Transboundary and Emerging Diseases
REVIEW ARTICLE
West Nile Disease Epidemiology in North-West Africa: Bibliographical Review A. Benjelloun1,2, M. El Harrak3 and B. Belkadi1 1 2 3
Laboratory of Microbiology and Molecular Biology, Faculty of Science, University Mohammed V, Rabat, Morocco Poste de Commandement Central de Lutte Contre La Grippe Aviaire, Rabat, Morocco Soci et e de Produits biologiques et pharmaceutiques v et erinaires (Biopharma), Rabat, Morocco
Keywords: North Africa; horse; human; Morocco; Tunisia; Algeria; West Nile Virus Correspondence: B. Belkadi. Laboratoire de Microbiologie et Biologie Mol eculaire, Facult e des Sciences, Universit e Mohammed V Agdal, B.P. 1014, Rabat, Morocco. Tel/Fax: 00212537775461; E-mail: [email protected] Received for publication October 28, 2014 doi:10.1111/tbed.12341
Summary West Nile fever (WNF) or West Nile disease (WND) is a mosquito-borne viral disease that can affect birds, humans and horses. West Nile virus (WNV) is a member of the genus Flavivirus in the family Flaviviridae. WNV is maintained in a mosquito–bird–mosquito transmission cycle, whereas humans and horses are considered dead-end hosts. In human and horses, symptoms range from unapparent infection to mild febrile illness, meningitis, encephalitis or death. WNV has a wide geographical range that includes portions of Europe, Asia, Africa, Australia (Kunjin virus), and in North, Central and South America. Migratory birds are thought to be primarily responsible for virus dispersal, including reintroduction of WNV from endemic areas into regions that experience sporadic outbreaks (Fields Virology, 2001, Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, USA, 1043–1125). The occurrence of disease in humans and animals along with birds and mosquitoes surveillance for WNV activity demonstrates that the virus range has dramatically expanded including North, Central and South America as well as Europe and countries facing the Mediterranean Basin. WND infection in humans has been reported in Morocco in 1996 (Virologie, 1, 1997, 248), in Tunisia in 2007 (Ann. N. Y. Acad., 951, 2001, 117) (Med. Trop., 61, 2001, 487) and 2003 (Epidemiologie de la fievre West Nile, 2012, These de doctorat, Universite Montpellier II, Sciences et techniques du Langueduc, Montpellier, France), and in Algeria in 1994 (Rev. Sci. Tech., 31, 2012, 829). Outbreaks of equine encephalitis have been also reported in Morocco in 1996 (Bull. OIE, 11, 1996, 867), in 2003 (Emerg. Infect. Dis., 11, 2005, 306) and in 2010 (World Animal Health Information Database. WAHID, 2010). Serological evidence of WNV has been demonstrated in the three countries in many species. The aim of this review was to assess the epidemiological situation of WND in northwest Africa comprising Morocco, Algeria and Tunisia, with an updated literature review based on of human cases and equine outbreaks reports as well as serological studies in these countries.
Introduction West Nile virus is a flavivirus belonging to the Flaviviridae family and to the Japanese encephalitis serocomplex, which contains a number of viruses also associated to human encephalitis (Petersen and Roehrig, 2001). It is commonly found in Africa, Europe, the Middle East, © 2015 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.
North America and West Asia. It is maintained in nature by a cycle involving transmission between birds and mosquitoes. In the vector insect, the virus follows a cycle of intrinsic development. The air temperature has a great influence on the speed of the cycle as well as on female survival and also the duration of the transmission period. 1
West Nile Disease in North-West Africa
When local ecological conditions are suitable for virus amplification, the infection of humans and horses can occur and other mammals can also be infected during the blood meals. There has been confirmed transmission of WNV in humans by blood transfusion, organ transfer and breast milk, but most human infections occur by natural transmission from mosquitoes (OIE, 2013). Horses, just like humans, are “dead-end” hosts, meaning that while they become infected, they do not spread the infection. Clinical signs in equines are fever, weakness, locomotor dysfunction, ataxia and blindness. In the most severe cases, paraplegia occurs and evolves in 5 to 10 days to death. In most humans, WNV infection is subclinical, but approximately 20%–40% of those infected may develop symptoms of WNV disease ranging from West Nile fever (fever, headache, malaise, lymphadenopathy, myalgia, fatigue, skin rash, diarrhoea and vomiting) to meningoencephalitis (muscle weakness, tremors, paralysis and cognitive impairment) or flaccid paralysis (a polio-like syndrome) and, less frequently, death (Lindsey et al., 2010). Hepatitis, pancreatitis and myocarditis have also infrequently been described to occur (Kramer et al., 2007). In addition, long-term sequelae, including weakness, persistent movement disorders and cognitive deficits, frequently occurring in patients that have suffered from West Nile neuro-invasive disease (Cao et al., 2005; Sejvar, 2007). Although inactivated and recombinant vaccines are available for animal use, no vaccines or antiviral therapies are currently approved for humans (De Filette et al., 2012). WND infection has been reported in Morocco, Tunisia and Algeria. Serological evidence of WND has been found in the three countries during last decades in both species, but outbreaks of equine encephalitis due to WNV have been reported only in Morocco; while in Algeria and Tunisia, epidemics in humans without any apparent clinical cases in horses were observed. Virus Isolation WNV was first isolated in North Africa in Algeria in 1968, from a pool of 215 mosquitoes of the genus Culex in the region of Djanet in Illizi’s province (extreme south-east of Algeria) as part of an investigation on African horse sickness outbreaks that occurred in 1965 (Pilo-Moro et al., 1970). The virus was also isolated for the first time in 1996 in Morocco from a horse’s brain tissue (El Harrak et al., 1997) that died when unusual disease appeared in horses living in the Atlantic coastal area north-west of the country as reported by veterinary services. The West Nile virus strains circulating in Morocco are closely related to other Western Mediterranean strains and are characterized by 2
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high virulence in horses. The genome analysis of the WNV strains isolated in Morocco showed that they belong to WNV Lignage1, Clade 1a (Zientara et al., 2009). Phylogenetic analyses showed also that WNV Morocco/ 96 strain was very similar to mosquitoes WNV Senegal/93 strain and equids France/2000 strain, (Schuffenecker et al., 2005). One year later in Tunisia, in 1997, WNV was isolated in humans during a meningo-encephalitis epidemic and the strain belonged also to lineage 1 but was very close to the virulent strains isolated in Israel in 1998 and in New York in 1999 (Bahri et al., 2010). In 2003, the WNV strain isolated in equids in Morocco during an outbreak proved to be far more pathogenic than other Western Mediterranean viruses (Sotelo et al., 2009, 2011). However, no human meningo-encephalitis caused by equine WN/2003 was reported. In the three countries, all the WNV isolated strains belong to the European/Mediterranean/Kenyan cluster, which are characterized by moderate pathogenicity for horses and humans and limited or no pathogenicity for birds (Calistri et al., 2010). This is not the case for the strains grouped in the Israeli/American cluster which are characterized by high rate of avian deaths and, in the United States by high rates of morbidity and mortality in humans and horses (Calistri et al., 2010). WND in humans Despite the virus isolation from the vector in 1968 (PiloMoro et al., 1970) in mosquitoes in Algeria, and serological evidence found in humans (1973–1975–1976) and in animals (1975) in the region WND, clinical cases were never reported in humans in north-west Africa until 1994 (Metallaoui, 2008) (Table 1). During this year, an outbreak was reported in the south of Algeria (Timimoun, Adrar province), where about 50 suspect cases including 8 deaths were reported (Murgue et al., 2001). The patients had a high fever associated with neurological signs and other symptoms, sometimes presenting additionally a comatose state. Among 18 samples collected, 83.3% were positive (Pradier et al., 2012). However, the virus could not be isolated. In Morocco, 1 fatal case was notified during 1996 WND outbreak, and a year later, during the autumn 1997, Tunisa reported human epidemics of meningo-encephalitis caused by WNV, 173 cases, with 8 deaths were observed. Cases were reported in south-eastern Tunisia (Sfax and Mehdia) (Murgue et al., 2001). In 2003, another epidemic reoccurred, mostly in the same areas but also in other localities, WND was confirmed in 31 cases from 94 suspected cases. No virus was isolated or characterized by molecular analyses, and no animal cases were declared (Bargaoui, 2012). © 2015 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.
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Table 1. Reports of WND infection in humans in North-west Africa Country
Year
Area
Tested
Results
Algeria
1965 (Metallaoui, 2008) 1973 (Metallaoui, 2008) 1975 (Metallaoui, 2008)
Northern Algeria Djanet (Illizi) Illizi et Djanet (Illizi) Tamanrasset
P = 0% P = 14.6% P = 58.3% P = 3.5 %
1976 (Metallaoui, 2008)
Biskra Ouled Djellal (Wilaya of Biskra)
1994 * (Pradier et al., 2012) In 2012 * (EpiSouth, 2012) 1996 (El Harrak et al., 1997) 2011 (El Rhaffouli et al., 2012)
Timimoune (Adrar) Jijel (littoral between Alger et Annaba) Gharb region (Northwest) Rabat Kenitra Meknes Different regions Jerba Tunis Gabes Other regions Sfax,Mahdia and Other regions
N = 281 171 48 143 24 21 18 1 case 1 case 200 149 150 705 1094 205 85 22 129
Morocco
Tunisia
1968 (Haddad,1980) 1970’s (Bargaoui, 2012)
1997* (Murgue et al., 2001) (Triki et al., 2001) 2003 * (Bargaoui, 2012) 2007 (Bargaoui, 2012)
2010 (Bargaoui, 2012) 2011 (Bargaoui, 2012) In 2012, (ONMNE, 2012)
Monastir, Mahdia, Sfax et Gabes Kairaouan Bizerte Sfax Jendouba (North) Kebili (South) Monastir, Kebili Jendouba , Bizerte Tozeur, Kairouan, Nabeul Sousse, Gabes Mahdia, Sfax Sidi Bouzid, Medenine.
94
2 3 86 confirmed cases
P = 3.5% 19% P = 83.3% 1 case 1 case 24 (12%) 28 (18.8%) 7 (4.7%) 1.80% 3.8% 7.8% 7% 9.0% 111 cases (87%) 31 27.7% 0.7% 7.5% 2 cases 3 86 confirmed 12 deaths
*Meningo-encephalitis epidemic
In October 2010, WND was diagnosed in 2 children from Jendouba region (northern Tunisia–Algeria border) and in October 2011, WND was diagnosed in 3 women aged 61, 70 and 77 years in Kebili, (south of Tunisia) in the region of the oasis located near Al Chott Eljerrid (ONMNE, 2012). In 2011, evidence of human infection in Morocco was confirmed serologically by the detection of WND neutralizing bodies in 59 (P = 11.8%) among 499 healthy persons living in the vicinities of Meknes, Rabat and Kenitra cities (centre and north-west) (El Rhaffouli et al., 2012). The prevalence varied between 4.7 and 28% depending on the distance from the coastline. In 2012, from July, through to December 21, the surveillance of West Nile Virus Infections in Tunisia (ONMNE, 2012) demonstrated the disease in 86 confirmed cases with neurological forms and the death of 12 persons. In the same time, one confirmed clinical case was reported in Algeria (EpiSouth, 2012).
and the infection spread to neighbouring cities (in the central and north-western regions) (Tber, 1996), where 42 horses and one person died. After an apparent epidemiological silence, WND reoccurred in Morocco in 2003 (Schuffenecker et al., 2005) when 9 equine cases (with 5 deaths) were detected. Equine clinical cases were reported from three locations (Ouled Slama, Ameur Seflia, Mograne) 20 to 30 km north-east of Kenitra (centre) close to the Sebou River delta and the Atlantic Ocean. In 2010, in central and north-western part of the country in Benslimane, Khemisset, Mohammedia and Casablanca provinces, WND were confirmed in 17 horses, within 111 suspected cases (with 8 deaths) (World Animal Health Information Database. WAHID, 2010). Neither in Algeria nor in Tunisia clinical cases in equids were reported. Instead, many serosurveys on equids and other mammals demonstrate WNV circulation in these countries (Table 2).
WND in horses
WND evidence in other animals
Equine encephalitis caused by WNV in North Africa was reported in 1996 in Morocco in Benslimane region (centre)
As many reports have suggested that several species of wild mammals are commonly exposed to WNV, occasionally
© 2015 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.
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Table 2. Reports of WND infection in Equids in North-west Africa Country
Year
Aera
Tested/Case
Confirmed
Algeria Morocco
1975 (Metallaoui, 2008) 1996 * (Tber, 1996)
Djanet (Southeast) Benslimane (Center) Gharb region (Northwest)
Donkeys (n = 52) Horses Horses, donkeys, mules (n = 1200)
2003* (Schuffenecker et al., 2005) 2010 * (World Animal Health Information Database. WAHID, 2010)
Gharb region (Northwest)
9 equine cases
P = 96.6% 42 deaths 63% horses 44% donkeys 37% mules 9 equines 5 deaths
Benslimane, Khemisset, Mohammedia and Casablanca provinces (Center and northwest) Benslimane, Khemisset and other regions Jerba, Tunis, Gabes and other regions
Horses : 111 cases
confirmed in 17 horses 8 deaths
Horses (n = 840)
248 positive P = 29.52 %
Donkeys (n = 205), horses (n = 296), and mules (n = 55) Horses, donkeys, mules. (n = 269) Equids (n = 127) Equids (n = 133) : Donkeys (n = 93) , horses (n = 23) , mules (n = 17)
2 positive
2011 (Benjelloun et al., 2012) Tunisia
1980 (Haddad, 1980) 2005 (Bargaoui, 2012) 2007 (Boubaker, 2008) 2008 (Ben Hassine et al., 2011)
Gabes, Sfax, Mahdia, Mounastir, Nabeul and Bizerte Mounastir, Sfax Bizerte, Jendouba and El Kef (North-west)
86 positive P = 25%/Horses P = 37 %/(Donkeys, mules) 30% positive 36 positive (P = 27.1%).
*Outbreaks
with high-associated seroprevalence rates, some studies concerning small animals were carried out in the region. In 1976, haemagglutination-inhibiting antibodies against West Nile virus were detected in 19.8% of 156 small animals’ sera, mainly from Mus spp., Rattus rattus, Eliomys tunetae in the northern part of Tunisia, and from Ctenodactylus gundi and Pipistrellus kuhlii in the south (Chastel et al., 1977). Small wild mammals (rodents, insectivora), trapped in Northern Morocco in March 1979, were found positive to West Nile: 0.8% (n = 128) (Chastel et al., 1982). In 2008, The circulation of West Nile virus has been reported in wild birds in Morocco, north-east Kenitra city, and in particular individuals of Black birds (Turdus merula), Sparrows (Passer domesticus) and Cetti’s warbler (Cettia cetti) (Figuerola et al., 2008). In Tunisia, in 2011, investigations, on migratory birds captured during migration period and on domestic fowl (Gallus gallus domesticus) living in areas frequented by wild birds, showed that the seroprevalence of antibodies against WNV in birds was 50% (n = 4), for the gazette egret (Egretta garzetta), 40% (n = 25) for the greylag goose (Anser anser), 25% (n = 4) for moorhen (Gallinula chloropus, 33% (n = 3) for avocet (Recurvirostra avosetta), 6% (n = 17) for mallard (Anas platyrhynchos), 41% (n = 75) in the domestic fowl (Gallus gallus domesticus) and 27% (n = 11) in the starling (Sturnus vulgaris) (Bargaoui, 2012). A serological survey, on camels in South Morocco was conducted on 1344 sera, over two different time spans 4
(2003 and 2009) and across different sites of South Morocco, proved that of 556 tested sera taken in 2003 and 788 sera taken in 2009, the seroprevalence was, respectively, 10% and 13.6% (Touil et al., 2012) (Fig. 1). Discussion The data collected, on the WND in North-west Africa on clinical cases of meningo-encephalitis due to WND in humans in Algeria (1994), Morocco (1996) and Tunisia (1997, 2003, 2012), the outbreaks of WND in horses Morocco (1996, 2003 and 2010) and the serological evidence found in humans, equids and other species, suggest that WNV is endemic in north-west Africa (Fig. 1, Table 3). The presence of the virus may be the result of the introduction by migratory birds or an endemization resulting of overwintering cycles in local birds and mosquitoes during the winter season (Monaco et al., 2011). Furthermore, the studied area is situated along major migratory flyways, and the role of migratory birds in relation with the introduction of virus in Europe and Mediterranean Basin was clearly assessed by numerous studies (Calistri et al., 2010). Even though the five-sixths (5/6) of this region is covered by the desert, a coastal plain exists delimited and demarcated by a large mountain range (Tell in Algeria, Atlas in Morocco). Thus, the existence natural and artificial inland wetlands, are favourable to the concentration and conflu© 2015 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.
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West Nile Disease in North-West Africa
Fig. 1. WNV circulation in Morocco, Algeria and Tunisia.
Table 3. Comparison of West Nile infection between Algeria, Morocco and Tunisia
Virus Isolation Human confirmed Cases Equid Outbreaks Serologic evidence Humans Equids Camels Birds Small mammals
Algeria
Morocco
Tunisia
+ +
+ + +
+ +
+ +
+ + + + +
+ + + +
ence of different species around water points increasing, as a consequence, the contact and between WND vectors and hosts putting human populations and animals at greatest risk of acquiring this arboviral disease. These countries have favourable conditions for maintaining the WND transmission cycle such as environmental factors and climatic conditions (Rogers and Randolph, 2006). Those conditions sustain virus circulation, and when the density of vector mosquitoes is enhanced and sensitive hosts are available, outbreaks are observed. Triggering factors for WND outbreaks in the Morocco were explored by the analysis of climatic and environmental variables such as normalized difference vegetation index (NDVI), precipitation and land surface temperature by Calistri et al. (2013). NDVI and precipitation values recorded during epidemic years (2003 and 2010) proved to be significantly higher than those observed during the years with no WND cases in Morocco (Calistri et al., 2013). © 2015 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.
We note that the recursive infection is cyclical notably in Morocco where the outbreaks occurred in seven years interval since 1996. This is probably due to a decline in the general immunity among the equids population when renewed by non-immunized individuals unable to fight against a reintroduced virus by migratory birds. We also see that there are differences between these three countries in reporting infections caused by WNV. While Morocco has experienced outbreaks of WND in equids and no meningo-encephalitis epidemics in humans have been reported, in Algeria and Tunisia, it is exactly the opposite that is observed: in these two countries, human’s meningoencephalitis epidemics with mortality have been reported but no outbreaks of WND in equids (Table 3). Two hypotheses can be proposed to explain this difference. The first one is that the virus’ strains circulating in these countries may have different patterns, in terms of sensitive species and clinical expression of the disease. Phylogeography can support this hypothesis because there are genetic and phenotypic differences between the circulating serotypes in the region which all belong to lineage 1 Clade a. For example, the Moroccan isolate (96-111) is contained in cluster 2 and more precisely in the Mediterranean subtype grouping isolates from France, Portugal and Italy, while the Tunisian isolate (PaH001) of 1997 belongs to the cluster 4 which contains all the isolates from Americas, Israel (1998) and Hungry (2003). However, the Tunisian isolate diverged by amino acid substitutions (May et al., 2011) and differentiated from all the remaining isolates in this cluster associated with avian mortality. The paucity of isolates from North Africa makes it difficult to refine this hypothesis and leads to a second more 5
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plausible hypothesis according to which WND is underreported or underdiagnosed in humans and in horses. This may be due to the non-specific symptoms of the infection or the lack of an effective surveillance system implementation in these countries. This assumption is supported by the serologically high prevalence reported by many serological surveys conducted in both human and animals. Otherwise, conclusions of this bibliographical review may be influenced by a bias due to the fact that the large majority of the reported studies are ELISA based with no WNV specific neutralization assay raising the risk of false positive due an immune response raised against other eventual circulating flaviviruses. Conclusion WNV is endemic in north-west Africa countries. Its circulation is permanent and is probably accentuated by the reintroduction by migratory birds. Although cases are mostly human in Algeria and Tunisia, as opposed to the prevalence in horses in Morocco being the situation, it is likely that the virus circulates in both species without distinction as evidenced by serology. This infection is cyclical and is probably dependent upon the immune status of the population, the abundance of the vector, the availability of amplifying hosts and climatic factors. This viral circulation requires further investigation including the possible viral persistence in some hosts and vectors, the identification of mosquito species responsible for the infection of birds and mammals, the role of other vectors in the maintenance of infection such as ticks, the identifying of the species of resident or migratory species birds involved in the introduction and reintroduction of the disease etc. Wetlands should be thoroughly monitored and any abnormal nearby mortality in wild or resident birds investigated, as should the occurrence of outbreaks in horses and epidemics of meningo-encephalitis in humans. A regional and an international collaboration would certainly improve the knowledge of the dynamic of viral circulation and other aspects of the disease in the region. Understanding WND epidemiology in the area will certainly contribute to prevent the reoccurrence of the infection among humans and animals. Acknowledgements This study was supported by the University Mohammed V, Science Faculty Rabat Morocco. The authors would like to thank the Central Command Post For the Fight Against Bird Flu and the Society of Veterinary Biological and Pharmaceutical Products (BIOPHARMA). 6
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Competing interests The authors declare that they have no competing interests. References Bahri, O., I. Dhifallah, N. Ben Alaya-Bouafif, H. Fekih, J. Gargouri, and H. Triki, 2010: Sero-epidemiological study of West Nile virus circulation in human in Tunisia. Bull. Soc. Pathol. Exot. 104, 272–276. Bargaoui, R., 2012: Epidemiologie de la fievre West Nile. These de doctorat, Universite Montpellier II, Sciences et techniques du Langueduc, Montpellier, France. Ben Hassine, T., S. Hammami, H. Elghoul, and A. Ghram, 2011: Detection de la circulation de virus West Nile chez les Equid es dans le nord-ouest de la Tunisie. Bull. Soc. Pathol. Exot. 104, 266–271. Benjelloun, A., M. El Harrak, C. Lotfi, H. Kabbaj, and B. Belkadi, 2012 : Preliminary attempt to identify areas at risk for WND in the Mediterranean Basin: Serosurvey in horses in Morocco, Proceeding Risk analysis as a tool for the control of animal diseases and zoonoses in the Mediterranean Basin conference, Teramo 05-06 Italy Nov 2013 p:36. Boubaker, M., 2008: Contribution a l’etude des maladies nerveuses de groupe chez les equides en Tunisie. These med, Vet., Ecole Nationale Veterinaire de Sidi Tabet. Sidi Tabet, Tunisia. Burke, D. S., and T. P. Monath, 2001: Flaviviruses. In: Knipe, D. M. and P. M. Howley (eds), Fields Virology, 4th edn, pp. 1043–1125. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, USA. Calistri, P., A. Giovanni, Z. Hubalek, A. Ionescu, F. Monaco, G. Savini, and R. Lel, 2010: Epidemiology of West Nile in Europe and in the Mediterranean Basin. Open Virol. J. 4, 29–37. Calistri, P., C. Ippoliti, L. Candeloro, A. Benjelloun, M. El Harrak, B. Belkadi, M. Danzetta, D. Di Sabatino, and A. Conte, 2013: Analysis of climatic and environmental variables associated with the occurrence of West Nile virus in Morocco. Prev. Vet. Med. 110, 549–553. Cao, N. J., C. Ranganathan, W. J. Kupsky, and J. Li, 2005: Recovery and prognosticators of paralysis in West Nile virus infection. J. Neurol. Sci. 236, 73–80. Chastel, C., G. Rogues, F. Beaucournu-Saguez, H. Hellal, F. Le Goff, and J. C. Beaucournu, 1977: Mixed sero-epidemiologic study of arbovirus-arenavirus in the small mammals of Tunisia. Bull. Soc. Pathol. Exot. Filiales 70, 471–479. Chastel, C., H. Launay, H. Bailly-Choumara, G. Le Lay, and J. C. Beaucournu, 1982: Arbovirus infections in Morocco: serosurvey in small wild mammals in the northern part of the country. Bull. Soc. Pathol. Exot. Filiales 75, 466–475. De Filette, M., S. Ulbert, M. Diamond, and N. N. Sanders, 2012: Recent progress in West Nile virus diagnosis and vaccination. Vet. Res. doi:10.1186/1297-9716-43-16. El Harrak, M., B. Le Guenno, and P. Le Gounon, 1997: Isolation of West Nile virus in Morocco. Virologie 1, 248–249.
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Petersen, L. R., and J. T. Roehrig, 2001: West Nile virus: a reemerging global pathogen. Emerg. Infect. Dis. 7, 611–614. Pilo-Moro, E., J. Vincent, and Y. Le Coroller, 1970: Isolation of a West-Nile virus in the extreme south of algerian Sahara (Djanet). Arch. Inst. Pasteur Alger. 46, 181–184. Pradier, S., S. Lecollinet, and A. Leblond, 2012: West Nile virus epidemiology and factors triggering change in its distribution in Europe. Rev. Sci. Tech., 31, 829–844. Rogers, D. J., and S. E. Randolph, 2006: Climate change and vector-borne diseases. Adv. Parasitol. 62, 345–381. Schuffenecker, I., C. N. Peyrefitte, M. El Harrak, S. Murri, A. Leblond, and H. Zeller, 2005: West Nile virus in Morocco, 2003. Emerg. Infect. Dis. 11, 306–309. Sejvar, J. J., 2007: The long-term outcomes of human West Nile virus infection. Clin. Infect. Dis. 44, 1617–1624. Sotelo, E., J. Fernandez-Pinero, F. Llorente, M. Ag^ uero, U. Hoefle, J. M. Blanco, and M. A. Jimenez-Clavero, 2009: Characterization of West Nile virus isolates from Spain: new insights into the distinct West Nile virus ecoepidemiology in the Western Mediterranean. Virology 395, 289–297. Sotelo, E., A. V. Gutierrez-Guzman, J. Del Amo, F. Llorente, M. El-Harrak, E. Perez-Ramirez, J. M. Blanco, U. H^ ofle, and M. A. Jimenez-Clavero, 2011: Pathogenicity of two recent Western Mediterranean West Nile virus isolates in a wild bird species indigenous to Southern Europe: the red-legged partridge. Vet. Res. 42, 11. Tber, A., 1996: West-Nile fever in horses in Morocco. Bull. OIE 11, 867–869. Touil, N., N. Cherkaoui, Z. Lmrabih, C. Loutfi, B. Harif, and M. El Harrak, 2012: Emerging Viral Diseases in Dromedary Camels in the Southern Morocco. Transbound. Emerg. Dis. 59, 177–182. Triki, H., S. Murri, and B. Le Guenno, 2001: West Nile viral meningo-encephalitis in Tunisia. Med. Trop. 61, 487–490. World Animal Health Information Database. WAHID 2010: Event summary. Available at http://www.oie.int/wahis_2/pub lic/wahid.php/Reviewreport/semestrial/review?year=2010and semester=0andwild=0andcountry=MARandthis_country_ code=MARanddetailed=1 (Accessed December 04, 2011). Zientara, S., S. Lecollinet, E. Breard, C. Sailleau, and P. Boireau, 2009: La fievre du Nil Occidental et La fievre catarrhale ovine, deux viroses en progression inattendue. Bull. Acad. Vet. France 162, 73–87.
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REVIEW ARTICLE
West Nile Disease Epidemiology in North-West Africa: Bibliographical Review A. Benjelloun1,2, M. El Harrak3 and B. Belkadi1 1 2 3
Laboratory of Microbiology and Molecular Biology, Faculty of Science, University Mohammed V, Rabat, Morocco Poste de Commandement Central de Lutte Contre La Grippe Aviaire, Rabat, Morocco Soci et e de Produits biologiques et pharmaceutiques v et erinaires (Biopharma), Rabat, Morocco
Keywords: North Africa; horse; human; Morocco; Tunisia; Algeria; West Nile Virus Correspondence: B. Belkadi. Laboratoire de Microbiologie et Biologie Mol eculaire, Facult e des Sciences, Universit e Mohammed V Agdal, B.P. 1014, Rabat, Morocco. Tel/Fax: 00212537775461; E-mail: [email protected] Received for publication October 28, 2014 doi:10.1111/tbed.12341
Summary West Nile fever (WNF) or West Nile disease (WND) is a mosquito-borne viral disease that can affect birds, humans and horses. West Nile virus (WNV) is a member of the genus Flavivirus in the family Flaviviridae. WNV is maintained in a mosquito–bird–mosquito transmission cycle, whereas humans and horses are considered dead-end hosts. In human and horses, symptoms range from unapparent infection to mild febrile illness, meningitis, encephalitis or death. WNV has a wide geographical range that includes portions of Europe, Asia, Africa, Australia (Kunjin virus), and in North, Central and South America. Migratory birds are thought to be primarily responsible for virus dispersal, including reintroduction of WNV from endemic areas into regions that experience sporadic outbreaks (Fields Virology, 2001, Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, USA, 1043–1125). The occurrence of disease in humans and animals along with birds and mosquitoes surveillance for WNV activity demonstrates that the virus range has dramatically expanded including North, Central and South America as well as Europe and countries facing the Mediterranean Basin. WND infection in humans has been reported in Morocco in 1996 (Virologie, 1, 1997, 248), in Tunisia in 2007 (Ann. N. Y. Acad., 951, 2001, 117) (Med. Trop., 61, 2001, 487) and 2003 (Epidemiologie de la fievre West Nile, 2012, These de doctorat, Universite Montpellier II, Sciences et techniques du Langueduc, Montpellier, France), and in Algeria in 1994 (Rev. Sci. Tech., 31, 2012, 829). Outbreaks of equine encephalitis have been also reported in Morocco in 1996 (Bull. OIE, 11, 1996, 867), in 2003 (Emerg. Infect. Dis., 11, 2005, 306) and in 2010 (World Animal Health Information Database. WAHID, 2010). Serological evidence of WNV has been demonstrated in the three countries in many species. The aim of this review was to assess the epidemiological situation of WND in northwest Africa comprising Morocco, Algeria and Tunisia, with an updated literature review based on of human cases and equine outbreaks reports as well as serological studies in these countries.
Introduction West Nile virus is a flavivirus belonging to the Flaviviridae family and to the Japanese encephalitis serocomplex, which contains a number of viruses also associated to human encephalitis (Petersen and Roehrig, 2001). It is commonly found in Africa, Europe, the Middle East, © 2015 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.
North America and West Asia. It is maintained in nature by a cycle involving transmission between birds and mosquitoes. In the vector insect, the virus follows a cycle of intrinsic development. The air temperature has a great influence on the speed of the cycle as well as on female survival and also the duration of the transmission period. 1
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When local ecological conditions are suitable for virus amplification, the infection of humans and horses can occur and other mammals can also be infected during the blood meals. There has been confirmed transmission of WNV in humans by blood transfusion, organ transfer and breast milk, but most human infections occur by natural transmission from mosquitoes (OIE, 2013). Horses, just like humans, are “dead-end” hosts, meaning that while they become infected, they do not spread the infection. Clinical signs in equines are fever, weakness, locomotor dysfunction, ataxia and blindness. In the most severe cases, paraplegia occurs and evolves in 5 to 10 days to death. In most humans, WNV infection is subclinical, but approximately 20%–40% of those infected may develop symptoms of WNV disease ranging from West Nile fever (fever, headache, malaise, lymphadenopathy, myalgia, fatigue, skin rash, diarrhoea and vomiting) to meningoencephalitis (muscle weakness, tremors, paralysis and cognitive impairment) or flaccid paralysis (a polio-like syndrome) and, less frequently, death (Lindsey et al., 2010). Hepatitis, pancreatitis and myocarditis have also infrequently been described to occur (Kramer et al., 2007). In addition, long-term sequelae, including weakness, persistent movement disorders and cognitive deficits, frequently occurring in patients that have suffered from West Nile neuro-invasive disease (Cao et al., 2005; Sejvar, 2007). Although inactivated and recombinant vaccines are available for animal use, no vaccines or antiviral therapies are currently approved for humans (De Filette et al., 2012). WND infection has been reported in Morocco, Tunisia and Algeria. Serological evidence of WND has been found in the three countries during last decades in both species, but outbreaks of equine encephalitis due to WNV have been reported only in Morocco; while in Algeria and Tunisia, epidemics in humans without any apparent clinical cases in horses were observed. Virus Isolation WNV was first isolated in North Africa in Algeria in 1968, from a pool of 215 mosquitoes of the genus Culex in the region of Djanet in Illizi’s province (extreme south-east of Algeria) as part of an investigation on African horse sickness outbreaks that occurred in 1965 (Pilo-Moro et al., 1970). The virus was also isolated for the first time in 1996 in Morocco from a horse’s brain tissue (El Harrak et al., 1997) that died when unusual disease appeared in horses living in the Atlantic coastal area north-west of the country as reported by veterinary services. The West Nile virus strains circulating in Morocco are closely related to other Western Mediterranean strains and are characterized by 2
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high virulence in horses. The genome analysis of the WNV strains isolated in Morocco showed that they belong to WNV Lignage1, Clade 1a (Zientara et al., 2009). Phylogenetic analyses showed also that WNV Morocco/ 96 strain was very similar to mosquitoes WNV Senegal/93 strain and equids France/2000 strain, (Schuffenecker et al., 2005). One year later in Tunisia, in 1997, WNV was isolated in humans during a meningo-encephalitis epidemic and the strain belonged also to lineage 1 but was very close to the virulent strains isolated in Israel in 1998 and in New York in 1999 (Bahri et al., 2010). In 2003, the WNV strain isolated in equids in Morocco during an outbreak proved to be far more pathogenic than other Western Mediterranean viruses (Sotelo et al., 2009, 2011). However, no human meningo-encephalitis caused by equine WN/2003 was reported. In the three countries, all the WNV isolated strains belong to the European/Mediterranean/Kenyan cluster, which are characterized by moderate pathogenicity for horses and humans and limited or no pathogenicity for birds (Calistri et al., 2010). This is not the case for the strains grouped in the Israeli/American cluster which are characterized by high rate of avian deaths and, in the United States by high rates of morbidity and mortality in humans and horses (Calistri et al., 2010). WND in humans Despite the virus isolation from the vector in 1968 (PiloMoro et al., 1970) in mosquitoes in Algeria, and serological evidence found in humans (1973–1975–1976) and in animals (1975) in the region WND, clinical cases were never reported in humans in north-west Africa until 1994 (Metallaoui, 2008) (Table 1). During this year, an outbreak was reported in the south of Algeria (Timimoun, Adrar province), where about 50 suspect cases including 8 deaths were reported (Murgue et al., 2001). The patients had a high fever associated with neurological signs and other symptoms, sometimes presenting additionally a comatose state. Among 18 samples collected, 83.3% were positive (Pradier et al., 2012). However, the virus could not be isolated. In Morocco, 1 fatal case was notified during 1996 WND outbreak, and a year later, during the autumn 1997, Tunisa reported human epidemics of meningo-encephalitis caused by WNV, 173 cases, with 8 deaths were observed. Cases were reported in south-eastern Tunisia (Sfax and Mehdia) (Murgue et al., 2001). In 2003, another epidemic reoccurred, mostly in the same areas but also in other localities, WND was confirmed in 31 cases from 94 suspected cases. No virus was isolated or characterized by molecular analyses, and no animal cases were declared (Bargaoui, 2012). © 2015 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.
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Table 1. Reports of WND infection in humans in North-west Africa Country
Year
Area
Tested
Results
Algeria
1965 (Metallaoui, 2008) 1973 (Metallaoui, 2008) 1975 (Metallaoui, 2008)
Northern Algeria Djanet (Illizi) Illizi et Djanet (Illizi) Tamanrasset
P = 0% P = 14.6% P = 58.3% P = 3.5 %
1976 (Metallaoui, 2008)
Biskra Ouled Djellal (Wilaya of Biskra)
1994 * (Pradier et al., 2012) In 2012 * (EpiSouth, 2012) 1996 (El Harrak et al., 1997) 2011 (El Rhaffouli et al., 2012)
Timimoune (Adrar) Jijel (littoral between Alger et Annaba) Gharb region (Northwest) Rabat Kenitra Meknes Different regions Jerba Tunis Gabes Other regions Sfax,Mahdia and Other regions
N = 281 171 48 143 24 21 18 1 case 1 case 200 149 150 705 1094 205 85 22 129
Morocco
Tunisia
1968 (Haddad,1980) 1970’s (Bargaoui, 2012)
1997* (Murgue et al., 2001) (Triki et al., 2001) 2003 * (Bargaoui, 2012) 2007 (Bargaoui, 2012)
2010 (Bargaoui, 2012) 2011 (Bargaoui, 2012) In 2012, (ONMNE, 2012)
Monastir, Mahdia, Sfax et Gabes Kairaouan Bizerte Sfax Jendouba (North) Kebili (South) Monastir, Kebili Jendouba , Bizerte Tozeur, Kairouan, Nabeul Sousse, Gabes Mahdia, Sfax Sidi Bouzid, Medenine.
94
2 3 86 confirmed cases
P = 3.5% 19% P = 83.3% 1 case 1 case 24 (12%) 28 (18.8%) 7 (4.7%) 1.80% 3.8% 7.8% 7% 9.0% 111 cases (87%) 31 27.7% 0.7% 7.5% 2 cases 3 86 confirmed 12 deaths
*Meningo-encephalitis epidemic
In October 2010, WND was diagnosed in 2 children from Jendouba region (northern Tunisia–Algeria border) and in October 2011, WND was diagnosed in 3 women aged 61, 70 and 77 years in Kebili, (south of Tunisia) in the region of the oasis located near Al Chott Eljerrid (ONMNE, 2012). In 2011, evidence of human infection in Morocco was confirmed serologically by the detection of WND neutralizing bodies in 59 (P = 11.8%) among 499 healthy persons living in the vicinities of Meknes, Rabat and Kenitra cities (centre and north-west) (El Rhaffouli et al., 2012). The prevalence varied between 4.7 and 28% depending on the distance from the coastline. In 2012, from July, through to December 21, the surveillance of West Nile Virus Infections in Tunisia (ONMNE, 2012) demonstrated the disease in 86 confirmed cases with neurological forms and the death of 12 persons. In the same time, one confirmed clinical case was reported in Algeria (EpiSouth, 2012).
and the infection spread to neighbouring cities (in the central and north-western regions) (Tber, 1996), where 42 horses and one person died. After an apparent epidemiological silence, WND reoccurred in Morocco in 2003 (Schuffenecker et al., 2005) when 9 equine cases (with 5 deaths) were detected. Equine clinical cases were reported from three locations (Ouled Slama, Ameur Seflia, Mograne) 20 to 30 km north-east of Kenitra (centre) close to the Sebou River delta and the Atlantic Ocean. In 2010, in central and north-western part of the country in Benslimane, Khemisset, Mohammedia and Casablanca provinces, WND were confirmed in 17 horses, within 111 suspected cases (with 8 deaths) (World Animal Health Information Database. WAHID, 2010). Neither in Algeria nor in Tunisia clinical cases in equids were reported. Instead, many serosurveys on equids and other mammals demonstrate WNV circulation in these countries (Table 2).
WND in horses
WND evidence in other animals
Equine encephalitis caused by WNV in North Africa was reported in 1996 in Morocco in Benslimane region (centre)
As many reports have suggested that several species of wild mammals are commonly exposed to WNV, occasionally
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Table 2. Reports of WND infection in Equids in North-west Africa Country
Year
Aera
Tested/Case
Confirmed
Algeria Morocco
1975 (Metallaoui, 2008) 1996 * (Tber, 1996)
Djanet (Southeast) Benslimane (Center) Gharb region (Northwest)
Donkeys (n = 52) Horses Horses, donkeys, mules (n = 1200)
2003* (Schuffenecker et al., 2005) 2010 * (World Animal Health Information Database. WAHID, 2010)
Gharb region (Northwest)
9 equine cases
P = 96.6% 42 deaths 63% horses 44% donkeys 37% mules 9 equines 5 deaths
Benslimane, Khemisset, Mohammedia and Casablanca provinces (Center and northwest) Benslimane, Khemisset and other regions Jerba, Tunis, Gabes and other regions
Horses : 111 cases
confirmed in 17 horses 8 deaths
Horses (n = 840)
248 positive P = 29.52 %
Donkeys (n = 205), horses (n = 296), and mules (n = 55) Horses, donkeys, mules. (n = 269) Equids (n = 127) Equids (n = 133) : Donkeys (n = 93) , horses (n = 23) , mules (n = 17)
2 positive
2011 (Benjelloun et al., 2012) Tunisia
1980 (Haddad, 1980) 2005 (Bargaoui, 2012) 2007 (Boubaker, 2008) 2008 (Ben Hassine et al., 2011)
Gabes, Sfax, Mahdia, Mounastir, Nabeul and Bizerte Mounastir, Sfax Bizerte, Jendouba and El Kef (North-west)
86 positive P = 25%/Horses P = 37 %/(Donkeys, mules) 30% positive 36 positive (P = 27.1%).
*Outbreaks
with high-associated seroprevalence rates, some studies concerning small animals were carried out in the region. In 1976, haemagglutination-inhibiting antibodies against West Nile virus were detected in 19.8% of 156 small animals’ sera, mainly from Mus spp., Rattus rattus, Eliomys tunetae in the northern part of Tunisia, and from Ctenodactylus gundi and Pipistrellus kuhlii in the south (Chastel et al., 1977). Small wild mammals (rodents, insectivora), trapped in Northern Morocco in March 1979, were found positive to West Nile: 0.8% (n = 128) (Chastel et al., 1982). In 2008, The circulation of West Nile virus has been reported in wild birds in Morocco, north-east Kenitra city, and in particular individuals of Black birds (Turdus merula), Sparrows (Passer domesticus) and Cetti’s warbler (Cettia cetti) (Figuerola et al., 2008). In Tunisia, in 2011, investigations, on migratory birds captured during migration period and on domestic fowl (Gallus gallus domesticus) living in areas frequented by wild birds, showed that the seroprevalence of antibodies against WNV in birds was 50% (n = 4), for the gazette egret (Egretta garzetta), 40% (n = 25) for the greylag goose (Anser anser), 25% (n = 4) for moorhen (Gallinula chloropus, 33% (n = 3) for avocet (Recurvirostra avosetta), 6% (n = 17) for mallard (Anas platyrhynchos), 41% (n = 75) in the domestic fowl (Gallus gallus domesticus) and 27% (n = 11) in the starling (Sturnus vulgaris) (Bargaoui, 2012). A serological survey, on camels in South Morocco was conducted on 1344 sera, over two different time spans 4
(2003 and 2009) and across different sites of South Morocco, proved that of 556 tested sera taken in 2003 and 788 sera taken in 2009, the seroprevalence was, respectively, 10% and 13.6% (Touil et al., 2012) (Fig. 1). Discussion The data collected, on the WND in North-west Africa on clinical cases of meningo-encephalitis due to WND in humans in Algeria (1994), Morocco (1996) and Tunisia (1997, 2003, 2012), the outbreaks of WND in horses Morocco (1996, 2003 and 2010) and the serological evidence found in humans, equids and other species, suggest that WNV is endemic in north-west Africa (Fig. 1, Table 3). The presence of the virus may be the result of the introduction by migratory birds or an endemization resulting of overwintering cycles in local birds and mosquitoes during the winter season (Monaco et al., 2011). Furthermore, the studied area is situated along major migratory flyways, and the role of migratory birds in relation with the introduction of virus in Europe and Mediterranean Basin was clearly assessed by numerous studies (Calistri et al., 2010). Even though the five-sixths (5/6) of this region is covered by the desert, a coastal plain exists delimited and demarcated by a large mountain range (Tell in Algeria, Atlas in Morocco). Thus, the existence natural and artificial inland wetlands, are favourable to the concentration and conflu© 2015 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.
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Fig. 1. WNV circulation in Morocco, Algeria and Tunisia.
Table 3. Comparison of West Nile infection between Algeria, Morocco and Tunisia
Virus Isolation Human confirmed Cases Equid Outbreaks Serologic evidence Humans Equids Camels Birds Small mammals
Algeria
Morocco
Tunisia
+ +
+ + +
+ +
+ +
+ + + + +
+ + + +
ence of different species around water points increasing, as a consequence, the contact and between WND vectors and hosts putting human populations and animals at greatest risk of acquiring this arboviral disease. These countries have favourable conditions for maintaining the WND transmission cycle such as environmental factors and climatic conditions (Rogers and Randolph, 2006). Those conditions sustain virus circulation, and when the density of vector mosquitoes is enhanced and sensitive hosts are available, outbreaks are observed. Triggering factors for WND outbreaks in the Morocco were explored by the analysis of climatic and environmental variables such as normalized difference vegetation index (NDVI), precipitation and land surface temperature by Calistri et al. (2013). NDVI and precipitation values recorded during epidemic years (2003 and 2010) proved to be significantly higher than those observed during the years with no WND cases in Morocco (Calistri et al., 2013). © 2015 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.
We note that the recursive infection is cyclical notably in Morocco where the outbreaks occurred in seven years interval since 1996. This is probably due to a decline in the general immunity among the equids population when renewed by non-immunized individuals unable to fight against a reintroduced virus by migratory birds. We also see that there are differences between these three countries in reporting infections caused by WNV. While Morocco has experienced outbreaks of WND in equids and no meningo-encephalitis epidemics in humans have been reported, in Algeria and Tunisia, it is exactly the opposite that is observed: in these two countries, human’s meningoencephalitis epidemics with mortality have been reported but no outbreaks of WND in equids (Table 3). Two hypotheses can be proposed to explain this difference. The first one is that the virus’ strains circulating in these countries may have different patterns, in terms of sensitive species and clinical expression of the disease. Phylogeography can support this hypothesis because there are genetic and phenotypic differences between the circulating serotypes in the region which all belong to lineage 1 Clade a. For example, the Moroccan isolate (96-111) is contained in cluster 2 and more precisely in the Mediterranean subtype grouping isolates from France, Portugal and Italy, while the Tunisian isolate (PaH001) of 1997 belongs to the cluster 4 which contains all the isolates from Americas, Israel (1998) and Hungry (2003). However, the Tunisian isolate diverged by amino acid substitutions (May et al., 2011) and differentiated from all the remaining isolates in this cluster associated with avian mortality. The paucity of isolates from North Africa makes it difficult to refine this hypothesis and leads to a second more 5
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plausible hypothesis according to which WND is underreported or underdiagnosed in humans and in horses. This may be due to the non-specific symptoms of the infection or the lack of an effective surveillance system implementation in these countries. This assumption is supported by the serologically high prevalence reported by many serological surveys conducted in both human and animals. Otherwise, conclusions of this bibliographical review may be influenced by a bias due to the fact that the large majority of the reported studies are ELISA based with no WNV specific neutralization assay raising the risk of false positive due an immune response raised against other eventual circulating flaviviruses. Conclusion WNV is endemic in north-west Africa countries. Its circulation is permanent and is probably accentuated by the reintroduction by migratory birds. Although cases are mostly human in Algeria and Tunisia, as opposed to the prevalence in horses in Morocco being the situation, it is likely that the virus circulates in both species without distinction as evidenced by serology. This infection is cyclical and is probably dependent upon the immune status of the population, the abundance of the vector, the availability of amplifying hosts and climatic factors. This viral circulation requires further investigation including the possible viral persistence in some hosts and vectors, the identification of mosquito species responsible for the infection of birds and mammals, the role of other vectors in the maintenance of infection such as ticks, the identifying of the species of resident or migratory species birds involved in the introduction and reintroduction of the disease etc. Wetlands should be thoroughly monitored and any abnormal nearby mortality in wild or resident birds investigated, as should the occurrence of outbreaks in horses and epidemics of meningo-encephalitis in humans. A regional and an international collaboration would certainly improve the knowledge of the dynamic of viral circulation and other aspects of the disease in the region. Understanding WND epidemiology in the area will certainly contribute to prevent the reoccurrence of the infection among humans and animals. Acknowledgements This study was supported by the University Mohammed V, Science Faculty Rabat Morocco. The authors would like to thank the Central Command Post For the Fight Against Bird Flu and the Society of Veterinary Biological and Pharmaceutical Products (BIOPHARMA). 6
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Competing interests The authors declare that they have no competing interests. References Bahri, O., I. Dhifallah, N. Ben Alaya-Bouafif, H. Fekih, J. Gargouri, and H. Triki, 2010: Sero-epidemiological study of West Nile virus circulation in human in Tunisia. Bull. Soc. Pathol. Exot. 104, 272–276. Bargaoui, R., 2012: Epidemiologie de la fievre West Nile. These de doctorat, Universite Montpellier II, Sciences et techniques du Langueduc, Montpellier, France. Ben Hassine, T., S. Hammami, H. Elghoul, and A. Ghram, 2011: Detection de la circulation de virus West Nile chez les Equid es dans le nord-ouest de la Tunisie. Bull. Soc. Pathol. Exot. 104, 266–271. Benjelloun, A., M. El Harrak, C. Lotfi, H. Kabbaj, and B. Belkadi, 2012 : Preliminary attempt to identify areas at risk for WND in the Mediterranean Basin: Serosurvey in horses in Morocco, Proceeding Risk analysis as a tool for the control of animal diseases and zoonoses in the Mediterranean Basin conference, Teramo 05-06 Italy Nov 2013 p:36. Boubaker, M., 2008: Contribution a l’etude des maladies nerveuses de groupe chez les equides en Tunisie. These med, Vet., Ecole Nationale Veterinaire de Sidi Tabet. Sidi Tabet, Tunisia. Burke, D. S., and T. P. Monath, 2001: Flaviviruses. In: Knipe, D. M. and P. M. Howley (eds), Fields Virology, 4th edn, pp. 1043–1125. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, USA. Calistri, P., A. Giovanni, Z. Hubalek, A. Ionescu, F. Monaco, G. Savini, and R. Lel, 2010: Epidemiology of West Nile in Europe and in the Mediterranean Basin. Open Virol. J. 4, 29–37. Calistri, P., C. Ippoliti, L. Candeloro, A. Benjelloun, M. El Harrak, B. Belkadi, M. Danzetta, D. Di Sabatino, and A. Conte, 2013: Analysis of climatic and environmental variables associated with the occurrence of West Nile virus in Morocco. Prev. Vet. Med. 110, 549–553. Cao, N. J., C. Ranganathan, W. J. Kupsky, and J. Li, 2005: Recovery and prognosticators of paralysis in West Nile virus infection. J. Neurol. Sci. 236, 73–80. Chastel, C., G. Rogues, F. Beaucournu-Saguez, H. Hellal, F. Le Goff, and J. C. Beaucournu, 1977: Mixed sero-epidemiologic study of arbovirus-arenavirus in the small mammals of Tunisia. Bull. Soc. Pathol. Exot. Filiales 70, 471–479. Chastel, C., H. Launay, H. Bailly-Choumara, G. Le Lay, and J. C. Beaucournu, 1982: Arbovirus infections in Morocco: serosurvey in small wild mammals in the northern part of the country. Bull. Soc. Pathol. Exot. Filiales 75, 466–475. De Filette, M., S. Ulbert, M. Diamond, and N. N. Sanders, 2012: Recent progress in West Nile virus diagnosis and vaccination. Vet. Res. doi:10.1186/1297-9716-43-16. El Harrak, M., B. Le Guenno, and P. Le Gounon, 1997: Isolation of West Nile virus in Morocco. Virologie 1, 248–249.
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