West Nile Virus

Background

The West Nile virus has made its way to the United States. It is a well known virus in the Old World but with the advent of air travel, it has made its appearance in the New World as well. Recently, an outbreak in New York in 1999 brought home the seriousness of the disease.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION

PREVALENCE

West Nile Virus Crow Deaths as a Sentinel Surveillance System for West Nile Virus in the Northeastern United States, 1999

Millicent Eidson,* Nicholas Komar,† Faye Sorhage,‡ Randall Nelson,§ Tom Talbot,* Farzad Mostashari,¶ Robert McLean,# and the West Nile Virus Avian Mortality Surveillance Group (1)

*New York State Department of Health, Albany, New York, USA; †Centers for Disease Control and Prevention, Fort Collins, Colorado, USA; ‡New Jersey Department of Health and Senior Services, Trenton, New Jersey, USA; §Connecticut Department of Public Health, Hartford, Connecticut, USA;

Emerging Infect Disease 2001;Vol. 7, No. 4 Abstract quote

In addition to human encephalitis and meningitis cases, the West Nile (WN) virus outbreak in the summer and fall of 1999 in New York State resulted in bird deaths in New York, New Jersey, and Connecticut.

From August to December 1999, 295 dead birds were laboratory-confirmed with WN virus infection; 262 (89%) were American Crows (Corvus brachyrhynchos). The New York State Department of Health received reports of 17,339 dead birds, including 5,697 (33%) crows; in Connecticut 1,040 dead crows were reported. Bird deaths were critical in identifying WN virus as the cause of the human outbreak and defining its geographic and temporal limits.

If established before a WN virus outbreak, a surveillance system based on bird deaths may provide a sensitive method of detecting WN virus

GEOGRAPHY

ISRAEL

Clinical Characteristics of the West Nile Fever Outbreak, Israel, 2000

Michal Y. Chowers,* Ruth Lang,* Faris Nassar,† Debora Ben-David,‡, Michael Giladi§, Eitan Rubinshtein,‡ Avi Itzhaki,¶ Josef Mishal,# Yardena Siegman-Igra,§ Ruth Kitzes,** Neora Pick,†† Zvi Landau,‡‡ Dana Wolf,§§ Hanna Bin,¶¶ Ella Mendelson,¶¶ Silvio D. Pitlik,## and Miriam Weinberger##

*Meir Medical Center, Kfar Sava, Israel; †Western Galilee Hospital, Nahariya, Israel; ‡Chaim Sheba Medical Center, Tel Hashomer, Israel; §Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel; ¶Assaf Harofeh Medical Center, Zrifin, Israel; #Barzilai Medical Center, Ashkelon, Israel; **Carmel Medical Center, Haifa, Israel; ††Bnei-Zion Medical Center, Haifa, Israel; ‡‡Kaplan Medical Center, Rehovot, Israel; §§Hadassah Medical Center, Jerusalem, Israel; ¶¶Public Health Services, Ministry of Health, Tel Hashomer, Israel; and ##Rabin Medical Center, Belinson Campus, Petach Tikva, Israel

Emer Infect Dis 2001;Vol. 7, No. 4 Jul–Aug Abstract quote

West Nile (WN) virus is endemic in Israel. The last reported outbreak had occurred in 1981. From August to October 2000, a large-scale epidemic of WN fever occurred in Israel; 417 cases were confirmed, with 326 hospitalizations. The main clinical presentations were encephalitis (57.9%), febrile disease (24.4%), and meningitis (15.9%).

Within the study group, 33 (14.1%) hospitalized patients died. Mortality was higher among patients >70 years (29.3%). On multivariate regressional analysis, independent predictors of death were age >70 years (odds ratio [OR] 7.7), change in level of consciousness (OR 9.0), and anemia (OR 2.7).

In contrast to prior reports, WN fever appears to be a severe illness with high rate of central nervous system involvement and a particularly grim outcome in the elderly.

DISEASE ASSOCIATIONS CHARACTERIZATION

BREAST FEEDING

Possible West Nile virus transmission to an infant through breast-feeding--Michigan, 2002. MMWR Morb Mortal Wkly Rep 2002 Oct 4;51(39):877-8 Abstract quote
CDC and the Michigan Department of Community Health (MDCH) continue to investigate West Nile Virus (WNV) infection in a woman, who received a blood product later found with evidence of WNV, and in her child, who was exposed to breast milk later found to be WNV positive by TaqMan.

This report updates the findings of this investigation.

TRANSPLANTATION ORGAN RECIPIENTS

Fatal West Nile Virus Encephalitis in a Renal Transplant Recipient

Melissa M. Cushing, MD, Daniel J. Brat, MD, PhD, Mario I. Mosunjac, MD, etal. Am J Clin Pathol 2004:121:26-31 Abstract quote

West Nile virus (WNV), a mosquito-transmitted single-stranded RNA flavivirus, causes human disease of variable severity.

We report clinical and pathologic findings of fatal encephalitis from the transmission of WNV from an organ donor to a kidney transplant recipient. The patient developed a febrile illness 18 days after transplantation, which progressed to encephalitis. Postmortem examination demonstrated extensive viral encephalopathic changes. Immunohistochemical studies highlighted WNV antigens within neurons, especially in the cerebellum and brainstem.

Flavivirus virions were detected ultrastructurally within the cerebellum, and WNV was isolated from the brain and the brainstem. Thus, this case demonstrates the first death in the first solid organ transplant–associated transmission of WNV. Immunosuppression of the transplant recipient might have been responsible for the fulminant viral effects.

The pathologic diagnosis helped guide subsequent epidemiologic and laboratory studies.

Update: Investigations of West Nile virus infections in recipients of organ transplantation and blood transfusion.
MMWR Morb Mortal Wkly Rep 2002 Sep 20;51(37):833-6 Abstract quote
An investigation involving CDC, the Food and Drug Administration (FDA), the Health Resources and Services Administration (HRSA), the Georgia Division of Public Health, and the Florida Department of Health identified West Nile virus (WNV)-associated illnesses in four recipients of organs from the same donor.

Although the transplanted organs were the source of infection for the four organ recipients, the source of the organ donor's infection remains unknown; an investigation of the numerous transfusions received by the organ donor is ongoing.

TRANSFUSION OF BLOOD PRODUCTS

MMWR Morb Mortal Wkly Rep 2002 Nov 1;51(43):973-4 Related Articles, Links

Investigations of West Nile virus infections in recipients of blood transfusions.
MMWR Morb Mortal Wkly Rep 2002 Nov 1;51(43):973-4 Abstract quote
CDC, the Food and Drug Administration (FDA), and the Health Resources and Services Administration (HRSA), in collaboration with blood collection agencies and state and local health departments, continue to investigate West Nile virus (WNV) infections in recipients of blood transfusions. During August 28-October 26, CDC received reports of 47 persons with possible transfusion-related WNV infection.

Investigations showed that 14 of these persons either did not have WNV infection or did not acquire WNV infection through transfusion. The remaining 33 cases, reported from 17 states, occurred among persons who had confirmed or probable WNV infection and had received blood components in the month before illness onset.

To date, evidence that WNV can be transmitted through blood transfusion has been found in six of the 33 cases; investigations are ongoing for the other 27 cases.

PATHOGENESIS CHARACTERIZATION

Flavivirus Old world virus
Single stranded RNA virus

Two genetic lineages

Lineage 1

Isolated from Africa, India, Europe, Asia, and North America.

Kunjin virus, an apparent subtype of lineage 1 WN viruses, cocirculates in Australia with a second encephalitis virus member of the JE virus complex, Murray Valley encephalitis virus

Viruses causing the recent human and equine outbreaks throughout Europe and Asia have been most closely related to a WN virus first isolated in Romania in 1996 (ROM96) and subsequently in Kenya in 1998

The WN virus responsible for the U.S. outbreak (NY99) is genetically distinguishable from the ROM96-like viruses

Closest relative of NY99 virus was a virus circulating in Israel from 1997 to 2000 (Isr98). Genotype of NY99 WN virus in the United States has remained stable.

Very few genomic changes occurred in the NY99 WN virus between the 1999 and 2000 WN virus outbreaks

Lineage 2
Lineage 2 WN viruses are maintained in enzootic foci in Africa and have not been associated with clinical human encephalitis.

Widespread West Nile virus activity, eastern United States, 2000.

Marfin AA, Petersen LR, Eidson M, Miller J, Hadler J, Farello C, et al.

Vector-Culex mosquito

Emerging Infect Dise 2001;Vol. 7, No. 4 Abstract quote

An outbreak of encephalitis due to West Nile (WN) virus occurred in New York City and the surrounding areas during 1999. Mosquitoes were collected as part of a comprehensive surveillance program implemented to monitor the outbreak. More than 32,000 mosquitoes representing 24 species were tested, and 15 WN virus isolates were obtained.

Molecular techniques were used to identify the species represented in the WN virus-positive mosquito pools. Most isolates were from pools containing Culex pipiens mosquitoes, but several pools contained two or more Culex species.

LABORATORY/
RADIOLOGIC/
OTHER CHARACTERIZATION

EEG

Electroencephalography findings in adult patients with West Nile virus-associated meningitis and meningoencephalitis.

Gandelman-Marton R, Kimiagar I, Itzhaki A, Klein C, Theitler J, Rabey JM.

Department of Neurology, Assaf-Harofeh Medical Center, Zerifin, Israel.

Clin Infect Dis. 2003 Dec 1;37(11):1573-8. Epub 2003 Oct 14. Abstract quote

Eighteen adult patients with serologically confirmed West Nile virus (WNV)-associated meningitis or meningoencephalitis were admitted to our hospital during the 2000 West Nile fever outbreak in Israel.

Thirteen of the patients had a more severe and prolonged clinical course, and an electroencephalogram (EEG) was, therefore, requested. A specific EEG pattern was seen in 8 patients, consisting of generalized slowing, which was more prominent over the anterior regions. Generalized slowing that was prominent over the temporal area was seen in 2 patients, and intermittent slowing over the temporal region was seen in 1 patient. Two patients had normal EEG findings.

We suggest that WNV meningoencephalitis should be considered in the differential diagnosis of meningitis or meningoencephalitis with a prolonged clinical course and anteriorly predominant slowing on an EEG.

POLYMERASE CHAIN REACTION

High-throughput detection of West Nile virus RNA.

Shi PY, Kauffman EB, Ren P, Felton A, Tai JH, Dupuis AP 2nd, Jones SA, Ngo KA, Nicholas DC, Maffei J, Ebel GD, Bernard KA, Kramer LD.

Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York 12201, USA.

J Clin Microbiol 2001 Apr;39(4):1264-71 Abstract quote

The recent outbreaks of West Nile virus (WNV) in the northeastern United States and other regions of the world have made it essential to develop an efficient protocol for surveillance of WNV.

In the present report, we describe a high-throughput procedure that combines automated RNA extraction, amplification, and detection of WNV RNA. The procedure analyzed 96 samples in approximately 4.5 h. A robotic system, the ABI Prism 6700 Automated Nucleic Acid workstation, extracted RNA and set up reactions for real-time reverse transcription (RT)-PCR in a 96-well format. The robot extracted RNA with a recovery as efficient as that of a commercial RNA extraction kit. A real-time RT-PCR assay was used to detect and quantitate WNV RNA. Using in vitro transcribed RNA, we estimated the detection limit of the real-time RT-PCR to be approximately 40 copies of RNA. A standard RT-PCR assay was optimized to a sensitivity similar to that of the real-time RT-PCR. The standard assay can be reliably used to test a small number of samples or to confirm previous test results. Using internal primers in a nested RT-PCR, we increased the sensitivity by approximately 10-fold compared to that of the standard RT-PCR.

The results of the study demonstrated for the first time that the use of an automated system for the purpose of large-scale viral RNA surveillance dramatically increased the speed and efficiency of sample throughput for diagnosis.

SEROLOGY

Detection of IgG and IgM to West Nile Virus
Development of an Immunofluorescence Assay

Annette K. Malan
Priscilla J. Stipanovich
Thomas B. Martins
Harry R. Hill, MD
and Christine M. Litwin, MD
Am J Clin Pathol 2003;119:508-515 Abstract quote
West Nile virus (WNV) had its first recorded appearance in the western hemisphere in 1999 and has continued to spread across the United States, necessitating the development of serologic procedures to diagnose infection.

We developed an immunofluorescence assay (IFA) protocol for the detection of WNV-specific IgG and IgM antibodies in serum and cerebrospinal fluid (CSF) specimens. We tested 82 serum and 16 CSF samples and compared the results with WNV IgG enzyme-linked immunosorbent assay (ELISA) and IgM antibody-capture (MAC) ELISA results. Agreement, clinical sensitivity, and clinical specificity for the IgG IFA were 92%, 100%, and 90%, respectively, and 98%, 96%, and 100% for the IgM IFA, respectively. Extensive arbovirus cross-reactions occurred in the IgG assays, but only minimal cross-reactions were observed in the IgM assays.

The IFA protocol described herein is a cost-effective and sensitive alternative to ELISA and MAC-ELISA for the serologic diagnosis of WNV infection.

CLINICAL VARIANTS CHARACTERIZATION

GENERAL

The West Nile Virus outbreak of 1999 in New York: the Flushing Hospital experience.

Asnis DS, Conetta R, Teixeira AA, Waldman G, Sampson BA.

Department of Internal Medicine, Flushing Hospital Medical Center, Flushing, New York 11355, USA.
Clin Infect Dis 2000 Mar;30(3):413-8 Abstract quote
West Nile Virus (WNV) is a mosquito-borne flavivirus, which has been known to cause human infection in Africa, the Middle East, and southwestern Asia.

It has also been isolated in Australia and sporadically in Europe but never in the Americas. Clinical features include acute fever, severe myalgias, headache, conjunctivitis, lymphadenopathy, and a roseolar rash. Rarely is encephalitis or meningitis seen. During the month of August 1999, a cluster of 5 patients with fever, confusion, and weakness were admitted to the intensive care unit of the same hospital in New York City.

Ultimately 4 of the 5 developed flaccid paralysis and required ventilatory support. Three patients with less-severe cases presented shortly thereafter. With the assistance of the New York City and New York State health departments and the Centers for Disease Control and Prevention, these were documented as the first cases of WNV infection on this continent.

VARIANTS

POLIOMYELITIS

West Nile virus causes poliomyelitis-like syndrome.

Shetty P.
Lancet Infect Dis 2002 Nov;2(11):653

HISTOLOGICAL TYPES CHARACTERIZATION

NEUROPATHOLOGY

Clinicopathologic study and laboratory diagnosis of 23 cases with West Nile virus encephalomyelitis.

Guarner J, Shieh WJ, Hunter S, Paddock CD, Morken T, Campbell GL, Marfin AA, Zaki SR.

Hum Pathol. 2004 Aug;35(8):983-90. Abstract quote

The differences in pathologic findings of fatal cases of West Nile virus (WNV) encephalitis in the context of underlying conditions and illness duration are not well known.

During 2002, we studied central nervous system (CNS) tissue samples from 23 patients who had serologic and immunohistochemical (IHC) evidence of a recent WNV infection. Fifteen patients had underlying medical conditions (5 malignancies, 3 renal transplants, 3 with diabetes or on dialysis, 2 with AIDS, and 2 receiving steroids). WNV serology was positive for 18 patients, negative for 2, and not available for 3. Perivascular lymphocytic infiltrates, microglial nodules, and loss of neurons were predominantly observed in the brainstem and anterior horns in the spinal cord. IHC using antibodies against flaviviruses and WNV showed viral antigens in 12 (52%) of 23 patients. Viral antigens were found inside neurons and neuronal processes predominantly in the brainstem and anterior horns.

In general, the antigens were focal and sparse; however, in 4 severely immunosuppressed patients, extensive viral antigens were seen throughout the CNS. Positive IHC staining was observed in tissues of 7 of 8 patients who died within 1 week after illness onset, compared with 4 of 14 with more than 2 weeks' illness duration. WNV causes an encephalomyelitis by primarily affecting brainstem and spinal cord.

Differences in the amount of viral antigen may be related to underlying medical conditions and length of survival. IHC can be an important diagnostic method, particularly during the 1st week of illness, when antigen levels are high.

Spinal cord neuropathology in human West Nile virus infection.

Fratkin JD, Leis AA, Stokic DS, Slavinski SA, Geiss RW.

Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA.

Arch Pathol Lab Med. 2004 May;128(5):533-7. Abstract quote

CONTEXT: During the 1999 New York City West Nile virus (WNV) outbreak, 4 patients with profound muscle weakness, attributed to Guillain-Barre syndrome, were autopsied. These cases were the first deaths caused by WNV, a flavivirus, to be reported in the United States. The patients' brains had signs of mild viral encephalitis; spinal cords were not examined. During the 2002 national epidemic, several patients in Mississippi had acute flaccid paralysis. Electrophysiologic studies localized the lesions to the anterior horn cells in the spinal gray matter. Four of 193 infected patients in Mississippi died and were autopsied. All 4 experienced muscular weakness and respiratory failure that required intubation. Postmortem examinations focused on the spinal cord.

OBJECTIVE: To emphasize apparent tropism of WNV for the ventral gray matter of the spinal cord.

DESIGN: Cerebral hemispheres, basal ganglia, diencephalon, brainstem, cerebellum, and spinal cord sections were stained with hematoxylin-eosin and incubated with antibodies to T cells, B cells, and macrophages/microglial cells.

RESULTS: We identified neuronophagia, neuronal disappearance, perivascular chronic inflammation, and microglial proliferation in the ventral horns of the spinal cord, especially in the cervical and lumbar segments. Loss of ganglionic neurons, nodules of Nageotte, and perivascular lymphocyte aggregates were found in dorsal root and sympathetic ganglia. Severity of cellular reaction was proportional to the interval length between patient presentation and death.

CONCLUSION: West Nile virus caused poliomyelitis. Injury to spinal and sympathetic ganglia mirrored the damage to the spinal gray matter. The disappearance of sympathetic neurons could lead to the autonomic instability observed in some WNV patients, including labile vital signs, hypotension, and potentially lethal cardiac arrhythmias.

The Neuropathology of West Nile Virus Meningoencephalitis
A Report of Two Cases and Review of the Literature

Todd W. KelleyMD1, , Richard A. PraysonMD1, , Angela I. RuizMD1, , Carlos M. IsadaMD2, , and Steven M. GordonMD
Am J Clin Pathol 2003;119:749-753 Abstract quote
West Nile virus (WNV) is an emerging mosquito-transmitted encephalitis virus first recognized in North America in 1999. The pathologic manifestations of WNV infection have not been well defined.

This study documents the clinicopathologic features, including autopsy findings, of 2 cases: an 81-year-old man who contracted WNV infection with meningoencephalitis and a polio-like paralysis and a hospitalized 74-year-old woman with meningoencephalitis who acquired WNV through transfusion.

The pathologic findings in both cases were marked by perivascular and leptomeningeal chronic inflammation, microglial nodules, and neuronophagia, predominantly involving the temporal lobes and brainstem. These findings also were present in the spinal cord, especially the lumbar region, of the patient with polio-like paralysis. In both cases, most of the inflammatory infiltrate was composed of CD3+ T lymphocytes (a predominance of CD8+ over CD4+ T cells), CD68+ macrophages, and rare CD20+ B lymphocytes.

These cases further define the clinical and pathologic spectrum of central nervous system disease in WNV infection.

The pathology of human West Nile Virus infection.

Sampson BA, Ambrosi C, Charlot A, Reiber K, Veress JF, Armbrustmacher V.

Office of Chief Medical Examiner of the City of New York, NY 10016, USA.

Hum Pathol 2000 May;31(5):527-31 Abstract quote

West Nile Virus (WNV) was identified by immunohistochemistry (IHC) and polymerase chain reaction (PCR) as the etiologic agent in 4 encephalitis fatalities in New York City in the late summer of 1999. The fatalities occurred in persons with a mean age of 81.5 years, each of whom had underlying medical problems.

Cardinal clinical manifestations included fever and profound muscle weakness.

Autopsy disclosed encephalitis in 2 instances and meningoencephalitis in the remaining 2. The inflammation was mostly mononuclear and formed microglial nodules and perivascular clusters in the white and gray matter. The brainstem, particularly the medulla, was involved most extensively. In 2 brains, cranial nerve roots had endoneural mononuclear inflammation. In addition, 1 person had acute pancreatitis.

Based on our experience, we offer recommendations for the autopsy evaluation of suspected WNV fatalities.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS

Neurologic manifestations and outcome of west nile virus infection.

Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfin AA, Van Gerpen JA, Fleischauer A, Leis AA, Stokic DS, Petersen LR.

Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, and Epidemic Intelligence Service, Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, Ga.

JAMA. 2003 Jul 23;290(4):511-5 Abstract quote
CONTEXT: The neurologic manifestations, laboratory findings, and outcome of patients with West Nile virus (WNV) infection have not been prospectively characterized.

OBJECTIVE: To describe prospectively the clinical and laboratory features and long-term outcome of patients with neurologic manifestations of WNV infection.

DESIGN, SETTING, AND PARTICIPANTS: From August 1 to September 2, 2002, a community-based, prospective case series was conducted in St Tammany Parish, La. Standardized clinical data were collected on patients with suspected WNV infection. Confirmed WNV-seropositive patients were reassessed at 8 months.

MAIN OUTCOME MEASURES: Clinical, neurologic, and laboratory features at initial presentation, and long-term neurologic outcome.

RESULTS: Sixteen (37%) of 39 suspected cases had antibodies against WNV; 5 had meningitis, 8 had encephalitis, and 3 had poliomyelitis-like acute flaccid paralysis. Movement disorders, including tremor (15 [94%]), myoclonus (5 [31%]), and parkinsonism (11 [69%]), were common among WNV-seropositive patients. One patient died. At 8-month follow-up, fatigue, headache, and myalgias were persistent symptoms; gait and movement disorders persisted in 6 patients. Patients with WNV meningitis or encephalitis had favorable outcomes, although patients with acute flaccid paralysis did not recover limb strength.

CONCLUSIONS: Movement disorders, including tremor, myoclonus, and parkinsonism, may be present during acute illness with WNV infection. Some patients with WNV infection and meningitis or encephalitis ultimately may have good long-term outcome, although an irreversible poliomyelitis-like syndrome may result.

TREATMENT
Supportive

Extensive early season larval control has been recommended and undertaken, as have the development and dissemination of public health messages for reducing personal exposure to mosquito bites

Emerging Infect Dis 2001;7:611-614.
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Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
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Internet Links

Last Updated 8/16/2004

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGIC ASSOCIATIONS	CHARACTERIZATION
PREVALENCE
West Nile Virus Crow Deaths as a Sentinel Surveillance System for West Nile Virus in the Northeastern United States, 1999 Millicent Eidson,* Nicholas Komar,† Faye Sorhage,‡ Randall Nelson,§ Tom Talbot,* Farzad Mostashari,¶ Robert McLean,# and the West Nile Virus Avian Mortality Surveillance Group (1) *New York State Department of Health, Albany, New York, USA; †Centers for Disease Control and Prevention, Fort Collins, Colorado, USA; ‡New Jersey Department of Health and Senior Services, Trenton, New Jersey, USA; §Connecticut Department of Public Health, Hartford, Connecticut, USA;	Emerging Infect Disease 2001;Vol. 7, No. 4 Abstract quote In addition to human encephalitis and meningitis cases, the West Nile (WN) virus outbreak in the summer and fall of 1999 in New York State resulted in bird deaths in New York, New Jersey, and Connecticut. From August to December 1999, 295 dead birds were laboratory-confirmed with WN virus infection; 262 (89%) were American Crows (Corvus brachyrhynchos). The New York State Department of Health received reports of 17,339 dead birds, including 5,697 (33%) crows; in Connecticut 1,040 dead crows were reported. Bird deaths were critical in identifying WN virus as the cause of the human outbreak and defining its geographic and temporal limits. If established before a WN virus outbreak, a surveillance system based on bird deaths may provide a sensitive method of detecting WN virus
GEOGRAPHY
ISRAEL
Clinical Characteristics of the West Nile Fever Outbreak, Israel, 2000 Michal Y. Chowers,* Ruth Lang,* Faris Nassar,† Debora Ben-David,‡, Michael Giladi§, Eitan Rubinshtein,‡ Avi Itzhaki,¶ Josef Mishal,# Yardena Siegman-Igra,§ Ruth Kitzes,** Neora Pick,†† Zvi Landau,‡‡ Dana Wolf,§§ Hanna Bin,¶¶ Ella Mendelson,¶¶ Silvio D. Pitlik,## and Miriam Weinberger## Meir Medical Center, Kfar Sava, Israel; †Western Galilee Hospital, Nahariya, Israel; ‡Chaim Sheba Medical Center, Tel Hashomer, Israel; §Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel; ¶Assaf Harofeh Medical Center, Zrifin, Israel; #Barzilai Medical Center, Ashkelon, Israel; *Carmel Medical Center, Haifa, Israel; ††Bnei-Zion Medical Center, Haifa, Israel; ‡‡Kaplan Medical Center, Rehovot, Israel; §§Hadassah Medical Center, Jerusalem, Israel; ¶¶Public Health Services, Ministry of Health, Tel Hashomer, Israel; and ##Rabin Medical Center, Belinson Campus, Petach Tikva, Israel	Emer Infect Dis 2001;Vol. 7, No. 4 Jul–Aug Abstract quote West Nile (WN) virus is endemic in Israel. The last reported outbreak had occurred in 1981. From August to October 2000, a large-scale epidemic of WN fever occurred in Israel; 417 cases were confirmed, with 326 hospitalizations. The main clinical presentations were encephalitis (57.9%), febrile disease (24.4%), and meningitis (15.9%). Within the study group, 33 (14.1%) hospitalized patients died. Mortality was higher among patients >70 years (29.3%). On multivariate regressional analysis, independent predictors of death were age >70 years (odds ratio [OR] 7.7), change in level of consciousness (OR 9.0), and anemia (OR 2.7). In contrast to prior reports, WN fever appears to be a severe illness with high rate of central nervous system involvement and a particularly grim outcome in the elderly.

DISEASE ASSOCIATIONS	CHARACTERIZATION
BREAST FEEDING
Possible West Nile virus transmission to an infant through breast-feeding--Michigan, 2002.	MMWR Morb Mortal Wkly Rep 2002 Oct 4;51(39):877-8 Abstract quote CDC and the Michigan Department of Community Health (MDCH) continue to investigate West Nile Virus (WNV) infection in a woman, who received a blood product later found with evidence of WNV, and in her child, who was exposed to breast milk later found to be WNV positive by TaqMan. This report updates the findings of this investigation.
TRANSPLANTATION ORGAN RECIPIENTS
Fatal West Nile Virus Encephalitis in a Renal Transplant Recipient Melissa M. Cushing, MD, Daniel J. Brat, MD, PhD, Mario I. Mosunjac, MD, etal.	Am J Clin Pathol 2004:121:26-31 Abstract quote West Nile virus (WNV), a mosquito-transmitted single-stranded RNA flavivirus, causes human disease of variable severity. We report clinical and pathologic findings of fatal encephalitis from the transmission of WNV from an organ donor to a kidney transplant recipient. The patient developed a febrile illness 18 days after transplantation, which progressed to encephalitis. Postmortem examination demonstrated extensive viral encephalopathic changes. Immunohistochemical studies highlighted WNV antigens within neurons, especially in the cerebellum and brainstem. Flavivirus virions were detected ultrastructurally within the cerebellum, and WNV was isolated from the brain and the brainstem. Thus, this case demonstrates the first death in the first solid organ transplant–associated transmission of WNV. Immunosuppression of the transplant recipient might have been responsible for the fulminant viral effects. The pathologic diagnosis helped guide subsequent epidemiologic and laboratory studies.
Update: Investigations of West Nile virus infections in recipients of organ transplantation and blood transfusion.	MMWR Morb Mortal Wkly Rep 2002 Sep 20;51(37):833-6 Abstract quote An investigation involving CDC, the Food and Drug Administration (FDA), the Health Resources and Services Administration (HRSA), the Georgia Division of Public Health, and the Florida Department of Health identified West Nile virus (WNV)-associated illnesses in four recipients of organs from the same donor. Although the transplanted organs were the source of infection for the four organ recipients, the source of the organ donor's infection remains unknown; an investigation of the numerous transfusions received by the organ donor is ongoing.
TRANSFUSION OF BLOOD PRODUCTS
MMWR Morb Mortal Wkly Rep 2002 Nov 1;51(43):973-4 Related Articles, Links Investigations of West Nile virus infections in recipients of blood transfusions.	MMWR Morb Mortal Wkly Rep 2002 Nov 1;51(43):973-4 Abstract quote CDC, the Food and Drug Administration (FDA), and the Health Resources and Services Administration (HRSA), in collaboration with blood collection agencies and state and local health departments, continue to investigate West Nile virus (WNV) infections in recipients of blood transfusions. During August 28-October 26, CDC received reports of 47 persons with possible transfusion-related WNV infection. Investigations showed that 14 of these persons either did not have WNV infection or did not acquire WNV infection through transfusion. The remaining 33 cases, reported from 17 states, occurred among persons who had confirmed or probable WNV infection and had received blood components in the month before illness onset. To date, evidence that WNV can be transmitted through blood transfusion has been found in six of the 33 cases; investigations are ongoing for the other 27 cases.

PATHOGENESIS	CHARACTERIZATION
Flavivirus	Old world virus Single stranded RNA virus
Two genetic lineages
Lineage 1	Isolated from Africa, India, Europe, Asia, and North America. Kunjin virus, an apparent subtype of lineage 1 WN viruses, cocirculates in Australia with a second encephalitis virus member of the JE virus complex, Murray Valley encephalitis virus Viruses causing the recent human and equine outbreaks throughout Europe and Asia have been most closely related to a WN virus first isolated in Romania in 1996 (ROM96) and subsequently in Kenya in 1998 The WN virus responsible for the U.S. outbreak (NY99) is genetically distinguishable from the ROM96-like viruses Closest relative of NY99 virus was a virus circulating in Israel from 1997 to 2000 (Isr98). Genotype of NY99 WN virus in the United States has remained stable. Very few genomic changes occurred in the NY99 WN virus between the 1999 and 2000 WN virus outbreaks
Lineage 2	Lineage 2 WN viruses are maintained in enzootic foci in Africa and have not been associated with clinical human encephalitis.
Widespread West Nile virus activity, eastern United States, 2000. Marfin AA, Petersen LR, Eidson M, Miller J, Hadler J, Farello C, et al. Vector-Culex mosquito	Emerging Infect Dise 2001;Vol. 7, No. 4 Abstract quote An outbreak of encephalitis due to West Nile (WN) virus occurred in New York City and the surrounding areas during 1999. Mosquitoes were collected as part of a comprehensive surveillance program implemented to monitor the outbreak. More than 32,000 mosquitoes representing 24 species were tested, and 15 WN virus isolates were obtained. Molecular techniques were used to identify the species represented in the WN virus-positive mosquito pools. Most isolates were from pools containing Culex pipiens mosquitoes, but several pools contained two or more Culex species.

CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
The West Nile Virus outbreak of 1999 in New York: the Flushing Hospital experience. Asnis DS, Conetta R, Teixeira AA, Waldman G, Sampson BA. Department of Internal Medicine, Flushing Hospital Medical Center, Flushing, New York 11355, USA.	Clin Infect Dis 2000 Mar;30(3):413-8 Abstract quote West Nile Virus (WNV) is a mosquito-borne flavivirus, which has been known to cause human infection in Africa, the Middle East, and southwestern Asia. It has also been isolated in Australia and sporadically in Europe but never in the Americas. Clinical features include acute fever, severe myalgias, headache, conjunctivitis, lymphadenopathy, and a roseolar rash. Rarely is encephalitis or meningitis seen. During the month of August 1999, a cluster of 5 patients with fever, confusion, and weakness were admitted to the intensive care unit of the same hospital in New York City. Ultimately 4 of the 5 developed flaccid paralysis and required ventilatory support. Three patients with less-severe cases presented shortly thereafter. With the assistance of the New York City and New York State health departments and the Centers for Disease Control and Prevention, these were documented as the first cases of WNV infection on this continent.
VARIANTS
POLIOMYELITIS
West Nile virus causes poliomyelitis-like syndrome. Shetty P.	Lancet Infect Dis 2002 Nov;2(11):653

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Neurologic manifestations and outcome of west nile virus infection. Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfin AA, Van Gerpen JA, Fleischauer A, Leis AA, Stokic DS, Petersen LR. Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, and Epidemic Intelligence Service, Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, Ga.	JAMA. 2003 Jul 23;290(4):511-5 Abstract quote CONTEXT: The neurologic manifestations, laboratory findings, and outcome of patients with West Nile virus (WNV) infection have not been prospectively characterized. OBJECTIVE: To describe prospectively the clinical and laboratory features and long-term outcome of patients with neurologic manifestations of WNV infection. DESIGN, SETTING, AND PARTICIPANTS: From August 1 to September 2, 2002, a community-based, prospective case series was conducted in St Tammany Parish, La. Standardized clinical data were collected on patients with suspected WNV infection. Confirmed WNV-seropositive patients were reassessed at 8 months. MAIN OUTCOME MEASURES: Clinical, neurologic, and laboratory features at initial presentation, and long-term neurologic outcome. RESULTS: Sixteen (37%) of 39 suspected cases had antibodies against WNV; 5 had meningitis, 8 had encephalitis, and 3 had poliomyelitis-like acute flaccid paralysis. Movement disorders, including tremor (15 [94%]), myoclonus (5 [31%]), and parkinsonism (11 [69%]), were common among WNV-seropositive patients. One patient died. At 8-month follow-up, fatigue, headache, and myalgias were persistent symptoms; gait and movement disorders persisted in 6 patients. Patients with WNV meningitis or encephalitis had favorable outcomes, although patients with acute flaccid paralysis did not recover limb strength. CONCLUSIONS: Movement disorders, including tremor, myoclonus, and parkinsonism, may be present during acute illness with WNV infection. Some patients with WNV infection and meningitis or encephalitis ultimately may have good long-term outcome, although an irreversible poliomyelitis-like syndrome may result.
TREATMENT	Supportive Extensive early season larval control has been recommended and undertaken, as have the development and dissemination of public health messages for reducing personal exposure to mosquito bites