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Background: West Nile virus (WNV) causes a spectrum of human disease ranging from a febrile illness (WNV fever) to severe neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis). Since WNV gained entry into North America in 1999, clinicians caring for WNV survivors have observed persistent neurological symptoms occurring long-after the production of neutralizing antibodies and clearance of the virus. Accordingly, alternative pathogeneses other than direct viral invasion have been hypothesized to explain these post-infectious symptoms. The dominant hypothesis is that antiviral inflammatory responses triggered initially to clear WNV may persist to promote a post-infectious proinflammatory state . Methods: In 4 serologically-confirmed WNV patients with persistent post-infectious symptoms (3 WNV fever, 1 neuroinvasive disease), we ordered a comprehensive cytokine panel at weeks 8, 10, 12, and 36 months post-onset of illness, respectively, to better understand the pathophysiology of the protracted symptoms. Results: All patients had abnormally elevated tumor necrosis factor alpha (TNF-α), a major molecule triggering antiviral cytokines and chronic inflammation in many human autoimmune diseases, but heretofore not reported to be upregulated in human WNV infection. Three patients also had elevations of other proinflammatory proteins. Major symptoms included fatigue, arthralgias, myalgias, generalized or multifocal pain or weakness, imbalance, headaches, cognitive problems, and symptoms of dysautonomia. Conclusion: The findings provide support for an extended post-infectious proinflammatory state that may contribute to chronic inflammation and long-term morbidity in some WNV survivors and further suggest that TNF-α may play a pathogenic role in initiating this inflammatory environment. Clinical trials may be warranted to determine if TNF-α inhibitors or other immunosuppressive agents can improve patient outcomes., (Copyright © 2020 Leis, Grill, Goodman, Sadiq, Sinclair, Vig and Bai.)

West Nile virus (WNV) causes severe neuroinvasive disease in humans characterized by meningitis, encephalitis, and acute flaccid paralysis (poliomyelitis variant). In neuroinvasive disease, WNV infection of neurons resulting in neuronal loss is generally presumed to be the anatomical substrate for the high morbidity and mortality. However, on a molecular level, WNV infection also results in a significant upregulation of important proinflammatory molecules that have been reported to promote neuroinflammation and cytotoxicity. Currently, there is no specific treatment for the neurological complications of WNV infection. We present a 71-year-old woman who developed WNV infection that rapidly progressed to severe generalized weakness and encephalitis manifesting with bulbar signs (dysphagia, dysarthria) and persistent delirium and stupor. Consciousness remained impaired for 9 days and then she received a 5-day course of high-dose intravenous methylprednisolone (1,000 mg daily). After the first day, voluntary movement and spontaneous eye-opening increased and by the end of the second day, she was awake and responding to commands. Thereafter, she remained awake and responsive. Although the rapid improvement from stupor to wakefulness following treatment with an anti-inflammatory immunosuppressant could merely be coincidence, since these observations are of one patient, it may also provide a clue that in some cases of WNV neuroinvasive disease a post-infectious pro-inflammatory state , rather than neuronal loss, may also contribute to morbidity. Further clinical trials are warranted to determine if high dose corticosteroids and other drugs that can alter this neuro-inflammatory cascade may be potentially beneficial in the treatment of WNV neuroinvasive disease.