Zoonosis Update - American Veterinary Medical Association

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

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ift Valley fever virus is a mosquito-borne pathogen of livestock and humans that historically has been responsible for widespread and devastating outbreaks of severe disease throughout Africa and, more recently, the Arabian Peninsula. The virus was first isolated and RVF disease was initially characterized following the sudden 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 that time, RVF virus has caused numerous economically devastating epizootics that were characterized by sweeping abortion storms and mortality ratios of approximately 100% among neonatal animals and of 10% to 20% among adult ruminant livestock (especially sheep and cattle).2–4 Infections in humans are typically associated with selflimiting febrile illnesses. However, in 1% to 2% of affected individuals, RVF infections can progress to more severe disease including fulminant hepatitis, encephalitis, retinitis, blindness, or a hemorrhagic syndrome; among severely affected persons who are hospitalized, the case fatality ratio is approximately 10% to 20%.5 Rift Valley fever epizootics and epidemics can rapidly overwhelm the capacities of the public health and veterinary medical communities to provide rapid diagnostic testing and adequate medical care for affected humans and other animals, which can number in the tens if not hundreds of thousands. Veterinarians, other health personnel, farmers, and abattoir workers also are at high risk of infection from direct contact with infected animals and patients; indeed, many historical outbreaks of RVF disease in Africa were initially detected because of illnesses among veterinarians and their assistants after they performed necropsies on infected animals. In 2008, several veterinarians, staff, and veterinary students at a South African veterinary college were infected after handling and performing necropsies From the Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616 (Bird, MacLachlan); and Special Pathogens Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333 (Ksiazek, Nichol). Dr. Ksiazek’s present address is Galveston National Laboratory, Department of Pathology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555. Dr. Bird was supported by the dual-degree DVM/PhD Veterinary Scientist Training Program, the Graduate Group of Comparative Pathology, and the Students Training in Advanced Research programs of the University of California, Davis, School of Veterinary Medicine. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agencies or the Centers for Disease Control and Prevention. The authors thank Dr. Robert Swanepoel for technical assistance. Address correspondence to Dr. Bird. JAVMA, Vol 234, No. 7, April 1, 2009

ABBREVIATIONS BSL MP-12 PFU RT RVF

Biosafety level Modified passage-12x Plaque-forming unit Reverse transcription Rift Valley fever

on animals that were only later identified as infected with RVF virus.6,7 The need for a 1-medicine approach to the diagnosis, treatment, surveillance, and control of RVF virus infection cannot be overstated. The close coordination of veterinary and human medical efforts (especially in countries in which the virus is not endemic and health-care personnel are therefore unfamiliar with RVF) is critical to combat this important threat to the health of humans and other animals. Because of the potential for severe consequences during outbreaks, RVF virus is considered a major zoonotic threat. Rift Valley fever virus is classified as a Category A overlap Select Agent by the CDC and the USDA8 and as a high-consequence pathogen with the potential for international spread (List A) by the World Organization for Animal Health (Office International des Épizooties).9 As such, RVF virus is considered a potential threat as a biological terrorism agent that could have dramatic direct (morbidity and death) and indirect (international trade restrictions) impact in countries that are currently free of the virus. Furthermore, numerous species of potentially competent mosquito vectors are present throughout North America and Europe.10 This review will focus on the current understanding of RVF virus ecology; pathogenesis and clinical signs of RVF disease among livestock, humans, and wildlife; the use and limitations of rapid diagnostic testing during outbreaks; and recent advances in vaccine design and development, as well as potential veterinary medical and public health consequences following introduction of the virus into previously unaffected areas. Etiologic Agent and Biosafety Rift Valley fever virus (Family, Bunyaviridae; genus, Phlebovirus) is an enveloped spherical particle (80 to 100 nm in diameter) with a tripartite single-stranded negative-sense RNA genome (approx 11.9 kilobases).11 The Bunyaviridae include several important veterinary and human medical pathogens such as Nairobi sheep disease virus, Akabane virus, Crimean-Congo hemorrhagic fever virus, La Crosse virus, sandfly fever Sicilian virus, and the hantaviruses. Vet Med Today: Zoonosis Update

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Rift Valley fever virus is a notorious cause of accidental infection among laboratory workers and veterinarians. Direct contact with infected animals, especially during necropsy and obstetric procedures, is associated with a high risk of infection; in any circumstances involving such contact, strict adherence to universal blood-borne pathogen precautions and to good biosafety practices is required.12–15 Rift Valley fever virus particles in serum retain infectivity when stored at 4°C for several weeks, which is an important consideration in the safe handling of diagnostic specimens.16 The virus is readily inactivated by use of strong detergents or 10% solutions of sodium hypochlorite (bleach) and via formalin fixation.16,17 Because of the ease of horizontal transmission, laboratory-based investigations must be performed in BSL 3–enhanced (ie, BSL-3+ or BSL-3 Agriculture) facilities in the United States.18 Epidemiology and Ecology

including movements of infected camels along trade routes with Sudan, windblown infected mosquitoes, or infected passengers on commercial airlines.24 Since the 1977–1979 outbreak, RVF virus activity has occurred sporadically in Egypt, with deaths among livestock and low numbers of human infections.25–27 In 2000, the presence of RVF virus outside of Africa was reported for the first time. In the western provinces of Saudi Arabia and Yemen, an outbreak of severe human and livestock disease associated with RVF virus occurred; there were an estimated 2,000 human infections and at least 245 deaths, and thousands of goats and sheep also died.19,28 This outbreak was preceded by exceptionally heavy rainfall, which resulted in large increases in the mosquito population and subsequent transmission of the virus.29,30 Genetic analyses of RVF virus isolates collected during the Saudi Arabia–Yemen outbreak revealed high similarity to viruses present during a 1997–1998 Kenyan outbreak, which suggested that the virus was introduced into Saudi Arabia and Yemen from eastern Africa.31,32 However, as for the 1977–1979 Egyptian outbreak, the precise route of introduction is enigmatic because no epizootics in eastern Africa were reported at that time. It is possible that viremic animals were imported into Saudi Arabia or Yemen during the preceding 1997–1998 east African epizootic and that RVF virus circulated at levels below the detection threshold until climactic conditions

Impact of major epizootics and epidemics—Rift Valley fever virus infection of humans and other animals has been identified in approximately 30 countries, and major epizootics and epidemics occur periodically throughout the known geographic range of the virus (Figure 1). The disease was initially thought to be restricted to the eastern Rift Valley region of Africa. However, in 1951, a severe epizootic in South Africa occurred 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 veterinarian and several assistants following the necropsy of a dead bull.15 This outbreak initiated what has since become a repeating 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 massive epidemic-epizootic along the Nile river and delta in Egypt.20–22 This outbreak, 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 human RVF disease became apparent and ranged from subclinical infection to severe cases of hepatic necrosis with fatal hemorrhagic complications, delayed onset encephalitis and permanent neurologic deficits, or severe retinitis with permanent blindness.22 The route by which RVF virus was introduced into Egypt Figure 1—Geographic distribution of RVF virus. Countries in which epizootics or epidemics are known to have occurred are indicated in red with the date of each outbreak. Counwill 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

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occurred in 2000 that were conducive to widespread virus activity.19 Most recently, an outbreak of RVF occurred in 2006 and 2007 following heavy rains over much of eastern Africa. This outbreak caused considerable losses of livestock, and 698 human deaths were reported from Somalia, Kenya, and Tanzania.33,34 As in the 1997–1998 outbreak, the focus of RVF virus activity extended as the heavy rains shifted southwards from Kenya toward Tanzania. The extension of RVF epizootic and epidemic foci over broad areas and across international boundaries obviously complicates both surveillance and control efforts. Overall, since its original detection in the Rift Valley of Kenya, RVF virus has been identified in extensive areas of Africa—from the Cape of Good Hope in South Africa to the Nile Delta in Egypt. During this interval, the remarkable ability of the virus to cross extensive geographic barriers including the Sahara desert (Egypt), the Red Sea (Saudi Arabia and Yemen), and the Indian Ocean (Madagascar) has become apparent. Clearly, RVF virus will continue to impact both veterinary and human health throughout Africa with risk of further spread into Europe and Asia or even into the Americas. Vectors and RVF transmission— Mosquitoes are the only important biological vectors of RVF virus; however, experimental infection has been established in several other arthropods, 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, Eretmapodites, Mansonia, and Coquillettidia).43 Importantly, 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 sollicitans, Aedes taeniorhynchus, Aedes triseriatus, 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 establishment of epizootic and perhaps enzootic transmission cycles. In eastern and southern Africa, the ecology of RVF virus involves 2 distinct but overlapping cycles of low-level enzootic 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 disease in the 1931.1 It is now known that the development of epizootic- or epidemic-associated transmission is dependent on large-scale weather events such as the warm El Niño Southern Oscillation, which can lead to heavy precipitaJAVMA, Vol 234, No. 7, April 1, 2009

tion over eastern and southern Africa.46 In western and central Africa, where rainfall is generally more abundant, RVF virus transmission characteristically follows a more continuous enzootic or endemic pattern and is likely dependent on both the availability of mosquito breeding habitats and the presence of sufficient numbers of susceptible animals. A critical link between rainfall and mosquitoes was made when transovarial transmission of RVF virus in Aedes lineatopennis mosquitoes was identified.47 In semiarid regions that compose the eastern and southern African enzootic zone of RVF virus transmission, normal rainfall patterns greatly limit the period available for vector activity. In those areas, the survival of floodwater Aedes (subgenera Neomelaniconium and Aedimorphus) mosquitoes is dependent on drought-resistant eggs that remain viable for long periods (perhaps many years) following the drying of breeding habitats. The breeding habitats are usually shallow depressions or pans (referred to as dambos) that range in size from a few meters to over a kilometer in diameter; when flooded, dambos provide an ideal environment for Aedes mosquito breeding and egg deposition. An essential

Figure 2—Enzootic and epidemic-epizootic transmission cycles of RVF virus. In the enzootic transmission cycle (top left panel), wildlife (eg, African buffalo species) are potential maintenance hosts. In the epidemic-epizootic transmission cycle (remainder of figure), livestock amplification hosts and secondary bridge vectors are involved. (Symbols courtesy of the Integration and Application Network (ian.umces.edu/symbols/), University of Maryland Center for Environmental Science. Accessed Jan 1, 2009.) Vet Med Today: Zoonosis Update

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feature of the floodwater Aedes mosquito life cycle is the requirement for drying followed by heavy rainfall that is sufficient to reflood the dambos, thereby creating pools of sufficient depth to inundate dormant eggs and provide an aquatic habitat for development of mosquito larvae.19 The dynamics of mosquito emergence and species succession (broadly defined as the temporal relationship of individual mosquito species emerging from a given flooded habitat) were examined following natural or artificial flooding of Kenyan dambos and revealed that the first species to emerge were floodwater Aedes mosquitoes (A lineatopennis, Aedes cumminsii, and Aedes sudanensis) followed a few days later by secondary bridge vectors including Culex and Anopheles spp.48,49 Taken together, these findings facilitate development of a model of the RVF virus life cycle (Figure 2). Clearly, regardless of geographic location, a complex interplay of rainfall, mosquito abundance, transovarial transmission, and availability of suitable naïve amplification hosts influences the development of either enzootic stability or periodic waves of undetectable activity punctuated by geographically extensive epizootics and epidemics. Enzootic cycle—During periods with normal (nonexcessive) amounts of rainfall, RVF virus is likely maintained by low-level enzootic activity within the mosquito vector population involving transovarial transmission with occasional infection 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

comes that range from subclinical illness to sudden death.16,56 Although RVF virus is primarily a pathogen of livestock and humans, experimental infections of laboratory animals (mice, rats, hamsters, dogs, cats, and macaques) can result in rapid onset of clinical disease and death.57–59 The epidemiologic and ecologic importance of these infections of laboratory and companion animal species is limited; thus, this review article focuses on infections of domestic livestock, wildlife, and humans. General features among livestock—A typical hallmark of RVF virus epizootics is the sudden development of extensive abortion storms over wide areas following exceptionally heavy rainfall.19 Rift Valley fever disease in livestock is characterized by peracute to acute onset of inappetence, nasal discharge, and diarrhea; affected animals are highly viremic (approx 1 X 106 PFUs/mL to 1.0 X 108 PFUs/mL; Figure 3). At necropsy, pathologic findings include diffuse hepatic necrosis, splenomegaly, and gastrointestinal hemorrhage. Viral antigen is abundant in the reticulo-endothelial system and in multiple organs, including the liver, kidneys, adrenal glands, gastrointestinal tract, brain parenchyma, and ovaries or endometrium.2,3,60–62

Epizootic or epidemic cycle—A shift from enzootic to epizootic or epidemic RVF virus activity typically occurs following extended periods of exceptionally plentiful rainfall and subsequent inundation of dambos, which results in the emergence of abundant numbers of floodwater Aedes mosquitoes (Figure 2). These transovarially infected 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 mosquitoes (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 epizootic or epidemic life cycle. Pathogenesis and Clinical Signs Many mammalian species are susceptible to RVF virus infection, with out886


Figure 3—Generalized time course of viremia and antibody response against RVF virus in livestock (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 serologic (RVF virus–specific IgM or IgG) assays are appropriate are indicated in relation to the period of viremia. To convert degrees Celsius to degrees Fahrenheit, multiply by 9/5 and add 32. JAVMA, Vol 234, No. 7, April 1, 2009

Sheep—Young (< 1-month-old) lambs are highly susceptible to RVF virus infection, with mortality ratios typically reaching approximately 90% to 100%. The clinical course of the disease in lambs is short, with an incubation period of approximately 12 to 24 hours followed by a marked febrile response (rectal temperature, 41° to 42°C [105.8° to 107.6°F]) and rapid progression to death within 24 to 72 hours.63 Adult sheep are less susceptible to infection, with mortality ratios among affected adults of approximately 10% to 30%. Abortion rates can be high (90% to 100%), which gives rise to the characteristic abortion storms associated with RVF virus epizootics.19 Fetal loss and abortion are characterized by multiple-organ infection and necrosis in the fetus as well as RVF virus infection and necrosis of placental cotyledons and caruncles.2,64 Interestingly, vaccination of pregnant ewes during early to midgestation (30 to 105 days of gestation) with live-attenuated Smithburn strain RVF virus vaccine reportedly results in hydrops amnii, arthrogryposis, and hydranencephaly.65 Rift Valley fever disease in adult sheep is characterized by an incubation period of 24 to 72 hours and a generalized febrile response, lethargy, hematemesis, hematochezia, and nasal discharge.2,61,63,66 Gross and histopathologic findings in naturally infected sheep also confirm widespread organ involvement. The liver typically is large, soft, friable, and discolored (yellow to tan), and numerous pale foci of necrosis are disseminated throughout the liver parenchyma. Subcutaneous, visceral, and serosal hemorrhages are present, often accompanied by icterus and abomasal and intestinal hemorrhage.63 Lethal infections are histologically characterized by multifocal to coalescing or diffuse hepatocellular necrosis with an accompanying infiltrate of neutrophils and macrophages. Lymphoid necrosis is present in the cortex and medulla of lymph nodes with scant lymphoid necrosis within the splenic white pulp. Pulmonary congestion and edema with multifocal necrosis of alveolar and peribronchiolar lymphoid tissue develop in some animals.62

nated intravascular coagulation.3,63 As in sheep, marked lymphoid necrosis and depletion is evident in lymphoid tissues.3

Cattle—Neonatal (< 1-month-old) calves are less susceptible to lethal RVF virus infections than are neonatal lambs, although estimates of mortality ratios range from 10% to 70%.3,19,60,67 The disease course and histologic findings are similar to those in lambs. Although susceptible to RVF virus infection, adult bovids are more resistant to lethal infection than sheep; among adult cattle, the case fatality ratio is approximately 5% to 10%.63 Rift Valley fever disease in cattle is characterized by fever of 1 to 4 days’ duration, which is accompanied by inappetence, lethargy, hematochezia, and occasionally epistaxis.68 A notable but temporary decrease in milk production can occur in lactating cows,63,68 and there are anecdotal reports of RVF virus transmission to humans via unpasteurized milk.16,69 As for RVF virus–infected sheep, abortions are common and often the only evident sign of infection among pregnant cattle.63,68 Apart from lower mortality ratio, the characteristics of severe RVF virus infections in cattle are similar to those in sheep; histopathologic findings include multifocal to diffuse centrilobular hepatocellular necrosis with accompanying inflammatory infiltrates and occasional fibrin thrombi in the hepatic sinusoids, central veins, and portal triads that are suggestive of dissemi-

Horses—Although investigations have been limited, the prevalences of anti–RVF virus IgG antibody among horses from RVF virus–endemic areas of Nigeria and in horses in locations affected by the 1977–1979 Egyptian epidemic-epizootic were approximately 3% to 10%.21,78,79 Results of a classic study by Yedloutshnig et al80 indicated that Shetland ponies were susceptible to infection following administration of high doses of virulent RVF virus (1.0 X 105 PFUs/mL to 1.0 X 107 PFUs/mL); however, signs of clinical disease were not apparent, and peak postchallenge viremia did not exceed 1.0 X 102.5 mouse LD50/mL. The authors concluded that horses were likely of little relevance to the overall ecology of RVF virus infection.


Goats—There are relatively few published data on the pathogenesis of RVF virus infection in goats. Although goats are highly susceptible to infection, they appear to be more refractory to severe or lethal disease than sheep. Studies67,70–74 in western Africa (Senegal, Mauritania, and Cameroon) revealed that approximately 2% to 10% of goats are seropositive for anti–RVF virus antibody during enzootic periods; following epizootics, this proportion rose to > 70%. High mortality ratios (approx 48%) occurred in kids among 223 goat flocks studied following a 1998 epizootic in Mauritania.67 Results of recent investigation of the 2006–2007 epidemic-epizootic in Kenya indicate that the prevalence of RVF virus–specific IgM is similar among sheep and goats.34 Severe RVF disease (abortion, lethargy, and inappetence) in RVF virus–infected goats is similar to that in sheep.4,56,60 Camels—Rift Valley fever virus infection in camels (Camelus dromedarius) was described after an extensive outbreak of abortion in northern Kenya in 1961.75 Although the report confirmed high prevalence (45%) of serum RVF virus–specific IgG antibody among the 60 camels evaluated, RVF virus was not definitively proven to be the causative agent of the disease outbreak. Investigations21,76 conducted during and following the 1977– 1979 Egyptian epizootic revealed that the prevalence of serum anti–RVF virus IgG antibody was approximately 21% among 466 camels that underwent testing; there were reports of abortion among this Egyptian camel herd. Rift Valley fever virus was isolated from at least 1 animal during this outbreak.77 During an RVF epizootic and epidemic in Mauritania in 1998, a low proportion (approx 3%) of adult camels had serum IgM or IgG antibodies against RVF virus, and the neonatal mortality ratio among calves was high (approx 20%).67

Wildlife—To date, there have been few controlled studies of the pathogenesis of RVF virus infection in wildlife. Results of 2 experimental studies81,82 that focused on infection in African buffaloes (S caffer) have been reported. In those studies, 1 of 2 pregnant buffaloes aborted 16 days after infection, and 4 of 5 buffaloes developed viremia (approx 104.4 TCID50/mL) that persisted for at least 48 to 72 hours, similar to that which developed in control cattle (Bos spp) following Vet Med Today: Zoonosis Update

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infection. This high-titer viremia suggests that African buffaloes may have a role in the natural enzootic transmission cycle of RVF virus. In numerous field investigations, results of serologic testing and virus isolation have confirmed the importance of wildlife in the natural ecology of RVF virus infection as either susceptible hosts during epizootics or potential maintenance hosts during interepizootic periods. Evidence of previous RVF virus infection was recently confirmed in a variety of wildlife (16 species) in Kenya, including African buffalo (S caffer), elephant (Loxodonta africana), warthog (Phacochoerus aethiopicus), black rhino (Diceros bicornis), zebra (Equus burchelli), Thompson’s gazelle (Gazella thompsonii), lesser kudu (Tragelaphus strepsiceros), impala (Aepyceros melampus), and waterbuck (Kobus ellipsiprymnus).83 Another large study84 of African carnivores from western Kenya south to the Kruger National park in South Africa revealed evidence of RVF virus infection in lions (Panthera leo), cheetahs (Acinonyx jubatus), African wild dogs (Lycaon pictus), and jackals (Canis spp). The role of chiropterans in the natural cycle of RVF virus infection is controversial. Rift Valley fever virus was isolated from 2 bat species (Micropteropus pusillus and Hipposideros abae) in the Republic of Guinea.85 Miniopterus schreibersii and Eptesicus capensis are known to be susceptible to experimentally induced RVF virus infection.86 Interestingly, following inoculation with RVF virus, none of the bats developed signs of clinical illness, but RVF virus antigen was detected in tissues or urine for up to 18 days; this suggests that these species of bat may contribute to RVF virus maintenance during interepizootic periods. However, a large antibody prevalence survey revealed no evidence of prior RVF virus infection among 150 wildtrapped bats (7 species), including those species that were subsequently experimentally infected.86 Thus, the impact of chiropterans on the cycle of RVF virus infection remains unclear and requires further investigation. Humans—Following an incubation period of 2 to 6 days, RVF virus infection in humans is usually associated with a self-limiting febrile illness that is characterized by abrupt onset of malaise, myalgia, and arthralgia and is analogous in clinical appearance to dengue fever (also called breakbone fever).87 Resolution of acute clinical signs is coincident with the development of neutralizing antibodies and cessation of viremia.87,88 However, in a small percentage of individuals (approx 1% to 2%), infection progresses to more severe disease, such as acute hepatic necrosis or hepatitis, delayed-onset encephalitis, and retinitis.5,89–91 A hemorrhagic syndrome that is characterized by profound coagulopathy, disseminated intravascular coagulation, and multiple organ dysfunction including renal failure can develop in the most severely affected individuals and is associated with a 10% to 20% case fatality ratio.11,91 Evaluation of patient sera from the outbreak in Saudi Arabia in 2000 revealed that high RVF virus loads (mean titer, > 1.0 X 106 PFUs/mL of blood) at the time of initial examination were significantly linked to fatal outcomes.88 Diagnostic Evaluations The rapid onset and potential for very high numbers of affected individuals and livestock associated 888


with RVF virus outbreaks highlight the necessity for regional and national reference diagnostic laboratories with appropriate expertise. These laboratories must have the capacity to accurately evaluate large numbers of samples. The consequences of any delay or error in the diagnosis of RVF virus infection in the early stages of a nascent epizootic are considerable. The clinical signs of RVF virus infection in livestock are not distinctive; however, outbreaks of abortion (80% to 100% of animals affected), high neonatal mortality ratios, and large numbers of deaths among adult sheep, cattle, or goats are suggestive of RVF disease. In the United States, such abortion storms or unexplained increases in livestock mortality ratios should be reported to the office of the relevant State Veterinarian as a suspected outbreak of a foreign animal disease. Differential diagnoses include other abortifacient agent infections such as brucellosis, leptospirosis, chlamydiosis, campylobacteriosis, Coxiella burnetii infection, and salmonellosis. Although infections with those agents can cause large numbers of abortions, RVF virus abortion storms are usually accompanied by higher adult animal mortality ratios than would be expected as a result of infections with the endemic abortifacient agents. Other potential differential diagnoses include diseases associated with exotic viral pathogens (eg, nonendemic bluetongue, Wesselsbron’s disease, rinderpest, Peste des petits ruminants, and Nairobi sheep disease). An important clinical feature helpful to distinguish those diseases from RVF disease is the characteristic oral lesions that accompany bluetongue, rinderpest, or Peste des petits ruminants. In North America, very few, if any, endemic pathogens are likely to cause the extensive morbidity and high numbers of deaths that are associated with epizootics of RVF infection in Africa. Because of the high-titer viremia and pantropic nature of RVF virus infection in animals, a wide variety of specimens can be used for diagnostic testing (eg, serum, whole blood, and tissues [including those from aborted fetuses]). The necropsy of infected animals poses considerable risk to veterinarians and herdsmen and should only be performed by trained personnel who use appropriate personal protective equipment. It is essential that good field-biosafety practices be followed during the collection of blood or tissue specimens (wearing of gloves, gowns, and eye protection and, if available, use of a fitted N95 respirator to filter airborne particles). Blood samples should be stored in sealed containers at 4°C, and tissues should be fixed in 10% formalin. The surfaces of all specimen containers should be decontaminated with 10% sodium hypochlorite (bleach) and immediately submitted to reference laboratories. Equipment used to collect samples of RVF virus–contaminated blood should not be reused and should be decontaminated via immersion in a solution of 10% sodium hypochlorite prior to disposal. For the detection of RVF virus, an integrated approach involving nucleic acid detection assays (RTPCR assays or, preferably, real-time quantitative RTPCR assays), virus antigen detection, and anti-RVF IgM or IgG antibody detection assays is essential. Additionally, RVF virus infection should be definitively confirmed via virus isolation and RVF virus–specific JAVMA, Vol 234, No. 7, April 1, 2009

indirect fluorescent antibody screening performed in reference laboratories with BSL-3+ facilities. Each detection technique has advantages and should be used in a complementary diagnostic strategy that ensures the accurate identification of affected humans and other animals regardless of the stage of infection (approx 24 hours after infection through convalescence). Serologic assays for the detection of anti–RVF virus IgM and IgG antibodies have been used since the 1930s.5,92–94 Development of this type of assay requires access to live RVF virus for the production of reagents and to sera from infected patients for assay validation. As such, these assays are labor-intensive to design, validate, and deploy operationally but are critical for comprehensive diagnostic testing. Their ability to detect evidence of RVF virus infection in convalescent patients after clearance of the viremic phase is invaluable, especially in settings in which the initial wave of RVF virus activity may have occurred some weeks earlier. In cattle, assessment of titers of anti–RVF virus IgM antibody relative to anti–RVF virus IgG antibody can be used to differentiate recent from historical RVF virus infection because the duration of detectable anti-RVF IgM antibody in these animals is transient (approx 60 to 90 days).95 This use of serologic testing to differentiate acute and convalescent phases of RVF virus infections has been applied in various species (including humans and domestic animals).26,34,67,74,96 Recently, a test for detection of total RVF virus–specific immunoglobulins (IgM and IgG) in cattle, sheep, and African buffaloes has become commercially available.93 Although this assay is unable to differentiate acute and convalescent phases of infection, it may be useful in emergency situations. Molecular detection assays have evolved from standard RT-PCR assays97–100 to high-throughput rapid real-time quantitative RT-PCR procedures.88,101,102 The exquisitely sensitive detection capability of quantitative RT-PCR assays (approx 5 to 10 RNA copies/sample) allows for the detection of infection early in the course of disease, and the technique is easily adapted to high-throughput use during epizootics and epidemics. However, RVF virus molecular detection assays can detect viral nucleic acids only during the viremic period, which is relatively transient. As with all molecular assays, a narrowly defined window of opportunity exists to identify acute cases before antibody responses in convalescent humans and other animals diminish the diagnostic usefulness of the test procedure (Figure 3). Treatment In humans and other animals, there is no specific treatment for RVF virus infection other than supportive care. Experimentally, recombinant human interferon-G can prevent severe disease in Rhesus macaques when administered 24 hours prior to inoculation with RVF virus,103 but evaluation of this treatment in naturally infected humans or other animal species has not been reported to the authors’ knowledge. The most widely tested antiviral agent is the nucleoside analogue ribavirin along with its closely related chemical derivatives. The protective efficacy of these compounds has been JAVMA, Vol 234, No. 7, April 1, 2009

determined in experiments in laboratory animal species including mice, rats, and rhesus macaques.104–106 However, the limited penetration of ribavirin across the blood-brain barrier may limit the effectiveness of this treatment in preventing delayed-onset neurologic disease. In RVF virus-infected laboratory animals, ribavirin treatment has been associated with an apparent shift in disease characteristics from sudden-onset hepatic disease to delayed-onset neurologic disease.57 Thus, ribavirin is not recommended in the treatment of uncomplicated RVF disease. Prevention and Control Vaccines—Currently, there is no vaccine to prevent RVF virus infection that is approved for veterinary use in North America or Europe. Since the first isolation of RVF virus, various vaccines against RVF virus have been developed, including vaccines produced through formalin inactivation107–111; through attenuation (liveattenuated virus) via in vivo serial passage112,113 or via in vitro chemical mutagenesis114; by use of naturally occurring attenuated mutant virus,115–117 viral subunits,118 recombinant virus vectors,119,120 or viral cDNA121; and by use of recombinant live-attenuated RVF virus containing complete deletions of known virulence genes.122 Over the past 50 years, each of these approaches have led to further refinements in efficacy and safety of vaccines and have increased understanding of RVF virus vaccinology. Formalin-inactivated vaccines are considered safe, but have drawbacks for field use because of the typical requirement for 3 initial inoculations over a period of 1 to 2 months followed by annual booster inoculations.110,113,123 This requirement renders inactivated vaccines impractical for livestock use in locations in which RVF virus is endemic. However, for human use, a formalin-inactivated product (designated as TSI-GSD-200) was produced in the mid-1970s under an investigational new drug license from the FDA.124 The use of this vaccine was targeted at laboratory and other service personnel with high occupational risk of exposure to the virus. Although no longer produced and in limited supply, TSI-GSD-200 was proven safe, immunogenic, and effective in preventing laboratory-acquired infections among 598 volunteer human vacinees.111 Because of the convenience of protection against RVF virus provided by a single inoculation of a liveattenuated vaccine, use of these vaccines became the preferred strategy for vaccination of livestock throughout Africa beginning in the 1950s. The live-attenuated Smithburn strain of RVF virus is immunogenic and efficacious in adult sheep and cattle, but also causes abortion or teratologic effects in fetuses in up to 25% of pregnant animals.56,65,112,125 Thus, this vaccine is likely unsuitable for use in regions outside of the endemic zone of RVF virus activity. Efforts to create more highly attenuated and safe vaccine products led to the development of the MP-12 vaccine that was derived via chemical mutagenesis of the RVF virus.114,126–128 Administration of a single dose of this vaccine was proven to be safe and efficacious in sheep and cattle, inducing high serum concentrations of Vet Med Today: Zoonosis Update

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neutralizing antibodies and providing protection from virulent virus challenge.64,129,130 The abortifacient properties of the MP-12 vaccine are controversial—in some studies,64,129–131 no abortions occurred following its use, whereas in another,132 the vaccine was associated with fetal losses. Further safety and efficacy studies are likely required before widespread use of MP-12–based vaccines could be considered in countries in which RVF virus is not endemic. Recently, the development of a highly immunogenic recombinant vaccine candidate containing complete deletions of the major RVF virus virulence genes (NSs and NSm) was reported.122 Wistar-Furth rats vaccinated with this construct were protected from challenge with virulent virus at doses as high as 500 times the LD50 value. An advantage of this vaccine design is the ability to differentiate naturally infected from vaccinated animals on the basis of the presence or absence of anti-NSs antibodies or through the incorporation of exogenous immunogenic peptides for detection via differential serologic screening assays. This capability is essential if countries in which RVF virus is nonendemic implement large-scale vaccination programs following RVF virus introduction. Integrated control and surveillance strategies— The importance of RVF virus as a pathogen of livestock and humans further underscores the need for safe and effective antiviral treatments and vaccines and for integrated national and international control and surveillance strategies. The increasing concern over the potential use of RVF virus as an agent of biological terrorism only heightens this need. Control of RVF virus incursions can only be achieved by close coordination of agricultural, veterinary, entomologic, and medical efforts. Once RVF virus is established in an area with competent arthropod vectors, elimination of the virus may be impossible, as graphically illustrated by the emergence of West Nile virus in the Americas since 1999. Successful control will require a multifaceted intervention strategy involving rapid diagnostic tests to identify infected humans, other animals, and vectors and resources for appropriate supportive care of infected individuals. Animal quarantine or slaughter and integrated insect control measures also are required for effective control. If safe and effective vaccines become available, their rational use will be essential to stop the spread of RVF virus among livestock. Because RVF virus is a zoonotic agent, it is critical that the news media be engaged at the outset for the dissemination of factual information regarding the real health risks of RVF virus infection and to highlight measures the public can take to reduce potential exposures. Once the virus is newly introduced into areas, stopping its spread is possible, but difficult. During the 1977–1979 epidemic-epizootic in Egypt along the Nile River, the Israeli government rapidly began an extensive vaccination and testing program in the occupied regions of the Sinai Peninsula. During this effort, > 1.2 million doses of inactivated RVF virus vaccine were used in conjunction with quarantine and destruction of infected animals and intensive insect control measures throughout the Sinai Peninsula and in the Gaza Strip, all of which contributed toward preventing the spread of the virus northward into 890


Israel.133,134 This program was likely successful because of the integration of control strategies and, importantly, because of the climate and geography of the area affected. Control of any incursion of RVF virus into North America or Europe will likely be more difficult because there are few geographic barriers to slow mosquito dispersal and the movement of livestock throughout these regions is extensive and rapid. Public Health Implications The history of RVF virus is one of periodically extensive outbreaks of severe animal and human disease throughout Africa. The virus has repeatedly overridden international boundaries and geographic barriers and now is present throughout much of the African continent and Arabian Peninsula. Each successive incursion into previously RVF virus–free regions has resulted in large epidemics among humans: in Egypt (1977–1979), approximately 200,000 persons were affected; in Senegal-Mauritania (1987), approximately 89,000 persons were affected; in Kenya (1997–1998), approximately 27,000 persons were affected; and in Saudi Arabia and Yemen (2000), approximately 2,000 persons were severely affected or hospitalized. Fortunately, most human illnesses are self-limiting and do not result in serious complications or death. However, the clinical signs of uncomplicated RVF can be debilitating (eg, lethargy, fever, arthralgia, and myalgia) and will lead many people to seek medical intervention, thereby potentially overwhelming the local medical care system. The principal public health impact of RVF virus introduction into areas in which the virus was not endemic will be direct infection of humans. However, important secondary effects including fears regarding food safety (especially livestock-derived meat products), financial impacts on farmers, stigmatization of infected individuals, distrust of scientific and medical authorities, and mental health effects among the general population will likely develop as an outbreak unfolds. Similarly, veterinary and human medical resources will be severely strained in any outbreak. During the recent foot-and-mouth disease epizootic in the United Kingdom in 2001, unanticipated issues regarding the environmental and societal impact of large-scale animal euthanasia and carcass disposal became important public concerns. Each of these problems requires an appropriate response at the public health level and careful thought regarding the dissemination of health information and engagement of the media to help allay fears among the general population. Overview The potential impacts of RVF virus on North American and European agriculture and public health are considerable. Veterinarians in food animal practice will likely be the first medically trained professionals to encounter RVF virus in these regions because animals with clinical signs of RVF disease will likely be the first indication of virus introduction via natural processes or intentional acts of bioterrorism. The early recognition of an outbreak of a foreign animal disease by veterinary practitioners is a critical link in the control and evenJAVMA, Vol 234, No. 7, April 1, 2009

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