Follow-up of 2003 human West Nile virus infections, Denver, Colorado.

Tri-County Health Department and Boulder County Public Health conducted a follow-up study of all nonfatal West Nile virus (WNV) cases reported during 2003 in 4 metropolitan Denver, Colorado, counties. Self-reported patient information was obtained [approximately equals] 6 months after onset. A total of 656 (81.2%) eligible WNV patients are included in this study.

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In 2003, Colorado experienced a large West Nile virus (WNV) epidemic, which accounted for 29.9% of the nation's 9,862 reported WNV infections (1). Tri-County Health Department, which serves Adams, Arapahoe, and Douglas counties, and Boulder County Public Health collaborated to conduct a follow-up study of all WNV cases reported in these 4 counties in 2003. We conducted this follow-up study with 3 objectives: 1) to identify potential risk factors for developing neuroinvasive disease, 2) to describe the symptoms of patients 6 months after onset, and 3) to describe healthcare utilization and impact on daily activities associated with all types of WNV infection.

The Study

Since 2002, healthcare providers and laboratories have been required to report patients with laboratory evidence of acute WNV infection in Colorado. Patients were included in this study if WNV-specific immunoglobulin M (IgM) antibodies were found in either cerebrospinal fluid (CSF) or serum by enzyme-linked immunosorbent assay, or symptoms later developed in blood donors with a positive nucleic acid test result. In addition to laboratory confirmation, patients had to meet one of the following case definitions to be included in the study: 1) encephalitis cases required a physician's diagnosis and clinical manifestation of encephalitis, including mental status changes, delirium, disorientation, or coma; 2) meningitis cases required a physician's diagnosis or clinical exhibition of meningitis and abnormal CSF findings consistent with viral meningitis; and 3) fever cases required mild to moderate illness without clinical or laboratory evidence of central nervous system involvement. A compatible illness of WNV fever was defined as symptoms consisting of [greater than or equal to] 2 of the following occurring within 90 days of testing: fever, headache, chills, myalgia, arthralgia, rash, lymphadenopathy, muscle weakness, or severe malaise. Any patient with a positive IgM test result on CSF was considered to have neuroinvasive disease.

Self-reported patient information was solicited through a standardized survey sent to 808 patients with nonfatal cases. Cases of meningitis and encephalitis were compared with cases of WNV fever. Measures of association between diagnosis and relevant patient characteristics were determined by Wald [chi square], odds ratios, and associated 95% confidence intervals for categorical variables and analysis of variance (ANOVA) testing for continuous variables. Multivariate logistic regression modeling was used to test for potential predictors of more severe disease at time of diagnosis. Variables were considered significant at the p = 0.05 level. Data were entered into EpiInfo 2002 (available from www.cdc.gov/epiinfo/) and analyzed with SAS version 9.1 software (SAS Institute, Inc., Cary, NC, USA).

A total of 656 (81.2%) patients completed the survey: 52.1% were female, 42.8% were [greater than or equal to] 50 years of age, 80.9% had a diagnosis of fever, 12.8% had a diagnosis of meningitis, and 6.3% had a diagnosis of encephalitis. Nineteen cases were detected through blood donor screening, and all were categorized as uncomplicated fever cases. Nonrespondents were less likely to be female (42.1%, p = 0.0259) and [greater than or equal to] 50 years of age (27.6%, p = 0.0007) but were similar by diagnosis category (p = 0.5846).

Mean ages by diagnosis were 60 years for encephalitis patients, 48 years for meningitis patients, and 46 years for fever patients. Encephalitis patients were significantly older than meningitis and fever patients (p<0.0001). The median period between onset of illness and completion of the follow-up survey was 178 days (range 102-299 days); 80% responded within 5-7 months after illness onset.

The overall prevalences of several chronic conditions and treatments are shown in Table 1. After adjustment for sex and age [greater than or equal to] 50 years, encephalitis patients were significantly more likely than fever patients to report having several chronic conditions and to report having been on chemotherapy. Meningitis patients were more likely than fever patients to report having cancer and to have undergone chemotherapy.

Symptom duration was reported as >3 months for 48.7% of encephalitis patients, 26.2% of meningitis patients, and 20.3% of fever patients (Table 2). Muscle weakness and muscular pain at time of follow-up were reported by more than one third of encephalitis patients (Table 3). No notable differences in symptoms were reported based on the difference in the interval between onset date and date of completing the follow-up survey.

Hospital admission was significantly more common among encephalitis (97.6%) and meningitis (91.7%) patients than fever patients (13.9%). The mean length of stay for all hospitalized patients was 11 days (range 1-165 days) and was significantly higher for encephalitis patients (20 days) than meningitis patients (10 days) and fever patients (7 days). Significantly more encephalitis and meningitis patients sought physical therapy (65.9% and 34.9%, respectively), occupational therapy (50.0% and 18.3%, respectively), and speech therapy (30.8% and 10.8%, respectively) than fever patients. Among fever patients, 6.6% reported receiving at least 1 of the 3 therapies.

Missing time from work was reported by most all categories of cases. For the 485 patients who were working at the time of illness onset, encephalitis patients and meningitis patients were significantly more likely to report missing work (100.0% and 98.3 %, respectively) than fever patients (78.9%). The median number of work days missed was significantly higher among encephalitis patients (65 days) and meningitis patients (51 days) than fever patients (16 days). In addition, 91.0% of all patients reported that their routine daily activities were prevented by their WNV infection.

Conclusions

This study characterizes the severe impact that WNV infection had on all age groups and categories of WNV illness in a defined population-based cohort of 656 nonfatal infections. Our study results corroborated findings from previous studies that older age is predictive of more severe WNV illness, such as encephalitis (2-4) and death (2,4-7). In our study, the mean age of meningitis patients did not differ significantly from that of fever patients.

Additionally, we identified several preexisting medical conditions, as well as prior utilization of chemotherapy, that may predispose infected persons to the development of encephalitis or meningitis. The risk for encephalitis has been found to be higher among organ transplant recipients (8); however, the literature is inconsistent regarding whether preexisting medical conditions are predictive of neuroinvasive disease (2,4, 7,9). The studies that did not detect such associations used different comparison groups than did our study and were limited by small sample size or low prevalence of these chronic medical conditions.

Only 1 other study has characterized the clinical spectrum of symptom duration among West Nile fever patients and missed work or school days (10). This study of 98 fever patients found that 39% had ongoing symptoms after an average of almost 6 months of follow-up, 82% reported limitations in household activities, and a median number of 10 missed work or school days (10). Our fever patients reported a higher number of missed work or school days with a median of 16. Additional studies with objective measures could better elucidate the long-lasting effects of WNV infection.

Because of the nature of self-reported data, both recall bias and misclassification of self-reported information are potential limitations of this study. However, we validated self-reporting of definitive fields such as sex and hospitalization because they were highly correlated with the initial data maintained in our statewide surveillance database.

Another limitation of our study was that a clinical diagnosis of flaccid paralysis or lack thereof was not confirmed in study cases. Estimated rates of flaccid paralysis are low (2,11) and therefore should not have had a large impact on our study findings. In addition, patients who had died were excluded from the study; therefore, we were not able to characterize this group for preexisting chronic conditions. Our study was limited to reported case-patients who sought medical attention and laboratory testing; therefore, our findings likely represent the more severe spectrum of infections.

Our study demonstrates that WNV infection caused considerable, long-lasting, severe illness during the 2003 Colorado epidemic and that the economic impact in terms of associated healthcare utilization and days of missed work was substantial. Public health officials should intensify prevention messages to help limit the severe manifestations of WNV infection and especially target those at greatest risk for severe disease.

Acknowledgments

We thank Katie Flaherty, Patricia Heller, and Keri McClory for their assistance in contacting patients for telephone interviews. In addition, we also thank the staff members of the Tri-County Health Department and Boulder County Public Health in disease control, public health nursing, and environmental health, who assisted in this effort, particularly Laura Dippold and Judith Silverman for their coordination efforts.

References

(1.) Centers for Disease Control and Prevention. [cited 2005 Sep 19]. Available from http://www.cdc.gov/ncidod/dvbid/westnile/index.htm

(2.) Nash D, Mostashari F, Fine A, Miler J, O'Leary D, Murray K, et al. The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med. 2001;344:1807-14.

(3.) Weiss D, Carr D, Kellachan J, Tan C, Phillips M, Bresnitz E, et al. Clinical findings of West Nile virus infection in hospitalized patients, New York and New Jersey, 2000. Emerg Infect Dis. 2001;7:654-8.

(4.) Chowers MY, Lang R, Nassar F, Ben-David D, Giladi M, Rubinshtein E, et al. Clinical characteristics of the West Nile fever outbreak, Israel, 2000. Emerg Infect Dis. 2001;7:675-8.

(5.) Tsai TF, Popovici F, Cernescu C, Campbell GL, Nedelcu NI. West Nile encephalitis epidemic in southeastern Romania. Lancet. 1998;352:767-71.

(6.) Weinberger M, Pitlik SD, Gandacu D, Lang R, Nassar F, Ben-David D, et al. West Nile fever outbreak, Israel, 2000: epidemiologic aspects. Emerg Infect Dis. 2001 ;7:686-91.

(7.) Berner YN, Lang R, Chowers M. Outcome of West Nile fever in older adults. J Am Geriatr Soc. 2002;50:1844-6.

(8.) Kumar D, Prasad GVR, Zaltzman J, Levy GA, Humar A. Community-acquired West Nile virus infection in solid-organ transplant recipients. Transplantation. 2004;77:399402.

(9.) Han LL, Popovici F, Alexander JP Jr, Laurentia V, Tengelsen LA, Cernescu C, et al. Risk factors for West Nile virus infection and meningoencephalitis, Romania, 1996. J Infect Dis. 1999; 179:230-3.

(10.) Watson JT, Pertel PE, Jones RC, Siston AM, Paul WS, Austin CC, et al. Clinical characteristics and functional outcomes of West Nile fever. Ann Intern Med. 2004; 141:360-5.

(11.) Sejvar JJ, Leis AA, Stokic DS, van Gerpen JA, Martin AA, Webb R, et al. Acute flaccid paralysis and West Nile virus infection. Emerg Infect Dis. 2003;9:788-93.

Jennifer L. Patnaik, * Heath Harmon, ([dagger]) and Richard L. Vogt *

* Tri-County Health Department, Greenwood Village, Colorado, USA; and l-Boulder County Public Health, Boulder, Colorado, USA

Address for correspondence: Jennifer L. Patnaik, MHS Tri-County Health Department, 7000 E Belleview Ave, Suite 301, Greenwood Village, CO 80111, USA; email: [e-mail]

Ms Patnaik is the epidemiology program coordinator at Tri-County Health Department, in metropolitan Denver, Colorado. She manages agencywide epidemiologic research on various topics and is also involved in communicable disease and emergency preparedness activities.

Table 1. Prevalence of chronic health conditions and medication use
among West Nile virus (WNV) study patients and multivariate model
of predictors of more severe illness *

                                                 Meningitis
                        All WNV patients     patients (n = 84);
                           (n = 656);            adjusted OR
Condition                 prevalence, %      (95% CI) ([dagger])

High blood pressure           12.2              1.0 (0.4-2.1)
Diabetes                       6.1              0.8 (0.3-2.5)
Heart disease                  3.8              1.4 (0.5-4.5)
Cancer                         1.5             6.6 (1.6-27.5)
Kidney disease                 1.2             2.3 (0.2-22.9)
Steroids                       3.0              1.3 (0.4-4.6)
Chemotherapy                   1.4             7.7 (1.5-40.0)

                          Encephalitis
                       patients (n = 41);
                           adjusted OR
Condition              (95% CI) ([dagger])

High blood pressure       2.1 (1.0-4.6)
Diabetes                  2.6 (1.0-6.5)
Heart disease             2.7 (0.9-8.2)
Cancer                   7.5 (1.2-45.4)
Kidney disease          24.9 (4.7-132.5)
Steroids                  1.8 (0.4-8.5)
Chemotherapy            25.9 (4.2-159.7)

* CI, confidence interval, OR, odds ratio.

([dagger]) Adjusted for sex and age [greater than or equal to] 50 y.

Table 2. Duration of symptoms for West Nile virus study patients

                               Fever      Meningitis    Encephalitis
                              patients     patients       patients
                             (n = 531);    (n = 84);     (n = 41),
Duration of symptoms, d       no. (%)       no. (%)       no. (%)

[less than or equal to] 30   241 (46.3)    20 (23.8)      8 (20.5)
31-90                        174 (33.4)    42 (50.0)     12 (30.8)
>90                          106 (20.3)    22 (26.2) *   19 (48.7) *

* Significantly different than among fever patients; p<0.05 (applies
to overall distribution of 3 categories).

Table 3. Symptoms ever experienced and still experiencing at time of
follow-up for West Nile virus study patients

                            Fever patients (n = 531)

Symptom                    Ever, %     At follow-up, %

Muscle weakness             80.4            12.2
Muscle pain                 85.9            12.1
Headache                    88.6            11.8
Stiff neck                  78.6            10.4
Sensitivity to light        52.6             5.6

                          Meningitis patients (n = 84)

Symptom                    Ever, %     At follow-up, %

Muscle weakness             96.3            28.0 *
Muscle pain                 92.6            14.8
Headache                    91.5            19.5
Stiff neck                  84.1            12.2
Sensitivity to light        71.6 *          11.1

                         Encephalitis patients (n = 41)

Symptom                    Ever, %     At follow-up, %

Muscle weakness             92.7            46.3 *
Muscle pain                 76.3            39.5 *
Headache                    65.0 *          12.5
Stiff neck                  59.0 *          12.8
Sensitivity to light        63.4            12.2

* Significantly different than among fever patients; p<0.05.