Risk Factors for West Nile Neuroinvasive Disease and Mortality in the US, 2013-2024.

Importance: West Nile virus (WNV) is the leading mosquito-borne infection in the US, causing West Nile fever or West Nile neuroinvasive disease (WNND) with substantial morbidity and mortality. Contemporary analyses are needed to identify at-risk populations and to target interventions. Objective: To assess risk factors associated with WNND and mortality among adults with WNV infection using a national cohort from federated data. Design, Setting, and Participants: This retrospective cohort study of deidentified electronic medical record data from the TriNetX research network from January 2013 to December 2024 included patients from 65 health care organizations from across the US. Data were accessed from March 28 to April 30, 2025. Exposures: Demographic characteristics (age, sex, race, and ethnicity), comorbidities (hematologic malignant neoplasms, heart disease, diabetes, HIV infection, chronic kidney disease [CKD], liver disease, hypertension, alcohol-related disorders, cerebrovascular disease [CEVD], chronic obstructive pulmonary disease, asthma, multiple sclerosis, dementia, rheumatoid arthritis, and organ transplant), and medications (immune suppressants, antineoplastics). Main Outcomes and Measures: Primary outcomes were WNND development and all-cause mortality (at 30 days, 90 days, and overall). Results: Among the initial cohort of 3064 patients with a diagnosis of WNV infection (per the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes), those with demographic data included 1249 (53%) who were consistent with West Nile fever (624 females [50%]; mean [SD] age, 55 [17] years) and 1127 (47%) who were consistent with WNND (691 males [61%]; mean [SD] age, 59 [17] years). Risk factors associated with WNND included age (adjusted hazard ratio [AHR], 1.10 [95% CI, 1.06-1.15] per decade), male sex (AHR, 1.29 [95% CI, 1.15-1.45]), CKD (AHR, 1.21 [95% CI, 1.00-1.45]), CEVD (AHR, 1.22 [95% CI, 1.03-1.45]), hematologic malignant neoplasms (AHR, 1.38 [95% CI, 1.09-1.76]), immune suppressant use (AHR, 1.43 [95% CI, 1.11-1.83]), hypertension (AHR, 1.18 [95% CI, 1.04-1.34]), alcohol-related disorders (AHR, 1.54 [95% CI, 1.20-1.97]), and multiple sclerosis (AHR, 2.34 [95% CI, 1.62-3.37]). Significant risk factors associated with mortality were WNND (AHR, 2.49 [95% CI, 1.37-4.52] for 30-day mortality), age (AHR, 1.32 [95% CI, 1.07-1.60] per decade), CKD (AHR, 2.08 [95% CI, 1.01-3.93]), and CEVD (AHR, 2.00 [95% CI, 1.14-3.50]). Conclusions and Relevance: In this cohort study of patients with WNV infection, multiple comorbidities were identified as risk factors associated with WNND; and patients who developed WNND had increased mortality risk. Targeted prevention strategies and countermeasures for high-risk individuals may substantially reduce morbidity and mortality.