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West Nile virus infections are here! Are we prepared to face another flavivirus epidemic?

Abstract

Emerging arthropod-borne viruses (arboviruses), such as chikungunya and Zika viruses, are a major threat to public health in countries like Brazil where biodiversity is high and medical care is sometimes precarious. West Nile fever is a disease caused by the West Nile Virus (WNV), an RNA virus belonging to the Flaviviridae family. It is transmitted by infected mosquitoes to numerous animals like birds, reptiles and mammals, including human and non-human primates. In the last decade, the number of reported cases of WNV infection in humans and animals has increased in the Americas. Circulation of WNV in forests and rural areas in Brazil has been detected based on serological surveys and, in 2014, the first case of West Nile fever was confirmed in a patient from Piauí State. In 2018, the virus was isolated for the first time from a horse from a rural area in the state of Espírito Santo presenting with a neurological disorder; this raises the possibility that other cases of WNV encephalitis may have occurred without clinical recognition and without laboratory diagnosis by specific assays. The imminent WNV outbreak poses a challenge for Brazilian clinicians and researchers. In this review, we summarize the basic biological and ecological characteristics of this virus and the clinical presentation and treatment of febrile illnesses caused by WNV. We also discuss the epidemiological aspects, prophylaxis of WNV infections, and monitoring strategies that could be applied in the possibility of a WNV outbreak in Brazil.

Keywords:
West Nile virus (WNV); Arbovirus; Outbreak; Surveillance

BACKGROUND

The West Nile virus (WNV) was first isolated in 1937 from a patient presenting with a febrile disease residing in the West Nile district in northern Uganda11. Hughes TP, Paul JH, Smithburn KC, Burke AW. A Neurotropic Virus Isolated from the Blood of a Native of Uganda 1. Am J Trop Med Hyg. 1940;1-20(4):471-92.,22. Sejvar JJ. West nile virus: an historical overview. Ochsner J. 2003;5(3):6-10.. The first documented WNV epidemic occurred in Israel in 1951 with young children representing the majority of cases33. Bernkopf H, Levine S, Nerson R. Isolation of West Nile virus in Israel. J Infect Dis. 1953;93(3):207-18.. The disease was mild, with no reported fatalities, and it was the first time that the main clinical manifestations were thoroughly described, and consisted mainly of fever, headache, anorexia, exanthema, myalgia, abdominal pain, and vomiting. Lymphadenopathy, sore throat, and diarrhea occurred occasionally. Outbreaks in Egypt, occurred between 1951 and 1954, also led to a better understanding of the various clinical and epidemiologic aspects of the virus44. Murgue B, Murri S, Triki H, Deubel V, Zeller HG. West Nile in the Mediterranean basin: 1950-2000. Ann N Y Acad Sci. 2001;951:117-26.,55. Hurlbut HS, Rizk F, Taylor RM, Work TH. A study of the ecology of West Nile virus in Egypt. Am J Trop Med Hyg . 1956;5(4):579-620.. Studies performed in the Nile Delta region demonstrated that the virus was infectious in a wide range of species, including birds and non-human mammals, and that WNV was endemic along the Nile, with a 60% seroprevalence rate in humans55. Hurlbut HS, Rizk F, Taylor RM, Work TH. A study of the ecology of West Nile virus in Egypt. Am J Trop Med Hyg . 1956;5(4):579-620.. The WNV arthropod-borne nature was suggested in 1943 and later characterized as one of the most widespread arboviruses since more than 65 mosquito species have been shown to be infected by WNV66. Colpitts TM, Conway MJ, Montgomery RR, Fikrig E. West Nile Virus : Biology , Transmission, and Human Infection. Clin Microbiol Rev 2012;25(4):635-48..

Until the 1990s, WNV was considered to be an old world flavivirus but, in 1999, it was detected in the United States of America and caused a high mortality in both free-living and captive birds in the New York zoos77. 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 J Med. 2001;344(24):1807-14.

8. World Health Organization (WHO). West Nile virus [Internet]. Fact sheet N°354. 2011 [cited 2019 Jan 10]. Available from: Available from: https://www.who.int/en/news-room/fact-sheets/detail/west-nile-virus
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-99. Contigiani MS, Díaz LA, Spinsanti L. Arthropod Borne Diseases. Marcondes C., editor. Springer International Publishing: Switzerland; 2017. 73-88 p.. In that same year, 67 people were affected, 21 of which died. The virus subsequently spread to practically all the states of the USA, affecting birds, horses and humans1010. LaDeau SL, Kilpatrick AM, Marra PP. West Nile virus emergence and large-scale declines of North American bird populations. Nature. 2007;447(7145):710-3.

11. Ward MP, Schuermann JA, Highfield LD, Murray KO. Characteristics of an outbreak of West Nile virus encephalomyelitis in a previously uninfected population of horses. Vet Microbiol. 2006;118(3-4):255-9.

12. Hayes EB, Komar N, Nasci RS, Montgomery SP, O’Leary DR, Campbell GL. Epidemiology and transmission dynamics of West Nile virus disease. Emerg Infect Dis. 2005;11(8):1167-73.

13. van der Meulen KM, Pensaert MB, Nauwynck HJ. West Nile virus in the vertebrate world. Arch Virol. 2005;150(4):637-57.
-1414. Komar N. West Nile virus: epidemiology and ecology in North America. Adv Virus Res. 2003;61:185-234.. Over the past three decades, WNV has become a concern for both public health and veterinary medicine in Europe and the Americas1515. Centers for Disease Control and Prevention (CDC). Outbreak of West Nile-like viral encephalitis--New York, 1999. MMWR Morb Mortal Wkly Rep. 1999;48(38):845-9.-1616. Pesko KN, Ebel GD. West Nile virus population genetics and evolution. Infect Genet Evol. 2012;12(2):181-90.. Virus circulation has also been detected in other regions of the world, such as Africa, the Middle East, Mediterranean Europe, India, Asia , and Australia.

Serological evidence of WNV circulation in animals in South America was first documented in Colombia in 2005 in horses that had likely been infected with WNV in 2004, and then in Argentina in 2006 in horses that died from encephalitis that same year. However, it was later shown that WNV may have been introduced into Argentina in 20041717. Diaz LA, Komar N, Visintin A, Dantur Juri MJ, Stein M, Lobo Allende R, et al. West Nile virus in birds, Argentina. Emerg Infect Dis . 2008;14(4):689-91.

18. Mattar S, Edwards E, Laguado J, González M, Alvarez J, Komar N. West Nile virus antibodies in Colombian horses. Emerg Infect Dis . 2005;11(9):1497-8.
-1919. Morales MA, Barrandeguy M, Fabbri C, Garcia JB, Vissani A, Trono K, et al. West Nile virus isolation from equines in Argentina, 2006. Emerg Infect Dis . 2006;12(10):1559-61.. In Venezuela, WNV was detected in sylvatic birds in 2006 and in horses in 20042020. Bosch I, Herrera F, Navarro J-C, Lentino M, Dupuis A, Maffei J, et al. West Nile Virus, Venezuela. Emerg Infect Dis . 2007;13(4):651-3.. However, only the Argentinean report presented evidence for an equine neurological disease associated with the WNV1919. Morales MA, Barrandeguy M, Fabbri C, Garcia JB, Vissani A, Trono K, et al. West Nile virus isolation from equines in Argentina, 2006. Emerg Infect Dis . 2006;12(10):1559-61.. Serological evidence of WNV infection in Brazilian horses and birds has been reported from animal sera collected since 2008 from the Central and Western Brazilian regions, particularly the Pantanal region2121. Pauvolid-Corrêa A, Morales MA, Levis S, Figueiredo LTM, Couto-Lima D, Campos Z, et al. Neutralising antibodies for West Nile virus in horses from Brazilian Pantanal. Mem Inst Oswaldo Cruz. 2011;106(4):467-74.

22. Ometto T, Durigon EL, de Araujo J, Aprelon R, de Aguiar DM, Cavalcante GT, et al. West Nile virus surveillance, Brazil, 2008-2010. Trans R Soc Trop Med Hyg. 2013;107(11):723-30.

23. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Coordenação-Geral de Desenvolvimento da Epidemiologia em Serviços. Guia Vigilância em Saúde. 2016.
-2424. Silva ASG, Matos ACD, da Cunha MACR, Rehfeld IS, Galinari GCF, Marcelino SAC, et al. West Nile virus associated with equid encephalitis in Brazil, 2018. Transbound Emerg Dis. 2018;1-9.. Serological evidence of WNV circulation in Brazil outside of Pantanal was reported in 2013, namely in Paraiba State, suggesting that WNV was spreading towards the northeast part of the country2525. Silva JR, de Medeiros LC, dos Reis VP, Chávez JH, Munhoz TD, Borges GP, et al. Serologic survey of West Nile virus in horses from Central-West, Northeast and Southeast Brazil. Mem Inst Oswaldo Cruz . 2013 ;108(7):921-3.; this spread was confirmed in 2014 with the description of the first human case of WNV infection. The patient was a rural worker from Piauí State (Northeast region) that presented clinical symptoms of acute encephalitis2626. Vieira MACS, Romano APM, Borba AS, Silva EVP, Chiang JO, Eulálio KD, et al. West Nile Virus Encephalitis: The First Human Case Recorded in Brazil. Am J Trop Med Hyg . 2015;93(2):377-9.. The first isolation of WNV in Brazil was documented in 2018 when the virus was isolated from the central nervous system (CNS) of a dead horse with neurologic manifestations. The sample from this animal was collected in a rural area of Espírito Santo State, further confirming the spread of this virus to different Brazilian regions, as depicted in Figure 1 2727. Martins LC, da Silva EVP, Casseb LMN, da Silva SP, Cruz ACR, Pantoja JAS. First isolation of West Nile virus in Brazil. Mem Inst Oswaldo Cruz . 2018;1-19..

FIGURE 1:
West Nile virus dispersion in South America and Brazil. Site, year of sampling, and infected host are represented. The diagnostic tools applied are indicated by different colors, as follows: virus isolation and PCR (orange), serologic detection by a plaque-reduction neutralization test (PRNT90 or PRNT80; light orange), serologic detection by ELISA (light orange with stripes), and undefined Flavivirus by PRNT90 (gray with dots).

THE VIRUS

WNV belongs to the Flaviviridae family and the genus Flavivirus which contains more than 70 species of viruses that can be divided into tick-borne and mosquito-borne virus groups2828. Simmonds P, Becher B, Bukh J, Gould EA, Meyers G, Monath T, et al. ICTV Virus Taxonomy Profile: Flaviviridae. J Gen Virol. 2017;(98):2-3.,2929. Kuno G, Chang GJ, Tsuchiya KR, Karabatsos N, Cropp CB. Phylogeny of the Genus Flavivirus. J Virol. 1998;72(1):73-83.. The mosquito-borne viruses can be further subdivided into the encephalitic clade (or the Japanese encephalitis virus (JEV) serocomplex), which includes WNV, St. Louis encephalitis virus (SLEV), and JEV; and the non-encephalitic or hemorrhagic fever clade, which includes the dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV)2929. Kuno G, Chang GJ, Tsuchiya KR, Karabatsos N, Cropp CB. Phylogeny of the Genus Flavivirus. J Virol. 1998;72(1):73-83.. The geographic distribution of the mosquito-borne flaviviruses depends largely on the habitat of the preferred mosquito vector.

Like all mosquito-borne flaviviruses, WNV is a positive-sense, single-stranded RNA virus, with a genome of approximately 11,000 nucleotides. The viral RNA is translated into a single polyprotein which is processed by cellular and virus proteases, giving rise to three structural (envelope [E], pre-membrane/membrane [prM/M], and nucleocapsid [C)]) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5)3030. Lindenbach BD, Murray CL, Thiel H-J, Rice CM. Flaviviridae: The Viruses and Their Replication. In: Fields BN, Knipe DM, Howley PM, editors. Fields Virology. 6th Edition. New York: Lippincott Williams & Wilkins; 2013 ;712-46.. Following a bite of an infected mosquito, WNV enters cells by clathrin-mediated endocytosis and the low pH inside the endosome generates a conformational change in E glycoprotein, leading to the fusion of the virus envelope with the endosome membrane and the subsequent release of the viral genome into the cytoplasm3131. Chu JJH, Ng ML. Infectious entry of West Nile virus occurs through a clathrin-mediated endocytic pathway. J Virol. 2004;78(19):10543-55.,3232. Rey FA. Dengue virus envelope glycoprotein structure: New insight into its interactions during viral entry. Proc Natl Acad Sci. 2003;100(12):6899-901.. Virus replication starts as soon as the RNA genome is released into the cytosol and virion assembly begins with membrane components derived from the endoplasmic reticulum (ER)3030. Lindenbach BD, Murray CL, Thiel H-J, Rice CM. Flaviviridae: The Viruses and Their Replication. In: Fields BN, Knipe DM, Howley PM, editors. Fields Virology. 6th Edition. New York: Lippincott Williams & Wilkins; 2013 ;712-46.. During virus release from infected cells, the prM protein is cleaved by the cellular protease furin, which is very important for virus infectivity, and this cleavage turns immature particles into mature ones that are then released into the extracellular space3030. Lindenbach BD, Murray CL, Thiel H-J, Rice CM. Flaviviridae: The Viruses and Their Replication. In: Fields BN, Knipe DM, Howley PM, editors. Fields Virology. 6th Edition. New York: Lippincott Williams & Wilkins; 2013 ;712-46..

TRANSMISSION CYCLE

The classic WNV transmission cycle involves birds as well as mosquitoes primarily of the genus Culex, such as Cx. pipiens and Cx. restuans; other species like Aedes albopictus and Ae. vexans are considered potential vectors3333. Turell MJ, Dohm DJ, Sardelis MR, Oguinn ML, Andreadis TG, Blow JA. An update on the potential of north American mosquitoes (Diptera: Culicidae) to transmit West Nile Virus. J Med Entomol. 2005;42(1):57-62.

34. Kulasekera VL, Kramer L, Nasci RS, Mostashari F, Cherry B, Trock SC, et al. West Nile virus infection in mosquitoes, birds, horses, and humans, Staten Island, New York, 2000. Emerg Infect Dis . 2001;7(4):722-5.
-3535. World Health Organization (WHO). West Nile virus [Internet]. 2017 [cited 2019 Jan 16]. Available from: Available from: https://www.who.int/news-room/fact-sheets/detail/west-nile-virus
https://www.who.int/news-room/fact-sheet...
. These Culex species represent the primary vectors in enzootic/epizootic transmission; other species, like Cx. salinarius and Aedes/Ochlerotatus spp., serve as bridge vectors for humans and horses3434. Kulasekera VL, Kramer L, Nasci RS, Mostashari F, Cherry B, Trock SC, et al. West Nile virus infection in mosquitoes, birds, horses, and humans, Staten Island, New York, 2000. Emerg Infect Dis . 2001;7(4):722-5.. From 1999 to 2017, the Centers for Disease Control and Prevention (CDC), in the USA, detected WNV in several mosquito species of the genera Anopheles, Coquillettidia, Culiseta, and Psorophora. The ability to infect several mosquito species could be related to the high host species diversity, leading to many different transmission cycles3636. Centers for Disease Control and Prevention (CDC). Mosquito species in which West Nile virus has been detected, United States, 1999-2017. ArboNET, Arboviral Dis Branch [Internet]. 2017; Available from: https://stacks.cdc.gov/view/cdc/46971
https://stacks.cdc.gov/view/cdc/46971...
. New hypotheses about the maintenance cycle of WNV have generated a broader view of the classical WNV transmission cycle, involving the house sparrow - Cx. pipiens - house sparrow, in which several species of vectors (mosquitos and ticks) and hosts (birds and small rodents) are also involved3737. Diaz LA, Flores FS, Quaglia A, Contigiani MS. Intertwined arbovirus transmission activity: reassessing the transmission cycle paradigm. Front Physiol. 2013 ;3(493):1-7.. However, it is unclear how the mosquito population influences the timing and intensity of avian epizootics and human epidemics3838. LaDeau SL, Glass GE, Hobbs NT, Latimer A, Ostfeld RS. Data-model fusion to better understand emerging pathogens and improve infectious disease forecasting. Ecol Appl. 2011;21(5):1443-60..

Some species of birds from the orders Passeriformes (songbirds), Charadriiformes (shorebirds), Strigiformes (owls), and Falconiformes (hawks) can act as reservoirs and amplifiers of the virus due to the high and prolonged viremia2323. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Coordenação-Geral de Desenvolvimento da Epidemiologia em Serviços. Guia Vigilância em Saúde. 2016.,3333. Turell MJ, Dohm DJ, Sardelis MR, Oguinn ML, Andreadis TG, Blow JA. An update on the potential of north American mosquitoes (Diptera: Culicidae) to transmit West Nile Virus. J Med Entomol. 2005;42(1):57-62.,3939. Komar N, Langevin S, Hinten S, Nemeth N, Edwards E, Hettler D, et al. Experimental Infection of North American Birds with the New York 1999 Strain of West Nile Virus. Emerg Infect Dis . 2003;9(3):311-22.,4040. Hayes EB, Sejvar JJ, Zaki SR, Lanciotti RS, Bode AV, Campbell GL. Virology, Pathology, and Clinical Manifestations of West Nile Virus Disease. Emerg Infect Dis . 2005;11(8):1174-9.. However, in the order Passeriformes, the mortality rates can exceed 40%4040. Hayes EB, Sejvar JJ, Zaki SR, Lanciotti RS, Bode AV, Campbell GL. Virology, Pathology, and Clinical Manifestations of West Nile Virus Disease. Emerg Infect Dis . 2005;11(8):1174-9.. In addition to birds, WNV can also infect humans, horses, non-human primates, and various other mammalian species. Ectothermic animals, such as reptiles and amphibians, can also become infected by WNV, attaining sufficient levels of viremia to infect mosquitoes4040. Hayes EB, Sejvar JJ, Zaki SR, Lanciotti RS, Bode AV, Campbell GL. Virology, Pathology, and Clinical Manifestations of West Nile Virus Disease. Emerg Infect Dis . 2005;11(8):1174-9.

41. Kostiukov MA, Gordeeva ZE, Bulychev VP, Nemova NV, Daniiarov OA. [The lake frog (Rana ridibunda)--one of the food hosts of blood-sucking mosquitoes in Tadzhikistan--a reservoir of the West Nile fever virus]. Med Parazitol (Mosk). 1985;(3):49-50.

42. Steinman A, Banet-Noach C, Tal S, Levi O, Simanov L, Perk S, et al. West Nile virus infection in crocodiles [3]. Vol. 9, Emerging Infectious Diseases. Centers for Disease Control and Prevention; 2003. p. 887-9.

43. Klenk K, Komar N. Poor replication of West Nile virus (New York 1999 strain) in three reptilian and one amphibian species. Am J Trop Med Hyg . 2003;69(3):260-2.

44. Klenk K, Snow J, Morgan K, Bowen R, Stephens M, Foster F, et al. Alligators as West Nile virus amplifiers. Emerg Infect Dis . 2004;10(12):2150-5.
-4545. Jacobson ER, Ginn PE, Troutman JM, Farina L, Stark L, Klenk K, et al. West Nile Virus Infection in Farmed American Alligators (Alligator Mississippiensis) in Florida. J Wildl Dis. 2005;41(1):96-106.. Human and equine hosts are considered accidental/terminal hosts because the viremia is short and insufficient to infect mosquitoes, thus ending the transmission cycle2323. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Coordenação-Geral de Desenvolvimento da Epidemiologia em Serviços. Guia Vigilância em Saúde. 2016.. Although the transmission cycle is well understood in the United States3636. Centers for Disease Control and Prevention (CDC). Mosquito species in which West Nile virus has been detected, United States, 1999-2017. ArboNET, Arboviral Dis Branch [Internet]. 2017; Available from: https://stacks.cdc.gov/view/cdc/46971
https://stacks.cdc.gov/view/cdc/46971...
,3737. Diaz LA, Flores FS, Quaglia A, Contigiani MS. Intertwined arbovirus transmission activity: reassessing the transmission cycle paradigm. Front Physiol. 2013 ;3(493):1-7.,3939. Komar N, Langevin S, Hinten S, Nemeth N, Edwards E, Hettler D, et al. Experimental Infection of North American Birds with the New York 1999 Strain of West Nile Virus. Emerg Infect Dis . 2003;9(3):311-22., the exact nature of WNV transmission cycle in Brazil is not known; but based on the species that were positive for the virus by serology or PCR in Brazil, as well as on the transmission cycle reported in other countries3737. Diaz LA, Flores FS, Quaglia A, Contigiani MS. Intertwined arbovirus transmission activity: reassessing the transmission cycle paradigm. Front Physiol. 2013 ;3(493):1-7., a model can be proposed for the probable WNV transmission cycle in Brazil, as depicted in Figure 2.

FIGURE 2:
The probable WNV transmission cycle in Brazil. Black arrows: possible, but not confirmed, WNV cycle amplification. Black arrows with white spots: confirmed transmission cycle to dead-end hosts. White arrows with black lines: native birds with laboratory, serological, and/or molecular evidence of WNV. White arrows with black squares: native birds of the northern hemisphere that migrate to Brazil, in which West Nile infection has been confirmed. White arrow: no evidence has been found in Brazil, but some cases have been confirmed in other countries. Images sources 54-63.

Culex quinquefasciatus and Ae. albopictus mosquitoes are highly abundant and widely distributed in Brazil, and are an important risk factor for the transmission of the WNV in Brazil as their WNV infection produce high enough viremia levels to transmit the virus. Consequently, the Brazilian Ministry of Health released a guideline in 2011 for the surveillance of Cx. quinquefasciatus4646. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Guia de Vigiläncia do Culex quinquefasciatus. Série A, Normas e Manuais Técnicos. 1st ed. Brasilia: Ministério da Saúde; 2011. 76 p.. Although WNV transmission is carried out primarily through mosquito bites, other routes such as blood transfusion and organ transplantation can also represent a threat, mostly for immunocompromised people4747. Iwamoto M, Jernigan DB, Guasch A, Trepka MJ, Blackmore CG, Hellinger WC, et al. Transmission of West Nile Virus from an Organ Donor to Four Transplant Recipients. N Engl J Med . 2003;348(22):2196-203.

48. Pealer LN, Marfin AA, Petersen LR, Lanciotti RS, Page PL, Stramer SL, et al. Transmission of West Nile Virus through Blood Transfusion in the United States in 2002. N Engl J Med . 2003;349(13):1236-45.
-4949. Blau DM, Rabe IB, Bhatnagar J, Civen R, Trivedi KK, Rollin D, et al. West Nile virus RNA in tissues from donor associated with transmission to organ transplant recipients. Emerg Infect Dis . 2013 ;19(9):1518-20.. Vertical transmission during pregnancy, perinatally, or through breastfeeding, although possible, do not appear to represent an important transmission route5050. Hayes EB, O’Leary DR. West Nile Virus Infection: A Pediatric Perspective. Pediatrics. 2004;113(5):1375-81.

51. Hinckley AF, O’Leary DR, Hayes EB. Transmission of West Nile Virus Through Human Breast Milk Seems to Be Rare. Pediatrics. 2007;119(3):e666-71.

52. Sirois PA, Pridjian G, McRae S, Hinckley AF, Rasmussen SA, Kissinger P, et al. Developmental outcomes in young children born to mothers with West Nile illness during pregnancy. Birth Defects Res A Clin Mol Teratol. 2014;100(10):792-6.
-5353. Pridjian G, Sirois PA, Mcrae S, Hinckley AF, Sonja A, Kissinger P, et al. Mothers with West Nile Illness during Pregnancy. Birth Defects Res Part A Clin Mol Teratol. 2016;106(8):1-15..

CLINICAL MANIFESTATIONS IN HUMANS

In humans, WNV infection is predominantly subclinical. It is estimated that only 20% of infected patients develop symptoms after an incubation period ranging from 3 to 15 days3535. World Health Organization (WHO). West Nile virus [Internet]. 2017 [cited 2019 Jan 16]. Available from: Available from: https://www.who.int/news-room/fact-sheets/detail/west-nile-virus
https://www.who.int/news-room/fact-sheet...

36. Centers for Disease Control and Prevention (CDC). Mosquito species in which West Nile virus has been detected, United States, 1999-2017. ArboNET, Arboviral Dis Branch [Internet]. 2017; Available from: https://stacks.cdc.gov/view/cdc/46971
https://stacks.cdc.gov/view/cdc/46971...

37. Diaz LA, Flores FS, Quaglia A, Contigiani MS. Intertwined arbovirus transmission activity: reassessing the transmission cycle paradigm. Front Physiol. 2013 ;3(493):1-7.

38. LaDeau SL, Glass GE, Hobbs NT, Latimer A, Ostfeld RS. Data-model fusion to better understand emerging pathogens and improve infectious disease forecasting. Ecol Appl. 2011;21(5):1443-60.

39. Komar N, Langevin S, Hinten S, Nemeth N, Edwards E, Hettler D, et al. Experimental Infection of North American Birds with the New York 1999 Strain of West Nile Virus. Emerg Infect Dis . 2003;9(3):311-22.

40. Hayes EB, Sejvar JJ, Zaki SR, Lanciotti RS, Bode AV, Campbell GL. Virology, Pathology, and Clinical Manifestations of West Nile Virus Disease. Emerg Infect Dis . 2005;11(8):1174-9.

41. Kostiukov MA, Gordeeva ZE, Bulychev VP, Nemova NV, Daniiarov OA. [The lake frog (Rana ridibunda)--one of the food hosts of blood-sucking mosquitoes in Tadzhikistan--a reservoir of the West Nile fever virus]. Med Parazitol (Mosk). 1985;(3):49-50.

42. Steinman A, Banet-Noach C, Tal S, Levi O, Simanov L, Perk S, et al. West Nile virus infection in crocodiles [3]. Vol. 9, Emerging Infectious Diseases. Centers for Disease Control and Prevention; 2003. p. 887-9.

43. Klenk K, Komar N. Poor replication of West Nile virus (New York 1999 strain) in three reptilian and one amphibian species. Am J Trop Med Hyg . 2003;69(3):260-2.

44. Klenk K, Snow J, Morgan K, Bowen R, Stephens M, Foster F, et al. Alligators as West Nile virus amplifiers. Emerg Infect Dis . 2004;10(12):2150-5.

45. Jacobson ER, Ginn PE, Troutman JM, Farina L, Stark L, Klenk K, et al. West Nile Virus Infection in Farmed American Alligators (Alligator Mississippiensis) in Florida. J Wildl Dis. 2005;41(1):96-106.

46. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Guia de Vigiläncia do Culex quinquefasciatus. Série A, Normas e Manuais Técnicos. 1st ed. Brasilia: Ministério da Saúde; 2011. 76 p.

47. Iwamoto M, Jernigan DB, Guasch A, Trepka MJ, Blackmore CG, Hellinger WC, et al. Transmission of West Nile Virus from an Organ Donor to Four Transplant Recipients. N Engl J Med . 2003;348(22):2196-203.

48. Pealer LN, Marfin AA, Petersen LR, Lanciotti RS, Page PL, Stramer SL, et al. Transmission of West Nile Virus through Blood Transfusion in the United States in 2002. N Engl J Med . 2003;349(13):1236-45.

49. Blau DM, Rabe IB, Bhatnagar J, Civen R, Trivedi KK, Rollin D, et al. West Nile virus RNA in tissues from donor associated with transmission to organ transplant recipients. Emerg Infect Dis . 2013 ;19(9):1518-20.

50. Hayes EB, O’Leary DR. West Nile Virus Infection: A Pediatric Perspective. Pediatrics. 2004;113(5):1375-81.

51. Hinckley AF, O’Leary DR, Hayes EB. Transmission of West Nile Virus Through Human Breast Milk Seems to Be Rare. Pediatrics. 2007;119(3):e666-71.

52. Sirois PA, Pridjian G, McRae S, Hinckley AF, Rasmussen SA, Kissinger P, et al. Developmental outcomes in young children born to mothers with West Nile illness during pregnancy. Birth Defects Res A Clin Mol Teratol. 2014;100(10):792-6.

53. Pridjian G, Sirois PA, Mcrae S, Hinckley AF, Sonja A, Kissinger P, et al. Mothers with West Nile Illness during Pregnancy. Birth Defects Res Part A Clin Mol Teratol. 2016;106(8):1-15.

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62. Szabolcs Kókay. Common Tern (Sterna hirundo) [Internet]. Hungarianbirdwatching.com. 2019 [cited 2019 Jan 25]. Available from: Available from: https://www.hungarianbirdwatching.com/04_Birds/210-Common-Tern-(Sterna-hirundo).html
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63. Nancy Lowe. Rynchops niger [Internet]. Discover Life. 2004 [cited 2019 Jan 25]. Available from: Available from: https://www.discoverlife.org/mp/20p?see=I_DL177&res=640
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-6464. Zou S, Foster GA, Dodd RY, Petersen LR, Stramer SL. West Nile Fever Characteristics among Viremic Persons Identified through Blood Donor Screening. J Infect Dis . 2010;202(9):1354-61.. When symptomatic, the clinical manifestations may range from fever and myalgias to meningoencephalitis and death6565. Petersen LR, Roehrig JT, Hughes JM. West Nile Virus Encephalitis. N Engl J Med . 2002;347(16):1225-6.. The majority of symptomatic cases in humans infected with WNV present with an acute febrile illness called West Nile fever that is characterized by an abrupt onset of fever, malaise, loss of appetite, headache, myalgia, fatigue, ocular pain, nausea, vomiting, and lymphadenopathy4040. Hayes EB, Sejvar JJ, Zaki SR, Lanciotti RS, Bode AV, Campbell GL. Virology, Pathology, and Clinical Manifestations of West Nile Virus Disease. Emerg Infect Dis . 2005;11(8):1174-9.,6666. Watson JT, Pertel PE, Jones RC, Siston AM, Paul WS, Austin CC, et al. Clinical Characteristics and Functional Outcomes of West Nile Fever. Ann Intern Med. 2004;141(5):360-5.. A maculopapular, non-pruritic rash can often occur in the extremities, palms, soles, and torso; the rash usually occurs on days 5-12 of the disease, lasts for approximately one week, and resolves without scaling6767. Ferguson DD, Gershman K, Lebailly A, Petersen LR. Characteristics of the Rash Associated with West Nile Virus Fever. Vol. 41, Clinical Infectious Diseases. 2005.. West Nile fever is usually a mild illness and although symptoms may last a few days, they can also persist for weeks, causing a debilitating illness6666. Watson JT, Pertel PE, Jones RC, Siston AM, Paul WS, Austin CC, et al. Clinical Characteristics and Functional Outcomes of West Nile Fever. Ann Intern Med. 2004;141(5):360-5..

Less than 1% of infected individuals develop a neuroinvasive disease characterized as meningitis, encephalitis, poliomyelitis-like syndrome or acute flaccid paralysis. Patients with West Nile meningitis can present with fever or hypothermia, headache, photophobia, and gastrointestinal symptoms, like nausea, vomiting, and diarrhea, and meningeal signs, such as nuchal rigidity, Kernig and/or Brudzinski signs6868. Sejvar JJ, Curns AT, Welburg L, Jones JF, Lundgren LM, Capuron L, et al. Neurocognitive and functional outcomes in persons recovering from West Nile virus illness. J Neuropsychol. 2008;2(2):477-99.. Individuals with West Nile encephalitis can present either a mild illness, with symptoms that include fever or hypothermia, headache, nausea, vomiting, tremors, weakness, and confusion; or a more severe illness characterized by encephalopathy and death6969. Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfin AA, Van Gerpen JA, et al. Neurologic Manifestations and Outcome of West Nile Virus Infection. Vol. 290, JAMA. 2003.. Patients with West Nile encephalitis also present with extrapyramidal disorders, myoclonus mainly during sleep, and characteristics of Parkinsonism7070. Robinson RL, Shahida S, Madan N, Rao S, Khardori N. Transient parkinsonism in West Nile virus encephalitis. Am J Med. 2003;115(3):252-3.

71. Solomon T, Fisher AF, Beasley DWC, Mandava P, Granwehr BP, Langsjoen H, et al. Natural and Nosocomial Infection in a Patient with West Nile Encephalitis and Extrapyramidal Movement Disorders. Clin Infect Dis. 2003;36(11):e140-5.
-7272. Maharaj S, Seegobin K, Bajric B, Chang S. Myoclonus as a late manifestation of West Nile disease. BMJ Case Rep. 2017.. Magnetic resonance imaging (MRI) is more helpful than computerized tomography in detecting central nervous system inflammation, as up to one-third of patients undergoing MRI showed acute meningeal enhancement consistent with encephalitis. Cerebrospinal fluid analyses usually show a normal glucose level, increased protein concentration, and a lymphocytic pleocytosis ranging from 10-100 cells/mm3.

West Nile-associated neurologic diseases can also manifest as a poliomyelitis-like syndrome and acute flaccid paralysis characterized mainly by muscle weakness that, in most cases, evolves to respiratory failure7373. Sejvar JJ. West Nile virus and “poliomyelitis.” Neurology. 2004;63(2):206-7.-7474. Alker A. West Nile virus-associated acute flaccid paralysis. BMJ Case Rep . 2015;2015:1-4.. Although neurological diseases associated with WNV infections can arise at any age, the elderly and immunocompromised patients, like those with cancer, diabetes, hypertension, kidney disease, and transplant recipients, are at greater risk7575. Hawkes MA, Carabenciov ID, Wijdicks EFM, Rabinstein AA. Critical West Nile Neuroinvasive Disease. Neurocrit Care. 2018;29(1):47-53.-7676. Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) D of V-BD (DVBD). Symptoms, Diagnosis, & Treatment | West Nile Virus | CDC [Internet]. CDC. 2018 [cited 2019 Jan 16]. Available from: Available from: https://www.cdc.gov/westnile/symptoms/index.html
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. The case fatality rate is higher in elderly people, especially those over 65 years of age.

These diseases occur due to the ability of WNV to cross the blood-brain barrier (BBB) and infect the CNS through dissemination by axonal transport. The replication of the WNV in neurons, astrocytes, and microglia triggers the release of immune mediators by these cells, resulting in increased BBB permeability, inflammation of the meninges, damage to CNS cells, and consequently, CNS diseases7777. Daniels BP, Holman DW, Cruz-Orengo L, Jujjavarapu H, Durrant DM, Klein RS. Viral pathogen-associated molecular patterns regulate blood-brain barrier integrity via competing innate cytokine signals. MBio. 2014;5(5):e01476-14.

78. Winkelmann ER, Luo H, Wang T. West Nile Virus Infection in the Central Nervous System. F1000Research. 2016;5:105.
-7979. Maximova OA, Bernbaum JG, Pletnev AG. West Nile Virus Spreads Transsynaptically within the Pathways of Motor Control: Anatomical and Ultrastructural Mapping of Neuronal Virus Infection in the Primate Central Nervous System. PLoS Negl Trop Dis. 2016;10(9):1-23.. WNV-associated neurologic illnesses do not necessarily correlate with a bad outcome, as some patients with initial severe encephalopathy and associated coma can show a good recovery and minimal sequelae6969. Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfin AA, Van Gerpen JA, et al. Neurologic Manifestations and Outcome of West Nile Virus Infection. Vol. 290, JAMA. 2003.. Following acute illness, approximately 40% of patients experience persistent symptoms for over a year, including fatigue, muscle aches, headaches, movement disorders, and difficulties with memory and concentration8080. Klee AL, Maidin B, Edwin B, Poshni I, Mostashari F, Fine A, et al. Long-term prognosis for clinical West Nile virus infection. Emerg Infect Dis . 2004;10(8):1405-11.,8181. Cook RL, Xu X, Yablonsky EJ, Sakata N, Tripp JH, Hess R, et al. Demographic and clinical factors associated with persistent symptoms after West Nile virus infection. Am J Trop Med Hyg . 2010;83(5):1133-6.. Patients with severe West Nile encephalitis may require assistance with daily activities following hospital discharge8282. Emig M, Apple DJ. Severe West Nile Virus Disease in Healthy Adults. Clin Infect Dis . 2004;38(2):289-92.,8383. Pepperell C, Rau N, Krajden S, Kern R, Humar A, Mederski B, et al. West Nile virus infection in 2002: morbidity and mortality among patients admitted to hospital in southcentral Ontario. CMAJ. 2003;168(11):1399-405..

CLINICAL MANIFESTATIONS IN ANIMALS

West Nile infections in animals cause a very similar disease to the one seen in humans. The clinical signs vary according to which animal species is infected from among all species that can be infected by the virus and succumb from the disease; the most affected animals are birds (mainly exotic) and horses8484. OIE World Organisation for Animal Health. West Nile Fever. In: OIE Terrestrial Manual 2018 [Internet]. OIE.int; 2018. Available from: http://www.oie.int/fileadmin/Home/eng/Health_standards/tahc/current/chapitre_wnf.pdf
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,8585. Araújo F. Febre do Nilo Ocidental. In: Cubas ZS, Silva JCR, Catão-Dias JL, editors. Tratado de animais selvagens vol 2 : medicina veterinária. 2nd ed. São Paulo: Roca; 2014.. Some bird orders, i.e., the Passeriformes, Charadriiformes, and Falconiformes, are considerably more prone to developing disease than others, like the Galliformes, that can be infected but do not manifest any clinical signs8585. Araújo F. Febre do Nilo Ocidental. In: Cubas ZS, Silva JCR, Catão-Dias JL, editors. Tratado de animais selvagens vol 2 : medicina veterinária. 2nd ed. São Paulo: Roca; 2014.,8686. Cannon AB, Luff JA, Brault AC, Maclachlan NJ, Case JB, Green ENG, et al. Acute Encephalitis, Polyarthritis, and Myocarditis Associated with West Nile Virus Infection in a Dog. J Vet Intern Med. 2006;20(5):1219-23.. In species belonging to Galliformes order, the clinical signs may be nonspecific and include depression, lethargy, erect feathers, anorexia, rapid weight loss, and neurological signs such as ataxia, paralysis, tremors, pedaling movements, circling, swimming in circles, abnormal head posture, torticollis, nystagmus, seizures, opisthotonos, and death8787. D’Agostino JJ, Isaza R. Clinical signs and results of specific diagnostic testing among captive birds housed at zoological institutions and infected with West Nile virus. J Am Vet Med Assoc. 2004;224(10):1640-3.

88. Trevejo RT, Eidson M. Zoonosis update: West Nile virus. J Am Vet Med Assoc . 2008;232(9):1302-9.

89. Flores EF, Weiblen R. O vírus do Nilo Ocidental. Ciëncia Rural. 2009;39(2):604-12.
-9090. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Febre do Nilo Ocidental. Guia de Vigilância Epidemiológica. Série A, Normas e Manuais Técnicos. 7th ed. Brasilia: Secretaria de Vigilância em Saúde; 2010. 4348 p..

Among mammals, squirrels, chipmunks, bats, dogs, cats, white-tailed deer, reindeer, sheep, alpacas, non-human primates, horses, harbor seals, dromedary camels, and some others can be infected by WNV, but only a small number will manifest clinical signs and become ill8585. Araújo F. Febre do Nilo Ocidental. In: Cubas ZS, Silva JCR, Catão-Dias JL, editors. Tratado de animais selvagens vol 2 : medicina veterinária. 2nd ed. São Paulo: Roca; 2014.,9191. Callan RJ, Van Metre DC. Viral diseases of the ruminant nervous system. Vet Clin North Am Food Anim Pract. 2004;20(2):327-62.,9292. Joseph S, Wernery U, Teng JL, Wernery R, Huang Y, Patteril NA, et al. First isolation of West Nile virus from a dromedary camel. Emerg Microbes Infect. 2016;5(6):e53-e53.. After humans, horses are the mammals that are most affected by WNV as they can develop a disease with the same level of severity8888. Trevejo RT, Eidson M. Zoonosis update: West Nile virus. J Am Vet Med Assoc . 2008;232(9):1302-9.,9393. Saegerman C, Alba-Casals A, García-Bocanegra I, Dal Pozzo F, van Galen G. Clinical Sentinel Surveillance of Equine West Nile Fever, Spain. Transbound Emerg Dis . 2016;63(2):184-93.. The incubation period of the West Nile infection in horses is estimated at 3 - 15 days, similar to that seen in humans8484. OIE World Organisation for Animal Health. West Nile Fever. In: OIE Terrestrial Manual 2018 [Internet]. OIE.int; 2018. Available from: http://www.oie.int/fileadmin/Home/eng/Health_standards/tahc/current/chapitre_wnf.pdf
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,9494. Schmidt JR, Elmansoury HK. Natural and Experimental Infection of Egyptian Equines with West Nile Virus. Ann Trop Med Parasitol. 1963;57:415-27.

95. Bunning ML, Bowen RA, Cropp BC, Sullivan KG, Davis BS, Komar N, et al. Experimental Infection of Horses with West Nile virus. Emerg Infect Dis . 2002;8(4):380-6.

96. Ward MP. Epidemic West Nile virus encephalomyelitis: A temperature-dependent, spatial model of disease dynamics. Prev Vet Med. 2005;71(3-4):253-64.
-9797. Pradier S, Lecollinet S, Leblond A. West Nile virus epidemiology and factors triggering change in its distribution in Europe. Rev Sci Tech. 2012;31(3):829-44.. Like humans, most infected horses do not manifest any clinical signs, but a small percentage can develop encephalitis and die8888. Trevejo RT, Eidson M. Zoonosis update: West Nile virus. J Am Vet Med Assoc . 2008;232(9):1302-9.,9898. Ostlund EN, Andresen JE, Andresen M. West Nile encephalitis. Vet Clin North Am Equine Pract. 2000;16(3):427-41.. Other clinical signs include depression, loss of appetite, colic, limb weakness, recumbency, and muscle fasciculation2727. Martins LC, da Silva EVP, Casseb LMN, da Silva SP, Cruz ACR, Pantoja JAS. First isolation of West Nile virus in Brazil. Mem Inst Oswaldo Cruz . 2018;1-19.,8484. OIE World Organisation for Animal Health. West Nile Fever. In: OIE Terrestrial Manual 2018 [Internet]. OIE.int; 2018. Available from: http://www.oie.int/fileadmin/Home/eng/Health_standards/tahc/current/chapitre_wnf.pdf
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,9393. Saegerman C, Alba-Casals A, García-Bocanegra I, Dal Pozzo F, van Galen G. Clinical Sentinel Surveillance of Equine West Nile Fever, Spain. Transbound Emerg Dis . 2016;63(2):184-93.,9898. Ostlund EN, Andresen JE, Andresen M. West Nile encephalitis. Vet Clin North Am Equine Pract. 2000;16(3):427-41.

99. Cantile C, Di Guardo G, Eleni C, Arispici M. Clinical and neuropathological features of West Nile virus equine encephalomyelitis in Italy. Equine Vet J. 2000;32(1):31-5.

100. Ostlund EN, Crom RL, Pedersen DD, Johnson DJ, Williams WO, Schmitt BJ. Equine West Nile encephalitis, United States. Emerg Infect Dis . 2001;7(4):665-9.
-101101. Snook CS, Hyman SS, Del Piero F, Palmer JE, Ostlund EN, Barr BS, et al. West Nile virus encephalomyelitis in eight horses. J Am Vet Med Assoc . 2001;218(10):1576-9.. A neurological syndrome may set in, manifesting as ataxia, stupor, behavioral changes, paralysis of one or more limbs, lateral decubitus, intense sweating, pedaling movements, seizures, and cranial nerve palsy opisthotonos, as well as other alterations like hemineglect2727. Martins LC, da Silva EVP, Casseb LMN, da Silva SP, Cruz ACR, Pantoja JAS. First isolation of West Nile virus in Brazil. Mem Inst Oswaldo Cruz . 2018;1-19.,9393. Saegerman C, Alba-Casals A, García-Bocanegra I, Dal Pozzo F, van Galen G. Clinical Sentinel Surveillance of Equine West Nile Fever, Spain. Transbound Emerg Dis . 2016;63(2):184-93..

DIAGNOSIS AND TREATMENT

Clinical manifestations alone are insufficient to confirm the diagnosis of West Nile disease since most common clinical signs of symptomatic WNV infection are similar to those of other flavivirus infections. However, differently from other flaviviruses such as DENV and ZIKV, severe WNV infection is accompanied by neurological signs. Patients with severe WNV disease usually present with a febrile disease accompanied by neurological manifestations like meningitis, encephalitis, meningoencephalitis, and flaccid paralysis of unknown etiology, but compatible with a viral disease102102. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Vigilância Nilo [Internet]. portalms. 2018 [cited 2019 Jan 16]. Available from: Available from: http://portalms.saude.gov.br/saude-de-a-z/febre-do-nilo-ocidental/21160-vigilancia-nilo
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. Diagnosis can be made during the viremic phase of infection, with high sensitivity and specificity, through the detection of viral RNA in the blood, urine, and cerebrospinal fluid (CSF) by quantitative Real-Time Polymerase Chain Reaction (RT-qPCR). However, it is not routinely used because West Nile infection usually has a short-lived viremia103103. Lustig Y, Mannasse B, Koren R, Katz-Likvornik S, Hindiyeh M, Mandelboim M, et al. Superiority of west nile virus RNA detection in whole blood for diagnosis of acute infection. J Clin Microbiol. 2016;54(9):2294-7.,104104. Busch MP, Kleinman SH, Tobler LH, Kamel HT, Norris PJ, Walsh I, et al. Virus and Antibody Dynamics in Acute West Nile Virus Infection. J Infect Dis . 2008;198(7):984-93.. Consequently, detection of IgM antibodies by enzyme-linked immunosorbent assay (ELISA) in serum or CSF, collected 5 or 8 days after the onset of symptoms, respectively, is routinely used for diagnosis, indicating recent infection, although cross-reactivity may occur105105. Lustig Y, Sofer D, Bucris ED, Mendelson E. Surveillance and diagnosis of west nile virus in the face of flavivirus cross-reactivity. Front Microbiol. 2018;9:2421.. To validate the results, a neutralization assay, considered to be the gold standard test, can be performed to detect neutralizing antibodies. Antibody detection can also be performed using an immunofluorescence assay105105. Lustig Y, Sofer D, Bucris ED, Mendelson E. Surveillance and diagnosis of west nile virus in the face of flavivirus cross-reactivity. Front Microbiol. 2018;9:2421.,106106. Zanoni F, Alfieri C, Moroni G, Passerini P, Regalia A, Meneghini M, et al. Delayed Diagnosis of West Nile Virus Infection in a Kidney Transplant Patient Due to Inaccuracies in Commonly Available Diagnostic Tests. Exp Clin Transplant. 2018.. In postmortem patients, immunohistochemical assays of brain tissue samples can be carried out to detect antigens in fixed tissues107107. Centers for Disease Control and Prevention (CDC). Division of Vector-Borne Diseases. West Nile Virus in the United States: Guidelines for Surveillance, Prevention, and Control. Fort Collins, CO; 2013 ..

Patients diagnosed with uncomplicated West Nile disease usually do not require specific intervention, needing only adequate hydration and pain management. However, the patients most at risk, such as the elderly and immunocompromised patients, need close monitoring to quickly detect the progression to a more severe neuroinvasive disease. If seizures and increased intracranial pressure are present, they should be managed under intensive care, paying special attention to the level of alertness108108. Sejvar JJ. Clinical manifestations and outcomes of West Nile virus infection. Viruses. 2014;6(2):606-23.. West Nile virus infection may not be initially suspected in patients with a West Nile neurologic disease characterized as meningitis or encephalitis, but should be suspected in patients developing acute asymmetric paralysis108108. Sejvar JJ. Clinical manifestations and outcomes of West Nile virus infection. Viruses. 2014;6(2):606-23.. Diagnosis of WNV infection might be difficult in areas where other flaviviruses circulate, but a high level of suspicion must be in place, especially by the combination of epidemiologic features and clinical manifestations.

The design of specific anti-viral therapies represents a challenge because WNV viremic period in humans is short and the virus infection is generally cleared shortly after disease onset108108. Sejvar JJ. Clinical manifestations and outcomes of West Nile virus infection. Viruses. 2014;6(2):606-23.. Treatment trials with interferon-α have not suggested a clear benefit even though it has a protective effect in vitro and was shown to improve convalescence in a case study of two WNV patients with encephalitis109109. Morrey JD, Day CW, Julander JG, Blatt LM, Smee DF, Sidwell RW. Effect of interferon-alpha and interferon-inducers on West Nile virus in mouse and hamster animal models. Antivir Chem Chemother. 2004;15(2):101-9.,110110. Kalil AC, Devetten MP, Singh S, Lesiak B, Poage DP, Bargenquast K, et al. Use of Interferon-a in Patients with West Nile Encephalitis: Report of 2 Cases. Clin Infect Dis . 2005;40(5):764-6.. Treatment of animal models with either WNV-specific intravenous immune globulin (IVIG) from pooled donors or humanized monoclonal WNV antibodies has shown good efficacy if treatment is started prior to, or shortly after disease onset. However, a reliable efficacy assessment in human randomized clinical trials has been difficult to obtain111111. Shimoni Z, Niven MJ, Pitlick S, Bulvik S. Treatment of West Nile virus encephalitis with intravenous immunoglobulin. Emerg Infect Dis . 2001;7(4):759.

112. Agrawal AG, Petersen LR. Human Immunoglobulin as a Treatment for West Nile Virus Infection. J Infect Dis . 2003;188(1):1-4.

113. Oliphant T, Engle M, Nybakken GE, Doane C, Johnson S, Huang L, et al. Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat Med. 2005;11(5):522-30.

114. Beigel JH, Nordstrom JL, Pillemer SR, Roncal C, Goldwater DR, Li H, et al. Safety and pharmacokinetics of single intravenous dose of MGAWN1, a novel monoclonal antibody to West Nile virus. Antimicrob Agents Chemother. 2010;54(6):2431-6.

115. Morrey JD, Siddharthan V, Olsen AL, Roper GY, Wang H, Baldwin TJ, et al. Humanized monoclonal antibody against West Nile virus envelope protein administered after neuronal infection protects against lethal encephalitis in hamsters. J Infect Dis . 2006;194(9):1300-8.
-116116. Smeraski CA, Siddharthan V, Morrey JD. Treatment of spatial memory impairment in hamsters infected with West Nile virus using a humanized monoclonal antibody MGAWN1. Antiviral Res. 2011;91(1):43-9..

SURVEILLANCE AND PREVENTION

Therapeutic approaches against WN disease are mainly supportive since there are no approved vaccines or specific antiviral treatments available for human use108108. Sejvar JJ. Clinical manifestations and outcomes of West Nile virus infection. Viruses. 2014;6(2):606-23.

109. Morrey JD, Day CW, Julander JG, Blatt LM, Smee DF, Sidwell RW. Effect of interferon-alpha and interferon-inducers on West Nile virus in mouse and hamster animal models. Antivir Chem Chemother. 2004;15(2):101-9.

110. Kalil AC, Devetten MP, Singh S, Lesiak B, Poage DP, Bargenquast K, et al. Use of Interferon-a in Patients with West Nile Encephalitis: Report of 2 Cases. Clin Infect Dis . 2005;40(5):764-6.

111. Shimoni Z, Niven MJ, Pitlick S, Bulvik S. Treatment of West Nile virus encephalitis with intravenous immunoglobulin. Emerg Infect Dis . 2001;7(4):759.

112. Agrawal AG, Petersen LR. Human Immunoglobulin as a Treatment for West Nile Virus Infection. J Infect Dis . 2003;188(1):1-4.

113. Oliphant T, Engle M, Nybakken GE, Doane C, Johnson S, Huang L, et al. Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat Med. 2005;11(5):522-30.

114. Beigel JH, Nordstrom JL, Pillemer SR, Roncal C, Goldwater DR, Li H, et al. Safety and pharmacokinetics of single intravenous dose of MGAWN1, a novel monoclonal antibody to West Nile virus. Antimicrob Agents Chemother. 2010;54(6):2431-6.

115. Morrey JD, Siddharthan V, Olsen AL, Roper GY, Wang H, Baldwin TJ, et al. Humanized monoclonal antibody against West Nile virus envelope protein administered after neuronal infection protects against lethal encephalitis in hamsters. J Infect Dis . 2006;194(9):1300-8.

116. Smeraski CA, Siddharthan V, Morrey JD. Treatment of spatial memory impairment in hamsters infected with West Nile virus using a humanized monoclonal antibody MGAWN1. Antiviral Res. 2011;91(1):43-9.
-117117. Diamond MS. Development of effective therapies against West Nile virus infection. Expert Rev Anti Infect Ther. 2005;3(6):931-44.. However, successful strategies to prevent WNV infections have already been developed in veterinary practice. There are four USDA-licensed vaccines available for equines that confer immunity for at least one year118118. Balasuriya U, Johnson A, Lunn P, Morgan K, Pusterla N, Timoney P, et al. AAEP Vaccination Guidelines [Internet]. Vol. 1. 2015. Available from: https://aaep.org/guidelines/vaccination-guidelines/core-vaccination-guidelines/west-nile-virus
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. The West Nile-Innovator DNA vaccine was developed by Fort Dodge Animal Health in 2005 for use in horses and became the first licensed DNA vaccine, but was later removed from the market119119. Iyer AV, Kousoulas KG. A review of vaccine approaches for West Nile virus. Int J Environ Res Public Health. 2013 ;10(9):4200-23.. The current approved equine vaccine formulations consist of inactivated whole WNV (two vaccines), a nonreplicating live canarypox recombinant vector vaccine, and an inactivated flavivirus chimeric vaccine118118. Balasuriya U, Johnson A, Lunn P, Morgan K, Pusterla N, Timoney P, et al. AAEP Vaccination Guidelines [Internet]. Vol. 1. 2015. Available from: https://aaep.org/guidelines/vaccination-guidelines/core-vaccination-guidelines/west-nile-virus
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. Since these vaccines were licensed, the incidence of West Nile diseases in horses have declined in the USA120120. Ng T, Hathaway D, Jennings N, Champ D, Chiang YW, Chu HJ. Equine vaccine for West Nile virus. Dev Biol (Basel). 2003;114:221-7.-121121. El Garch H, Minke JM, Rehder J, Richard S, Edlund Toulemonde C, Dinic S, et al. A West Nile virus (WNV) recombinant canarypox virus vaccine elicits WNV-specific neutralizing antibodies and cell-mediated immune responses in the horse. Vet Immunol Immunopathol. 2008;123(3-4):230-9.. Vaccine formulations are also being developed for non-human primates and small mammals. Potent induction of neutralizing antibodies against WNV infections in non-human primates has been observed with live-attenuated WNV vaccine strains, developed either by site-directed mutagenesis or chimerization, where WNV genetic material is inserted into a yellow fever virus vaccine strain backbone122122. Whiteman MC, Li L, Wicker JA, Kinney RM, Huang C, Beasley DWC, et al. Development and characterization of non-glycosylated E and NS1 mutant viruses as a potential candidate vaccine for West Nile virus. Vaccine. 2010;28(4):1075-83.-123123. Guy B, Guirakhoo F, Barban V, Higgs S, Monath TP, Lang J. Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses. Vaccine. 2010;28(3):632-49.. Subunit and DNA vaccines have also been developed to protect small animals and have provided good protection against viral infection124124. Ledgerwood JE, Pierson TC, Hubka SA, Desai N, Rucker S, Gordon IJ, et al. A West Nile virus DNA vaccine utilizing a modified promoter induces neutralizing antibody in younger and older healthy adults in a phase I clinical trial. J Infect Dis . 2011;203(10):1396-404.-125125. Ledizet M, Kar K, Foellmer HG, Wang T, Bushmich SL, Anderson JF, et al. A recombinant envelope protein vaccine against West Nile virus. Vaccine. 2005;23(30):3915-24..

Until a WNV vaccine designed for human use is commercially available, the most effective prophylaxis against WNV infection remains vector control and the use of insect repellents to prevent the bites of infected mosquitoes. Furthermore, considering the evidence for viral circulation among several animal species, confirmation of a human case of WNV infection in Brazil in 2014, and WNV isolation in 2018, the epizootic surveillance system must remain in place and in close association with active reporting of human cases126126. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Guia de vigilância em saúde. [Internet]. 2nd ed. Vol. único, Ministério da Saúde. Brasília: Coordenação-Geral de Desenvolvimento da Epidemiologia em Serviços; 2017. 705 p. Available from: http://bvsms.saude.gov.br/bvs/publicacoes/guia_vigilancia_saude_2ed.pdf
http://bvsms.saude.gov.br/bvs/publicacoe...
. Cases of encephalitis, meningitis, and other diseases that affect the CNS without a clear etiology, either in animals or humans, should always include West Nile neurologic disease in the differential diagnosis. Reporting and testing dead birds for the presence of WNV infections are important resource for surveillance programs. Entomological and sentinel animal surveillance regimens must be continuously carried out aiming at early identification of viral circulation126126. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Guia de vigilância em saúde. [Internet]. 2nd ed. Vol. único, Ministério da Saúde. Brasília: Coordenação-Geral de Desenvolvimento da Epidemiologia em Serviços; 2017. 705 p. Available from: http://bvsms.saude.gov.br/bvs/publicacoes/guia_vigilancia_saude_2ed.pdf
http://bvsms.saude.gov.br/bvs/publicacoe...
. Active surveillance for WNV infections in mosquito and bird populations, in combination with climate and environmental data analysis, may also allow for the detection of WNV prior to disease onset in equine or human populations, and thereby predict the time and sites of future WNV-associated disease outbreaks105105. Lustig Y, Sofer D, Bucris ED, Mendelson E. Surveillance and diagnosis of west nile virus in the face of flavivirus cross-reactivity. Front Microbiol. 2018;9:2421..

The introduction of exotic diseases, whether zoonotic or not, in new territories such as Brazil is inevitable since globalization allows for the translocation of pathogens to occur at speed not previously experienced in the past. In addition, Brazil has a high diversity of hosts and vectors that allows the maintenance and perpetuation of new viruses with previously unknown cycles. Therefore, implementing active surveillance in strategic areas of the country is necessary for the early detection of new pathogens and to restrain their entry and dissemination, mitigating as much as possible the establishment of enzootic cycles and avoiding losses in public health and in the economy.

CONCLUSIONS

WNV is considered an emerging virus throughout Latin America. A pioneer sentinel surveillance system for encephalitis and other neurological syndromes has been implemented in Piauí State, Brazil, since 2013. According to the Brazilian Ministry of Health, 285 suspected cases have been investigated in the region. In 2014, a patient was diagnosed with WNV infection and, in 2017, 10 suspected cases of neuroinvasive disease were reported, although diagnosis has yet to be confirmed127127. SBMT - Sociedade Brasileira de Medicina Tropical. Nile fever in Piauí: 285 investigated cases since 2013 [Internet]. 2017 [cited 2019 Jan 25]. Available from: Available from: http://www.sbmt.org.br/portal/febre-do-nilo-no-piaui-285-casos-investigados-desde-2013/?lang=en
http://www.sbmt.org.br/portal/febre-do-n...
. In a note released on February 8, 2019, the Secretary of Health (SESAPI) for Piauí State confirmed one additional human case of WNV in that state in 2017, where the patient presented with acute muscular flaccid paralysis128128. Assessoria de Comunicação SESAPI. Nota sobre a ocorrência de Febre do Nilo Ocidental no estado [Internet]. Portal da Saúde - Secretaria de Estado da Saúde do Piauí. 2019 [cited 2019 Feb 11]. Available from: Available from: http://www.saude.pi.gov.br/noticias/2019-02-08/8933/nota-sobre-a-ocorrencia-de-febre-do-nilo-ocidental-no-estado.html
http://www.saude.pi.gov.br/noticias/2019...
,129129. International Society for Infectious Diseases. PRO/AH/EDR> West Nile virus (03): Americas (Brazil) human [Internet]. ProMEDmail. 2019 [cited 2019 Feb 11]. Available fromAvailable fromhttp://www.promedmail.org/direct.php?id=20190208.6306915 .
http://www.promedmail.org/direct.php?id=...
. With the recent increase in suspected cases in that region and the first isolation of WNV from an infected horse in Espírito Santo State, many investigators and health professionals are concerned with the possibility that WNV establish itself in Brazil. Considering that most patients are asymptomatic and symptoms of West Nile disease are very similar to those of other viral infections, without an adequate degree of suspicion the number of cases of West Nile fever could go unnoticed and outbreaks may occur in areas considered free of WNV circulation. The widespread lack of capacity for molecular or serological diagnosis specific to WNV infections in hospitals and clinical laboratories prevents the acquisition of the knowledge on the true number of infected individuals.

Because mosquitoes found throughout Brazil, such as those of the genera Culex and Aedes, can transmit WNV, there is a growing concern that the virus may spread itself to the whole country. The Culex genus is abundant in Brazil and its life cycle is based on water bodies with a high burden of organic material; as such, vector control is extremely important in areas where the basic sanitation is deficient or absent, presenting a higher risk for WNV transmission. Considering the reservoirs of migratory birds present in Brazil and the potential availability of new animal reservoirs due to the vast size of the Brazilian biome, it is only a matter of time before the WNV spreads across the country once its replication cycle has been established in the environment, as it was observed following its emergence in the United States. Mammals presenting with neurological syndromes and birds that die without a definite cause or are found dead should both be investigated for WNV infection. Finally, it is necessary to increase active epidemiological surveillance in animals and humans and promote preventive actions to minimize the possibility of WNV infection in humans before it becomes a major public health issue, as occurred with other arbovirus infections such as dengue, zika, chikungunya and, more recently, the sylvatic resurgence of yellow fever virus.

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Publication Dates

  • Publication in this collection
    28 Mar 2019
  • Date of issue
    2019

History

  • Received
    21 Feb 2019
  • Accepted
    26 Feb 2019
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