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Clinical description and follow-up investigation of human West Nile virus cases.

Objectives: The objective of this study was to investigate long-term outcomes after West Nile virus infection.

Methods: We reviewed the medical records of persons reported with West Nile virus in Tennessee in 2002 and interviewed cases 1 year after acute illness.

Results: In 2002, 56 cases of West Nile virus were reported in Tennessee; 48 (84%) had meningitis or encephalitis. Of those, 9 (19%) died during acute infection and 12 (25%) died within 6 months of illness onset. Patients with West Nile virus neurologic illness spent a median of 10 days in the hospital and were unable to resume normal activities for a median of 25 days. One year later, 12 of 22 (55%) persons reported that they were not fully recovered, with symptoms including fatigue, weakness, difficulty ambulating, and memory problems.

Conclusions: West Nile virus infection leads to high rates of mortality and substantial persistent morbidity. Prevention efforts should be targeted to populations at highest risk of severe sequelae.

Key Words: encephalitis, outcome, sequelae, West Nile virus

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West Nile virus (WNV) is a mosquito-borne flavivirus that can cause meningitis and encephalitis in humans. West Nile virus has commonly been found in humans in the Eastern hemisphere but was not documented in the Western hemisphere until 1999, when it was introduced into New York City. By 2003, the virus had spread to 46 states in the continental United States.

Clinical manifestations of WNV infection range from asymptomatic to severe neurologic illness and death. West Nile virus serosurveys conducted in New York City and Connecticut estimate that approximately 1 in 5 infected persons will have a febrile illness, and approximately 1 in 150 infected persons will have severe illness. (1-3) Few data exist on long-term sequelae in persons after WNV infection. (3)

We conducted a retrospective study among persons with WNV in Tennessee to assess the clinical manifestations of acute illness and self-reported morbidity 1 year after acute illness.

Materials and Methods

During 2002, the Tennessee Department of Health actively enhanced surveillance for cases of WNV infection. Diagnostic testing was performed free of charge at the state health department laboratory. Specimens tested for WNV were submitted from numerous sources: directly from physicians, from local health departments, and from commercial and reference laboratories. Primary care clinicians were mailed information on WNV and provided opportunities to attend formal presentations by health department staff. All persons reported to the health department with tests indicating possible WNV infection were interviewed by health department staff and followed closely to ensure appropriate laboratory follow-up.

All Tennessee residents diagnosed with WNV infection in 2002 were included in the study. The Centers for Disease Control and Prevention case definition was used. Cases had clinically compatible symptoms (acute onset of fever, headache, arthralgias, myalgias, and fatigue), with a fourfold or greater change in virus-specific serum antibody titer, isolation of WNV from or demonstration of specific viral antigen in tissue, blood, or cerebrospinal fluid (CSF), or WNV IgM antibodies demonstrated in CSF by antibody-capture enzyme immunoassay. (4)

Cases were classified as "WNV meningoencephalitis" (meningitis and/or encephalitis) if they had fever with either nuchal rigidity and CSF pleocytosis, altered mental status (including confusion or coma), or focal neurologic deficits. Cases without clinical signs of neurologic illness were classified as WNV fever. (4)

Health department staff interviewed and reviewed medical records of all reported cases. Data were collected on signs and symptoms at presentation, previous medical history, clinical course during acute illness, and status at time of hospital discharge. From June 15 to September 15, 2003, health department staff administered a telephone follow-up survey to determine disease outcome 1 year after the acute illness. The 2002 to 2003 state death registry was examined to determine whether persons who could not be contacted for a follow-up interview had died.

This study was approved by the Tennessee Department of Health Institutional Review Board.

Results

During 2002, 56 human cases of WNV were reported to the Tennessee Department of Health. Of reported cases, 48 (86%) met the criteria for WNV meningoencephalitis and 8 (14%) were diagnosed with WNV fever. Nine deaths occurred among persons diagnosed with WNV meningoencephalitis infections during their initial hospitalization, for a case fatality rate of 19%. The case fatality rate for patients 70 years of age or older was 22%.

Among persons with WNV meningoencephalitis (n = 48), the median age was 72 years (range, 17 to 99 years). All patients were hospitalized, with a median length of stay of 10 days (range, 2 to 92 days). Common acute symptoms included fever (94%), profound weakness (88%), altered mental state (71%), headache (52%), stiff neck (50%), nausea (48%), vomiting (44%), muscle aches (46%), rash (21%), diarrhea (17%), and sore throat (17%). Underlying health problems such as heart disease (40%), malignancy (25%), alcoholism (19%), diabetes (17%), and hematologic disease (6%) were common (Table 1).

At the 1-year follow up of patients with WNV meningoencephalitis, 12 (25%) had died. Of survivors, 22 (61%) were successfully contacted and 14 (29%) were unable to be reached. Of survivors interviewed, 3 (14%) resided in a full-time care nursing facility, 10 (45%) were reported to be fully recovered, and 9 (41%) reported long-term sequelae (Figure). We were unable to confirm the cause of death for those occurring after initial hospitalization. The median age of persons reporting long-term sequelae differed significantly from those without sequelae (75 and 51 years, respectively). The most common symptoms were persistent fatigue (75%), muscle weakness (58%), difficulty ambulating (42%), joint weakness (42%), memory problems (25%), and persistent headaches (25%) (Table 2).

Of the WNV meningoencephalitis survivors interviewed, 9 (41%) reported missing work for a median of 90 days (range, 6 to 365). Thirteen patients (59%) reported being unable to return to preillness activity levels for a median of 90 days (range, 9 to 365). Four patients (18%) reported a loss of income during the acute illness and recovery period.

Persons with WNV fever (n = 8) had a median age of 49 years (range, 22 to 74). Three (37%) were hospitalized, with a median length of stay of 5 days (range, 3 to 7) (Table 1). Common symptoms during acute illness included fever (75%), headache (87%), muscle aches/pains (75%), profound weakness (63%), stiff neck (63%), rash (63%), nausea (50%), vomiting (25%), diarrhea (25%), and sore throat (13%). Five persons with WNV fever were successfully contacted for follow up 1 year after their acute illness. Of these, 4 (80%) reported having missed work, for a median of 4 days. Three persons (60%) reported being unable to return to preillness level activities, for a median of 150 days (range, 90 to 180). One person reported a decrease in income directly related to the illness.

Discussion

During 2002, 56 cases of West Nile virus infection were reported in Tennessee. This includes all known cases identified from a variety of sources, including clinicians, infection control practitioners, health departments, and laboratories statewide. By law, WNV is required to be reported to the Department of Health in Tennessee. During 2002, vigorous educational efforts, media campaigns, and frequent communication with professional organizations throughout the state as well as with other state health departments and the Centers for Disease Control and Prevention was maintained to ensure that all laboratory-confirmed cases were reported. Case fatality rates for patients with WNV meningoencephalitis in this study were somewhat higher than previously reported rates (19% compared with 4 to 14%). (5) Although intensity of surveillance and follow up clearly affects this observation, it will be important to study this further in other areas and in future seasons in Tennessee. The case fatality rate of patients with WNV meningoencephalitis older than 70 years of age was similar to those reported from Romania (15%) and Israel (29%). (5)

Advanced age (>50) is the greatest risk factor for severe neurologic disease, long-term morbidity, and death from WNV. (5) In this study, 44% of patients with WNV meningoencephalitis older than 70 years of age who were able to function independently before infection did not survive the acute illness, died within 6 months, or required the services of a full-time nursing care facility for at least 1 year after infection. As others have suggested, we found that preexisting health conditions were common among patients with WNV meningoencephalitis and may be independent risk factors for severe illness and death. (5-7)

Patients with West Nile virus meningoencephalitis reporting sequelae 1 year after acute illness noted symptoms consistent with studies conducted in New York City and New Jersey in 2000, which found that more than half had not returned to their previous functional level at the time of hospital discharge, and, of those, only one third were fully ambulatory. (8,9) It is probably underappreciated that survivors of WNV meningoencephalitis have substantial morbidity and decreased quality of life 1 year after acute illness.

A substantial proportion of patients in this study with acute WNV meningoencephalitis reported symptoms of nausea, vomiting, and diarrhea as has been reported elsewhere. (6,9,10) Gastrointestinal symptoms may not be recognized by many clinicians as part of the spectrum of WNV disease. It is important that physicians maintain a high index of suspicion for WNV in high-risk patients during the season of transmission.

Although WNV fever is considered a "milder" form of the illness than meningoencephalitis, our findings suggest that WNV fever can be associated with substantial morbidity. Over one third of the patients with WNV fever in this study were hospitalized. West Nile virus fever can result in work absenteeism, extended recovery periods, and substantial economic burden. Further study of persons with nonneurologic WNV illness will be important to better understand the spectrum of potential morbidity from this disease.

Although inpatient medical records pertaining to hospitalization for acute WNV were reviewed, assessment of health status after discharge was limited to self-report. In addition, no control groups were interviewed. Because WNV disproportionately affects older persons, the presence of substantial underlying comorbidities was not surprising and probably contributed significantly to the observed outcomes. Because these data were collected retrospectively and sometimes from a surrogate, recall bias may have affected the results. Despite these limitations, the findings are remarkably similar to those in other studies (8) and can contribute meaningfully to our understanding of the impact of this disease on the populations most at risk of adverse sequelae. Case-control or cohort studies to better understand risk factors for particular outcomes will be important to pursue as this disease becomes endemic nationwide.

All persons at risk, particular older adults and those with underlying medical conditions, should take appropriate personal precautions to prevent WNV infection. Such measures include the use of insect repellents, wearing clothing that will provide a physical barrier from mosquito bites, and elimination of breeding habitats near residences. The substantial mortality rates and potentially devastating long-term morbidity associated with WNV infections highlight the importance of continuing to develop effective methods of targeting preventive education to high-risk populations while continuing to pursue longer-term solutions such as vaccines to prevent this emerging infection.

Conclusion

WNV infection leads to high rates of mortality and substantial persistent morbidity. People of advanced age with preexisting health conditions are particularly susceptible to severe neurologic disease, long-term morbidity, and death from WNV. Of patients with WNV meningoencephalitis older than 70 years of age, 44% had died or had not returned to previous functional levels at least 1 year after acute illness. Although WNV fever is considered a "milder" form of the illness than meningoencephalitis, our findings suggest that WNV fever can also be associated with substantial morbidity. Prevention efforts should be targeted to populations at highest risk of severe sequelae.
Make money your god and it will plague you like the devil.
--Henry Fielding

Table 1. Characteristics of human cases of West Nile virus fever and
West Nile virus meningoencephalitis in Tennessee, 2002 (a)

 WNV ME WNV fever
 (n = 48) (n = 8)

Age median (range) 72 (17-99) 49 (22-74)
Male (%) 32 (67%) 6 (75%)
Hospitalized 48 (100%) 3 (37%)
Median (range) of days 10 (2-92) 0 (0-7)
 hospitalized
Death during acute infection 9 (19%) 0
Total deaths within 6 months 12 (25%) 0
 of acute infection
Acute symptoms
 Fever 45 (94%) 6 (75%)
 Profound weakness 42 (88%) 5 (63%)
 Altered mental state 34 (71%) 0 (0%)
 Headache 25 (52%) 7 (87%)
 Stiff neck 24 (50%) 5 (63%)
 Nausea 23 (48%) 4 (50%)
 Vomiting 21 (44%) 2 (25%)
 Muscle aches/pains 22 (46%) 6 (75%)
 Rash 10 (21%) 5 (63%)
 Diarrhea 8 (17%) 2 (25%)
 Sore throat 8 (17%) 1 (13%)
Underlying health conditions
 Heart disease 19 (40%) 1 (13%)
 Malignancy 12 (25%) 1 (13%)
 Alcoholism 9 (19%) 0 (0%)
 Diabetes 8 (17%) 0 (0%)
 Hematologic disease 3 (6%) 0 (0%)

(a) WNV, West Nile virus; ME, meningoencephalitis.

Long Term Sequelae 19%
Died 25%
Nursing Facility 6%
Unknown 29%
Fully Recovered 21%

Status of patients with West Nile virus meningoencephalitis 1 year after
Acute illness.

Note: Table made from pie chart.

Table 2. Persistent symptoms of survivors of West Nile virus
meningoencephalitis one year after acute illness

Symptoms (n = 12)

Fatigue 9 (75%)
Muscle weakness 7 (58%)
Difficulty ambulating 5 (42%)
Joint weakness 5 (42%)
Headaches 3 (25%)
Memory problems 3 (25%)
Anxiety 3 (25%)
Difficulty concentrating 2 (17%)
Depression 2 (17%)
Numbness 2 (17%)


Accepted November 13, 2004.

References

1. Mostashari F, Bunning MS, Kitsutani PT, et al. Epidemic West Nile encephalitis, New York, 1999: Results of a household-based seroepidemiological survey. Lancet 2001;28:261-264.

2. Centers of Disease and Prevention. Serosurveys for WNV infection: New York and Connecticut counties, 2000. JAMA 2001;285:727-728.

3. Huhn G, Sejvar J, Montgomery S, et al. West Nile virus in the United States: An update on an emerging infectious disease. Am Fam Physician 2003;68:653-660.

4. Centers for Disease Control and Prevention. 2003. Epidemic/epizootic West Nile virus in the United States: Guidelines for surveillance, prevention, and control. 3rd revision. http://www.cdc.gov/ncidod/dvbid/westnile/resources/wnvguidelines2003.pdf Accessed January 22, 2004.

5. Petersen L, Marfin AA. West Nile virus: A primer for the clinician. Ann Intern Med 2002;137:173-179.

6. Nash D, Mostashari F, Fine A, et al. The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med 2001;344:1807-1814.

7. Chowers MY, Lang R, Nassar F, et al. Clinical characteristics of the West Nile fever outbreak, Israel, 2000. Emerg Infect Dis 2001;7:675-678.

8. New York Department of Health, West Nile virus surveillance and control: an update for healthcare providers in New York City. City Health Information 2001:20.

9. Weiss D, Carr D, Kellachan J, et al. Clinical findings of West Nile virus infection in hospitalized patients, New York and New Jersey, 2000. Emerg Infect Dis 2001;7:654-658.

10. Pepperell C, Rau N, Krajden S, et al. West Nile virus infection in 2002: Morbidity and mortality among patients admitted to hospital in south-central Ontario. CMAJ 2003; 168:1399-1405.

RELATED ARTICLE: Key Points

* Of patients with West Nile virus (WNV) meningoencephalitis older than 70 years of age, 44% had not returned to previous functional levels at least 1 year after acute illness.

* Preexisting health conditions were common among patients with WNV meningoencephalitis.

* Gastrointestinal symptoms may not be recognized by many clinicians as part of the spectrum of WNV illness.

* Although WNV fever is considered a "milder" form of the illness than meningoencephalitis, WNV fever can be associated with substantial morbidity.

Kristy Gottfried, MS, Robbie Quinn, BS, and Tim Jones, MD

From the Tennessee Department of Health, Communicable and Environmental Disease Service, Nashville, TN.

This study design and implementation plan was approved by the Tennessee Department of Health's Institutional Review Board.

Reprint requests to Dr. Tim Jones, Tennessee Department of Health, Communicable and Environmental Disease Services, 425 5th Avenue North, 4th Floor, Cordell Hull Building, Nashville, TN 37247-3901. Email: Tim.F.Jones@state.tn.us
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Author:Jones, Tim
Publication:Southern Medical Journal
Geographic Code:1USA
Date:Jun 1, 2005
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