Rift valley fever

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aakash Hans, MD[2]

Rift valley fever (RVF) is a zoonotic disease caused by the RVF Virus (RVFV) that mainly affects livestock and is responsible for illness in humans. The disease process in humans ranges from a simple febrile illness to fatal hemorrhagic conditions. Other symptoms include eye involvement and encephalitis. RVF is also known to have caused miscarriage in women. Mosquitoes, livestock and humans form parts of the virus’ life cycle. With a complex transmission process and lack of specific vaccines or treatment makes the disease difficult to control. Since mosquito breeding is an important factor for the spread of disease, regions with heavy rainfall are at risk to have increased numbers of cases and mortality.

In the year 1930, Rift Valley fever virus (RVFV) was discovered as the pathogen causing an increased incidence of hepatitis in animals belonging to the Rift Valley in Kenya.^[1] The primarily affected animals were sheep, with deaths and miscarriages in sheep along with mortality in lambs born recently.

• There is no classification used for Rift valley fever.

RVF is transmitted to humans either via mosquito bite or via exposure to infected animals. There is no evidence of human to human transmission of the disease. The disease manifests in three major stages:

• Early infection
  • It is mainly due to entry and survival of the virus in macrophages and dendritic cells.
• Liver infection
  • The virus most commonly infects liver cells and causes inflammation via IL-10.
• Late infection
  • The virus begins to invade neuronal cells leading to neurological symptoms.

Rift valley fever is caused by the Rift Valley fever virus (RVFV). The virus is a single-stranded RNA virus belonging to the Bunyaviridae family.

The majority of differential diagnoses for RVF arise from other diseases which are prevalent in travelers and present with fever. All these disease would share a similar history of recent travel to an endemic area, followed by development of fever and body aches.

The virus is able to stay active outside the human body even when it is not being actively transmitted amongst animals. Heavy rain causes mosquitos to breed in large numbers, which translates into increased transmission to livestock. As more animals get infected, the risk of the virus being transmitted to humans increases. Humans acquire the infection by being exposed to animal fluids and products. Most of the disease surges till now have been seen in some regions of Africa and countries belonging to the Arabian peninsula. Since its discovery around the year 1930, there have been outbreaks of RVF, starting in the 1950 in the African countries, South Africa and Kenya.

Risk factors applicable to Rift valley fever are similar to other zoonotic diseases. Exposure to mosquitos feeding on infected animals is the main cause of acquiring the infection. All human activities and habits which expose them to mosquitos or the infected animals would qualify as risk factors of the disease.

Rift valley fever is a self-limiting illness in majority of patients. The symptoms appear around 2-3 days after exposure. The main symptoms are fever and body aches. Fever usually subsides by 3-4 days after the beginning of symptoms. Complications can arise if the fever recurs again after remission and the patient continues to be febrile. Neurological, ophthalmological and hemorrhagic features are the commonly seen complications. Prognosis is good for most of the patients who only have the febrile illness which subsides on its own. The patients who suffer from complications usually recover at a slower pace out of which some succumb to the complications.

Diagnosing Rift valley fever requires index of suspicion for individuals presenting with fever, especially after exposure to infected animals or mosquitos.

• RT-PCR is used to diagnose RFV in the earlier days of the illness.
• ELISA test can also be used for diagnosis during the early phase of the disease.
• IgM Antibodies test can be used if 3-4 days have passed since the onset of symptoms

• The hallmark of Rift valley fever is the development of a febrile illness in the individual with a history of recent exposure to animals or mosquitos.
• Other common symptoms include headache, fatigue, joint pain and loss of appetite.
• Individuals may also present directly with complications of RVF like disorientation, yellowish discoloration of skin or bleeding from mucosal sites.

• The physical examination in individuals with Rift valley fever can be significant for:
  • Fever
  • Low Blood Pressure
  • In cases of severe RVF, findings like body rash, yellow colored skin or disorientation may be seen.

• Anemia
• Deranged coagulation profile
• Raised serum bilirubin

There are no ECG findings associated with Rift valley fever.

There are no x-ray findings associated with Rift valley fever.

On ultrasound imaging of the abdomen Rift valley fever may show an enlarged liver and an enlarged spleen.

There are no CT scan findings associated with Rift valley fever.

There are no MRI findings findings associated with Rift valley fever.

The optimal therapy for Rift valley fever is conservative and supportive management with anti-pyretics and intravenous fluids.

There are no established surgical therapies for Rift valley fever.

• Avoiding exposure to ill animals.
• Protection from mosquito bites.
• Vaccination of the livestock.

There are no established measures for the secondary prevention of Rift valley fever.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aakash Hans, MD[2]

Rift valley fever was predominantly seen in the African continent and Arabian peninsula since the 1950s. The RVF virus was discovered in 1930 when it was seen to cause liver infection in large numbers of sheep. Only after 1975, was Rift valley fever considered a disease of humans as before 1975 it was majorly considered a disease of African livestock. Various outbreaks of RVF have taken place in Africa since the 1950s, causing a deep socio-economic impact on the regions affected.

• In the year 1930, Rift Valley fever virus (RVFV) was discovered as the pathogen causing an increased incidence of hepatitis in animals belonging to the Rift Valley in Kenya.^[1]
• The primarily affected animals were sheep, with deaths and miscarriages in sheep along with mortality in lambs born recently.
• Blood from diseased sheep was injected in healthy sheep which then replicated to symptoms of the disease.
• It was also noted that many diseased sheep belonged to areas heavily infested with mosquitos. Therefore, to test this hypothesis, all the healthy sheep were moved to an area with low to no mosquitos, which when showed no symptoms of the disease, confirmed the hypothesis that the disease was transmitted from animal to animal (directly) or through mosquitos.^[2]
• Upon further investigation, many farmers and herders taking care of these diseased sheep reported symptoms of fever and body aches. This suggested the possibility of human susceptibility which was confirmed in a similar manner when healthy humans developed symptoms when blood from ill sheep was transfused to humans.
• The outbreaks of Rift valley fever were noted to be occurring in regions which received heavy rainfall. These environment and climate conditions enhance the breeding of mosquitos, which play an essential role in transmission of the virus to both humans and animals.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aakash Hans, MD[2]

Rift valley fever is known to cause human infection by infecting the first line of defense in the body. The virus is able to survive and replicate inside macrophages and dendritic cells and release IL-10 which further enhances the inflammation and spread of infection within the body. Liver cells are commonly infected by the virus which translated to right upper quadrant abdominal pain in the patient.

The pathophysiology of Rift valley fever mainly has three main stages:

• Early infection :
  • The RVFV is an arbovirus, which means that it enters the human body during a mosquito bite. The salivary content of the mosquito has properties amenable to the virus, which results in a higher load of virus to be transferred inside the human body.
  • Once inside the body, the virus is able to evade the first line of defense formed by the macrophages and dendritic cells. The virus possesses the ability to multiply inside macrophages. It also renders the macrophage incapable of releasing cytokines which would attract other white blood cells to eliminate the virus. ^[1]
  • It is speculated that the virus uses macrophages and dendritic cells to increase its numbers by significant proportions. This is supported by the observation that the spread of the virus in animal models with no dendritic cells and macrophages is suppressed and slowed down by tremendous proportions. ^[2]

• Liver infection :
  • Regardless of the route of entry of the virus, it has the tendency to infect liver cells which is corroborated by the fact that postmortem examination of RVF cases show hepatic inflammation and injury.
  • Factors inducing apoptosis are suppressed while those inhibiting apoptosis are increased when the virus infects liver cells. ^[3]
  • It is postulated that the virus causes increased production of cytokines responsible for liver damage due to enhanced inflammatory response. IL-10 is one of the cytokines which are released in increased amounts during viral infection.
  • It is only when factors of adaptive immunity kick in, does the viral get cleared from the body. The removal and control IL-10 and IL-12 production form a key component of successful recovery. ^[4]

• Late Infection :
  • In cases where the virus persists in the body for longer periods of time, the virus is able to infect various types of neuronal cells.
  • It has been seen in animal models that neurons present in the olfactory mucosa provide the virus with a potential entry point into the central nervous system. ^[5]
  • Other studies have suggested that the virus also enters the central nervous system through the blood-brain barrier and through layers protecting the CSF.
  • The anti-inflammatory factors in mosquito-saliva aid the virus cross the blood-brain barrier. Further clarification about viral invasion mechanisms will require more studies.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aakash Hans, MD[2]

Rift valley fever is caused by the Rift Valley fever virus (RVFV). The virus is a single-stranded RNA virus belonging to the Bunyaviridae family. The virus is contracted by humans via exposure to animals exhibiting symptoms of RVF or via mosquito bites. Farmers and herdsman may be exposed to body fluids of animals with Rift valley fever, which is another source of infection for humans.

• RVF is caused by the Rift Valley fever virus or RVFV, which belongs to the Bunyaviridae family.
• The genetic composition of the virus is a single-stranded RNA consisting of three segments (L, M and S) out of which L and M possess a negative charge while the S segment has both sense and antisense orientation.^[1]
• The virus’ RNA polymerase is coded by the L component which is responsible for replication and transcription of messenger RNA (mRNA) while glycoproteins and protein are encoded via the M segment. ^[2]
• Nucleoproteins and non-structural proteins are coded by the S segment in its antisense and sense orientation respectively.

• 
  High magnification transmission electron micrograph (TEM) reveals some of the ultrastructural morphology seen in an unknown tissue sample, which had been caused by the spherical-shaped, enveloped Rift Valley fever (RVF) virus. Virions budding from the cell membrane are indicated by arrowheads. From Public Health Image Library (PHIL). ^[3]
• 
  Transmission electron micrograph (TEM) depicts a highly magnified view of a tissue that had been infected with Rift Valley fever (RVF) virus. From Public Health Image Library (PHIL). ^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]Associate Editor(s)-in-Chief: Aakash Hans, MD[3]

The majority of differential diagnoses for Rift valley fever arise from other diseases which are prevalent in travelers and present with fever. All these disease would share a similar history of recent travel to an endemic area, followed by development of fever and body aches. A few of these diseases are listed below.

• Malaria
  • The disease presents with fever like Rift valley fever, but the major difference is the pattern of fever in malaria. The fever recurs every 3-4 days in malaria while no such patterns are seen in RVF.
  • Malaria is common in African countries, so paying attention to the time and onset of fevers can be useful in distinguishing between the two diseases.^[1] The vast majority of cases of malaria occur in children under the age of 5 years.^[2]
• Typhoid fever
  • Typhoid usually has a pattern of step-ladder form of fever, meaning the temperature rises with each passing day.^[3]
  • The patient also complaints of bowel abnormalities along with fever. Individuals report either constipation or diarrhea along with fever.
  • A rash is seen on the chest, known as rose-spots in patients with Typhoid.
• Crimean-Congo hemorrhagic fever
  • It is a tick-borne viral disease of both wild animals and domestic animals, affecting humans.^[4]
  • The virus belongs to the Bunyaviridae family, which is commonly found in Africa.
  • Risk factors include handling body fluids of infected humans or animals.
• Ebola virus disease
  • It is caused by a virus belonging to the Filoviridae family.^[5]
  • It should be suspected in febrile indivisuals who have done the following within a time span 3 weeks before fever :
    • Traveled to an area of a country where the disease had recently occurred.
    • Have had contact with body fluids like blood and other secretions of animals or humans infected with the disease.
• Dengue
  • Patients with dengue also complain of fever but have greater joint pains than in Rift valley fever.^[6]
  • A characteristic feature of dengue fever is retro-orbital pain.
  • Dengue has a longer incubation period of 7 days, followed by a week of febrile phase, 1-2 days of the critical phase and 3-5 days of the recovery phase.
• Yellow fever
  • It is a rare disease caused by mosquitos found in South America and Africa.^[7]
  • There are vaccines for travelers traveling to these areas.
  • The disease is usually a self limiting febrile illness but may lead to cardiac, renal and hepatic complications.
• Lassa fever
  • The disease is usually seen in West Africa.^[8]
  • It is transmitted by rats and risk factors include handling food materials infected with rat feces or contact with infected humans.
  • The incubation period ranges from 2-21 days and most of the people do not report any symptoms.
  • Common symptoms are fever, throat pain, headache, swelling of the face, vomiting and diarrhea.
• Chikungunya
  • It is caused by the Aedes aegypti mosquito and is commonly seen in African and Asian countries.^[9]
  • The course of the disease is self limiting and involves fever, headaches and generalized body pain.
• Q fever
  • Q fever is caused by infection by a bacteria called Coxiella burnetii.^[10]
  • The bacteria is usually found in domestic animals such as sheep, goats, cats and ticks also.
  • Risk factors include drinking raw milk, breathing in contaminated dust or droplets.
  • Acute infection is characterised by fever, pneumonia and hepatitis. Chronic infections presents with cardiac, musculoskeletal or vascular symptoms.
• Zika virus
  • Patients exposed to the virus develop illness 3-12 days after being exposed.^[11]
  • Symptoms include headache,rash,fever and back pain.
  • Symptoms last for the next 4-7 days with most of patients having a full recovery.
• Marburg virus disease
  • Marburg virus is the pathogen responsible for the disease.^[12]
  • Infection in humans is caused due to exposure to mines and caves where Rousettus bats can be found.
  • Once the virus is transmitted from animals to humans, further spread is usually human-to-human and results from contact with bodyfluids.
  • Hypotension, metabolic disorders, immunosuppression and coagulopathy are the initial symptoms.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]Associate Editor(s)-in-Chief: Aakash Hans, MD[3]

The virus is able to stay active outside the human body even when it is not being actively transmitted amongst animals. Heavy rain causes mosquitos to breed in large numbers, which translates into increased transmission to livestock. As more animals get infected, the risk of the virus being transmitted to humans increases. Humans acquire the infection by being exposed to animal fluids and products. Most of the disease surges till now have been seen in some regions of Africa and countries belonging to the Arabian peninsula. Since its discovery around the year 1930, there have been outbreaks of RVF, starting in the 1950 in the African countries, South Africa and Kenya.

• The virus is able to stay active outside the human body even when it is not being actively transmitted amongst animals as the Mcintoshi specie of the Aedes mosquito is able to pass on the virus to its progeny. ^[2]
• Heavy rain causes mosquitos to breed in large numbers, which translates into increased transmission to livestock.
• Many species of mosquitos and even sandflies and ticks are able to transmit the virus. Other animals like elephants, giraffes and buffaloes are also know to receive the virus through these arthropods.
• As more animals get infected, the risk of the virus being transmitted to humans increases.
• Humans acquire the infection by being exposed to animal fluids and products. There is no evidence suggesting transmission of the virus via mosquito bites. ^[3]
• Human to human transmission has not been reported till date. Medical personnel did not contract the virus during outbreaks even when they wore little to no personal protective equipment. ^[4]
• Sexual transmission in humans has not been recorded yet while vertical transmission has been reported in humans and livestock both.
• Most of the disease surges till now have been seen in some regions of Africa and countries belonging to the Arabian peninsula.
• Since its discovery around the year 1930, there have been outbreaks of RVF, starting in the 1950 in the African countries, South Africa and Kenya.
• In 1974, another episode of increased cases of RVF occurred in South Africa, where around 110 confirmed cases and seven fatalities were reported. ^[5]
• Outbreak of the greatest proportion was later recorded during a two year span starting from 1977 in Egypt, where approximately 200,000 cases were detected which resulted in 598 deaths.^[6]
• In the year 1997, after a period of heavy rain in East Africa, another outbreak was observed with around 89,000 cases of RVF. ^[7] This led to the first incidence of RVF cases outside the African continent, in Saudi Arabia in the year 2000, with 880 cases and 123 fatalities. ^[8]
• There have been numerous incidence of RVF cases in East Africa, since the year 2016.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aakash Hans, MD[2]

Risk factors applicable to Rift valley fever are similar to other zoonotic diseases. Exposure to mosquitos feeding on infected animals is the main cause of acquiring the infection. All human activities and habits which expose them to mosquitos or the infected animals would qualify as risk factors of the disease.

• Travel to endemic areas of RVF is associated with increased risk of exposure to the disease.
• Visiting rural areas and sleeping outside in locations where RVF incidence is high can increase exposure to mosquitos.
• Farmers, herdsman and veterinarians, who handle livestock in endemic areas increase their risk of exposure to the virus.
• Milking animals infected with RVF can increase the risk of transmission to humans ^[1]
• Skinning an animal with symptoms of RVF has also been seen to increase risk of exposure in humans. ^[2]
• Giving an animal infected with the virus, shelter at home, can lead to transmission of the virus from the animal to humans.^[3]
• Birthing animals with symptoms of RVF can lead to significant exposure to humans performing said act.^[4]
• Male gender, consuming raw milk of infected animals and coming in contact with aborted tissues of affected animals are associated with increased risk of transmission of RVF to humans.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aakash Hans, MD[2]

Rift valley fever is a self-limiting illness in majority of patients. The symptoms appear around 2-3 days after exposure. The main symptoms are fever and body aches. Fever usually subsides by 3-4 days after the beginning of symptoms. Complications can arise if the fever recurs again after remission and the patient continues to be febrile. Neurological, ophthalmological and hemorrhagic features are the commonly seen complications. Prognosis is good for most of the patients who only have the febrile illness which subsides on its own. The patients who suffer from complications usually recover at a slower pace out of which some succumb to the complications.

Rift Valley fever (RVF) is caused by a virus belonging to the Bunyaviridae family and Phlebovirus genus, known as Rift Valley fever virus (RVFV). Majority of humans experience fever which subsides on its own, while a few go on to develop neurological symptoms, clot formation, hemorrhage or vision abnormalities.

• Natural History
  • Febrile Illness :
    • The patient does not develop symptoms until 4 to 5 days after exposure.
    • Symptoms of fever develop all of a sudden and include generalized weakness, feeling cold, headaches, nausea and a feeling of heaviness in the righty upper abdomen.^[1]
    • Next, the patient develops high body temperatures 101.8 to 103.1 F along with body aches, sensitivity to light and low blood pressure. ^[2]
    • Various other manifestations like vomiting accompanied with abdominal pain, loss of sense of taste, nosebleeds and loose stools may also be seen in some individuals.^[3]
    • After three to four days since the onset of illness, symptoms begin to subside and body temperatures drop back to normal.
    • Some individuals may experience repeat episodes of fever and headache one to three days following recovery.^[4]
    • Once the body temperature becomes normal some patients develop clots in their coronary vessels or have severe pain in the abdomen or lower limbs.
    • The virus is detected in the blood until third day of illness while antibodies begin to appear in the blood from the fourth day onward.^[5]

• Complications
  • Neurological manifestations :
    • Cases of encephalitis following infection with RVFV have been described in the literature. ^{[6] [7]}
    • Signs and symptoms included increased leukocytes and decreased levels of antibodies in the cerebrospinal fluid, retinal changes, confusion and gait disturbances.
    • Paralysis of body like hemiparesis has also been reported in RVF cases. ^[8]
    • Brain lesions due to RVF present with features of coma, increased salivation, irregular flailing movements of the upper limbs and hallucinations. ^[9]
  • Hemorrhage :
    • Cases with hemorrhage due to RVF can be fatal, with variable times reported till the occurrence of death.
    • The patient develops febrile symptoms suddenly along with rashes and ecchymotic patches all over the body, bleeding from the gastrointestinal tract and gums, jaundice along with decreased blood pressure. ^[10]
    • These patients have increased hepatic enzymes and raised levels of lactate dehydrogenase(LDH) along with decreased hemoglobin and platelet count.
    • Postmortem examination shows focal involvement of liver cells pointing towards injury to hepatocytes during the illness.
    • Individuals who show no signs of jaundice or any bleeding, often have kidney failure or develop disseminated intravascular coagulation (DIC), which can become fatal.^[11]
  • Clot formation:
    • A case was reported which developed several clots after being infected with RVFV. ^[12]
    • After the patient’s fever subsided, he developed patches on his lower limbs around the fifth day of illness.
    • This was followed by inflammatory changes in the patient’s popliteal vein by the twelfth day followed by formation of pulmonary infarcts at various locations from twentieth day onwards.
    • The patient developed a pulmonary embolus on the 45th day of illness which proved to be fatal.
    • No liver involvement was observed during postmortem examination.
  • Ophthalmological manifestations :
    • Individuals can present with symptoms at variable intervals after the disease onset.
    • Loss of peripheral vision or blurred vision is commonly reported after infection.
    • Unilateral or bilateral eyes may be involved with features of edema in the macula, retinal bleeding or loss of transparency in the vitreous.^[13]
    • Majority of cases do not regain complete eye function, even after the viral infections subsides.^[14]

• Prognosis
  • Majority of individuals develop a mild to moderate course of fever and body aches, from which they recover spontaneously.
  • Complications are seen rarely with ocular problems occurring in about 1 to 2% cases, while encephalitis and hemorrhage developing in approximately 1% cases or less. ^[15]
  • Hemorrhagic fever is associated with a high fatality rate of 50%, while the fatalities reported overall are only around 1% of total cases.
  • Only 1 to 10% of cases with ocular manifestations continue to have lifelong, irreversible impairment of vision.

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