Tuesday, October 30, 2012

Rift Valley Fever


This week we will cover the last of the Bunyaviridae in this extended series on the viral hemorrhagic fevers. This is the Phlebovirus that causes Rift Valley fever. Rift Valley fever is another zoonotic vector-borne infection and occurs throughout much of Africa and parts the Arabian Peninsula.

The Pathogen. Rift Valley fever (RVF) is caused by Rift Valley fever virus (RVFV), which is a Phlebovirus in the Bunyaviridae family. RVFV is approximately 90 to 110 nanometers in diameter. It is an enveloped virus with a single-stranded RNA genome in three segments. The three genome segments are circular and classified as large (L), medium (M), and small (S). The S segment is ambisense, while the L and M segments are negative-sense:

RVFV structure (Published in: Vet. Res. 2010. 41(6): 61.)

Macrophages, hepatocytes and endothelial cells are the target cells in the human host and, like hantaviruses and Crimean-Congo hemorrhagic fever virus, RVFV invades host cells by endocytosis and replicates via the ER-Golgi intermediate compartment.

Bunyaviridae infection cycle (Published in: Antiviral Research, Volume 64, Issue 3, December 2004, Pages 145-160)

The Vector. RVFV is an exceptional virus in that it can be vectored by many, and quite varied, arthropods depending on the specific geographic location. For example, several species of mosquito, sandflies and ticks are all capable of transmitting RVFV between hosts. Nevertheless, mosquitoes are far and away the primary and most important vector for this virus. Mosquito vectors are central to the enzootic, epizootic, and epidemic ecology of the virus. In most of the geographic areas where RVFV is present, Aedes mosquitoes are the dominant mosquito vectors for enzootic transmission among animals, and for sporadic transmission among humans. These are the virus maintenance vectors. Aedes mcintoshi is the most important of these maintenance vectors.

Aedes mcintoshi

On the other hand, when specific features of the landscape emerge, Culex mosquitoes serve as important amplifying vectors, which transition virus circulation and transmission in animals from enzootic conditions to epizootic conditions, and subsequently also increase the risk for human epidemics. These dynamic landscape features of mosquito and disease ecology will be discussed in greater detail below.

Culex pipiens

The Disease. The vast majority of infections are mild or asymptomatic. The mild disease course typically presents as an influenza-like illness with abrupt onset of fever, mylagia and arthralgia, and headache. Some patients may additionally present with vomiting, neck stiffness, and photosensitivity, which may be initially identified incorrectly as meningitis. 

Approximately 2% to 5% of infected individuals develop complicated RVF, which is comprised of three syndromes that may or may not occur in concert.

Ocular disease is marked by lesions on the retina appearing approximately 1 to 3 weeks following the onset of initial symptoms. These lesions are usually associated with blurred vision and/or mild to severe vision loss, which may or may not resolve during convalescence. The mortality associated with this syndrome, when it is not accompanied by either of the other two, is quite low. 

Meningoencephalitis is marked by severe neurologic involvement approximately 1 to 4 weeks following the initial symptoms, but can even occur more than two months later. Confusion, loss of memory, convulsions, hallucination and headache are common features of this syndrome. Coma can also ensue. Mortality associated with this syndrome is also low, but chronic neurologic deficit often persists and can be quite severe.

Hemorrhagic fever is marked by serious hemorrhage. This syndrome typically begins much closer to the onset of initial symptoms. Approximately 2 to 4 days after initial symptoms appear, significant liver dysfunction, which may include jaundice, presents. Following the onset of liver involvement, widespread hemorrhage typically ensues. Bleeding from the nose and gums is common, as is hematemesis and blood in the stool (either melena or hematochezia). Purpuric rashes, which can develop into ecchymoses, are also frequently present with this syndrome. This syndrome is associated with a much higher mortality than the other two. Approximately 50% of those individuals who develop the hemorrhagic form of RVF succumb to the disease, and they typically do so within the first week of illness.

Livestock disease can be quite devastating and is often responsible for the greatest burden of RVF. Rift Valley fever typically causes severe disease in livestock animals much more frequently than it does in humans. In some domestic animals, the mortality attributable to RVF can approach 10%. In addition, spontaneous abortion occurs in almost all pregnant livestock if infection occurs during pregnancy. In fact, widespread spontaneous abortion among livestock populations often signals an RVF epizootic and human epidemic to follow.

The Epidemiology and the Landscape. The landscape epidemiology of RVF is extraordinarily complex. RVFV is transmitted to humans by way of mosquito vectors, primarily Aedes species, or through direct or aerosol contact with contaminated body fluids of infected livestock during animal husbandry or processing, or by consumption of contaminated animal products. Zoonotic transmission from livestock accounts for the vast majority of human infections. Human to human transmission has not been documented.

The map below produced by the Centers for Disease Control and Prevention shows the global distribution of RVF. Blue represents countries with endemic disease and substantial outbreaks of RVF, whereas green represents countries known to have some cases, periodic isolation of virus, or serologic evidence of RVF


While RVF is demonstrated in much of the African continent, endemicity has only been documented in parts of West, East, southern African, and the Arabian Peninsula. 

The graphic below nicely depicts the key features of the landscape of RVFV transmission and disease ecology. The sylvan infection cycle is maintained  directly by multiple mosquito vectors and perhaps some combination of mammal hosts in varied terrain, the full compliment of which is unknown but may include ruminants and rodents as important hosts and perhaps bats to a lesser degree. Mosquitoes also act as bridge vectors for transmission of RVFV to livestock, or less commonly, directly to humans. Transmission to humans occurs most frequently following exposure to their livestock. Thus, animal husbandry is the most significant conduit to human infection in the landscape even though direct transmission from mosquitoes to humans remains a distinctly viable route of infection.



The complexity of RVF landscape epidemiology is further compounded by the intersection of specific landscape features with climate factors and diverse mosquito ecology. In particular, Aedes mosquitoes are primarily responsible for maintaining endemicity in sylvan and domestic animal populations. The virus is transmitted transovarially in these Aedes mosquitoes and, because viremia remains relatively low among all mammalian hosts, ultimately the mosquitoes act as the primary natural reservoir for RVFV. This is unusual for arthropod-borne viruses as there is typically a vertebrate host in the environment that serves as a natural reservoir. The relevant Aedes mosquito vectors oviposit on dry surfaces close to intermittent or standing bodies of water and require a period of desiccation before hatching. Once they are newly submerged in water following a period of rain the eggs can hatch and the life cycle can proceed. These mosquitoes, as mentioned, transmit the virus vertically and act as the primary natural reservoir. These mosquitoes exploit dynamic water habitat in the landscape, which fluctuates between intermediate dry and wet periods according to the fluctuations in rainfall. Moreover, they tend to take their blood meals in proximity to these water sources, which also serve as water sources for ruminants (sylvan and domestic) and small mammals. These water features tend to be associated with geologic depressions that drain the landscape of water runoff, and are known locally as pans or Dambos.

Flooded Dambo

Thus, as the mosquitoes respond to and exploit the intermittent cycles of standing water in the landscape in hyperlocalized habitat, and because they acquire RVFV transovarially, they also maintain enzootic disease in animals as those animals exploit and share the same water resources. However, when more extensive water accumulates in the Dambos, due to periods of greater rainfall and flooding, the ecological niche expands and allows for population explosions of Culex species. These mosquitoes cannot transmit the virus vertically, but they do travel much farther afield in the landscape. After taking blood meals from local mammal populations whose enzootic levels of virus are maintained by the Aedes mosquitoes, Culex mosquitoes can then distribute RVFV much more widely and subsequently spark epizootic disease across a much larger geographic space.  This in turn increases the likelihood of human epidemic disease. The graphic below visually depicts the nuance of RVF landscape epidemiology and disease ecology.



Control and Prevention. Rift Valley Fever control is typically focused on livestock protection, which is accomplished through vaccination. There are two vaccines available. One is a single-dose live attenuated virus vaccine and provides good long-term immunity, although it causes spontaneous abortion in a small proportion of cattle. The other vaccine is inactivated and is not associated with aborted pregnancies in livestock, however it requires multiple doses to generate an effective immune response. Regardless of the vaccine used, any RVF intervention in livestock must be implemented before an epizootic emerges. Initiating a livestock vaccination campaign after an epizootic has begun in the livestock population can actually accelerate the outbreak. However, the implementation of these control methods require significant resources because of the costs of vaccination and good livestock infrastructure, neither of which are often available for poor subsistence farmers and herders in many areas where RVF is endemic.

Prevention of RVF in humans is focused on 1) maintaining hygienic animal processing techniques, particularly barrier protection and sanitary working conditions, to prevent or minimize contact with animal body fluids, 2) avoiding consumption of uncooked or undercooked animal products, and/or raw blood or milk, and 3) vector control, particularly around the home, which typically employs insecticide-treated bed nets and/or residual insecticide spraying.


While some of these strategies may be combined with other public health initiatives (e.g., malaria vector control programs), others may not be successfully combined with other programs and may not be adequately resourced to implement independently (e.g. providing rubber gloves, barrier gowns, and sanitary working conditions to all individuals who process cattle for human consumption). Moreover, some strategies may contradict social and cultural norms and thus unable to gain popular acceptance (e.g. consumption of raw cattle blood among some pastoral communities).

Given the complex landscape epidemiology of RVF with its multiple modes of transmission, mosquito ecology, and virus infection cycle, establishing complete prevention and control measures to effectively block RVFV along all transmission pathways will be very difficult.

11 comments:

  1. According to a CDC article, there is a high risk of introduction of Rift Valley Fever through illegal animal movements. IN Mayotte (Island near Mozambique), they have performed active surveillance with suspected ruminants. However, this may be difficult on a larger scale, especially on the mainland. Illegal animal transportation may pose a large obstacle to the surveillance of such illnesses.

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  2. Russel Sharif (MPH)November 16, 2012 at 1:03 AM

    As we all know that the vector control is an important step to prevent the disease.According to the WHO, larviciding measures at mosquito breeding sites are the most effective form of vector control if breeding sites can be clearly identified and are limited in size and extent. During periods of flooding, however, the number and extent of breeding sites is usually too high for larviciding measures to be feasible. So we should consider vector control while preventing the infection.

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  3. According to the WHO website, animal health workers can inadvertently transmit the virus from an already infected animal to uninfected animals in the herd, through the use of multi-dose vials and the reuse of needles and syringes. It may help in efforts to control the spread of Rift Valley Fever if an intervention/ training was developed to emphasize the importance using new needles and syringes for each animal in the herd. I know it is probably very expensive and time consuming for poor farmers or any farmer in general to use new vaccination instruments on every animal. However, it might be a good investment for their local governments, international governments (CDC), or international organizations (WHO) to fund these instruments and possible interventions /trainings to prevent the further spread of Rift Valley Fever to unaffected areas of the world.

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    1. @Bianca:

      I wonder if they'd consider a needle exchange program. (I kid.)

      But it'd be a good idea to invest in clean needles/syringes, especially in areas with a high prevalence of RVF -- it could help reduce transmission to uninfected cattle.

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  4. Transmission of the RVFV to humans typically occurs through mosquito vectors or direct/indirect contact with infected livestock and their body fluids. Would it be safe to say that outbreaks of Rift Valley Fever are common or unique to rural and farming areas as opposed to urban environments?

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  5. According to the Center for Food Security and Public Health, young livestock are the most severely affected. Young lambs for instance, will have a rapid onset (12-36 hours) of weakness, hemorrhaging, diarrhea, and death can occur within 36 hours. The mortality rate among neonates is 90-100% and among young calves it is 10-70%. Thus the disease can devastate a herd and a farmer's livelihood.

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  6. Center for Food Security and Public Health: http://www.cfsph.iastate.edu/DiseaseInfo/disease.php?name=rift-valley-fever

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  7. Since RVF has similar symptoms similar to influenza, it must be difficult for physicians in developing countries to diagnose the disease. According to WHO, there are several tests that can be used such as serological tests (ELISA), taking the patient's blood sample, and antigen detection test to diagnose for acute RVF. In developing countries, which is the most common type of testing is being used? Is one type of test for RVF more accurate/efficient/cost effective than another?

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    1. @ Thu Hong, it appears that all countries that are members of the OIE (World Organization for Animal Health) are required to use the serological test- Virus neutralization (the prescribed test for international trade) to test for Rift Valley Fever. The Virus neutralization test can detect antibodies against RVF in the serum of a variety of species, it is highly specific, and will record the earliest responses. These tests can only be performed in areas where Rift Valley Fever is endemic; thus should not be conducted in regions outside the endemic areas. However, I am not sure how much more accurate the Virus neutralization test is when compared to any other serological test used to detect Rift Valley Fever.

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    2. @ Bianca,
      In a study I looked up, Plaque reduction neutralization tests (used to titre the neutralizing antibody of the virus) are more sensitive than a tested alternatives which were indirect immunofluorescence (fluorescence in presence of antibodies of given disease), complement fixation (can detect actual antigen or antibodies, depending on selected test) was the least sensitive for Rift Valley Fever. So it may be the best test to use, but I really have no clue as to the mechanics of the tests.

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    3. Sheaba Daniel

      @ Flynn,

      Plaque Reduction Neutralization Test (PRNT) is considered the “best” test to measure and detect antibodies due to its high specificity and sensitivity. PRNT works by measuring the antibody response. The drawbacks are that the test takes several difficult steps to complete, is not widely available, and takes a few days to garner results.

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