Fatal Neuroinvasive West Nile Virus Encephalitis Cases in Elderly Immunocompromised Patients in Chicago, IL, Summer 2025
Adriana Sari1, Farrah Mateen1, Shailee Shah1
1Department of Neurology, Northwestern University
Objective:

To describe clinical and paraclinical markers and outcomes of neuroinvasive West Nile Virus (WNV), seen at an academic tertiary medical center in Chicago, IL in summer-autumn 2025.

Background:

WNV is a single-stranded RNA flavivirus that can cause neuroinvasive disease in 1% of patients. Overall mortality is 10%, but up to 40% in patients who are older than 70 and immunocompromised. Recurrent WNV outbreaks in the midwestern USA occur annually in summer and early autumn months with a neuroinvasive incidence of 0.9/100,000 WNV cases.

Design/Methods:

Single-institution case series.

Results:

Four patients (50% female) median age 72 years (range 68-87) presented with a viral prodrome followed by encephalopathy. All patients were either immunocompromised (post-lung-transplant n=1, chemotherapy n=2) and/or known malignancy (n=3).

All patients were diagnosed with WNV encephalitis; one with concomitant acute flaccid paralysis. One had confirmed electrographic seizures. MRI brain showed: no abnormalities (n=1), bilateral thalamic T2/FLAIR hyperintensities, (n=1), acute pontine infarct (n=1), and diffuse, bilateral T2/FLAIR hyperintensities of the mesial temporal lobes, thalami, cerebral peduncles, ventral spinal gray matter and gadolinium contrast-enhanced cauda equina (n=1).

Cerebrospinal fluid white cells were normal (4 cells/µL; n=1) or between 14-104 cells/µL (mixed pleocytosis; n=3). Two patients had CSF WNV IgG/IgM positivity. Two patients tested positive by CSF next generation metagenomic sequencing.  All patients showed no improvement with multiple antimicrobials. Two patients were treated with intravenous immunoglobulin without improvement. All patients died in the hospital; median length of stay was 14 (8-23) days.

Conclusions:
Neuroinvasive WNV is an ongoing public health threat in the USA. Between May and September 2025, Cook County had 29/39 cases of neuroinvasive WNV. Diagnosis of neuroinvasive WNV can be elusive in elderly and immunocompromised patients, but advanced testing may be more sensitive than IgM testing alone. Despite advances in diagnostics, therapeutic and vaccine development for WNV neuroinvasive disease remain an unmet need. 
10.1212/WNL.0000000000217574
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