Anthony A. Marfin

West Nile Virus: A Primer for the Clinician

Four centuries of travel and commerce have led to the North American importation of several important vector-borne human pathogens, including dengue, yellow fever, malaria, and plague. The 1999 appearance of the West Nile virus in New York City may prove to be the best-documented introduction of a new, vector-borne human pathogen into the United States in the past century (1). It remains unknown how the West Nile virus came to North America. However, because it first appeared in a major international gateway, travel and commerce may have played a role. The viruss rapid geographic expansion and subsequent persistence in newly established enzootic areas in North America indicate that West Nile virus has become a permanent fixture of the U.S. medical landscape. Key features of the West Nile virus in North America are indicated in Table 1. Table 1. Key Clinical Facts about West Nile Virus in North America Epidemiology West Nile virus was first isolated and identified in 1937 from an infected person in the West Nile district of Uganda (2). Until 1999, the virus was found only in the Eastern Hemisphere, with wide distribution in Africa, Asia, the Middle East, and Europe (3). Since 1937, infrequent human outbreaks, mainly associated with mild febrile illnesses, were reported mostly in groups of soldiers, children, and healthy adults in Israel and Africa (4-7). However, one notable outbreak in Israeli nursing homes in 1957 was associated with severe neurologic disease and death (8). Since the mid-1990s, the frequency and apparent clinical severity of West Nile virus outbreaks have increased (4). Outbreaks in Romania (1996) (9), Russia (1999) (10), and Israel (2000) (11) involved hundreds of persons with severe neurologic disease. It is unclear if this apparent change in disease severity and frequency is due to differences in the circulating viruss virulence or to changes in the age structure, background immunity, or prevalence of other predisposing chronic conditions in the affected populations (12). A large outbreak of West Nile virus infection has yet to occur in the United States. However, national surveillance has documented persons with illness caused by West Nile virus, mostly encephalitis and meningitis, each year since 1999 (62 persons in 1999, 21 in 2000, and 66 in 2001) (13). These persons have been identified over an expanding geographic area (1 state in 1999, 3 in 2000, and 10 in 2001) (Figure 1). From 1999 to 2001, illness onset ranged from 13 July to 7 December, with peak incidence in late August and early September (Figure 2). Figure 1. States reporting epizootic activity and human infections of the West Nile virus, 19992001. Figure 2. Week of symptom onset for persons reported to have West Nile virus infection, 19992001. Ecology In the Eastern Hemisphere, West Nile virus is maintained in an enzootic cycle involving culicine mosquitoes and birds (3, 14). Evidence to date suggests a similar cycle in North America (Figure 3) (4). After passing through three aquatic stages (egg, larva, pupa), adult mosquitoes begin to emerge in the spring in temperate regions. Viral amplification occurs in the birdmosquitobird cycle until early fall, when female mosquitoes begin diapause and infrequently bite. Many environmental factors affect this viral amplification cycle (for example, weather or climate, host and vector predators and parasites, and host immune status). When environmental conditions promote significant amplification, sufficient numbers of bridge vector mosquitoesmosquitoes that bite both humans and birdsbecome infected in late summer and then pose an infection threat to humans. Year-round transmission is possible in more tropical climates. Through spring 2002, West Nile virus had been detected in 29 North American mosquito species; this number will undoubtedly increase as the virus spreads into new ecologic habitats. Although Culex pipiens, Culex restuans, and Culex quinquefasciatus are probably the most important maintenance vectors in the eastern United States, it is unknown which species are most responsible for transmission to humans (15). Figure 3. Transmission cycle of West Nile virus. While arboviral maintenance cycles are normally not apparent, dramatic avian mortality rates have accompanied outbreaks in humans in Israel and the United States (4, 16). Particularly high mortality rates have been noted among American crows (Corvus brachyrhynchos) and other North American corvids (ravens, jays, and other crows). In the northeastern United States, deaths in crows have increased markedly shortly before human cases have developed (17). Surveillance systems involving testing dead birds, sentinel chickens, and ill horses for West Nile virus have demonstrated rapid geographic spread in the United States (4 states in 1999, 12 states and the District of Columbia in 2000, 27 states and the District of Columbia in 2001) and into Canada (southern Ontario in 2001) (Figure 1). Up-to-date maps showing the U.S. distribution of West Nile virus are available at www.cdc.gov/ncidod/dvbid/westnile/surv&control.htm and at cindi.usgs.gov/hazard/event/west_nile/west_nile.html. Virology West Nile virus is a single-stranded RNA virus of the family Flaviviridae, genus Flavivirus. The E-glycoprotein is the viral hemagglutinin and mediates virushost cell binding. As the most immunologically important structural protein, the E-glycoprotein elicits most virus-neutralizing antibodies. West Nile virus is a member of the Japanese encephalitis virus serocomplex, which contains several medically important viruses associated with human encephalitis: Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, and Kunjin virus (an Australian subtype of West Nile virus). The close antigenic relationship of the flaviviruses, particularly those belonging to the Japanese encephalitis complex, accounts for the serologic cross-reactions observed in the diagnostic laboratory (18). West Nile virus can be divided genetically into two lineages. Only viruses of lineage 1 have been definitely associated with human disease. The West Nile virus responsible for the 1999 outbreak in New York City was a lineage 1 virus that circulated in Israel from 1997 to 2000, suggesting viral importation into North America from the Middle East (19, 20). Of interest, both birds and humans have died of West Nile virus infection only in the United States and Israel to date; the reason for this is not known. Since 1999, very few genetic changes have occurred in the variant of West Nile virus circulating in the United States. Clinical Features The incubation period of West Nile virus, although not precisely known, probably ranges from 3 to 14 days. Most human infections are not clinically apparent. A serosurvey conducted during the 1999 New York City epidemic indicated that approximately 20% of persons infected with West Nile virus had developed West Nile fever and only half of these had visited a physician for this illness (21). The frequencies of various symptoms and signs associated with West Nile fever during recent outbreaks are poorly defined because surveillance has focused on patients with neurologic disease. In earlier outbreaks, the disease was described as a febrile illness of sudden onset, often accompanied by malaise, anorexia, nausea, vomiting, eye pain, headache, myalgia, rash, and lymphadenopathy; these symptoms generally lasted 3 to 6 days. Among the 6 symptomatic persons positive for IgM antibody who were identified in the 1999 New York City serosurvey, all reported myalgia, 5 reported fatigue, 5 had headache, and 4 had arthralgia (21). Although recent outbreaks of West Nile virus seem to be associated with increased morbidity and mortality, severe neurologic disease remains uncommon. Two serosurveys conducted in New York City in 1999 and 2000 showed that approximately 1 in 150 infections resulted in meningitis or encephalitis, a result consistent with a 1996 Romanian serosurvey indicating that 1 in 140 to 320 infections led to these diseases (9, 21, 22). Advanced age is by far the most significant risk factor for severe neurologic disease after infection; risk increases markedly among persons 50 years of age and older. An analysis of attack rates per million persons during the 1999 New York City outbreak showed that compared with persons 0 to 19 years of age, the incidence of severe neurologic disease was 10 times higher in persons 50 to 59 years of age and 43 times higher in those at least 80 years of age (1). In addition, the household-based serosurvey in New York City showed that incidence of West Nile virus infection was fairly uniform according to age (21). These results indicated that the higher incidences of severe neurologic disease among older persons were not attributable simply to differences in mosquito exposure. A similar finding was noted during the 1996 Romanian outbreak (9). Among hospitalized persons with West Nile virus infection in the United States (1999), Romania (1996), and Israel (2000), encephalitismeningoencephalitis was more frequently reported than meningitis (62%, 60%, and 58% compared with 32%, 40%, and 16%, respectively) (1, 9, 11). More than 90% of patients hospitalized during these outbreaks had fever; weakness, gastrointestinal symptoms, headache, and changes in mental status were common reported symptoms (Table 2). A skin rash, present in a minority of patients, was described as an erythematous macular, papular, or morbilliform eruption involving the neck, trunk, arms, or legs (1, 23). Table 2. Symptoms of West Nile Virus Reported among Hospitalized Patients during Outbreaks in New York State (1999), Romania (1996), and Israel (2000) Approximately half of the hospitalized U.S. patients had severe muscle weakness. This symptom may provide a clinical clue to the presence of West Nile virus, particularly in the setting of encephalopathy (1, 23). Approximately 10% of patients in the New York outbreak had

Estimated global incidence of Japanese encephalitis: a systematic review.

OBJECTIVE To update the estimated global incidence of Japanese encephalitis (JE) using recent data for the purpose of guiding prevention and control efforts. METHODS Thirty-two areas endemic for JE in 24 Asian and Western Pacific countries were sorted into 10 incidence groups on the basis of published data and expert opinion. Population-based surveillance studies using laboratory-confirmed cases were sought for each incidence group by a computerized search of the scientific literature. When no eligible studies existed for a particular incidence group, incidence data were extrapolated from related groups. FINDINGS A total of 12 eligible studies representing 7 of 10 incidence groups in 24 JE-endemic countries were identified. Approximately 67,900 JE cases typically occur annually (overall incidence: 1.8 per 100,000), of which only about 10% are reported to the World Health Organization. Approximately 33,900 (50%) of these cases occur in China (excluding Taiwan) and approximately 51,000 (75%) occur in children aged 0-14 years (incidence: 5.4 per 100,000). Approximately 55,000 (81%) cases occur in areas with well established or developing JE vaccination programmes, while approximately 12,900 (19%) occur in areas with minimal or no JE vaccination programmes. CONCLUSION Recent data allowed us to refine the estimate of the global incidence of JE, which remains substantial despite improvements in vaccination coverage. More and better incidence studies in selected countries, particularly China and India, are needed to further refine these estimates.

The epidemic of West Nile virus in the United States, 2002.

Since 1999, health officials have documented the spread of West Nile virus across the eastern and southern states and into the central United States. In 2002, a large, multi-state, epidemic of neuroinvasive West Nile illness occurred. Using standardized guidelines, health departments conducted surveillance for West Nile virus illness in humans, and West Nile virus infection and illness in non-human species. Illnesses were reported to the Centers for Disease Control and Prevention (CDC) through the ArboNET system. In 2002, 39 states and the District of Columbia reported 4,156 human West Nile virus illness cases. Of these, 2,942 (71%) were neuroinvasive illnesses (i.e., meningitis, encephalitis, or meningoencephalitis) with onset dates from May 19 through December 14; 1,157 (28%) were uncomplicated West Nile fever cases, and 47 (1%) were clinically unspecified. Over 80% of neuroinvasive illnesses occurred in the central United States. Among meningitis cases, median age was 46 years (range, 3 months to 91 years), and the fatality-to-case ratio was 2%; for encephalitis cases (with or without meningitis), median age was 64 years (range, 1 month to 99 years) and the fatality-to-case ratio was 12%. Neuroinvasive illness incidence and mortality, respectively, were significantly associated with advanced age (p = 0.02; p = 0.01) and being male (p < 0.001; p = 0.002). In 89% of counties reporting neuroinvasive human illnesses, West Nile virus infections were first noted in non-human species, but no human illnesses were reported from 77% of counties in which non-human infections were detected. In 2002, West Nile virus caused the largest recognized epidemic of neuroinvasive arboviral illness in the Western Hemisphere and the largest epidemic of neuroinvasive West Nile virus ever recorded. It is unknown why males appeared to have higher risk of severe illness and death, but possibilities include higher prevalence of co-morbid conditions or behavioral factors leading to increased infection rates. Several observations, including major, multi-state West Nile virus epidemics in 2002 and 2003, suggest that major epidemics may annually reoccur in the United States. Non-human surveillance can warn of early West Nile virus activity and needs continued emphasis, along with control of Culex mosquitoes.

West Nile Encephalitis: An Emerging Disease in the United States

In 1999, an epidemic of West Nile virus (WNV) encephalitis occurred in New York City (NYC) and 2 surrounding New York counties. Simultaneously, an epizootic among American crows and other bird species occurred in 4 states. Indigenous transmission of WNV had never been documented in the western hemisphere until this epidemic. In 2000, the epizootic expanded to 12 states and the District of Columbia, and the epidemic continued in NYC, 5 New Jersey counties, and 1 Connecticut county. In addition to these outbreaks, several large epidemics of WNV have occurred in other regions of the world where this disease was absent or rare >5 years ago. Many of the WNV strains isolated during recent outbreaks demonstrate an extremely high degree of homology that strongly suggests widespread circulation of potentially epidemic strains of WNV. The high rates of severe neurologic illness and death among humans, horses, and birds in these outbreaks are unprecedented and unexplained. We review the current status of WNV in the United States.

Acute Flaccid Paralysis and West Nile Virus Infection

Acute weakness associated with West Nile virus (WNV) infection has previously been attributed to a peripheral demyelinating process (Guillain-Barré syndrome); however, the exact etiology of this acute flaccid paralysis has not been systematically assessed. To thoroughly describe the clinical, laboratory, and electrodiagnostic features of this paralysis syndrome, we evaluated acute flaccid paralysis that developed in seven patients in the setting of acute WNV infection, consecutively identified in four hospitals in St. Tammany Parish and New Orleans, Louisiana, and Jackson, Mississippi. All patients had acute onset of asymmetric weakness and areflexia but no sensory abnormalities. Clinical and electrodiagnostic data suggested the involvement of spinal anterior horn cells, resulting in a poliomyelitis-like syndrome. In areas in which transmission is occurring, WNV infection should be considered in patients with acute flaccid paralysis. Recognition that such weakness may be of spinal origin may prevent inappropriate treatment and diagnostic testing.

West Nile Virus Disease: A Descriptive Study of 228 Patients Hospitalized in a 4-County Region of Colorado in 2003

BACKGROUND Risk factors for complications of West Nile virus disease and prognosis in hospitalized patients are incompletely understood. METHODS Demographic characteristics and data regarding potential risk factors, hospitalization, and dispositions were abstracted from medical records for residents of 4 Colorado counties who were hospitalized in 2003 with West Nile virus disease. Univariate and multivariate analyses were used to identify factors associated with West Nile encephalitis (WNE), limb weakness, or death by comparing factors among persons with the outcome of interest with factors among those without the outcome of interest. RESULTS Medical records of 221 patients were reviewed; 103 had West Nile meningitis, 65 had WNE, and 53 had West Nile fever. Respiratory failure, limb weakness, and cardiac arrhythmia occurred in all groups, with significantly more cases of each in the WNE group. Age, alcohol abuse, and diabetes were associated with WNE. Age and WNE were associated with limb weakness. The mortality rate in the WNE group was 18%; age, immunosuppression, requirement of mechanical ventilation, and history of stroke were associated with death. Only 21% of patients with WNE who survived returned to a prehospitalization level of function. The estimated incidence of West Nile fever cases that required hospitalization was 6.0 cases per 100,000 persons; West Nile fever was associated with arrhythmia, limb weakness, and respiratory failure. CONCLUSIONS Persons with diabetes and a reported history of alcohol abuse and older persons appear to be at increased risk of developing WNE. Patients with WNE who have a history of stroke, who require mechanical ventilation, or who are immunosuppressed appear to be more likely to die. Respiratory failure, limb weakness, and arrhythmia occurred in all 3 categories, but there were significantly more cases of all in the WNE group.

West Nile Virus–associated Flaccid Paralysis

The causes and frequency of acute paralysis and respiratory failure with West Nile virus (WNV) infection are incompletely understood. During the summer and fall of 2003, we conducted a prospective, population-based study among residents of a 3-county area in Colorado, United States, with developing WNV-associated paralysis. Thirty-two patients with developing paralysis and acute WNV infection were identified. Causes included a poliomyelitislike syndrome in 27 (84%) patients and a Guillain-Barré–like syndrome in 4 (13%); 1 had brachial plexus involvement alone. The incidence of poliomyelitislike syndrome was 3.7/100,000. Twelve patients (38%), including 1 with Guillain-Barré–like syndrome, had acute respiratory failure that required endotracheal intubation. At 4 months, 3 patients with respiratory failure died, 2 remained intubated, 25 showed various degrees of improvement, and 2 were lost to followup. A poliomyelitislike syndrome likely involving spinal anterior horn cells is the most common mechanism of WNV-associated paralysis and is associated with significant short- and long-term illness and death.

Effects of hand hygiene campaigns on incidence of laboratory-confirmed influenza and absenteeism in schoolchildren, Cairo, Egypt.

To evaluate the effectiveness of an intensive hand hygiene campaign on reducing absenteeism caused by influenza-like illness (ILI), diarrhea, conjunctivitis, and laboratory-confirmed influenza, we conducted a randomized control trial in 60 elementary schools in Cairo, Egypt. Children in the intervention schools were required to wash hands twice each day, and health messages were provided through entertainment activities. Data were collected on student absenteeism and reasons for illness. School nurses collected nasal swabs from students with ILI, which were tested by using a qualitative diagnostic test for influenza A and B. Compared with results for the control group, in the intervention group, overall absences caused by ILI, diarrhea, conjunctivitis, and laboratory-confirmed influenza were reduced by 40%, 30%, 67%, and 50%, respectively (p<0.0001 for each illness). An intensive hand hygiene campaign was effective in reducing absenteeism caused by these illnesses.

West Nile virus infection transmitted by blood transfusion

BACKGROUND: A patient with transfusion‐transmitted West Nile virus (WNV) infection confirmed by viral culture of a blood component is described. A 24‐year‐old female with severe postpartum hemorrhage developed fever, chills, headache, and generalized malaise after transfusion of 18 units of blood components; a serum sample and the cerebrospinal fluid tested positive for the presence of WNV IgM antibodies. An investigation was initiated to determine a possible association between transfusion and WNV infection.

Mortality rates in displaced and resident populations of central Somalia during 1992 famine

Famine and civil war have resulted in high mortality rates and large population displacements in Somalia. To assess mortality rates and risk factors for mortality, we carried out surveys in the central Somali towns of Afgoi and Baidoa in November and December, 1992. In Baidoa we surveyed displaced persons living in camps; the average daily crude mortality rate was 16.8 (95% CI 14.6-19.1) per 10,000 population during the 232 days before the survey. An estimated 74% of children under 5 years living in displaced persons camps died during this period. In Afgoi, where both displaced and resident populations were surveyed, the crude mortality rate was 4.7 (3.9-5.5) deaths per 10,000 per day. Although mortality rates for all displaced persons were high, people living in temporary camps were at highest risk of death. As in other famine-related disasters, preventable infectious diseases such as measles and diarrhoea were the primary causes of death in both towns. These mortality rates are among the highest documented for a civilian population over a long period. Community-based public health interventions to prevent and control common infectious diseases are needed to reduce these exceptionally high mortality rates in Somalia.