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Seronegative West Nile Virus Infection in a Patient Treated with Rituximab for Rheumatoid Arthritis

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Seronegative West Nile virus infection has been described in organ transplant recipients and patients with cancer receiving rituximab in combination with other immunosuppressive therapies. We describe the first reported case of seronegative West Nile virus meningoencephalitis in a patient receiving rituximab for rheumatoid arthritis.

A 49-year-old woman from Colorado with a history of rheumatoid arthritis treated with rituximab and methotrexate developed fevers and myalgias approximately 3 months after her most recent rituximab infusion. Three days after the onset of fevers, she became acutely confused and dysarthric, prompting presentation to the hospital. The initial lumbar puncture demonstrated a mildly elevated white blood cell count, normal glucose, and mildly elevated protein. Cerebrospinal fluid gram stain was negative. Magnetic resonance imaging of the brain showed nonspecific white matter hyperintensities. Polymerase chain reaction testing of the cerebrospinal fluid for common infectious causes of meningoencephalitis was negative. Serologic testing for West Nile virus including immunoglobulin M and immunoglobulin G antibodies performed on the cerebrospinal fluid and serum were negative. The patient’s neurologic status gradually worsened to persistent unresponsiveness.

On hospital day 4, a more extensive workup for arboviruses was pursued, including cerebrospinal fluid polymerase chain reaction for West Nile virus. The patient continued to be unresponsive, and repeat magnetic resonance imaging of the brain on hospital day 8 was suggestive of tonsillar herniation. On the same day, polymerase chain reaction testing for West Nile virus from the cerebrospinal fluid showed positive results. Given the patient’s poor prognosis, the decision to withdraw care was made, and she died on hospital day 9. An autopsy was not pursued.

This is the first reported case of seronegative West Nile virus meningoencephalitis in a patient receiving rituximab for rheumatologic disease. West Nile virus serologic testing of the cerebrospinal fluid and serum was repeatedly negative, complicating the diagnosis. Similar cases have been reported in patients receiving rituximab in the setting of other immunocompromising states (Table).12345 It is thought that both the severity of disease and the absence of humoral response can be due to rituximab. However, the presence of other factors in each case makes it difficult to assess whether rituximab alone is sufficient to create this presentation. Our patient is unique because she lacked other immunosuppressing conditions aside from methotrexate exposure. In a study of patients with rheumatoid arthritis treated with methotrexate or rituximab, those treated with methotrexate alone were able to mount detectable immunoglobulin M and G responses to influenza vaccination, whereas patients treated with rituximab were not.6 This lends credence to our hypothesis that a blunted humoral response from rituximab led to both severe disease and complicated diagnosis. This case adds to the growing body of evidence suggesting that rituximab not only predisposes patients to more severe viral infections but also may result in negative serologic test results leading to delayed diagnosis.

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-Chris Goates, BS, Sanefumi Tsuha, MD, Selene Working, MPAS, PA-C, Jessica Carey, PharmD, Emily S. Spivak, MD, MHS

This article originally appeared in the June 2017 issue of The American Journal of Medicine.

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