To our knowledge, this is the largest study ever conducted to evaluate medical risk factors for severe WNV disease. Chronic renal disease, history of cancer, history of alcohol abuse, diabetes, and hypertension were independently associated with the development of severe illness and encephalitis among patients with WNV disease; only hypertension was independently associated with the development of meningitis. Immune suppression was not associated with severe illness or neuroinvasive disease, but it was associated with a fatal outcome. Although the highest aORs were estimated for chronic renal disease, history of cancer, and history of alcohol abuse, population-attributable risk estimates suggest that as much as one-quarter of all severe WNV disease might be attributable to hypertension and diabetes.
Our results corroborated findings from previous studies that older age is associated with more severe WNV disease, particularly hospitalization and development of encephalitis.1,3,5–8
In our study, the risk of severe illness increased with increasing age above 60 years. Although we found an increased risk of severe illness among males, sex was not associated with development of encephalitis or meningitis. Race/ethnicity was significantly associated with severe illness and development of meningitis but not encephalitis. It is unknown if this association is related to underreporting of less severe disease related to decreased access to healthcare among some minority groups or some other factor not accounted for in our analysis.
The literature is somewhat inconsistent regarding the association between underlying medical conditions and severe WNV disease. Many of the previously conducted studies examined factors associated with the most severe outcomes (e.g., encephalitis with muscle weakness and death) among cohorts of hospitalized patients.1,7,14–16
These studies generally included small numbers of patients, limiting power to detect associations. Two previous studies evaluated risk factors for neuroinvasive disease among all WNV disease cases reported to state health departments.5,6
The first of these studies described risk factors for development of WNV encephalitis and meningitis (separately) among 656 cases reported in Colorado in 2003.5
However, because of relatively small numbers of patients with the outcomes of interest and low prevalence of medical conditions being studied, age and sex aORs were calculated, but multivariable modeling was not conducted. Similar to our study, several medical conditions, such as renal disease, diabetes, hypertension, cancer, and undergoing chemotherapy, were found to be associated with the development of encephalitis after adjusting for age and sex. Only cancer and undergoing chemotherapy were associated with meningitis. A second study described risk factors for neuroinvasive disease among 880 patients with WNV disease reported in California in 2005.6
Standardized data were only collected for two pre-existing medical conditions (hypertension and diabetes); information about other underlying conditions was collected through an open-ended question about past medical history. This work noted that age > 64 years, male sex, and diabetes were identified as independent risk factors for neuroinvasive disease.6
Despite the use of different methodologies and different outcome measures, several studies have identified hypertension and/or diabetes as risk factors for progression to WNV neuroinvasive disease or death.1,5–7,14
It has been suggested that these conditions could increase the permeability of the blood–brain barrier to allow greater viral entry, leading to increased susceptibility of the patient to neuroinvasive disease.14,19
Chronic renal disease and history of alcohol abuse have also previously been associated with development of encephalitis and death, despite the low prevalence of these conditions.5,7,14
The results of our analysis further support these associations.
Most pre-existing medical conditions do not seem to increase risk of meningitis after infection with WNV. In our study, only hypertension was independently associated; the only other study that looked at medical conditions associated with meningitis reported associations with cancer and chemotherapy.5
Although outcomes among patients with WNV meningitis are generally favorable compared with patients with encephalitis, meningitis patients frequently require hospitalization for pain control for severe headache or other supportive care.20
Although solid organ transplantation has been identified as a potential risk for more severe disease,9,10
we did not find an association. This finding might have been caused by the limited power to detect an association because of the small number of case-patients with history of solid organ transplant, or perhaps, it is related to additional factors that were not accounted for in this analysis, such as time since transplantation and type of post-transplant immunosuppressive therapy. Our findings are consistent with a recent study conducted in a university organ transplant center that estimated that naturally acquired asymptomatic WNV infection occurred with equal prevalence among transplant recipients and non-immunocompromised controls.11
In that study, no documented WNV neuroinvasive disease was detected during retrospective review of medical charts of transplant recipients.
Although many of the conditions that have been associated with severe WNV disease are also associated with immune suppression (e.g., solid organ transplant, diabetes, alcohol abuse, and cancer), immune suppression, as defined in this study, was not independently associated with severe illness or neuroinvasive disease. Neither of the two previous studies that built multivariable models found immune suppression to be independently associated with development of encephalitis among hospitalized patients.7,14
However, as in this study, both of those studies reported an association between immune suppression and death. Additional research to better define the role of different immune suppressive conditions in the development of severe WNV disease and death would be useful.
There are several limitations of this study. Case-patients were identified through routine passive public health surveillance and may not be representative of all WNV disease cases that occur. Patients with more severe illness are more likely to seek medical attention and therefore, are more likely to be captured by passive surveillance systems. Case-patients included in the analysis differed from case-patients not included regarding race and development of neuroinvasive disease; the differences were driven by case-patients from non-participating states. Because of these differences, the results of this analysis may not be generalizable to all WNV disease cases occurring in the United States. Additionally, because ArboNET does not collect information regarding clinical signs and symptoms or specific laboratory findings (e.g., cerebrospinal fluid findings), misclassification of the various syndromes caused by WNV (i.e., encephalitis, meningitis, acute flaccid paralysis, and uncomplicated fever) cannot be detected. There were small numbers of case-patients with some underlying conditions (e.g., solid organ transplant), limiting power to detect associations. Case-patients who were hospitalized may have had a more complete medical history than those case-patients not hospitalized; this bias would likely have resulted in artificially inflated risk estimates. However, the proportion of case-patients missing risk factor data did not differ by disease severity. It is also possible that patients with severe neuroinvasive disease may not have been able to provide accurate medical histories, because such patients often present with altered mental status. This lack of accuracy could have led to an underreporting of underlying conditions, which would have biased risk estimates to the null. Finally, we had no information on severity of the underlying medical conditions (e.g., uncontrolled versus controlled diabetes and hypertension or specific type and dose of immunosuppressive medications), which could be important in determining if and to what degree these conditions increase the risk of severe disease.
In summary, hypertension, diabetes, history of alcohol abuse, history of cancer, and chronic renal disease seem to be significant medical risk factors for severe illness after WNV infection. As many as one of four cases of severe WNV illness may be attributable to hypertension or diabetes. The role of other low-prevalence medical conditions is less clear and not easily assessed through a population-based method. Because no specific treatment for WNV disease exists and no human vaccine is available, healthcare providers should encourage use of personal protection during the WNV transmission season, particularly among the high-risk groups for severe disease identified in this study. Prevention messages should be particularly targeted to persons with medical conditions identified in this analysis as well as older people.