West Nile neuroinvasive disease (WNND) is a severe neurological illness that can result from West Nile virus (WNV) infection, with long-term disability and death being common outcomes. Although WNV arrived in North America over two decades ago, risk factors for WNND are still being explored. The objective of this study was to identify WNND comorbid risk factors in the Ontario population using a retrospective, population-based cohort design. Incident WNV infections from laboratory records between 1 January 2002 – 31 December 2012 were individually-linked to health administrative databases to ascertain WNND outcomes and comorbid risk factors. WNND incidence was compared among individuals with and without comorbidities using risk ratios (RR) calculated with log binomial regression.

Three hundred and forty-five individuals developed WNND (18.3%) out of 1884 WNV infections. West Nile encephalitis was driving most associations with comorbidities. Immunocompromised (aRR 2.61 [95% CI 1.23–4.53]) and male sex (aRR 1.32 [95% CI 1.00–1.76]) were risk factors for encephalitis, in addition to age, for which each 1-year increase was associated with a 2% (aRR 1.02 [95% CI 1.02–1.03]) relative increase in risk. Our results suggest that individuals living with comorbidities are at higher risk for WNND, in particular encephalitis, following WNV infection.