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  • 1. Review West Nile Virus: A Primer for the Clinician Lyle R. Petersen, MD, MPH, and Anthony A. Marfin, MD, MPH This paper provides the clinician with an understanding of the states. Encephalitis is more commonly reported than meningitis, epidemiologic and biological characteristics of West Nile virus in and concomitant muscle weakness and flaccid paralysis may pro- North America, as well as useful information on the diagnosis, vide a clinical clue to the presence of West Nile virus infection. reporting, and management of patients with suspected West Nile Peak incidence occurs in late summer, although onset has oc- virus infection and on advising patients about prevention. Infor- curred from July through December. Immunoglobulin M antibody mation was gathered from the medical literature and from national testing of serum specimens and cerebrospinal fluid is the most surveillance data through May 2002. Since the identification of efficient method of diagnosis, although cross-reactions are possi- West Nile virus in New York City in 1999, enzootic activity has ble in patients recently vaccinated against or recently infected with been documented in 27 states and the District of Columbia. Con- related flaviviruses. Testing can be arranged through local, state, tinued geographic expansion is likely. Overall, one in 150 infec- or provincial (in Canada) health departments. Prevention rests on tions results in severe neurologic illness. Advanced age is by far elimination of mosquito breeding sites; judicious use of pesticides; the most important risk factor for neurologic disease and, once and avoidance of mosquito bites, including mosquito repellent use. disease develops, for worse clinical outcome. Surveillance has Ann Intern Med. 2002;137:173-179. identified 149 persons with West Nile virus–related illness in 10 For author affiliations, see end of text. F our centuries of travel and commerce have led to the North American importation of several important vec- tor-borne human pathogens, including dengue, yellow fe- ture, background immunity, or prevalence of other predis- posing chronic conditions in the affected populations (12). A large outbreak of West Nile virus infection has yet ver, malaria, and plague. The 1999 appearance of the West to occur in the United States. However, national surveil- Nile virus in New York City may prove to be the best- lance has documented persons with illness caused by West documented introduction of a new, vector-borne human Nile virus, mostly encephalitis and meningitis, each year pathogen into the United States in the past century (1). It since 1999 (62 persons in 1999, 21 in 2000, and 66 in remains unknown how the West Nile virus came to North 2001) (13). These persons have been identified over an America. However, because it first appeared in a major expanding geographic area (1 state in 1999, 3 in 2000, and international gateway, travel and commerce may have 10 in 2001) (Figure 1). From 1999 to 2001, illness onset played a role. The virus’s rapid geographic expansion and ranged from 13 July to 7 December, with peak incidence in subsequent persistence in newly established enzootic areas late August and early September (Figure 2). in North America indicate that West Nile virus has be- come a permanent fixture of the U.S. medical landscape. ECOLOGY Key features of the West Nile virus in North America are In the Eastern Hemisphere, West Nile virus is main- indicated in Table 1. tained 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 EPIDEMIOLOGY three aquatic stages (egg, larva, pupa), adult mosquitoes West Nile virus was first isolated and identified in begin to emerge in the spring in temperate regions. Viral 1937 from an infected person in the West Nile district of Uganda (2). Until 1999, the virus was found only in the Table 1. Key Clinical Facts about West Nile Virus in Eastern Hemisphere, with wide distribution in Africa, Asia, North America* the Middle East, and Europe (3). Since 1937, infrequent West Nile virus infection is a mosquito-borne infection with rapidly human outbreaks, mainly associated with mild febrile ill- expanding geographic distribution. nesses, were reported mostly in groups of soldiers, children, One in 5 infected persons develops mild febrile illness; 1 in 150 develops meningitis, encephalitis, or both. and healthy adults in Israel and Africa (4 –7). However, Advanced age is by far the greatest risk factor for severe neurologic disease, one notable outbreak in Israeli nursing homes in 1957 was long-term morbidity, and death. associated with severe neurologic disease and death (8). Presence of West Nile virus–infected birds, onset of meningitis or encephalitis in late summer or early fall, and profound muscle weakness Since the mid-1990s, the frequency and apparent clinical provide important diagnostic clues. severity of West Nile virus outbreaks have increased (4). IgM antibody-capture ELISA testing of CSF or serum is the most efficient diagnostic method; testing is available through state and local health Outbreaks in Romania (1996) (9), Russia (1999) (10), and departments; false-positive results may occur after other flaviviral Israel (2000) (11) involved hundreds of persons with severe infections or vaccinations. Rapid reporting of possible cases to health departments is essential to guide neurologic disease. It is unclear if this apparent change in public health control efforts. disease severity and frequency is due to differences in the circulating virus’s virulence or to changes in the age struc- * CSF cerebrospinal fluid; ELISA enzyme-linked immunosorbent assay. 6 August 2002 Annals of Internal Medicine Volume 137 • Number 3 E-173
  • 2. Review West Nile Virus Figure 1. States reporting epizootic activity and human While arboviral maintenance cycles are normally not infections of the West Nile virus, 1999 –2001. 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 in- creased markedly shortly before human cases have devel- oped (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 Co- lumbia in 2000, 27 states and the District of Columbia in 2001) and into Canada (southern Ontario in 2001) (Fig- ure 1). Up-to-date maps showing the U.S. distribution of West Nile virus are available at /westnile/surv&control.htm and at /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 virus– host cell bind- ing. 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 en- cephalitis: Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, and Kunjin virus (an Austra- lian subtype of West Nile virus). The close antigenic rela- tionship 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 re- sponsible for the 1999 outbreak in New York City was a amplification occurs in the bird–mosquito– bird cycle until lineage 1 virus that circulated in Israel from 1997 to 2000, early fall, when female mosquitoes begin diapause and in- suggesting viral importation into North America from the frequently bite. Many environmental factors affect this vi- Middle East (19, 20). Of interest, both birds and humans ral amplification cycle (for example, weather or climate, have died of West Nile virus infection only in the United host and vector predators and parasites, and host immune States and Israel to date; the reason for this is not known. status). When environmental conditions promote signifi- Since 1999, very few genetic changes have occurred in the cant amplification, sufficient numbers of “bridge vector” variant of West Nile virus circulating in the United States. mosquitoes—mosquitoes that bite both humans and birds—become infected in late summer and then pose an infection threat to humans. Year-round transmission is CLINICAL FEATURES possible in more tropical climates. Through spring 2002, The incubation period of West Nile virus, although West Nile virus had been detected in 29 North American not precisely known, probably ranges from 3 to 14 days. mosquito species; this number will undoubtedly increase as Most human infections are not clinically apparent. A sero- the virus spreads into new ecologic habitats. Although survey conducted during the 1999 New York City epi- Culex pipiens, Culex restuans, and Culex quinquefasciatus are demic indicated that approximately 20% of persons in- probably the most important maintenance vectors in the fected with West Nile virus had developed West Nile fever eastern United States, it is unknown which species are and only half of these had visited a physician for this illness most responsible for transmission to humans (15). (21). The frequencies of various symptoms and signs asso- E-174 6 August 2002 Annals of Internal Medicine Volume 137 • Number 3
  • 3. West Nile Virus Review ciated with West Nile fever during recent outbreaks are Figure 3. Transmission cycle of West Nile virus. 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 symp- tomatic persons positive for IgM antibody who were iden- tified 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, se- vere neurologic disease remains uncommon. Two serosur- veys 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 compared with 32%, 40%, and 16%, respectively) (1, 9, Romanian serosurvey indicating that 1 in 140 to 320 in- 11). More than 90% of patients hospitalized during these fections led to these diseases (9, 21, 22). Advanced age is outbreaks had fever; weakness, gastrointestinal symptoms, by far the most significant risk factor for severe neurologic headache, and changes in mental status were common re- disease after infection; risk increases markedly among per- ported symptoms (Table 2). A skin rash, present in a mi- sons 50 years of age and older. An analysis of attack rates nority of patients, was described as an erythematous mac- per million persons during the 1999 New York City out- ular, papular, or morbilliform eruption involving the neck, break showed that compared with persons 0 to 19 years of trunk, arms, or legs (1, 23). age, the incidence of severe neurologic disease was 10 times Approximately half of the hospitalized U.S. patients higher in persons 50 to 59 years of age and 43 times higher had severe muscle weakness. This symptom may provide a in those at least 80 years of age (1). In addition, the house- clinical clue to the presence of West Nile virus, particularly hold-based serosurvey in New York City showed that inci- in the setting of encephalopathy (1, 23). Approximately dence of West Nile virus infection was fairly uniform ac- 10% of patients in the New York outbreak had complete cording to age (21). These results indicated that the higher flaccid paralysis. In fact, several patients had such profound incidences of severe neurologic disease among older per- weakness that they were first thought to have the Guillain– sons were not attributable simply to differences in mos- Barre syndrome (24, 25). However, most studied persons ´ quito exposure. A similar finding was noted during the with clinical presentations consistent with the Guillain– 1996 Romanian outbreak (9). Barre syndrome had pleocytosis as well as electromyogra- ´ Among hospitalized persons with West Nile virus in- phy and nerve-conduction velocity studies indicating both fection in the United States (1999), Romania (1996), and axonal and demyelinating lesions, with axonal changes Israel (2000), encephalitis–meningoencephalitis was more most prominent (26). These findings would be unusual for frequently reported than meningitis (62%, 60%, and 58% the Guillain–Barre syndrome. Neurologic presentations ´ other than encephalitis or meningitis, which occur more rarely, include ataxia and extrapyramidal signs, cranial Figure 2. Week of symptom onset for persons reported to have nerve abnormalities, myelitis, optic neuritis, polyradiculi- West Nile virus infection, 1999–2001. tis, and seizures. Myocarditis, pancreatitis, and fulminant hepatitis have been described in outbreaks occurring before 1990. CLINICAL OUTCOME AND TREATMENT Case fatality rates among patients hospitalized during recent outbreaks have ranged from 4% in Romania (1996) to 12% in New York (1999) and 14% in Israel (2000) (1, 9, 11). Case fatality rates have remained constant among U.S. patients in 2000 and 2001 (13). Advanced age is the most important risk factor for death, and patients older than 70 years of age are at particularly high risk. For hos- pitalized persons older than 70 years of age, case fatality rates were 15% in Romania and 29% in Israel; in New York, persons 75 years of age and older were nearly nine 6 August 2002 Annals of Internal Medicine Volume 137 • Number 3 E-175
  • 4. Review West Nile Virus Table 2. Symptoms of West Nile Virus Reported among motic agents in the management of West Nile virus en- Hospitalized Patients during Outbreaks in New York State cephalitis. (1999), Romania (1996), and Israel (2000) LABORATORY FINDINGS AND DIAGNOSIS Symptom* Location During recent outbreaks, total leukocyte counts in pe- New York State Romania Israel ripheral blood were mostly normal or elevated; lymphocy- (n 59) (n 393) (n 233) topenia and anemia also occurred (1, 11, 23). Hyponatre- 4OOOOOOOOO % OOOOOOOOO3 mia was sometimes present, particularly among patients Fever 90 91 98 with encephalitis (11, 23). Examination of the cerebrospi- Weakness 56 Nausea 53 nal fluid showed pleocytosis, with leukocyte counts ranging Vomiting 51 53 31 from 0 to 1782 cells/mm3, usually with a predominance of Headache 47 77 58 lymphocytes (1, 11, 23, 25). Protein levels were universally Changes in mental status 46 34† 40† Diarrhea 27 19 elevated (51 to 899 mg/dL), and glucose levels were nor- Rash 19 21 mal. Computed tomography of the brain usually showed Cough 19 no evidence of acute disease (1, 11, 23). In approximately Stiff neck 19 57 29 Myalgia 17 15 one third of patients, magnetic resonance imaging showed Arthralgia 15 enhancement of the leptomeninges, the periventricular ar- Lymphadenopathy 2 10 eas, or both. The diagnosis rests on a high index of clinical suspi- * Some listed symptoms were not reported in Romania and Israel. † Reported as confusion. cion and on results of specific laboratory tests. West Nile virus or other arboviral diseases, such as St. Louis enceph- alitis, should be seriously considered in older adults who times more likely to die than younger persons (1, 9, 11). have onset of unexplained encephalitis or meningitis in late Encephalitis with severe muscle weakness and change in summer or early fall. The local presence of West Nile virus the level of consciousness were also prominent clinical risk enzootic activity or other human cases should further raise factors predicting death. Limited data suggest that certain the index of suspicion. However, because severe neurologic preexisting conditions, such as diabetes mellitus or immuno- disease due to West Nile virus infection has occurred in suppression, may be independent risk factors for death (1, persons of all ages and because year-round transmission is 11). In one study of induced West Nile infections in patients possible in more southern states, West Nile virus should with cancer, prolonged viremia and severe illness were always be considered in persons with unexplained enceph- more common among those with hematologic malignan- alitis and meningitis. cies than among those with other types of cancer (27). The most efficient diagnostic method is detection of Few data exist regarding long-term morbidity after IgM antibody to West Nile virus in serum or cerebrospinal hospitalization for West Nile infection; those that do sug- fluid. The IgM antibody-capture enzyme-linked immu- gest that many patients have substantial morbidity. Among nosorbent assay is optimal for IgM detection because it is patients hospitalized in New York and New Jersey in 2000, simple, sensitive, and applicable to serum samples and sam- more than half did not return to their functional level by ples of cerebrospinal fluid. Among the patients in New discharge and only one third were fully ambulatory (23). York City who were infected in 1999 and 2000 and for One-year follow-up of the 1999 New York patients by the whom a sample of cerebrospinal fluid was available, nearly New York City Department of Health found frequent per- all (95%) had demonstrable IgM antibody (28). Since IgM sistent symptoms (fatigue, 67%; memory loss, 50%; diffi- antibody does not cross the blood– brain barrier, IgM anti- culty walking, 49%; muscle weakness, 44%; and depres- body in cerebrospinal fluid strongly suggests central ner- sion, 38%) (28). vous system infection. Ninety percent of serum samples Treatment for West Nile virus infection is supportive. obtained within 8 days of symptom onset were also posi- Of 19 patients hospitalized in New York and New Jersey tive for IgM antibody. Tests of serum or cerebrospinal in 2000, 5 were admitted to intensive care units and 2 fluid are available commercially and can be obtained required mechanical ventilation (23). Ribavirin in high through local, state, or province (in Canada) health depart- doses and interferon- 2b were efficacious against the West ments for patients with encephalitis or meningitis. Nile virus in vitro; however, controlled clinical trials have Two caveats must be considered when interpreting se- not been completed for either agent (29). One comatose rologic tests. First, because of close antigenic relationships patient treated with both ribavirin and interferon- did among the flaviviruses, persons recently vaccinated with not improve (23). In Israel, patients treated with ribavirin yellow fever or Japanese encephalitis vaccines or persons had a higher mortality rate than those who did not receive recently infected with a related flavivirus (for example, St. ribavirin, although this difference could have been related Louis encephalitis or dengue) may have positive results on to patient selection (11). No controlled studies have exam- IgM antibody tests for West Nile virus (18). The plaque ined the use of steroids, antiseizure medications, or os- reduction neutralization test, the most specific test for the E-176 6 August 2002 Annals of Internal Medicine Volume 137 • Number 3
  • 5. West Nile Virus Review arthropod-borne flaviviruses, can be used to help distin- Table 3. U.S. National Case Definitions for West guish false-positive results on IgM antibody-capture en- Nile Encephalitis* zyme-linked immunosorbent assay or other assays (for ex- Possible case of West Nile encephalitis ample, indirect immunofluorescence and hemagglutination Febrile illness with neurologic syndrome (ranging from headache to inhibition). The plaque reduction neutralization test may serious neurologic illness [e.g., aseptic meningitis, myelitis, encephalitis]). Suggested specimens (if indicated) for West Nile virus diagnostic studies also help distinguish serologic cross-reactions among the are the following: flaviviruses, although some degree of cross-reaction in neu- Acute serum sample (collect within 7 days of illness onset)† tralizing antibody may still cause ambiguous results. Sec- Acute CSF sample (collect within 7 days of illness onset)† Convalescent serum sample (collect 14–21 days after illness onset)† ond, because most infected persons are asymptomatic and Probable case of West Nile encephalitis because IgM antibody may persist for 6 months or longer, Febrile illness with neurologic syndrome plus at least one of the following: residents in endemic areas may have persistent IgM anti- Demonstration of West Nile virus IgM antibody in acute serum sample using (MAC-ELISA) body from a previous infection that is unrelated to their Demonstration of elevated titer of West Nile virus–specific IgG (by current clinical illness (28). An increase in West Nile vi- ELISA) or HI antibody in a convalescent serum sample relative to titer in rus–specific neutralizing antibody titer in serum specimens an acute serum sample (confirm by PRNT) Confirmed case of West Nile encephalitis from persons with acute and convalescent disease confirms Febrile illness with neurologic manifestations plus at least one of the acute infection. following: It is also possible to isolate West Nile virus or to detect Isolation of West Nile virus from tissue, blood, CSF, or other body fluid Demonstration of West Nile viral antigen or genomic sequences in viral antigen or nucleic acid in cerebrospinal fluid, tissue, tissue, blood, CSF, or other body fluid blood, or other body fluids. Although a positive culture or Demonstration of West Nile virus IgM antibody in an acute CSF sample using MAC-ELISA positive results on the nucleic acid amplification test are Demonstration of fourfold change in PRNT antibody titer to West Nile diagnostic, low sensitivity precludes their use as routine virus in paired, appropriately timed acute and convalescent serum samples screening tests. Viral culture of cerebrospinal fluid or brain Demonstration of both West Nile virus–specific IgM (by MAC-ELISA) and IgG (by IgG ELISA or HI antibody titer; confirm by PRNT) in a single tissue has had very low yield among U.S. patients; results serum sample on nucleic acid amplification testing, such as real-time Non-case of West Nile encephalitis polymerase chain reaction, have been positive in up to Febrile illness with neurologic manifestations ranging from headache to aseptic meningitis or encephalitis that does not meet any of the above 55% of samples of cerebrospinal fluid and 10% of serum laboratory criteria. There should be a negative test result for at least one samples (28). One autopsy series of four New York pa- of the following: IgM antibody to West Nile virus (by MAC-ELISA) in serum or CSF tients infected in the 1999 outbreak showed a mostly collected 8–21 days after onset of illness mononuclear inflammation that formed microglial nodules IgG antibody to West Nile virus (by EIA, HI antibody titer, or PRNT) in and perivascular clusters in the white and gray matter. The serum collected 22 days after onset of illness brainstem, particularly the medulla, was most extensively * CSF cerebrospinal fluid; EIA enzyme immunoassay; HI hemagglutina- involved. Cranial nerve roots had mononuclear inflamma- tion inhibition; MAC-ELISA IgM antibody-capture enzyme-linked immuno- tion in two patients (30). sorbent assay; PRNT plaque reduction neutralization test. † All samples should be refrigerated at 4 °C to 8 °C or frozen. REPORTING the United States is available at West Nile virus encephalitis has recently been added /westnile/city_states.htm. to the list of designated nationally notifiable arboviral en- cephalitides; aseptic meningitis is reportable in some juris- dictions (31). Recommended clinical and laboratory case PREVENTION definitions for West Nile virus are available at www.cdc Although human vaccines for West Nile virus are un- .gov/ncidod/dvbid/westnile/resources/wnv-guidelines-apr- der development (34), for the foreseeable future West Nile 2001.pdf and are summarized in Table 3. Submission of infection prevention will rest on two broad general strate- serum specimens or specimens of cerebrospinal fluid to gies: 1) reducing the number of vector mosquitoes through state and local public health laboratories for arboviral di- actions taken by the public or by municipal authorities, agnosis facilitates rapid diagnosis and reporting. The timely and 2) preventing vector mosquitoes from biting humans identification of even a single person with acute West Nile by using mosquito repellents; avoiding locations where vec- virus or other arboviral infection may have substantial pub- tor mosquitoes are biting; and using barrier methods, such lic health implications and will probably augment the pub- as window screens or long-sleeved clothing. lic health response to reduce the risk for additional human Reducing the Number of Mosquitoes infections. An additional benefit of human West Nile virus Many vector mosquitoes have a limited flight range surveillance has been increased recognition of other arbo- and readily breed in containers or other objects containing viral encephalitides, such as Powassan encephalitis virus in small pools of water. Thus, homeowners or municipal au- the northeastern United States and Canada (32, 33). In- thorities can greatly reduce mosquitoes in residential or formation on how to report persons with suspected West urban areas by draining water from or eliminating mos- Nile virus infection or how to submit diagnostic samples in quito breeding sites. Larvicides can also be applied to still 6 August 2002 Annals of Internal Medicine Volume 137 • Number 3 E-177
  • 6. Review West Nile Virus or stagnant waters that are potential mosquito breeding skin. Many other repellents, such as citronella, are mar- sites. Bacillus thuringiensis var. israelensis and Bacillus spha- keted but are not as effective as DEET. ericus are two larvicides in which the active ingredient is a biological organism. Municipal authorities commonly use From U.S. National Center for Infectious Diseases, Division of Vector- these products with methoprene, a biochemical regulator borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado. that interferes with mosquito maturation, for West Nile virus prevention. None of these products is associated with Current author addresses are available at serious acute or chronic health effects. The U.S. Environmental Protection Agency–approved Current Author Addresses: Drs. Petersen and Marfin: Division of Vec- organophosphate or pyrethroid formulations are applied in tor-borne Infectious Diseases, Centers for Disease Control and Preven- very small volumes by ground or aerial spraying for control tion, PO Box 2087 (Foothills Campus), Fort Collins, CO 80522. of adult mosquitoes. Public health authorities use these “adulticides” for prevention of human West Nile virus in- fection when epidemiologic evidence suggests impending References or continuing human transmission. Serious adverse health 1. Nash D, Mostashari F, Fine A, Miller 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 events associated with pesticide spraying for West Nile vi- J Med. 2001;344:1807-14. [PMID: 11407341] rus control seem rare (28). Minor eye and skin irritation, as 2. Smithburn KC, Hughes TP, Burke AW, Paul JH. A neurotropic virus iso- well as breathing problems, have rarely been reported with lated from the blood of a native of Uganda. American Journal of Tropical Med- spraying of organophosphates and pyrethroids. Cholinergic icine. 1940;20:471-92. symptoms (for example, nausea, vomiting, diarrhea, sweat- 3. Hubalek Z, Halouzka J. West Nile fever—a reemerging mosquito-borne viral ´ disease in Europe. Emerg Infect Dis. 1999;5:643-50. [PMID: 10511520] ing, and bronchospasm) are associated with high-dose occu- 4. Petersen LR, Roehrig JT. West Nile virus: a reemerging global pathogen. pational or accidental organophosphate exposure. A cholin- Emerg Infect Dis. 2001;7:611-4. [PMID: 11585520] esterase level can be obtained to confirm organophosphate 5. Weinberger M, Pitlik SD, Gandacu D, Lang R, Nassar F, Ben David D, poisoning. Exposure to high doses of pyrethroids may et al. West Nile fever outbreak, Israel, 2000: epidemiologic aspects. Emerg Infect cause abnormal facial sensation, dizziness, salivation, head- Dis. 2001;7:686-91. [PMID: 11585533] 6. Murgue B, Murri S, Triki H, Deubel V, Zeller HG. West Nile in the ache, vomiting, diarrhea, irritability, pulmonary edema, Mediterranean basin: 1950-2000. Ann N Y Acad Sci. 2001;951:117-26. [PMID: and seizures. More detailed information about pesticides 11797769] and other mosquito control measures can be obtained from 7. Jupp PG. The ecology of West Nile virus in South Africa and the occurrence the U.S. National Pesticide Information Center at www.ace of outbreaks in humans. Ann N Y Acad Sci. 2001;951:143-52. [PMID: 11797772] Backyard “bug zappers” or car- 8. Spigland I, Jasinska-Klinberg W, Hofshi E, Goldblum N. Clinical and lab- oratory observations in an outbreak of West Nile fever in Israel. Harefuah. 1958; bon dioxide–baited devices have not been proven to signif- 54:275-81. icantly reduce exposure to mosquito bites. 9. Tsai TF, Popovici F, Cernescu C, Campbell GL, Nedelcu NI. West Nile encephalitis epidemic in southeastern Romania. Lancet. 1998;352:767-71. Using Mosquito Repellents [PMID: 9737281] An excellent clinician’s guide for mosquito repellents 10. Platonov AE, Shipulin GA, Shipulina OY, Tyutyunnik EN, Frolochkina has recently been published (35). The most widely used TI, Lanciotti RS, et al. Outbreak of West Nile virus infection, Volgograd Region, Russia, 1999. Emerg Infect Dis. 2001;7:128-32. [PMID: 11266303] repellent, DEET (N,N-diethyl-3-methylbenzamide), is 11. Chowers MY, Lang R, Nassar F, Ben-David D, Giladi M, Rubinshtein E, available in many formulations; however, concentrations et al. Clinical characteristics of the West Nile fever outbreak, Israel, 2000. Emerg higher than 50% show little incremental increase in effi- Infect Dis. 2001;7:675-8. [PMID: 11585531] cacy and only slightly longer durations of action. Extended- 12. Hubalek Z. Comparative symptomatology of West Nile fever. Lancet. 2001; ´ release preparations are available. Products containing 10% 358:254-5. [PMID: 11498205] to 50% DEET are sufficient under most conditions and 13. West Nile virus activity—United States, 2001. MMWR Morb Mortal Wkly Rep. 2002;51:497-501. [PMID: 12079245] can be reapplied according to the manufacturer’s instruc- 14. Hayes CG. West Nile virus: Uganda, 1937, to New York City, 1999. Ann tions. The American Academy of Pediatrics recommends N Y Acad Sci. 2001;951:25-37. [PMID: 11797781] that repellents containing no more than 10% DEET be 15. Turell MJ, Sardelis MR, Dohm DJ, O’Guinn ML. Potential North Amer- used on children. DEET is registered for direct application ican vectors of West Nile virus. Ann N Y Acad Sci. 2001;951:317-24. [PMID: to skin, pets, clothing, tents, bedrolls, and screens. It has a 11797788] remarkable safety profile, and serious toxicity has been lim- 16. Swayne DE, Beck JR, Smith CS, Shieh WJ, Zaki SR. Fatal encephalitis and myocarditis in young domestic geese (Anser anser domesticus) caused by West Nile ited to encephalopathy in a few children, most of whom virus. Emerg Infect Dis. 2001;7:751-3. [PMID: 11585545] had a history of long-term, excessive use of DEET repel- 17. Eidson M, Miller J, Kramer L, Cherry B, Hagiwara Y. Dead crow densities lents. DEET is not recommended for infants younger than and human cases of West Nile virus, New York State, 2000. Emerg Infect Dis. 2 months of age. 2001;7:662-4. [PMID: 11585529] Permethrin, a pyrethroid with repellent and insecti- 18. Martin DA, Biggerstaff BJ, Allen B, Johnson AJ, Lanciotti RS, Roehrig JT. Use of immunoglobulin m cross-reactions in differential diagnosis of human cidal characteristics, is found in Environmental Protection flaviviral encephalitis infections in the United States. Clin Diagn Lab Immunol. Agency–approved repellents that can be applied to cloth- 2002;9:544-9. [PMID: 11986257] ing, tent walls, mosquito nets, or other fabrics, but not to 19. Lanciotti RS, Roehrig JT, Deubel V, Smith J, Parker M, Steele K, et al. E-178 6 August 2002 Annals of Internal Medicine Volume 137 • Number 3
  • 7. West Nile Virus Review Origin of the West Nile virus responsible for an outbreak of encephalitis in the 11797774] northeastern United States. Science. 1999;286:2333-7. [PMID: 10600742] 27. Southam CM, Moore AE. Induced virus infections in man by the Egypt 20. Giladi M, Metzkor-Cotter E, Martin DA, Siegman-Igra Y, Korczyn AD, isolates of West Nile virus. Am J Trop Med Hyg. 1954;3:19-50. Rosso R, et al. West Nile encephalitis in Israel, 1999: the New York connection. 28. West Nile virus surveillance and control: an update for healthcare providers in Emerg Infect Dis. 2001;7:659-61. [PMID: 11585528] New York City. New York Department of Health. City Health Information. 21. Mostashari F, Bunning ML, Kitsutani PT, Singer DA, Nash D, Cooper 2001;20. MJ, et al. Epidemic West Nile encephalitis, New York, 1999: results of a house- 29. Anderson JF, Rahal JJ. Efficacy of interferon alpha-2b and ribavirin against hold-based seroepidemiological survey. Lancet. 2001;358:261-4. [PMID: 11498211] West Nile virus in vitro [Letter]. Emerg Infect Dis. 2002;8:107-8. [PMID: 22. Serosurveys for West Nile virus infection—New York and Connecticut 11749765] Counties, 2000. MMWR Morb Mortal Wkly Rep. 2001;50:37-9. [PMID: 30. Sampson BA, Armbrustmacher V. West Nile encephalitis: the neuropathol- 11215880] ogy of four fatalities. Ann N Y Acad Sci. 2001;951:172-8. [PMID: 11797775] 23. Weiss D, Carr D, Kellachan J, Tan C, Phillips M, Bresnitz E, et al. Clinical 31. Case definitions for infectious conditions under public health surveillance. findings of West Nile virus infection in hospitalized patients, New York and New MMWR Morb Mortal Wkly Rep. 1997;46(RR-10):12-3, 43-4. Jersey, 2000. Emerg Infect Dis. 2001;7:654-8. [PMID: 11589170] 24. Ahmed S, Libman R, Wesson K, Ahmed F, Einberg K. Guillain-Barre ´ 32. Outbreak of Powassan encephalitis—Maine and Vermont, 1999-2001. syndrome: an unusual presentation of West Nile virus infection. Neurology. MMWR Morb Mortal Wkly Rep. 2001;50:761-4. [PMID: 11787585] 2000;55:144-6. [PMID: 10891928] 33. Ford-Jones EL, Fearon M, Leber C, Dwight P, Myszak M, Cole B, et al. 25. Asnis DS, Conetta R, Teixeira AA, Waldman G, Sampson BA. The West Human surveillance for West Nile virus infection in Ontario in 2000. CMAJ. Nile Virus outbreak of 1999 in New York: the Flushing Hospital experience. 2002;166:29-35. [PMID: 11800244] Clin Infect Dis. 2000;30:413-8. [PMID: 10722421] 34. Monath TP. Prospects for development of a vaccine against the West Nile 26. Asnis DS, Conetta R, Waldman G, Teixeira AA. The West Nile virus virus. Ann N Y Acad Sci. 2001;951:1-12. [PMID: 11797767] encephalitis outbreak in the United States (1999-2000): from Flushing, New 35. Fradin MS. Mosquitoes and mosquito repellents: a clinician’s guide. Ann York, to beyond its borders. Ann N Y Acad Sci. 2001;951:161-71. [PMID: Intern Med. 1998;128:931-40. [PMID: 9634433] 6 August 2002 Annals of Internal Medicine Volume 137 • Number 3 E-179