocytes, and 10/μL unidentified cells. Protein was elevated at 4220 mg/L while glucose was low at 2.1 mmol/L. PCR examination of the CSF was positive for VZV and negative for Herpes simplex virus 1 and 2 and for enteroviruses. Gram stain and bacterial cultures were negative. A diagnosis of thoracic herpes zoster associated with VZV meningoencephalitis was made and the patient was treated with a course of IV acyclovir which she received for 14 days. Her early inpatient course included several short episodes of altered mental status. Following acyclovir treatment, all her symptoms completely resolved and she was discharged with long-term prophylaxis with oral acyclovir and continued administration of ruxolitinib. Six months later, she is doing well and without sequelae. Herpes zoster, reactivation of latent VZV, typically does not affect the immunocompetent, though waning immunity associated with older age is sufficient for it to develop. Central nervous system involvement in VZV disease is uncommon,4 and its occurrence suggests immunosuppression. The involvement of the JAK/STAT pathway in multiple processes including inflammation and the immune response suggests that its inhibition could cause such a compromise. Ruxolitinib (Jakafi and Jakavi, Incyte Pharmaceuticals and Novartis), is an inhibitor of JAK1 and JAK2 that has been FDA approved since 2011 for treatment of myelofibrosis and since December 2014 as a third-line treatment for PV. There have been reports of ruxolitinib associated infections including Cytomegalovirus retinitis2 and disseminated Herpes simplex virus.3 However, only mild VZV infections associated with ruxolitinib use have been previously reported5 though they are infrequent (less than 2% as per the 2011 package insert). The case we present here suggests severe disease can also occur, in a patient without obvious immune suppression other than ruxolitinib therapy. Further studies are required to evaluate the incidence of such infections and to delineate possible indications for prophylactic therapy in appropriate patients. At the present time, hematologists and their patients should be aware of potential serious viral infections in patients on ruxolitinib. Patients should be alerted to seek immediate medical attention if symptoms of cutaneous H. Zoster develop, in conjunction with other systemic symptoms. Nothing to report. Dr. Eyal and Dr.Flaschner wrote the manuscript, Prof. Ben Yehuda and Prof. Rund critically revised it.