Rift valley fever (RVF) is one of the most significant arthropod-borne disorders seen in the sub-Saharan African continent. The disease, which primarily affects ruminants such as sheep and cattle, was first described in 1931. During the past few decades, it has gradually spread to the northern parts of Africa and Arabia.
Epizootics of RVF usually occur periodically almost every 5 to 10 years. Outbreaks in humans have become more frequent during the past few decades. The first reported outbreak in humans occurred in 1951 in South Africa. A recent outbreak was reported from the Garissa region of northern Kenya in November 2006. By the end of January 2007, 404 cases and 118 fatalities had been reported (MMWR).1 More recently, almost 264 cases and 109 fatalities have been reported from Tanzania since January 2007 (World Health Organization).
Most of the outbreaks of RVF have so far occurred in the southern parts of Africa. However, the disease has gradually spread to involve other parts of the continent. The first epizootic of RVF in North Africa occurred in Egypt in August 1977. During this outbreak, nearly 200,000 people fell sick, with 18,000 confirmed cases.2 It is believed that this outbreak resulted because of infection carried by symptomatic camels brought from Sudan.3 The first outbreak in West Africa was reported from Senegal in 1987, whereas an outbreak was reported in Madagascar in 1990. One of the biggest human outbreaks of RVF occurred in 1997 in Kenya. Nearly 27,500 people were infected during this outbreak.4 In a recent study, Clements et al5 used spatial modeling approaches to show that most of sub-Saharan Africa is suitable for endemic circulation of the RVF virus. The first reported outbreak of the disease outside of Africa occurred in 2000 in the Jizan province of Saudi Arabia and Yemen. Nearly 886 cases were reported from Saudi Arabia during this outbreak.6 This outbreak has raised concerns that the disease may gradually spread further beyond the boundaries of Africa and Saudi Arabia.
Rift valley fever is caused by a 3-stranded RNA Arbovirus belonging to the genus Phlebovirus.7 This virus belongs to the family Bunyaviridae. Other Bunyaviruses that cause hemorrhagic fevers in humans include Hantavirus and the Crimean Congo viruses. The virus was first isolated by Daubney, Garnham, and Hudson in 1931 near Lake Naivashain in the Rift Valley of Kenya. The viral genome is characteristically split into a small, medium, and a large segment. Albarino et al8 recently showed that the RVF virus shares a common transcription termination signal with the Toscana and the Sandfly fever Sicilian viruses. At room temperature, the RVF viral particles can be viable for almost 3 months. The virus is inactivated by sodium hypochlorite. Bird et al9 recently completed a genome analysis of 33 different RVF strains. Their studies revealed that the virus has low genetic diversity most likely secondary to its recent common ancestry. The genetic diversity that was present was most likely due to mutations at a rate of 2.9 × 10−4 substitutions per site per year.9
An increase in disease incidence is commonly seen after heavy torrential rains leading to flooding. The flooding provides mosquitoes with a fertile water mass for proliferation.10 These mosquitoes then act as a vector for the disease. The chief vectors in sub-Saharan Africa are Aedes mcintoshi and Aedes ochraceus, whereas the chief vector in the Arabian outbreak was Aedes vexans arabiensis.11 Other vectors include Culex theileri and Culex pipiens. Overall, RVF can be transmitted by nearly 30 different species of mosquitoes, including Eretmapodites and Anopheles. The disease is maintained in mosquitoes by transovarial transmission. It has been shown that mosquito eggs can survive for long times even in drought conditions and then regrow after rainy showers. This might explain the periodicity associated with RVF outbreaks. Other hematophagous vectors such as Phlebotomous have also been implicated in the spread of the disease. In a recent study, Biscout et al12 used stochastic mapping of vector abundance to determine the prevalence of RVF.
Vertebrates that commonly acquire the disease from mosquito bites include goats and cattle that comprise most of the livestock in Africa. However, of all the domesticated livestock, sheep have the highest susceptibility. All these vertebrates ultimately act as amplifier hosts. Widespread appearance of the disease in animals has resulted in numerous epizootics. Humans usually acquire the disease from bites from infected mosquitoes during these epizootics. Persons most at risk include farmers, shepherds, wildlife rangers, and abattoir workers.13 Families that shelter infected animals in their homes and individuals who sleep in the open are undoubtedly at an increased risk. Interestingly, the 1993 outbreak of RVF in Egypt occurred after the construction of the Aswan dam. The excessive water as a result of damming served as an ideal breeding habitat for mosquitoes. Nearly 600 to 1500 cases were reported during this outbreak. Similarly, the 1987 outbreak in Senegal occurred after flooding secondary to construction of the Diama dam as a part of the Senegal river project. In a recent study, Linthicum et al14 showed that past outbreaks of RVF in southern parts of Africa have mostly occurred during cold El Nino-Southern Oscillation periods, whereas similar outbreaks in eastern parts of Africa have mostly occurred during warm El Nino-Southern Oscillation periods. They used normalized difference vegetation index time series data with the help of National Oceanographic and Atmospheric Administration satellites to arrive at this unique pattern of outbreaks.
Other routes of transfer include direct contact with the fluids of animals such as infected sheep. This usually occurs during the slaughtering of infected animals. Ingestion of milk from infected animals can also cause the disease. The disease can also be acquired through aerosols, as has been reported in laboratory personnel. Transmission by aerosols distinguishes RVF virus from other members of the family Bunyaviridae. Human-to-human transmission usually does not occur, although a recent fatal case of possible vertical transmission was reported by Arishi et al15 in a 5-day-old infant.
The incubation period varies from 3 to 7 days. After the mosquito bite, draining lymphatics carry the virus from the inoculation site to the local lymph nodes. Here, the virus multiplies, causing a systemic viremia. The liver and spleen are classically involved after the primary viremia. Severe hepatic necrosis is a characteristic feature of hemorrhagic RVF. Le May et al16 recently showed that the virulence of the virus is primarily because of disruption of synthesis of TFIIH (a transcription factor) by a NS (nonstructural) component of the virus.
CLINICAL PRESENTATION IN ANIMALS
Rift valley fever commonly affects sheep, goats, cattle, antelopes, and camels. Other reservoirs may include rodents and even bats. The incubation period in adult sheep is usually 3 days, whereas it can be much shorter in newborn lambs. A sudden increase in the rates of abortions in ruminant livestock, especially in sheep and goats, should always raise the consideration of RVF as a possible etiological cause. Abortion rates in pregnant livestock infected with the virus is as high as 100%. Other features characteristically seen include bloody diarrhea, generalized hemorrhages, anorexia, weakness, lymphadenopathy, and hepatic involvement, leading to death. The mortality rate in lambs less than a week old is as high as 90%, whereas it is lower (20%) in adult sheep.
CLINICAL PRESENTATION IN HUMANS
In a recent study, LaBeaud et al17 reported that RVF virus seroprevalence in Kenya alone was as high as 10.8%. In general, children are more susceptible to develop infection compared with adults. In humans, the disease is usually asymptomatic or may manifest as an acute syndrome of fevers, weakness, myalgias, dizziness, anorexia, weight loss, and headaches.18 The fever is biphasic, that is, the temperature rises for 2 days, decreases, and then rises again. Conjunctivitis and photophobia can also occur. This influenza-like illness is mostly self-limiting and usually resolves in 7 days. Nausea, vomiting, and diarrhea may also be present.
Some patients may also present with hemorrhagic features. Hemorrhagic fever occurs in less than 1% of patients and may appear as early as 2 days after the onset of symptoms.19 Epistaxis is usually the first indication of progression to hemorrhagic RVF. Soon, petechiae and purpurae start appearing on the skin. In severe cases, hematochezia and even hematemesis may occur. Simultaneous appearance of icterus is not uncommon. Shock, hepatorenal syndrome, and, finally, death can occur in patients with disseminated intravascular coagulation or fulminant hemorrhagic fever.20
The number of patients who develop ocular disease ranges from 0.5% to 2.0%. Unilateral eye involvement is more common than bilateral involvement. In the RVF outbreak in Egypt in 1993, a large number of the patients presented with ocular disease.21 The retina is primarily involved in ocular disease. Characteristically, retinitis and retinal hemorrhages are seen on fundoscopic examination. Patients may complain of a central scotoma. Complete resolution of vision problems occurs in most patients. However, permanent blindness secondary to macular involvement occurs in 1% to 10% of the patients.
Neurological lesions, including encephalitis, have also been described.19 These neurological complications occur in less than 1% of patients and usually appear 1 to 3 weeks after the onset of the disease. Riou et al22 reported an incidence rate of 5% in an outbreak in Mauritania. Development of severe headache, confusion, or drowsiness should point toward possible encephalitis. Besides, seizures can also occur. In a few instances, coma has also been reported. In a recent study, Bird et al23 showed that viruses lacking NSm proteins may have a significant role to play in delayed-onset neurological RVF.
Permanent blindness as a result of retinitis is the most common complication encountered in RVF outbreaks. The case fatality rate in RVF is less than 1%. Nearly 598 deaths were reported in the 1977 outbreak in Egypt, whereas 170 deaths occurred in the RVF outbreak in Kenya in 1997. Most fatal cases have hemorrhagic fever. Madani et al18 reported a much higher case fatality rate of 13.9% during the 2000 outbreak in Saudi Arabia. The case fatality rate is low compared with other Bunyaviruses such as Hantaviruses, which can cause fatality rates as high as 50%.
A complete blood count, liver function tests, and coagulation tests should be ordered for all patients suspected of having the disease. The white blood cell and platelet counts are usually decreased.18 Liver function tests may reveal elevated bilirubin and elevated liver enzymes (aspartate aminotransferase > alanine aminotransferase). Altered coagulation tests may be seen in patients who develop disseminated intravascular coagulation.
Serum samples should also be collected for serology. Detection of virus-specific immunoglobulin M in the serum by enzyme immunoassays aids in diagnosis. The virus particles can be detected in the blood by polymerase chain reaction.
Treatment is entirely composed of supportive measures.24 Volume replacement is necessary in patients with hemorrhagic fever and shock. Medications that are metabolized by the liver should be avoided.
In vitro and animal studies with ribavirin are currently underway and have shown promising results so far. Ribavirin, which has been used in the treatment of lassa fever, can be used and should be considered for the management of RVF. In severe cases of lassa fever, clinicians have used ribavirin at an initial dosage of 30 mg/kg. This loading dose should be followed by 16 mg/kg every 6 hours for 4 days and then 8 mg/kg every 8 hours for another 6 days. Although not a standardized therapy, the same regimen can be tried for RVF.25
Killed and live attenuated vaccines are available for livestock. Lambs conceived by ewes vaccinated with the live attenuated vaccine are protected for 3 months. Mutagenic living RVF vaccine provides immunity for 3 years. It has been used regularly in Egypt since 1994. Vaccination of all susceptible ruminants should be done in the case of an outbreak. This is one of the best and most efficient ways to control the outbreak. Recently, Spik et al26 reported that RVF vaccines produce similar levels of active immunity when used alone or in combination with tick-borne encephalitis virus or Hantaan virus vaccines.
For humans, a killed virus vaccine, TSI-GSD-200 (The Salk Institute-Government Service Division-200), is available. This is primarily indicated in laboratory personnel. In a study used to assess The Salk Institute-Government Service Division-200 vaccine, Pittman et al27 reported good results at 12 years' follow-up. This study involved 598 at-risk subjects. Only 3.5% of all subjects showed side effects during the study. The live attenuated MP 12 vaccine (developed by the US Army Medical Research Institute of Infectious Diseases) and the C-13 vaccines (developed at the Institut Pasteur) are also promising and have been tested in animals.28 Morrill et al29 have shown that interferon-α may be effective in disease prevention in animal models. Nonspecific immune sera have also been shown to be effective in disease prevention in animal models.25
In a recent study, Elfadil et al30 showed a definitive association between the presence of water bodies, mosquito populations, and RVF. Clearly, spraying of mosquito breeding grounds with larvicidals such as methopene is an effective way of interrupting the mosquito life cycle. Water-clogged bodies such as dambos, pools, and canals need to be targeted. Overall spraying may not prove effective because usually large areas need to be covered.
Use of mosquito repellants to prevent bites should be advised to local inhabitants and travelers. N, N-Diethylmethyltoluamide is a highly effective mosquito repellant. Use of bed nets and full-length clothes (preferably light colored) should be encouraged in outbreak areas. As reported by Linthicum et al,14 normalized difference vegetation indices obtained from satellite data may provide early warnings about conditions that might favor RVF outbreaks and thus help in prevention strategy planning.
Rift valley fever is a zoonosis currently limited to Africa and Arabia. Given the significant morbidity and mortality in both animals and humans, the disease needs special attention, especially because it has already spread across the Suez Canal to Arabia. Given the fact that vectors of the disease are found almost all over the world, the potential spread of the disease to other continents should not be overlooked.
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