Prognosis after West Nile Virus Infection

Context The long-term prognosis of West Nile virus infection is not well understood. Contribution In this longitudinal study of 156 patients with West Nile virus infection, physical and cognitive function seemed to return to population norms within about 1 year. Caution Patients who died were excluded from the analysis, and the analyses depended on statistical assumptions that the data did not always meet. Implication People infected with West Nile virus seem to recover physical and mental function within about 1 year. The Editors West Nile virus, endemic to Africa, Europe, the Middle East, and Asia, has caused recurrent outbreaks in the United States and Canada since 1999 (1, 2). Approximately 20% of infected persons develop a clinical presentation that can range from a mild influenza-like illness to neuroinvasive diseases, such as meningitis, encephalitis, and acute flaccid paralysis (3). Recent studies of persons infected with West Nile virus report that symptoms and signs, such as fatigue, cognitive dysfunction, and motor abnormalities, can persist for months after symptom onset (414). Little is known, however, about how physical and mental functioning changes over time or about long-term recovery among infected persons. Understanding such change patterns is essential to provide accurate prognostic information to patients and their families, as well as to help in the planning of care and evaluation of future interventions. Existing reports provide valuable information on self-reported outcomes (413) but have limitations, including single follow-up assessments (4, 69, 1113), follow-up until 12 months after symptom onset (4, 68, 1014), and lack of validated instruments to measure physical and mental functioning (48, 1113). Moreover, factors associated with slower recovery are unknown. The primary objectives of this study were to describe patterns of physical and mental outcomes after infection with West Nile virus by using longitudinal observations and to assess long-term outcomes. We hypothesized that such long-term outcomes would be worse in patients with neuroinvasive disease than in those with nonneuroinvasive disease. We conducted a longitudinal cohort study to develop prognostic curves for patient-relevant outcomes, such as physical and mental functioning, fatigue, and depression. We also assessed factors associated with delayed recovery of physical and mental outcomes. Methods Study Participants and Protocol Patients with positive West Nile virus IgM antibody-capture enzyme-linked immunosorbent assay (15) from serum or cerebrospinal fluid samples that was subsequently confirmed by plaque reduction neutralization assay (16) were eligible. We enrolled patients with neuroinvasive disease (meningitis, encephalitis, or acute flaccid paralysis) and nonneuroinvasive disease. We aimed to enroll participants within 4 weeks of symptom onset. To allow for feasibility of follow-up, we limited enrollment to geographic regions that had 4 or more infected individuals within an approximate radius of 200 km. Because complications of West Nile virus infection in children are generally less frequent, we excluded persons younger than age 18 years (17). Because the objective of the study was to assess prognosis attributable to West Nile virus, we excluded patients receiving experimental therapy for West Nile virus, as well as those being treated for an illness unrelated to West Nile virus that could interfere with interpretation of the outcome measures. Only 1 patient, who was receiving chemotherapy for a malignant solid organ condition, met the latter criterion. We classified participants with neuroinvasive disease by using previously published criteria for meningitis, encephalitis, and acute flaccid paralysis (4) (Table 1). We classified participants who met criteria for both meningitis and encephalitis as having meningoencephalitis. Only 3 patients had meningitis alone, so we combined them with the meningoencephalitis group for analysis. Table 1. Diagnostic Criteria for Meningitis, Encephalitis, and Acute Flaccid Paralysis We classified participants who were symptomatic but did not meet any of the case definitions for neuroinvasive disease as having nonneuroinvasive disease. We reviewed laboratory, hospital, and clinic medical records to confirm the case definition. Radiologic and laboratory assessments were performed at the discretion of the attending physician. Supportive care, such as physiotherapy or psychotherapy, was under the discretion of the attending physician. We enrolled the first participant on August 2003 and the last on November 2006, with the final follow-up visit on May 2007. Provincial laboratories in Canada conducted all West Nile virus testing and forwarded the names of the physicians whose patients tested IgM-positive for West Nile virus to the study office. We asked these physicians to approach the patients (whose identity remained unknown to the research team, thereby maintaining confidentiality) or their families to see whether they were willing to be contacted about the study. A research nurse then assessed patient eligibility and obtained informed consent. We obtained ethics approval for the study protocol from the relevant review committees at McMaster University, University of Manitoba, University of Saskatchewan, and University of Alberta. All patients or their designated surrogate decision makers who agreed to participate in the study gave informed consent. Outcomes A trained research nurse assessed outcomes on enrollment into the study (baseline visit); on days 10, 20, and 30; and then every month for 12 months. In our original protocol, we planned to obtain repeated measurements at 24 and 36 months for participants enrolled in the first year of the study and to measure outcomes at 24 months (third year of the study) for those participants enrolled in the second year. Because participants were being visited more frequently to obtain blood work for an unrelated study from 15 to 36 months from their enrollment in this study, we obtained additional measurements at 3-month intervals from 15 to 36 months in these participants. A trained research nurse made most assessments during home visits, minimizing missing visits or selection bias based on participant's ability to travel (although participants in Saskatchewan and Manitoba were seen in an ambulatory care setting at a tertiary care hospital for their convenience). We recorded age, sex, medical history, and premorbid chronic illnesses. Categories of comorbid conditions included cardiac disease (coronary artery disease and congestive heart failure), peripheral vascular disease, chronic obstructive pulmonary disease, diabetes, renal failure, peptic ulcer disease, cancer, and rheumatologic disease. We assessed all these conditions through interviews with participants and review of medical records. To assess physical functioning, we used the Physical Component Summary (PCS) of the Short Form-36 (18, 19). The Short Form-36 measures 8 health constructs by using 8 scales with 2 to 10 items per scale (total of 36 questions); raw scores range from 0 to 100 but are adjusted for population norms by using a linear transformation (18). For the PCS subscale, scores are standardized to the general U.S. population (mean score, 50 [SD, 10]). Very high scores indicate no physical limitations, disabilities, or decrements in well-being, as well as a high energy level. Very low scores indicate substantial limitations in self-care and physical, social, and role activities; severe bodily pain; or frequent tiredness. To assess mental functioning, we used the Mental Component Summary (MCS) of the Short Form-36. These scores are also standardized to the general U.S. population (mean score, 50 [SD, 10]). Very high scores indicate frequent positive affect and absence of psychological distress and limitations in usual social and role activities due to emotional problems. Very low scores indicate frequent psychological distress and substantial social and role disability due to emotional problems (18). We used the Depression Anxiety Stress Scale (DASS) (20, 21) and the Fatigue Severity Scale (FSS) (22) beginning in 2004 to capture depressive symptoms and persistent fatigue noted among participants after the study had begun. The DASS is a 14-item scale that assesses dysphoria and lack of interest or involvement. Scores range from 0 (no symptoms) to 42. Among a general adult population, 80% of people have a score of 9 or less and 70% have a score of 6 or less (23). The FSS measures the perceived level of fatigue by using a Likert scale, in which the score ranges from 1 (low fatigue level) to 7 (high fatigue level). Two thirds of the general population have a score between 2.7 and 5.3 (24). Statistical Analysis Prognosis We used data from 57 of 64 participants with neuroinvasive disease (meningoencephalitis [n= 32], encephalitis [n= 22], and meningitis [n= 3]) and 92 with nonneuroinvasive disease to estimate prognosis. We excluded 7 patients with acute flaccid paralysis from the analysis because this number was too small to estimate prognostic curves, and we grouped 3 participants with meningitis with the 32 participants in the meningoencephalitis group. We used nonlinear mixed-effects modeling to estimate the parameters of nonlinear models for PCS, MCS, DASS, and FSS scores (25). We compared participants with neuroinvasive disease with those with nonneuroinvasive disease. Of participants with neuroinvasive disease, we compared those with meningoencephalitis with those with encephalitis. The fixed effects in the nonlinear mixed-effects analysis describe the average pattern of change over time, and they indicate the typical course of recovery in this population. The random effects in the nonlinear mixed-effects analysis allow for orderly variations in the pattern of change among patients. We estimated predicted change curves for each patient, and we estimated the degree of i