Zoonosis Update

Rift Valley fever virus

Brian H. Bird, scm, phd; Thomas G. Ksiazek, dvm, phd; Stuart T. Nichol, phd; N. James MacLachlan, bvsc, phd, dacvp

ift Valley fever virus is a -borne pathogen Abbreviations Rof livestock and that historically has been responsible for widespread and devastating outbreaks of BSL Biosafety level severe disease throughout and, more recently, the MP-12 Modified passage-12x PFU Plaque-forming unit Arabian Peninsula. The virus was first isolated and RVF RT Reverse transcription disease was initially characterized following the sudden RVF Rift Valley fever deaths (over a 4-week period) of approximately 4,700 lambs and ewes on a single farm along the shores of Lake Naivasha in the Great Rift Valley of Kenya in 1931.1 Since on that were only later identified as infected 6,7 that time, RVF virus has caused numerous economically with RVF virus. The need for a 1-medicine approach devastating epizootics that were characterized by sweep- to the diagnosis, treatment, surveillance, and control of ing abortion storms and mortality ratios of approximately RVF virus infection cannot be overstated. The close co- 100% among neonatal animals and of 10% to 20% among ordination of veterinary and medical efforts (es- adult ruminant livestock (especially and ).2–4 pecially in countries in which the virus is not endemic Infections in humans are typically associated with self- and health-care personnel are therefore unfamiliar with limiting febrile illnesses. However, in 1% to 2% of affected RVF) is critical to combat this important threat to the individuals, RVF infections can progress to more severe health of humans and other animals. disease including fulminant hepatitis, encephalitis, retini- Because of the potential for severe consequences tis, blindness, or a hemorrhagic syndrome; among severe- during outbreaks, RVF virus is considered a major zoo- ly affected persons who are hospitalized, the case fatality notic threat. Rift Valley fever virus is classified as a Cat- 8 ratio is approximately 10% to 20%.5 egory A overlap Select Agent by the CDC and the USDA Rift Valley fever epizootics and epidemics can rap- and as a high-consequence pathogen with the potential idly overwhelm the capacities of the public health and for international spread (List A) by the World Organi- veterinary medical communities to provide rapid diag- zation for Health (Office International des Épi- 9 nostic testing and adequate medical care for affected zooties). As such, RVF virus is considered a potential humans and other animals, which can number in the threat as a biological terrorism agent that could have tens if not hundreds of thousands. Veterinarians, other dramatic direct (morbidity and death) and indirect (in- health personnel, farmers, and abattoir workers also ternational trade restrictions) impact in countries that are at high risk of infection from direct contact with are currently free of the virus. Furthermore, numerous infected animals and patients; indeed, many historical species of potentially competent mosquito vectors are 10 outbreaks of RVF disease in Africa were initially detect- present throughout North America and Europe. This ed because of illnesses among veterinarians and their review will focus on the current understanding of RVF assistants after they performed necropsies on infected virus ecology; pathogenesis and clinical signs of RVF animals. In 2008, several veterinarians, staff, and vet- disease among livestock, humans, and wildlife; the use erinary students at a South African veterinary college and limitations of rapid diagnostic testing during out- were infected after handling and performing necropsies breaks; and recent advances in vaccine design and de- velopment, as well as potential veterinary medical and From the Department of Pathology, Microbiology, and Immunology, public health consequences following introduction of School of Veterinary Medicine, University of California, Davis, CA the virus into previously unaffected areas. 95616 (Bird, MacLachlan); and Special Pathogens Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Preven- tion, Atlanta, GA 30333 (Ksiazek, Nichol). Dr. Ksiazek’s present address Etiologic Agent and Biosafety is Galveston National Laboratory, Department of Pathology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555. Rift Valley fever virus (Family, Bunyaviridae; ge- Dr. Bird was supported by the dual-degree DVM/PhD Veterinary Scien- nus, Phlebovirus) is an enveloped spherical particle (80 tist Training Program, the Graduate Group of Comparative Pathology, to 100 nm in diameter) with a tripartite single-stranded and the Students Training in Advanced Research programs of the Uni- negative-sense RNA genome (approx 11.9 kilobases).11 versity of California, Davis, School of Veterinary Medicine. The Bunyaviridae include several important veterinary The findings and conclusions in this report are those of the authors and and human medical pathogens such as Nairobi sheep do not necessarily represent the views of the funding agencies or the Centers for Disease Control and Prevention. disease virus, Akabane virus, Crimean-Congo hemor- The authors thank Dr. Robert Swanepoel for technical assistance. rhagic fever virus, La Crosse virus, sandfly fever Sicilian Address correspondence to Dr. Bird. virus, and the hantaviruses.

JAVMA, Vol 234, No. 7, April 1, 2009 Vet Med Today: Zoonosis Update 883 Rift Valley fever virus is a notorious cause of acci- including movements of infected camels along trade dental infection among laboratory workers and veterinar- routes with Sudan, windblown infected mosquitoes, or ians. Direct contact with infected animals, especially dur- infected passengers on commercial airlines.24 Since the ing necropsy and obstetric procedures, is associated with 1977–1979 outbreak, RVF virus activity has occurred a high risk of infection; in any circumstances involving sporadically in Egypt, with deaths among livestock and such contact, strict adherence to universal blood-borne low numbers of human infections.25–27 pathogen precautions and to good biosafety practices is re- In 2000, the presence of RVF virus outside of Africa quired.12–15 Rift Valley fever virus particles in serum retain was reported for the first time. In the western provinces infectivity when stored at 4°C for several weeks, which is of Saudi Arabia and Yemen, an outbreak of severe human an important consideration in the safe handling of diag- and livestock disease associated with RVF virus occurred; nostic specimens.16 The virus is readily inactivated by use there were an estimated 2,000 human infections and at of strong detergents or 10% solutions of sodium hypochlo- least 245 deaths, and thousands of and sheep also rite (bleach) and via formalin fixation.16,17 Because of the died.19,28 This outbreak was preceded by exceptionally ease of horizontal transmission, laboratory-based investi- heavy rainfall, which resulted in large increases in the gations must be performed in BSL 3–enhanced (ie, BSL-3+ mosquito population and subsequent transmission of the or BSL-3 Agriculture) facilities in the United States.18 virus.29,30 Genetic analyses of RVF virus isolates collected during the Saudi Arabia–Yemen outbreak revealed high Epidemiology and Ecology similarity to viruses present during a 1997–1998 Kenyan outbreak, which suggested that the virus was introduced Impact of major epizootics and epidemics—Rift into Saudi Arabia and Yemen from eastern Africa.31,32 Valley fever virus infection of humans and other ani- However, as for the 1977–1979 Egyptian outbreak, the mals has been identified in approximately 30 countries, precise route of introduction is enigmatic because no and major epizootics and epidemics occur periodically epizootics in eastern Africa were reported at that time. It throughout the known geographic range of the virus is possible that viremic animals were imported into Saudi (Figure 1). The disease was initially thought to be re- Arabia or Yemen during the preceding 1997–1998 east stricted to the eastern Rift Valley region of Africa. How- African epizootic and that RVF virus circulated at levels ever, in 1951, a severe epizootic in South Africa occurred below the detection threshold until climactic conditions during which an estimated 100,000 sheep died and 500,000 ewes aborted their fetuses.19 The cause of the epizootic was not recognized as RVF virus until severe disease occurred in a veterinar- ian and several assistants following the necropsy of a dead bull.15 This outbreak initiated what has since become a repeat- ing pattern in which the recognition of RVF virus infection among humans often precedes the detection of animal disease because of the difficulties of veterinary surveillance in resource-poor settings. Traditionally, RVF virus has been restricted to sub-Saharan Africa but was detected north of the Sahara desert in 1977, where it was the cause of a mas- sive epidemic-epizootic along the Nile river and delta in Egypt.20–22 This out- break, in an apparently RVF-free area, remains the largest on record, with an estimated 200,000 human infections and at least 594 deaths among hospitalized patients.22 Losses among livestock were extensive; the costs were more than US $115 million at that time.21,23 During that outbreak, the full spectrum of hu- man RVF disease became apparent and ranged from subclinical infection to se- vere cases of hepatic necrosis with fatal hemorrhagic complications, delayed on- set encephalitis and permanent neuro- logic deficits, or severe retinitis with per- manent blindness.22 The route by which RVF virus was introduced into Egypt Figure 1—Geographic distribution of RVF virus. Countries in which epizootics or epidem- ics are known to have occurred are indicated in red with the date of each outbreak. Coun- will likely never be known, but several tries with evidence of low-level enzootic activity (antibody prevalence or occasional RVF potential scenarios have been proposed, virus isolation) are indicated in pink. To convert kilometers to miles, multiply by 0.625.

884 Vet Med Today: Zoonosis Update JAVMA, Vol 234, No. 7, April 1, 2009 occurred in 2000 that were conducive to widespread vi- tion over eastern and southern Africa.46 In western and rus activity.19 central Africa, where rainfall is generally more abun- Most recently, an outbreak of RVF occurred in 2006 dant, RVF virus transmission characteristically follows and 2007 following heavy rains over much of eastern Afri- a more continuous enzootic or endemic pattern and is ca. This outbreak caused considerable losses of livestock, likely dependent on both the availability of mosquito and 698 human deaths were reported from Somalia, Ke- breeding habitats and the presence of sufficient num- nya, and Tanzania.33,34 As in the 1997–1998 outbreak, the bers of susceptible animals. focus of RVF virus activity extended as the heavy rains A critical link between rainfall and mosquitoes shifted southwards from Kenya toward Tanzania. The ex- was made when transovarial transmission of RVF virus tension of RVF epizootic and epidemic foci over broad in lineatopennis mosquitoes was identified.47 In areas and across international boundaries obviously com- semiarid regions that compose the eastern and south- plicates both surveillance and control efforts. ern African enzootic zone of RVF virus transmission, Overall, since its original detection in the Rift Val- normal rainfall patterns greatly limit the period avail- ley of Kenya, RVF virus has been identified in exten- able for vector activity. In those areas, the survival of sive areas of Africa—from the Cape of Good Hope in floodwater Aedes (subgenera Neomelaniconium and Ae- South Africa to the Nile Delta in Egypt. During this dimorphus) mosquitoes is dependent on drought-resis- interval, the remarkable ability of the virus to cross ex- tant eggs that remain viable for long periods (perhaps tensive geographic barriers including the Sahara desert many years) following the drying of breeding habitats. (Egypt), the Red Sea (Saudi Arabia and Yemen), and The breeding habitats are usually shallow depressions the Indian Ocean (Madagascar) has become apparent. or pans (referred to as dambos) that range in size from Clearly, RVF virus will continue to impact both veteri- a few meters to over a kilometer in diameter; when nary and human health throughout Africa with risk of flooded, dambos provide an ideal environment for Ae- further spread into Europe and Asia or even into the des mosquito breeding and egg deposition. An essential Americas.

Vectors and RVF transmission— Mosquitoes are the only important bio- logical vectors of RVF virus; however, ex- perimental infection has been established in several other , including phlebotomine sandflies and ticks.35–42 Rift Valley fever virus has been isolated from > 30 species of mosquitoes from at least 6 genera (Aedes, Culex, Anopheles, Eretmap- odites, Mansonia, and Coquillettidia).43 Im- portantly, experimental studies10,43–45 have revealed high vector competence among mosquito species in North America (ie, Aedes albopictus, Aedes canadensis, Aedes cantator, Aedes excrucians, Aedes sollici- tans, Aedes taeniorhynchus, Aedes triseria- tus, Culex salinarius, Culex tarsalis, Culex territans, and Culex pipiens). Thus, should RVF virus be introduced into the North American continent, potential competent vectors are clearly available for the estab- lishment of epizootic and perhaps enzo- otic transmission cycles. In eastern and southern Africa, the ecology of RVF virus involves 2 distinct but overlapping cycles of low-level enzo- otic activity and periodic epizootics and epidemics (Figure 2). The association of RVF virus epizootics and epidemics with heavy rainfall and high numbers of mosquitoes was first reported during the original characterization of the dis- ease in the 1931.1 It is now known that the development of epizootic- or epi- Figure 2—Enzootic and epidemic-epizootic transmission cycles of RVF virus. In the demic-associated transmission is depen- enzootic transmission cycle (top left panel), wildlife (eg, African buffalo species) are po- dent on large-scale weather events such tential maintenance hosts. In the epidemic-epizootic transmission cycle (remainder of figure), livestock amplification hosts and secondary bridge vectors are involved. (Sym- as the warm El Niño Southern Oscilla- bols courtesy of the Integration and Application Network (ian.umces.edu/symbols/), tion, which can lead to heavy precipita- University of Maryland Center for Environmental Science. Accessed Jan 1, 2009.)

JAVMA, Vol 234, No. 7, April 1, 2009 Vet Med Today: Zoonosis Update 885 feature of the floodwater Aedes mosquito life cycle is comes that range from subclinical illness to sudden the requirement for drying followed by heavy rainfall death.16,56 Although RVF virus is primarily a pathogen that is sufficient to reflood the dambos, thereby creating of livestock and humans, experimental infections of pools of sufficient depth to inundate dormant eggs and laboratory animals (mice, rats, hamsters, , cats, provide an aquatic habitat for development of mosquito and macaques) can result in rapid onset of clinical larvae.19 The dynamics of mosquito emergence and spe- disease and death.57–59 The epidemiologic and ecologic cies succession (broadly defined as the temporal rela- importance of these infections of laboratory and com- tionship of individual mosquito species emerging from panion animal species is limited; thus, this review ar- a given flooded habitat) were examined following natu- ticle focuses on infections of domestic livestock, wild- ral or artificial flooding of Kenyan dambos and revealed life, and humans. that the first species to emerge were floodwater Aedes mosquitoes (A lineatopennis, Aedes cumminsii, and Ae- General features among livestock—A typical hall- des sudanensis) followed a few days later by secondary mark of RVF virus epizootics is the sudden development bridge vectors including Culex and Anopheles spp.48,49 of extensive abortion storms over wide areas following Taken together, these findings facilitate development exceptionally heavy rainfall.19 Rift Valley fever disease of a model of the RVF virus life cycle (Figure 2). Clearly, in livestock is characterized by peracute to acute onset regardless of geographic location, a complex interplay of of inappetence, nasal discharge, and diarrhea; affected rainfall, mosquito abundance, transovarial transmission, animals are highly viremic (approx 1 X 106 PFUs/mL to and availability of suitable naïve amplification hosts in- 1.0 X 108 PFUs/mL; Figure 3). At necropsy, pathologic fluences the development of either enzootic stability or findings include diffuse hepatic necrosis, splenomegaly, periodic waves of undetectable activity punctuated by and gastrointestinal hemorrhage. Viral antigen is abun- geographically extensive epizootics and epidemics. dant in the reticulo-endothelial system and in multiple organs, including the liver, kidneys, adrenal glands, Enzootic cycle—During periods with normal (non- gastrointestinal tract, brain parenchyma, and ovaries or excessive) amounts of rainfall, RVF virus is likely main- endometrium.2,3,60–62 tained by low-level enzootic activity within the mosquito vector population involving transovarial transmission with occasional in- fection and amplification of virus in wildlife such as African buffaloes (Syncerus caffer) or susceptible livestock (Figure 2). Somewhat controversially, small rodents have also been proposed as potential hosts.50–53 Epizootic or epidemic cycle—A shift from enzootic to epizootic or epidemic RVF virus activity typically occurs following ex- tended periods of exceptionally plentiful rainfall and subsequent inundation of dam- bos, which results in the emergence of abun- dant numbers of floodwater Aedes mosqui- toes (Figure 2). These transovarially infect- ed mosquitoes feed on susceptible livestock (eg, sheep and cattle) that rapidly develop high-titer viremias (1.0 X 106 PFUs/mL of blood to 1.0 X 108 PFUs/mL of blood) and signs of clinical disease; in turn, the infected livestock infect secondary bridge mosquito vectors such as Culex or Anopheline spp.2,3,54 Soon thereafter, human infections develop either as a result of bites from infected mos- quitoes (Aedes, Culex, or Anopheline spp), exposure to infectious aerosols, handling of aborted fetal materials, or percutaneous injury during slaughtering or necropsy of viremic animals.21,22,55 It is unclear whether humans have any important biological role as amplification hosts in the RVF virus epi- zootic or epidemic life cycle.

Figure 3—Generalized time course of viremia and antibody response against RVF virus in live- Pathogenesis and Clinical Signs stock (A) and the development of RVF disease among livestock (B) and humans (C). In panel A, the intervals during which diagnostic testing involving nucleic acid–based (RT-PCR assays) and Many mammalian species are sus- serologic (RVF virus–specific IgM or IgG) assays are appropriate are indicated in relation to the ceptible to RVF virus infection, with out- period of viremia. To convert degrees Celsius to degrees Fahrenheit, multiply by 9/5 and add 32.

886 Vet Med Today: Zoonosis Update JAVMA, Vol 234, No. 7, April 1, 2009 Sheep—Young (< 1-month-old) lambs are highly nated intravascular coagulation.3,63 As in sheep, marked susceptible to RVF virus infection, with mortality ratios lymphoid necrosis and depletion is evident in lymphoid typically reaching approximately 90% to 100%. The clin- tissues.3 ical course of the disease in lambs is short, with an incu- bation period of approximately 12 to 24 hours followed Goats—There are relatively few published data on by a marked febrile response (rectal temperature, 41° to the pathogenesis of RVF virus infection in goats. Al- 42°C [105.8° to 107.6°F]) and rapid progression to death though goats are highly susceptible to infection, they 63 appear to be more refractory to severe or lethal disease within 24 to 72 hours. Adult sheep are less susceptible 67,70–74 to infection, with mortality ratios among affected adults than sheep. Studies in western Africa (Senegal, of approximately 10% to 30%. Abortion rates can be high Mauritania, and Cameroon) revealed that approximate- (90% to 100%), which gives rise to the characteristic ly 2% to 10% of goats are seropositive for anti–RVF abortion storms associated with RVF virus epizootics.19 virus antibody during enzootic periods; following epi- > Fetal loss and abortion are characterized by multiple-or- zootics, this proportion rose to 70%. High mortality gan infection and necrosis in the fetus as well as RVF ratios (approx 48%) occurred in kids among 223 flocks studied following a 1998 epizootic in Maurita- virus infection and necrosis of placental cotyledons and 67 caruncles.2,64 Interestingly, vaccination of pregnant ewes nia. Results of recent investigation of the 2006–2007 during early to midgestation (30 to 105 days of gestation) epidemic-epizootic in Kenya indicate that the preva- lence of RVF virus–specific IgM is similar among sheep with live-attenuated Smithburn strain RVF virus vac- 34 cine reportedly results in hydrops amnii, arthrogryposis, and goats. Severe RVF disease (abortion, lethargy, and 65 inappetence) in RVF virus–infected goats is similar to and hydranencephaly. Rift Valley fever disease in adult 4,56,60 sheep is characterized by an incubation period of 24 to that in sheep. 72 hours and a generalized febrile response, lethargy, he- Camels—Rift Valley fever virus infection in camels matemesis, hematochezia, and nasal discharge.2,61,63,66 (Camelus dromedarius) was described after an extensive Gross and histopathologic findings in naturally outbreak of abortion in northern Kenya in 1961.75 Al- infected sheep also confirm widespread organ involve- though the report confirmed high prevalence (45%) of ment. The liver typically is large, soft, friable, and discol- serum RVF virus–specific IgG antibody among the 60 ored (yellow to tan), and numerous pale foci of necro- camels evaluated, RVF virus was not definitively proven sis are disseminated throughout the liver parenchyma. to be the causative agent of the disease outbreak. Inves- Subcutaneous, visceral, and serosal hemorrhages are tigations21,76 conducted during and following the 1977– present, often accompanied by icterus and abomasal and 1979 Egyptian epizootic revealed that the prevalence of intestinal hemorrhage.63 Lethal infections are histologi- serum anti–RVF virus IgG antibody was approximately cally characterized by multifocal to coalescing or diffuse 21% among 466 camels that underwent testing; there hepatocellular necrosis with an accompanying infiltrate were reports of abortion among this Egyptian camel of neutrophils and macrophages. Lymphoid necrosis is herd. Rift Valley fever virus was isolated from at least 1 present in the cortex and medulla of lymph nodes with animal during this outbreak.77 During an RVF epizootic scant lymphoid necrosis within the splenic white pulp. and epidemic in Mauritania in 1998, a low proportion Pulmonary congestion and edema with multifocal ne- (approx 3%) of adult camels had serum IgM or IgG an- crosis of alveolar and peribronchiolar lymphoid tissue tibodies against RVF virus, and the neonatal mortality develop in some animals.62 ratio among calves was high (approx 20%).67 Cattle—Neonatal (< 1-month-old) calves are less Horses—Although investigations have been lim- susceptible to lethal RVF virus infections than are neo- ited, the prevalences of anti–RVF virus IgG antibody natal lambs, although estimates of mortality ratios range among horses from RVF virus–endemic areas of from 10% to 70%.3,19,60,67 The disease course and histo- and in horses in locations affected by the 1977–1979 logic findings are similar to those in lambs. Although Egyptian epidemic-epizootic were approximately 3% susceptible to RVF virus infection, adult bovids are to 10%.21,78,79 Results of a classic study by Yedloutshnig more resistant to lethal infection than sheep; among et al80 indicated that Shetland ponies were susceptible adult cattle, the case fatality ratio is approximately 5% to to infection following administration of high doses of 10%.63 Rift Valley fever disease in cattle is characterized virulent RVF virus (1.0 X 105 PFUs/mL to 1.0 X 107 by fever of 1 to 4 days’ duration, which is accompanied PFUs/mL); however, signs of clinical disease were not by inappetence, lethargy, hematochezia, and occasional- apparent, and peak postchallenge viremia did not ex- ly epistaxis.68 A notable but temporary decrease in milk 2.5 ceed 1.0 X 10 mouse LD50/mL. The authors concluded production can occur in lactating cows,63,68 and there are that horses were likely of little relevance to the overall anecdotal reports of RVF virus transmission to humans ecology of RVF virus infection. via unpasteurized milk.16,69 As for RVF virus–infected sheep, abortions are common and often the only evident Wildlife—To date, there have been few controlled sign of infection among pregnant cattle.63,68 studies of the pathogenesis of RVF virus infection in Apart from lower mortality ratio, the characteris- wildlife. Results of 2 experimental studies81,82 that fo- tics of severe RVF virus infections in cattle are similar to cused on infection in African buffaloes (S caffer) have those in sheep; histopathologic findings include mul- been reported. In those studies, 1 of 2 pregnant buf- tifocal to diffuse centrilobular hepatocellular necrosis faloes aborted 16 days after infection, and 4 of 5 buf- 4.4 with accompanying inflammatory infiltrates and occa- faloes developed viremia (approx 10 TCID50/mL) sional fibrin thrombi in the hepatic sinusoids, central that persisted for at least 48 to 72 hours, similar to that veins, and portal triads that are suggestive of dissemi- which developed in control cattle (Bos spp) following

JAVMA, Vol 234, No. 7, April 1, 2009 Vet Med Today: Zoonosis Update 887 infection. This high-titer viremia suggests that African with RVF virus outbreaks highlight the necessity for buffaloes may have a role in the natural enzootic trans- regional and national reference diagnostic laboratories mission cycle of RVF virus. with appropriate expertise. These laboratories must In numerous field investigations, results of sero- have the capacity to accurately evaluate large numbers logic testing and virus isolation have confirmed the of samples. The consequences of any delay or error in importance of wildlife in the natural ecology of RVF the diagnosis of RVF virus infection in the early stages virus infection as either susceptible hosts during epizo- of a nascent epizootic are considerable. The clinical otics or potential maintenance hosts during interepizo- signs of RVF virus infection in livestock are not distinc- otic periods. Evidence of previous RVF virus infection tive; however, outbreaks of abortion (80% to 100% of was recently confirmed in a variety of wildlife (16 spe- animals affected), high neonatal mortality ratios, and cies) in Kenya, including African buffalo (S caffer), el- large numbers of deaths among adult sheep, cattle, ephant (Loxodonta africana), warthog (Phacochoerus ae- or goats are suggestive of RVF disease. In the United thiopicus), black rhino (Diceros bicornis), zebra (Equus States, such abortion storms or unexplained increases burchelli), Thompson’s gazelle (Gazella thompsonii), in livestock mortality ratios should be reported to the lesser kudu (Tragelaphus strepsiceros), impala (Aepycer- office of the relevant State Veterinarian as a suspected os melampus), and waterbuck (Kobus ellipsiprymnus).83 outbreak of a foreign animal disease. Differential diag- Another large study84 of African carnivores from west- noses include other abortifacient agent infections such ern Kenya south to the Kruger National park in South as brucellosis, leptospirosis, chlamydiosis, campylobac- Africa revealed evidence of RVF virus infection in li- teriosis, Coxiella burnetii infection, and salmonellosis. ons (Panthera leo), cheetahs (Acinonyx jubatus), African Although infections with those agents can cause large wild dogs (Lycaon pictus), and jackals (Canis spp). numbers of abortions, RVF virus abortion storms are The role of chiropterans in the natural cycle of RVF usually accompanied by higher adult animal mortality virus infection is controversial. Rift Valley fever virus was ratios than would be expected as a result of infections isolated from 2 bat species (Micropteropus pusillus and with the endemic abortifacient agents. Other potential Hipposideros abae) in the Republic of Guinea.85 Miniopter- differential diagnoses include diseases associated with us schreibersii and Eptesicus capensis are known to be sus- exotic viral pathogens (eg, nonendemic bluetongue, ceptible to experimentally induced RVF virus infection.86 Wesselsbron’s disease, rinderpest, Peste des petits ru- Interestingly, following inoculation with RVF virus, none minants, and Nairobi sheep disease). An important of the bats developed signs of clinical illness, but RVF vi- clinical feature helpful to distinguish those diseases rus antigen was detected in tissues or urine for up to 18 from RVF disease is the characteristic oral lesions that days; this suggests that these species of bat may contribute accompany bluetongue, rinderpest, or Peste des petits to RVF virus maintenance during interepizootic periods. ruminants. In North America, very few, if any, endemic However, a large antibody prevalence survey revealed no pathogens are likely to cause the extensive morbidity evidence of prior RVF virus infection among 150 wild- and high numbers of deaths that are associated with trapped bats (7 species), including those species that were epizootics of RVF infection in Africa. subsequently experimentally infected.86 Thus, the impact Because of the high-titer viremia and pantropic na- of chiropterans on the cycle of RVF virus infection remains ture of RVF virus infection in animals, a wide variety of unclear and requires further investigation. specimens can be used for diagnostic testing (eg, serum, Humans—Following an incubation period of 2 to 6 whole blood, and tissues [including those from aborted days, RVF virus infection in humans is usually associated fetuses]). The necropsy of infected animals poses con- with a self-limiting febrile illness that is characterized by siderable risk to veterinarians and herdsmen and should abrupt onset of malaise, myalgia, and arthralgia and is anal- only be performed by trained personnel who use ap- ogous in clinical appearance to dengue fever (also called propriate personal protective equipment. It is essential breakbone fever).87 Resolution of acute clinical signs is co- that good field-biosafety practices be followed during incident with the development of neutralizing antibodies the collection of blood or tissue specimens (wearing of and cessation of viremia.87,88 However, in a small percent- gloves, gowns, and eye protection and, if available, use of age of individuals (approx 1% to 2%), infection progresses a fitted N95 respirator to filter airborne particles). Blood to more severe disease, such as acute hepatic necrosis or samples should be stored in sealed containers at 4°C, and hepatitis, delayed-onset encephalitis, and retinitis.5,89–91 A tissues should be fixed in 10% formalin. The surfaces of hemorrhagic syndrome that is characterized by profound all specimen containers should be decontaminated with coagulopathy, disseminated intravascular coagulation, 10% sodium hypochlorite (bleach) and immediately and multiple organ dysfunction including renal failure can submitted to reference laboratories. Equipment used to develop in the most severely affected individuals and is collect samples of RVF virus–contaminated blood should associated with a 10% to 20% case fatality ratio.11,91 Evalu- not be reused and should be decontaminated via immer- ation of patient sera from the outbreak in Saudi Arabia in sion in a solution of 10% sodium hypochlorite prior to 2000 revealed that high RVF virus loads (mean titer, > 1.0 disposal. X 106 PFUs/mL of blood) at the time of initial examination For the detection of RVF virus, an integrated ap- were significantly linked to fatal outcomes.88 proach involving nucleic acid detection assays (RT- PCR assays or, preferably, real-time quantitative RT- Diagnostic Evaluations PCR assays), virus antigen detection, and anti-RVF IgM or IgG antibody detection assays is essential. Ad- The rapid onset and potential for very high num- ditionally, RVF virus infection should be definitively bers of affected individuals and livestock associated confirmed via virus isolation and RVF virus–specific

888 Vet Med Today: Zoonosis Update JAVMA, Vol 234, No. 7, April 1, 2009 indirect fluorescent antibody screening performed in determined in experiments in laboratory animal spe- reference laboratories with BSL-3+ facilities. Each de- cies including mice, rats, and rhesus macaques.104–106 tection technique has advantages and should be used However, the limited penetration of ribavirin across in a complementary diagnostic strategy that ensures the blood-brain barrier may limit the effectiveness of the accurate identification of affected humans and oth- this treatment in preventing delayed-onset neurologic er animals regardless of the stage of infection (approx disease. In RVF virus-infected laboratory animals, riba- 24 hours after infection through convalescence). virin treatment has been associated with an apparent Serologic assays for the detection of anti–RVF vi- shift in disease characteristics from sudden-onset he- rus IgM and IgG antibodies have been used since the patic disease to delayed-onset neurologic disease.57 1930s.5,92–94 Development of this type of assay requires Thus, ribavirin is not recommended in the treatment of access to live RVF virus for the production of reagents uncomplicated RVF disease. and to sera from infected patients for assay validation. As such, these assays are labor-intensive to design, Prevention and Control validate, and deploy operationally but are critical for comprehensive diagnostic testing. Their ability to de- Vaccines—Currently, there is no vaccine to prevent tect evidence of RVF virus infection in convalescent pa- RVF virus infection that is approved for veterinary use tients after clearance of the viremic phase is invaluable, in North America or Europe. Since the first isolation especially in settings in which the initial wave of RVF of RVF virus, various vaccines against RVF virus have virus activity may have occurred some weeks earlier. been developed, including vaccines produced through In cattle, assessment of titers of anti–RVF virus formalin inactivation107–111; through attenuation (live- IgM antibody relative to anti–RVF virus IgG antibody attenuated virus) via in vivo serial passage112,113 or via can be used to differentiate recent from historical RVF in vitro chemical mutagenesis114; by use of naturally oc- virus infection because the duration of detectable curring attenuated mutant virus,115–117 viral subunits,118 anti-RVF IgM antibody in these animals is transient recombinant virus vectors,119,120 or viral cDNA121; and (approx 60 to 90 days).95 This use of serologic testing by use of recombinant live-attenuated RVF virus con- to differentiate acute and convalescent phases of RVF taining complete deletions of known virulence genes.122 virus infections has been applied in various species Over the past 50 years, each of these approaches have (including humans and domestic animals).26,34,67,74,96 led to further refinements in efficacy and safety of vac- Recently, a test for detection of total RVF virus–spe- cines and have increased understanding of RVF virus cific immunoglobulins (IgM and IgG) in cattle, sheep, vaccinology. and African buffaloes has become commercially avail- Formalin-inactivated vaccines are considered safe, able.93 Although this assay is unable to differentiate but have drawbacks for field use because of the typi- acute and convalescent phases of infection, it may be cal requirement for 3 initial inoculations over a period useful in emergency situations. of 1 to 2 months followed by annual booster inocula- Molecular detection assays have evolved from tions.110,113,123 This requirement renders inactivated vac- standard RT-PCR assays97–100 to high-throughput rapid cines impractical for livestock use in locations in which real-time quantitative RT-PCR procedures.88,101,102 The RVF virus is endemic. However, for human use, a for- exquisitely sensitive detection capability of quantita- malin-inactivated product (designated as TSI-GSD-200) tive RT-PCR assays (approx 5 to 10 RNA copies/sam- was produced in the mid-1970s under an investigational ple) allows for the detection of infection early in the new drug license from the FDA.124 The use of this vac- course of disease, and the technique is easily adapted cine was targeted at laboratory and other service per- to high-throughput use during epizootics and epidem- sonnel with high occupational risk of exposure to the ics. However, RVF virus molecular detection assays can virus. Although no longer produced and in limited sup- detect viral nucleic acids only during the viremic pe- ply, TSI-GSD-200 was proven safe, immunogenic, and riod, which is relatively transient. As with all molecular effective in preventing laboratory-acquired infections assays, a narrowly defined window of opportunity ex- among 598 volunteer human vacinees.111 ists to identify acute cases before antibody responses in Because of the convenience of protection against convalescent humans and other animals diminish the RVF virus provided by a single inoculation of a live- diagnostic usefulness of the test procedure (Figure 3). attenuated vaccine, use of these vaccines became the preferred strategy for vaccination of livestock through- Treatment out Africa beginning in the 1950s. The live-attenuated Smithburn strain of RVF virus is immunogenic and In humans and other animals, there is no specific efficacious in adult sheep and cattle, but also causes treatment for RVF virus infection other than supportive abortion or teratologic effects in fetuses in up to 25% of care. Experimentally, recombinant human interferon-γ pregnant animals.56,65,112,125 Thus, this vaccine is likely can prevent severe disease in Rhesus macaques when unsuitable for use in regions outside of the endemic administered 24 hours prior to inoculation with RVF zone of RVF virus activity. virus,103 but evaluation of this treatment in naturally Efforts to create more highly attenuated and safe infected humans or other animal species has not been vaccine products led to the development of the MP-12 reported to the authors’ knowledge. The most widely vaccine that was derived via chemical mutagenesis of tested antiviral agent is the nucleoside analogue ribavi- the RVF virus.114,126–128 Administration of a single dose rin along with its closely related chemical derivatives. of this vaccine was proven to be safe and efficacious in The protective efficacy of these compounds has been sheep and cattle, inducing high serum concentrations of

JAVMA, Vol 234, No. 7, April 1, 2009 Vet Med Today: Zoonosis Update 889 neutralizing antibodies and providing protection from Israel.133,134 This program was likely successful because virulent virus challenge.64,129,130 The abortifacient prop- of the integration of control strategies and, importantly, erties of the MP-12 vaccine are controversial—in some because of the climate and geography of the area affect- studies,64,129–131 no abortions occurred following its use, ed. Control of any incursion of RVF virus into North whereas in another,132 the vaccine was associated with America or Europe will likely be more difficult because fetal losses. Further safety and efficacy studies are likely there are few geographic barriers to slow mosquito dis- required before widespread use of MP-12–based vac- persal and the movement of livestock throughout these cines could be considered in countries in which RVF regions is extensive and rapid. virus is not endemic. Recently, the development of a highly immunogen- Public Health Implications ic recombinant vaccine candidate containing complete deletions of the major RVF virus virulence genes (NSs The history of RVF virus is one of periodically ex- and NSm) was reported.122 Wistar-Furth rats vaccinated tensive outbreaks of severe animal and human disease with this construct were protected from challenge with throughout Africa. The virus has repeatedly overridden international boundaries and geographic barriers and virulent virus at doses as high as 500 times the LD50 value. An advantage of this vaccine design is the ability now is present throughout much of the African conti- to differentiate naturally infected from vaccinated ani- nent and Arabian Peninsula. Each successive incursion mals on the basis of the presence or absence of anti-NSs into previously RVF virus–free regions has resulted in antibodies or through the incorporation of exogenous large epidemics among humans: in Egypt (1977–1979), immunogenic peptides for detection via differential approximately 200,000 persons were affected; in Sen- serologic screening assays. This capability is essential egal-Mauritania (1987), approximately 89,000 persons if countries in which RVF virus is nonendemic imple- were affected; in Kenya (1997–1998), approximate- ment large-scale vaccination programs following RVF ly 27,000 persons were affected; and in Saudi Arabia virus introduction. and Yemen (2000), approximately 2,000 persons were severely affected or hospitalized. Fortunately, most hu- Integrated control and surveillance strategies— man illnesses are self-limiting and do not result in seri- The importance of RVF virus as a pathogen of livestock ous complications or death. However, the clinical signs and humans further underscores the need for safe and of uncomplicated RVF can be debilitating (eg, lethargy, effective antiviral treatments and vaccines and for inte- fever, arthralgia, and myalgia) and will lead many peo- grated national and international control and surveil- ple to seek medical intervention, thereby potentially lance strategies. The increasing concern over the poten- overwhelming the local medical care system. tial use of RVF virus as an agent of biological terrorism The principal public health impact of RVF virus only heightens this need. Control of RVF virus incur- introduction into areas in which the virus was not en- sions can only be achieved by close coordination of ag- demic will be direct infection of humans. However, ricultural, veterinary, entomologic, and medical efforts. important secondary effects including fears regarding Once RVF virus is established in an area with compe- food safety (especially livestock-derived meat prod- tent vectors, elimination of the virus may be ucts), financial impacts on farmers, stigmatization of impossible, as graphically illustrated by the emergence infected individuals, distrust of scientific and medi- of West Nile virus in the Americas since 1999. cal authorities, and mental health effects among the Successful control will require a multifaceted in- general population will likely develop as an outbreak tervention strategy involving rapid diagnostic tests to unfolds. Similarly, veterinary and human medical re- identify infected humans, other animals, and vectors sources will be severely strained in any outbreak. Dur- and resources for appropriate supportive care of in- ing the recent foot-and-mouth disease epizootic in the fected individuals. Animal quarantine or slaughter and United Kingdom in 2001, unanticipated issues regard- integrated control measures also are required for ing the environmental and societal impact of large-scale effective control. If safe and effective vaccines become animal euthanasia and carcass disposal became impor- available, their rational use will be essential to stop the tant public concerns. Each of these problems requires spread of RVF virus among livestock. Because RVF vi- an appropriate response at the public health level and rus is a zoonotic agent, it is critical that the news media careful thought regarding the dissemination of health be engaged at the outset for the dissemination of factual information and engagement of the media to help allay information regarding the real health risks of RVF virus fears among the general population. infection and to highlight measures the public can take to reduce potential exposures. Once the virus is newly Overview introduced into areas, stopping its spread is possible, but difficult. During the 1977–1979 epidemic-epizootic The potential impacts of RVF virus on North in Egypt along the Nile River, the Israeli government American and European agriculture and public health rapidly began an extensive vaccination and testing pro- are considerable. Veterinarians in food animal practice gram in the occupied regions of the Sinai Peninsula. will likely be the first medically trained professionals to During this effort, > 1.2 million doses of inactivated encounter RVF virus in these regions because animals RVF virus vaccine were used in conjunction with quar- with clinical signs of RVF disease will likely be the first antine and destruction of infected animals and intensive indication of virus introduction via natural processes or insect control measures throughout the Sinai Peninsu- intentional acts of bioterrorism. The early recognition la and in the Gaza Strip, all of which contributed to- of an outbreak of a foreign animal disease by veterinary ward preventing the spread of the virus northward into practitioners is a critical link in the control and even-

890 Vet Med Today: Zoonosis Update JAVMA, Vol 234, No. 7, April 1, 2009 tual eradication of the disease. Only through a rapid 24. Hoogstraal H, Meegan JM, Khalil GM, et al. The Rift Valley fever and multidisciplinary response from entomologic and epizootic in Egypt 1977–78. 2. Ecological and entomological veterinary and human medical authorities can the po- studies. Trans R Soc Trop Med Hyg 1979;73:624–629. 25. Abd el-Rahim IH, Abd el-Hakim U, Hussein M. An epizootic of tential spread of RVF virus be halted. Rift Valley fever in Egypt in 1997. Rev Sci Tech 1999;18:741– 748. References 26. Abu-Elyazeed R, El-Sharkawy S, Olson J, et al. Prevalence of anti-Rift Valley fever IgM antibody in abattoir workers in the 1. Daubney R, Hudson JR, Garnham PC. Enzootic hepatitis or Rift Nile delta during the 1993 outbreak in Egypt. Bull World Health Valley fever. An undescribed virus disease of sheep cattle and Organ 1996;74:155–158. man from East Africa. J Pathol Bacteriol 1931;34:545–579. 27. Arthur RR, el-Sharkawy MS, Cope SE, et al. Recurrence of Rift 2. Coetzer JA. The pathology of Rift Valley fever. I. Lesions occur- Valley fever in Egypt. Lancet 1993;342:1149–1150. ring in natural cases in new-born lambs. Onderstepoort J Vet Res 28. CDC. Outbreak of Rift Valley fever—Saudi Arabia, August–Oc- 1977;44:205–211. tober, 2000. MMWR Morb Mortal Wkly Rep 2000;49:905–908. 3. Coetzer JA. The pathology of Rift Valley fever. II. Lesions occur- 29. Jup PG, Kemp A, Grobbelaar A, et al. The 2000 epidemic of Rift ring in field cases in adult cattle, calves and aborted foetuses. Valley fever in Saudi Arabia: mosquito vector studies. Med Vet Onderstepoort J Vet Res 1982;49:11–17. Entomol 2002;16:245–252. 4. Swanepoel RCJ. Rift Valley fever. In: Coetzer JAW, Thompson 30. Miller BR, Godsey MS, Crabtree MB, et al. Isolation and genetic GR, Tustin, RD, et al, eds. Infectious diseases of livestock with characterization of Rift Valley fever virus from Aedes vexans ara- special reference to southern Africa. Cape Town, South Africa: biensis, Kingdom of Saudi Arabia. Emerg Infect Dis 2002;8:1492– Oxford University Press, 1994;688–717. 1494. 5. Madani TA, Al-Mazrou YY, Al-Jeffri MH, et al. Rift Valley fever 31. Bird BH, Khristova ML, Rollin PE, et al. Complete genome epidemic in Saudi Arabia: epidemiological, clinical, and labora- analysis of 33 ecologically and biologically diverse Rift Val- tory characteristics. Clin Infect Dis 2003;37:1084–1092. ley fever virus strains reveals widespread virus movement and 6. National Institute for Communicable Diseases. Rift Valley fever. low genetic diversity due to recent common ancestry. J Virol Communicable Diseases Communiqué 2008;7(2):1–2. 2007;81:2805–2816. 7. National Institute for Communicable Diseases. Rift Valley fever out- 32. Shoemaker T, Boulianne C, Vincent MJ, et al. Genetic analysis break update. Communicable Diseases Communiqué 2008;7(4):2. of viruses associated with emergence of Rift Valley fever in Sau- 8. USDA, APHIS. Part II. 7 CFR Part 331 and 9 CFR Part 121 Ag- di Arabia and Yemen, 2000–01. Emerg Infect Dis 2002;8:1415– ricultural Bioterrorism Protection Act of 2002; possession, use, 1420. and transfer of biological agents and toxins; final rule. Fed Reg- 33. Anonymous. Rift Valley fever outbreak—Kenya, November ister 2005;70:13241–13292. 2006–January 2007. MMWR Morb Mortal Wkly Rep 2007;56:73– 9. OIE. 8.12: Rift Valley fever. In: Terrestrial animal health code. 76. Paris: OIE, 2008. Available at: www.oie.int/eng/normes/Mcode/ 34. Bird BH, Githinji J, Macharia J, et al. Multiple virus lineages en_chapitre_1.8.12.htm. Accessed Feb 26, 2009. sharing recent common ancestry were associated with a large 10. Gargan TP, Clark GG, Dohm DJ, et al. Vector potential of se- Rift Valley fever outbreak among livestock in Kenya during lected North American mosquito species for Rift Valley fever 2006–2007. J Virol 2008;82:11152–11166. virus. Am J Trop Med Hyg 1988;38:440–446. 35. Davies FG, Highton RB. Possible vectors of Rift Valley fever in 11. Schmaljohn CS, Nichol ST. Bunyaviridae. In: Knipe DM, ed. Kenya. Trans R Soc Trop Med Hyg 1980;74:815–816. Field’s virology. 5th ed. Philadelphia: Lippincott Williams & 36. McIntosh BM, Jupp PG. Epidemiological aspects of Rift Valley Wilkins, 2006;1741–1789. fever in South Africa with reference to vectors. Contrib Epide- 12. Kitchen SF. Laboratory infections with the virus of Rift Valley miol Biostat 1981;3:92–99. fever. Am J Trop Med Hyg 1934;14:547–564. 37. Meegan JM, Khalil GM, Hoogstraal H, et al. Experimental trans- 13. Schwentker FF, Rivers TM. Rift Valley fever in man. Report of mission and field isolation studies implicating Culex pipiens as a fatal laboratory infection complicated by thrombophlebitis. a vector of Rift Valley fever virus in Egypt. Am J Trop Med Hyg J Exp Med 1934;59:305–313. 1980;29:1405–1410. 14. Smithburn KC, Mahaffy AF, Haddow AJ, et al. Rift Valley fe- 38. Smithburn KC, Haddow AJ, Gillett JD. Rift Valley fever. Isolation ver. Accidental infections among laboratory workers. J Immunol of the virus from wild mosquitoes. Br J Exp Pathol 1948;29:107– 1949;62:213–227. 121. 15. Gear JHS. Rift Valley fever in South Africa. S Afr Med J 1951; 39. Linthicum KJ, Logan TM, Bailey CL, et al. Transstadial and hori- 25:620. zontal transmission of Rift Valley fever virus in Hyalomma trun- 16. Shimshony A, Barzilai R. Rift Valley fever. Adv Vet Sci Comp Med catum. Am J Trop Med Hyg 1989;41:491–496. 1983;27:347–425. 40. Hoch AL, Gargan Ii TP, Bailey CL. Mechanical transmission of 17. Committee on Foreign Animal Disease of the United States Animal Rift Valley fever virus by hematophagous diptera. Am J Trop Med Health Association. Foreign animal diseases (the gray book): Rift Val- Hyg 1985;34:188–193. ley fever. Richmond, Va: Pat Campbell and Associates, 1998. 41. Hoch AL, Turell MJ, Bailey CL. Replication of Rift Valley fever 18. US Department of Health and Human Services. Biosafety in mi- virus in the sandfly Lutzomyia longipalpis. Am J Trop Med Hyg crobiological and biomedical laboratories. 5th ed. Washington, 1984;33:295–299. DC: US Government Printing Office, 2007. 42. Turell MJ, Bailey CL. Transmission studies in mosquitoes (Dip- 19. Swanepoel R, Coetzer JAW. Rift Valley fever. In: Coetzer JAW, tera: Culicidae) with disseminated Rift valley fever virus infec- Thompson GR, Tustin RD, et al, eds. Infectious diseases of live- tions. J Med Entomol 1987;24:11–18. stock with special reference to southern Africa. 2nd ed. Cape 43. Meegan JM, Bailey CL, Monath TP. Rift Valley fever. In: Monath Town, South Africa: Oxford University Press, 2004;1037–1070. TP, ed. The arboviruses: epidemiology and ecology. Vol 4. Boca 20. Meegan JM. The Rift Valley fever epizootic in Egypt 1977–78. 1. Raton, Fla: CRC Press Inc, 1989;51–76. Description of the epizootic and virological studies. Trans R Soc 44. Turell MJ, Linthicum KJ, Patrican LA, et al. Vector competence Trop Med Hyg 1979;73:618–623. of selected African mosquito (Diptera: Culicidae) species for 21. Meegan JM. Rift Valley fever in Egypt: an overview of the epizoot- Rift Valley fever virus. J Med Entomol 2008;45:102–108. ics in 1977 and 1978. Contrib Epidemiol Biostat 1981;3:100–113. 45. Turell MJ, Bailey CL, Beaman JR. Vector competence of a Hous- 22. Meegan JM, Watten RH, Laughlin LW. Clinical experience with ton, Texas strain of Aedes albopictus for Rift Valley fever virus. Rift Valley fever in humans during the 1977 Egyptian epizootic. J Am Mosq Control Assoc 1988;4:94–96. Contrib Epidemiol Biostat 1981;3:114–123. 46. Linthicum KJ, Bailey CL, Davies FG, et al. Detection of Rift Val- 23. Shimshony A. Disease prevention and preparedness in cases ley fever viral activity in Kenya by satellite remote sensing im- of animal health emergencies in the Middle East. Rev Sci Tech agery. Science 1987;235:1656–1659. 1999;18:66–75. 47. Linthicum KJ, Davies FG, Kairo A, et al. Rift Valley fever virus

JAVMA, Vol 234, No. 7, April 1, 2009 Vet Med Today: Zoonosis Update 891 (family Bunyaviridae, genus Phlebovirus). Isolations from Dip- small ruminants in southern Mauritania (October 1993): risk of tera collected during an inter-epizootic period in Kenya. J Hyg extensive outbreaks. Ann Soc Belg Med Trop 1995;75:135–140. (Lond) 1985;95:197–209. 73. Zeller HG, Fontenille D, Traore-Lamizana M, et al. Enzootic ac- 48. Logan TM, Linthicum KJ, Thande PC, et al. Egg hatching of Aedes tivity of Rift Valley fever virus in Senegal. Am J Trop Med Hyg mosquitoes during successive floodings in a Rift Valley fever en- 1997;56:265–272. demic area in Kenya. J Am Mosq Control Assoc 1991;7:109–112. 74. Ksiazek TG, Jouan A, Meegan JM, et al. Rift Valley fever among 49. Logan TM, Linthicum KJ, Thande PC, et al. Mosquito species domestic animals in the recent west African outbreak. Res Virol collected from a marsh in western Kenya during the long rains. 1989;140:67–77. J Am Mosq Control Assoc 1991;7:395–399. 75. Scott GR, Coackley W, Roach RW, et al. Rift Valley fever in cam- 50. Pretorius A, Oelofsen MJ, Smith MS, et al. Rift Valley fever vi- els. J Pathol Bacteriol 1963;86:229–231. rus: a seroepidemiologic study of small terrestrial vertebrates in 76. Ali AM, Kamel S. Epidemiology of RVF in domestic animals in South Africa. Am J Trop Med Hyg 1997;57:693–698. Egypt. J Egypt Public Health Assoc 1978;53:255–263. 51. Weinbren MP, Hons BS, Mason PJ. Rift Valley fever in a wild 77. Imam IZ, Karamany RE, Darwish MA. Epidemic of Rift Val- field rat Arvicanthis( abyssincus): a possible natural host. S Afr ley fever (RVF) in Egypt: isolation of RVF virus from animals. Med J 1957;31:427–430. J Egypt Public Health Assoc 1978;53:265–269. 52. Youssef BZ, Donia HA. The potential role of Rattus rattus in en- 78. Meegan JM, Hoogstraal H, Moussa MI. An epizootic of Rift Val- zootic cycle of Rift Valley fever in Egypt. 1—detection of RVF ley fever in Egypt in 1977. Vet Rec 1979;105:124–125. antibodies in R. rattus blood samples by both enzyme linked im- 79. Olaleye OD, Tomori O, Schmitz H. Rift Valley fever in Nigeria muno sorbent assay (ELISA) and immuno-diffusion technique infections in domestic animals. Rev Sci Tech 1996;15:937–946. (ID). J Egypt Public Health Assoc 2001;76:431–441. 80. Yedloutschnig RJ, Dardiri AH, Walker JS. The response of po- 53. Youssef BZ, Donia HA. The potential role of Rattus rattus in nies to inoculation with Rift Valley fever virus. Contrib Epide- enzootic cycle of Rift Valley fever in Egypt. 2—application miol Biostat 1981;3:68–71. of reverse transcriptase polymerase chain reaction (RT-PCR) 81. Davies FG, Karstad L. Experimental infection of the African in blood samples of Rattus rattus. J Egypt Public Health Assoc buffalo with the virus of Rift Valley fever. Trop Anim Health Prod 2002;77:133–141. 1981;13:185–188. 54. Turell MJ, Bailey CL, Rossi CA. Increased mosquito feeding 82. Nafady A, Bayoumi AH, El Zaher MA, et al. Rift Valley fever: on Rift Valley fever virus-infected lambs. Am J Trop Med Hyg pathological changes on the suspected buffalo calves and abort- 1984;33:1232–1238. ed foetuses. Assiut Vet Med J (Egypt) 1985;14:95–104. 55. van Velden DJ, Meyer JD, Olivier J, et al. Rift Valley fever affect- 83. Evans A, Gakuya F, Paweska JT, et al. Prevalence of antibodies ing humans in South Africa: a clinicopathological study. S Afr against Rift Valley fever virus in Kenyan wildlife. Epidemiol In- Med J 1977;51:867–871. fect 2008;136:261–269. 56. Weiss KE. Rift Valley fever. A review. Bull Epizoot Dis Afr 84. House C, Alexander KA, Kat PW, et al. Serum antibody to 1957;5:431–458. Rift Valley fever in African carnivores. Ann N Y Acad Sci 57. Peters CJ, Anderson GW Jr. Pathogenesis of Rift Valley fever. 1996;791:345–349. Contrib Epidemiol Biostat 1981;3:21–41. 85. Boiro I, Konstaninov OK, Numerov AD. Isolation of Rift Valley 58. Walker JS, Remmele NS, Carter RC, et al. The clinical aspects of fever virus from bats in the Republic of Guinea [in French]. Bull Rift Valley fever virus in household pets. I. Susceptibility of the Soc Pathol Exot Filiales 1987;80:62–67. . J Infect Dis 1970;121:9–18. 86. Oelofsen MJ, Van der Ryst E. Could bats act as reservoir hosts 59. Walker JS, Stephen EL, Remmele NS, et al. The clinical aspects for Rift Valley fever virus? Onderstepoort J Vet Res 1999;66:51– of Rift Valley fever virus in household pets. II. Susceptibility of 54. the cat. J Infect Dis 1970;121:19–24. 87. Peters CJ, Nathanson N, Ahmed R, et al. Viral hemorrhagic fever. 60. Easterday BC, Murphy LC, Bennett DG. Experimental Rift Val- In: Nathanson N, Ahmed R, Gonzalez-Scarano F, et al, eds. Viral ley fever in calves, goats, and pigs. Am J Vet Res 1962;23:1224– pathogenesis. Philadelphia: Lippincott-Raven, 1997;779–799. 1230. 88. Bird BH, Bawiec DA, Ksiazek TG, et al. Highly sensitive and 61. Easterday BC, McGavran MH, Rooney JR, et al. The pathogene- broadly reactive quantitative reverse transcription-PCR assay sis of Rift Valley fever in lambs. Am J Vet Res 1962;23:470–479. for high-throughput detection of Rift Valley fever virus. J Clin 62. Van der Lugt JJ, Coetzer JA, Smit MM. Distribution of viral anti- Microbiol 2007;45:3506–3513. gen in tissues of new-born lambs infected with Rift Valley fever 89. McIntosh BM, Russell D, dos Santos I, et al. Rift Valley fever in virus. Onderstepoort J Vet Res 1996;63:341–347. humans in South Africa. S Afr Med J 1980;58:803–806. 63. Erasmus BJ, Coetzer JAW. The symptomatology and pathology 90. Alrajhi AA, Al-Semari A, Al-Watban J. Rift Valley fever encepha- of Rift Valley fever in domestic animals. Contrib Epidemiol Bio- litis. Emerg Infect Dis 2004;10:554–555. stat 1981;3:77–82. 91. Al-Hazmi M, Ayoola EA, Abdurahman M, et al. Epidemic Rift 64. Baskerville A, Hubbard KA, Stephenson JR. Comparison of the Valley fever in Saudi Arabia: a clinical study of severe illness in pathogenicity for pregnant sheep of Rift Valley fever virus and a humans. Clin Infect Dis 2003;36:245–252. live attenuated vaccine. Res Vet Sci 1992;52:307–311. 92. Findlay GM, Stefanopoulo GJ, Mc Callum FO. Présence 65. Coetzer JA, Barnard BJ. Hydrops amnii in sheep associated with d’anticorps contre la fièvre de la Vallée du Rift dans le sang des hydranencephaly and arthrogryposis with Wesselsbron disease Africains. Bull Soc Pathol Exot 1936;29:986–996. and Rift Valley fever viruses as aetiological agents. Onderstepoort 93. Paweska JT, Jansen van Vuren P, Swanepoel R. Validation of an J Vet Res 1977;44:119–126. indirect ELISA based on a recombinant nucleocapsid protein of 66. Easterday BC. Rift Valley fever. Adv Vet Sci 1965;10:65–127. Rift Valley fever virus for the detection of IgG antibody in hu- 67. Nabeth P, Kane Y, Abdalahi MO, et al. Rift valley fever outbreak, mans. J Virol Methods 2007;146:119–124. Mauritania, 1998: seroepidemiologic, virologic, entomologic, 94. Niklasson B, Grandien M, Peters CJ, et al. Detection of Rift Val- and zoologic investigations. Emerg Infect Dis 2001;7:1052– ley fever virus antigen by enzyme-linked immunosorbent assay. 1054. J Clin Microbiol 1983;17:1026–1031. 68. Coackley W, Pini A, Gosden D. Experimental infection of cattle 95. Morvan J, Rollin PE, Laventure S, et al. Duration of immuno- with pantropic Rift Valley fever virus. Res Vet Sci 1967;8:399– globulin M antibodies against Rift Valley fever virus in cattle 405. after natural infection. Trans R Soc Trop Med Hyg 1992;86:675. 69. Gerdes GH. Rift Valley fever. Rev Sci Tech 2004;23:613–623. 96. Mariner JC, Morrill J, Ksiazek TG. Antibodies to hemorrhagic 70. Chevalier V, Lancelot R, Thiongane Y, et al. Rift Valley fever in fever viruses in domestic livestock in Niger: Rift valley fever small ruminants, Senegal, 2003. Emerg Infect Dis 2005;11:1693– and Crimean Congo hemorrhagic fever. Am J Trop Med Hyg 1700. 1995;53:217–221. 71. LeBreton M, Umlauf S, Djoko CF, et al. Rift Valley fever in goats, 97. Ibrahim MS, Turell MJ, Knauert FK, et al. Detection of Rift Cameroon. Emerg Infect Dis 2006;12:702–703. Valley fever virus in mosquitoes by RT-PCR. Mol Cell Probes 72. Zeller HG, Akakpo AJ, Ba MM. Rift Valley fever epizootic in 1997;11:49–53.

892 Vet Med Today: Zoonosis Update JAVMA, Vol 234, No. 7, April 1, 2009 98. Sall AA, Thonnon J, Sene OK, et al. Single-tube and nested re- tion and protection of lambs with a minute plaque variant of verse transcriptase-polymerase chain reaction for detection of Rift Valley fever virus. Am J Trop Med Hyg 1986;35:660–662. Rift Valley fever virus in human and animal sera. J Virol Methods 117. Muller R, Saluzzo JF, Lopez N, et al. Characterization of clone 2001;91:85–92. 13, a naturally attenuated avirulent isolate of Rift Valley fever 99. Jupp PG, Grobbelaar AA, Leman PA, et al. Experimental de- virus, which is altered in the small segment. Am J Trop Med Hyg tection of Rift Valley fever virus by reverse transcription-poly- 1995;53:405–411. merase chain reaction assay in large samples of mosquitoes. 118. Collett MS, Keegan K, Hu SL, et al. Protective subunit immuno- J Med Entomol 2000;37:467–471. gens to Rift Valley fever virus from bacteria and recombinant vac- 100. Vahhabzadeh AR, Lenz O, Eickmann M. The first multiplex reverse cinia virus. In: Mahy BWJ, Kolakofsky D, eds. The biology of neg- transcriptase polymerase chain reaction (multiplex RT-PCR) for di- ative strand viruses. Oxford, England: Elsevier, 1987;321–329. agnostic of Lassa-, Marburg-, Ebola-, Rift-Valley- and Yellow fever 119. Wallace DB, Ellis CE, Espach A, et al. Protective immune re- virus in clinical specimen. Infection 2001;29(suppl 1):53–54. sponses induced by different recombinant vaccine regimes to 101. Garcia S, Crance J-M, Billecocq A, et al. Quantitative real- Rift Valley fever. Vaccine 2006;24:7181–7189. time PCR detection of Rift Valley fever virus and its applica- 120. Wallace DB, Weyer J, Nel LH, et al. Improved method for the gen- tion to evaluation of antiviral compounds. J Clin Microbiol eration and selection of homogeneous lumpy skin disease virus 2001;39:4456–4461. (SA-Neethling) recombinants. J Virol Methods 2007;146:52–60. 102. Drosten C, Gottig S, Schilling S, et al. Rapid detection and 121. Spik K, Shurtleff A, McElroy AK, et al. Immunogenicity of com- quantification of RNA of Ebola and Marburg viruses, Lassa vi- bination DNA vaccines for Rift Valley fever virus, tick-borne rus, Crimean-Congo hemorrhagic fever virus, Rift Valley fever encephalitis virus, Hantaan virus, and Crimean Congo hemor- virus, Dengue virus, and Yellow fever virus by real-time reverse rhagic fever virus. Vaccine 2006;24:4657–4666. transcription-PCR. J Clin Microbiol 2002;40:2323–2330. 122. Bird BH, Albarino CG, Hartman AL, et al. Rift Valley fever virus 103. Morrill JC, Czarniecki CW, Peters CJ. Recombinant human in- lacking the NSs and NSm genes is highly attenuated, confers terferon-gamma modulates Rift Valley fever virus infection in protective immunity from virulent virus challenge and allows the rhesus monkey. J Interferon Res 1991;11:297–304. for differential identification of infected and vaccinated animals. 104. Anderson GW Jr, Slone TW Jr, Peters CJ. Pathogenesis of J Virol 2008;82:2681–2691. Rift Valley fever virus (RVFV) in inbred rats. Microb Pathog 123. Barnard BJH, Botha MJ. An inactivated rift valley fever vaccine. 1987;2:283–293. J S Afr Vet Assoc 1977;48:45–48. 105. Kende M, Lupton HW, Rill WL, et al. Enhanced therapeutic 124. Eddy GA, Peters CJ, Meadors GF, et al. Rift Valley fever vaccine efficacity of Poly (ICLC) and Ribavirin combinations against for humans. Contrib Epidemiol Biostat 1981;3:124–141. Rift Valley virus infection in mice. Antimicrob Agents Chemother 125. Botros B, Omar A, Elian K, et al. Adverse response of non-indig- 1987;31:986–990. enous cattle of European breeds to live attenuated Smithburn 106. Peters CJ, Reynolds JA, Slone TW, et al. Prophylaxis of Rift Valley Rift Valley fever vaccine. J Med Virol 2006;78:787–791. fever with antiviral drugs, immune serum, an interferon inducer, 126. Takehara K, Min MK, Battles JK, et al. Identification of muta- and a macrophage activator. Antiviral Res 1986;6:285–297. tions in the M RNA of a candidate vaccine strain of Rift Valley 107. Randall R, Gibbs CJ Jr, Aulisio CG, et al. The development of fever virus. Virology 1989;169:452–457. a formalin-killed Rift Valley fever virus vaccine for use in man. 127. Saluzzo J-F, Smith JF. Use of reassortant viruses to map attenuat- J Immunol 1962;89:660–671. ing and temperature-sensitive mutations of the Rift Valley fever 108. Anderson GW Jr, Lee J-O, Anderson AO, et al. Efficacy of a Rift virus MP-12 vaccine. Vaccine 1990;8:369–375. Valley fever virus vaccine against an aerosol infection in rats. 128. Vialat P, Muller R, Vu TH, et al. Mapping of the mutations Vaccine 1991;9:710–714. present in the genome of the Rift Valley fever virus attenuated 109. Randall R, Binn LN, Harrison VR. Immunization against Rift MP12 strain and their putative role in attenuation. Virus Res Valley fever virus. Studies on the immunogenicity of lyophilized 1997;52:43–50. formalin-inactivated vaccine. J Immunol 1964;93:293–299. 129. Hubbard KA, Baskerville A, Stephenson JR. Ability of a muta- 110. Harrington DG, Lupton HW, Crabbs CL, et al. Evaluation of a genized virus variant to protect young lambs from Rift Valley formalin-inactivated Rift Valley fever vaccine in sheep. Am J Vet fever. Am J Vet Res 1991;52:50–55. Res 1980;41:1559–1564. 130. Morrill JC, Carpenter L, Taylor D, et al. Further evaluation of a 111. Pittman PR, Liu CT, Cannon TL, et al. Immunogenicity of an mutagen-attenuated Rift Valley fever vaccine in sheep. Vaccine inactivated Rift Valley fever vaccine in humans: a 12-year expe- 1991;9:35–41. rience. Vaccine 1999;18:181–189. 131. Morrill JC, Mebus CA, Peters CJ. Safety of a mutagen-attenu- 112. Smithburn KC. Rift Valley fever; the neurotropic adaptation of ated Rift Valley fever virus vaccine in fetal and neonatal bovids. the virus and the experimental use of this modified virus as a Am J Vet Res 1997;58:1110–1114. vaccine. Br J Exp Pathol 1949;30:1–16. 132. Hunter P, Erasmus BJ, Vorster JH. Teratogenicity of a muta- 113. Barnard BJH. Rift Valley fever vaccine—antibody and immune genised Rift Valley fever virus (MVP 12) in sheep. Onderstepoort response in cattle to a live and an inactivated vaccine. J S Afr Vet J Vet Res 2002;69:95–98. Assoc 1979;50:155–157. 133. Shimshony A, Klopfer-Orgad U, Bali S, et al. The influence of 114. Caplen H, Peters CJ, Bishop DH. Mutagen-directed attenuation information flow on the veterinary policy of Rift Valley fever of Rift Valley fever virus as a method for vaccine development. prevention in Israel, 1978–1979. Contrib Epidemiol Biostat J Gen Virol 1985;66:2271–2277. 1981;3:160–171. 115. Rossi CA, Turell MJ. Characterization of attenuated strains of 134. Klopfer-Orgad U, Peleg B-A, Braverman Y, et al. Activities of the Rift Valley fever virus. J Gen Virol 1988;69:817–823. Kimron Veterinary Institute in the framework of Rift Valley fever 116. Moussa MI, Abdel-Wahab KS, Wood OL. Experimental infec- prevention in Israel. Contrib Epidemiol Biostat 1981;3:172–177.

JAVMA, Vol 234, No. 7, April 1, 2009 Vet Med Today: Zoonosis Update 893