View source for Rift valley fever

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{{DiseaseDisorder infobox |
  Name        = Rift Valley fever |
  Image       = Rift Valley fever tissue.jpg | 
  Caption     = <center>[[Transmission electron microscopy|TEM]] [[micrograph]] of tissue infected with Rift Valley fever virus</center> |
}}
'''For patient information, click [[Rift valley fever (patient information)|here]]'''

{{Rift valley fever}}
{{CMG}}{{AE}} {{AAH}}

{{SK}} RVF infection, RVF, Rift Valley fever.

==[[Rift valley fever overview|Overview]]==
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.

==[[Rift valley fever historical perspective|Historical Perspective]]==
In the year 1930, Rift Valley fever virus (RVFV) was discovered as the pathogen causing an increased number of hepatitis in animals belonging to the Rift Valley in Kenya.<ref>Daubney R, Hudson JR, Garnham PC. Enzootic hepatitis or Rift Valley fever. an undescribed virus disease of sheep cattle and man from East Africa. J Pathol Bacteriol 1931; 34:545–579</ref> The primarily affected animals were sheep, with deaths and miscarriages in sheep along with mortalities 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.<ref>Daubney R, Hudson JR. Rift Valley fever. East African Medical Journal 1933; 10:2–19</ref>
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.


==[[Rift valley fever pathophysiology|Pathophysiology]]==
The pathophysiology of RVF has been understood and deduced by conducting studies on various animal models.
*'''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 defence 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. <ref>McElroy AK, Nichol ST: Rift Valley fever virus inhibits a pro-inflammatory response in experimentally infected human monocyte derived macrophages and a pro-inflammatory cytokine response may be associated with patient survival during natural infection. Virology 2012;422:6-12</ref>
**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. <ref>Gommet C, Billecocq A, Jouvion G, Hasan M, Zaverucha do Valle T, Guillemot L, Blanchet C, van Rooijen N, Montagutelli X, Bouloy M, Panthier JJ: Tissue tropism and target cells of NSs-deleted Rift Valley fever virus in live immunodeficient mice. PLoS Negl Trop Dis 2011;5:e1421.</ref>

*'''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 post-mortem 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. <ref>Jansen van Vuren P, Tiemessen CT, Paweska JT: Anti-nucleocapsid protein immune responses counteract pathogenic effects of Rift Valley fever virus infection in mice. PLoS One 2011;6:e25027.</ref>
**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. <ref>Dodd KA, McElroy AK, Jones ME, Nichol ST, Spiropoulou CF: Rift Valley fever virus clearance and protection from neurologic disease are dependent on CD4+ T cell and virus-specific antibody responses. J Virol 2013;87:6161-6171</ref>

*'''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. <ref>Smith DR, Steele KE, Shamblin J, Honko A, Johnson J, Reed C, Kennedy M, Chapman JL, Hensley LE: The pathogenesis of Rift Valley fever virus in the mouse model. Virology 2010;407:256-267.</ref>
**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.

==[[Rift valley fever causes|Causes]]==

==Gallery==
<gallery>

Image: Phlebovirus06.jpeg| 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. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name=PHIL> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>

Image: Phlebovirus04.jpeg| Transmission electron micrograph (TEM) depicts a highly magnified view of a tissue that had been infected with Rift Valley fever (RVF) virus. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name=PHIL> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>

</gallery>

==[[Rift valley fever differential diagnosis|Differentiating Rift valley fever from other Diseases]]==

==[[Rift valley fever epidemiology and demographics|Epidemiology and Demographics]]==
*The virus is able to stay active outside human bodies 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. <ref>Huang YM. A new african species of aedes (Diptera: Culicidae). Mosquito systematics 1985; 17:108–120</ref>
*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 buffalos 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. <ref>Nicholas DE, Jacobsen KH, Waters NM. Risk factors associated with human Rift Valley fever infection: systematic review and meta-analysis. Trop Med Int Health 2014; 19:1420–1429</ref>
*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. <ref>Al-Hamdan NA, Panackal AA, Al Bassam TH, Alrabea A, Al Hazmi M et al. The risk of nosocomial transmission of Rift Valley fever. PLoS Negl Trop Dis 2015; 9:e0004314</ref>
*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. <ref>McIntosh BM, Russell D, dos Santos I, Gear JH. Rift Valley fever in humans in South Africa. S Afr Med J 1980; 58:803–806</ref>
*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.<ref>Laughlin LW, Meegan JM, Strausbaugh LJ, Morens DM, Watten RH. Epidemic Rift Valley fever in Egypt: observations of the spectrum of human illness. Trans R Soc Trop Med Hyg 1979; 73:630–633</ref>
*In the year 1997, after a period of heavy rain in East Africa, another outbreak was observed with around 89,000 cases of RVF. <ref>An outbreak of Rift Valley Fever, eastern Africa, 1997-1998. EMHJ 1998; 4:379–381</ref> 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. <ref>Madani TA, Al-Mazrou YY, Al-Jeffri MH, Mishkhas AA, Al-Rabeah AM et al. Rift Valley fever epidemic in Saudi Arabia: epidemiological, clinical, and laboratory characteristics. Clin Infect Dis 2003; 37:1084–1092</ref>
*There have been numerous incidence of RVF cases in East Africa, since the year 2016.


==[[Rift valley fever risk factors|Risk Factors]]==
*Travel to endemic areas of RVF are at increased risk of exposure to the disease <ref>https://www.cdc.gov/vhf/rvf/exposure/index.html</ref>
*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.


==[[Rift valley fever natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
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 develop all of a sudden and include generalized weakness, feeling cold, headaches, nausea and a feeling of heaviness in the righty upper abdomen.<ref>Findlay GM, Daubney R. The virus of rift valley fever or enzootic hepatitis. Lancet. 1931;221:1350–1351</ref>
***Next, the patient develops high body temperatures 101.8 to 103.1 F along with body aches, sensitivity to light and low blood pressure. <ref>Kitchen SF. Laboratory infections with the virus of rift valley fever. Am J Trop Med. 1934;14:547–564</ref>
***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.<ref>Mundel B, Gear J. Rift valley fever; i. The occurrence of human cases in johannesburg. S Afr Med J. 1951;25:797–800.</ref>
***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.<ref>Rift Valley fever; accidental infections among laboratory workers.SMITHBURN KC, MAHAFFY AF J Immunol. 1949 Jun; 62(2):213-27.</ref>
***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 onwards.<ref>Rift Valley fever; accidental infections among laboratory workers.SMITHBURN KC, MAHAFFY AF J Immunol. 1949 Jun; 62(2):213-27.</ref>

*'''Complications'''
**'''Neurological manifestations''' : 
***Cases of encephalitis following infection with RVFV have been described in the literature. <ref>Maar SA, Swanepoel R, Gelfand M. Rift valley fever encephalitis. A description of a case. Cent Afr J Med. 1979;25:8–11.</ref> <ref>Alrajhi AA, Al-Semari A, Al-Watban J. Rift valley fever encephalitis. Emerg Infect Dis. 2004;10:554–555</ref>
***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. <ref>Laughlin LW, Girgis NI, Meegan JM, Strausbaugh LJ, Yassin MW, Watten RH. Clinical studies on rift valley fever. Part 2: Ophthalmologic and central nervous system complications. J Egypt Publ Health Assoc. 1978;53:183–184</ref>
***Brain lesions due to RVF present with features of coma, increased salivation, irregular flailing movements of the upper limbs and hallucinations. <ref>van Velden DJ, Meyer JD, Olivier J, Gear JH, McIntosh B. Rift valley fever affecting humans in south africa: A clinicopathological study. S Afr Med J. 1977;51:867–871.</ref>
**'''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. <ref>Yassin W. Clinico-pathological picture in five human cases died with rift valley fever. J Egypt Publ Health Assoc. 1978;53:191–193.</ref>
***These patients have increased hepatic enzymes and raised levels of lactate dehydrogenase (LDH) along with decreased hemoglobin and platelet counts. 
***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.<ref>Al-Khuwaitir TS, Al-Moghairi AM, Sherbeeni SM, Al-Ghamdi AS. Rift valley fever hepatitis complicated by disseminated intravascular coagulation and hepatorenal syndrome. Saudi Med J. 2004;25:528–531</ref>
**'''Clot formation''':
***A case was reported which developed several clots after being infected with RVFV. <ref>Schwentker FF, Rivers TM. Report of a fatal laboratory infection complicated by thrombophlebitis. J Exp Med. 1933;59:305–313</ref>
***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 post-mortem examination.
**'''Ophthalmologic 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.<ref>Siam AL, Meegan JM, Gharbawi KF. Rift valley fever ocular manifestations: Observations during the 1977 epidemic in egypt. Br J Ophthalmol. 1980;64:366–374</ref>
***Majority of cases do not regain complete eye function, even after the viral infections subsides.<ref>Ayoub M, Barhoma G, Zaghlol I. Ocular manifestations of rift valley fever. Bull Ophthalmol Soc Egypt. 1978;71:125–133.</ref>

*'''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. <ref>https://www.nj.gov/agriculture/divisions/ah/diseases/riftvalley.html</ref>
**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. 



==Diagnosis==
===Diagnostic studies===
*The main purpose is to detect the virus in the blood, which can be accomplished by a few tests.
*RT-PCR (reverse transcriptase-polymerase chain reaction) and ELISA test (for antigen detection) may be used during the initial phase of the illness.
*IgM Antibodies : Once the viral load decreases in the blood, IgM antibody tests are helpful in detecting the presence of ongoing infection.
*IgG Antibodies : In recovered cases, testing for IgG antibodies aid in identifying cases who may have had a recent episode of RVF.
===History and Symptoms===
*'''History''':
**Majority of patients have a self-limiting course of fever, so history will elicit complaints of high fever along with body aches.
**Patients may also be recognized by enquiring about recent exposure to livestock.
**Patients who are farmers may give history of their livestock being unwell, after which even they began to develop symptoms.
**In rare cases, patient may indicate that the fever has returned and is not subsiding now. This should alarm the physician towards possibility of a complicated course of RVF for that patient.
*'''Common Symptoms'''
**Fever
**Body aches
**Weakness
**Loss of Appetite
**Vomiting
**Profuse sweating
**Headaches
**Epistaxis

*'''Symptoms due to complications''' 
**Decreased vision
**Pain behind the eye
**Increased sensitivity to light
**Spots in the visual field
**Yellowish discoloration of skin
**Blood in vomit, urine or stools
**Body rash
**Hallucinations
**Disorientation
**Paralysis

===Physical Examination=== 
*Common physical finding include fever and low blood pressure.
*Findings of decreased vision, retinitis, uveitis and altered visual acuity should point towards ophthalmic involvement.
*Findings of jaundice, bleeding from mucosal sites (gums), hematuria, hemoptysis, bloody stools and body rash should indicate hemorrhagic complications of RVF.
*Disorientation, decreased reflexes and paralysis point towards CNS involvement of RVF.

===Lab finding===
*In majority of cases, lab findings will not be significant for anything else except fever and low blood pressure.
*Low hemoglobin levels, raised bilirubin levels along with deranged blood coagulation profile and decreased platelet counts are seen in hemorrhagic RVF.
*Increased leukocytes in CSF along with presence of viral load in CSF would indicate encephalitis or meningitis due to RVF.

===Imaging===
Modalities like ECG, X-ray, CT scan and MRI are seldom used in majority of RVF cases. They only provide supportive reports to diagnose and treat any other ongoing disease process along with RVF.



==Treatment==
===Medical Therapy===
*Mainstay of treatment in most RVF patients is usually supportive with monitoring of body temperature and blood pressure.
*Fluids may be given to patients reporting weakness or low blood pressure.
*There is no specific recommendations for treatment for RVF by the FDA. <ref>Hartman A. Rift Valley Fever. Clin Lab Med. 2017;37(2):285-301. doi:10.1016/j.cll.2017.01.004</ref>
*Drugs having renal, hepatic or coagulation side effects should be avoided in RVF patients.
*Ribavirin showed promise in rodent models but was stopped after development of neurological symptoms in some of the patients it was administered during the RVF outbreak in Saudi Arabia in the year 2000. <ref>Bird BH, Reynes JM, Nichol ST. Rift Valley Fever. In: Magill AJ, Strickland GT, Maguire JH, Ryan ET, Solomon T, editors. Hunter’s Tropical Medicine and Emerging Infectious Disease. 9. Elsevier Health Sciences; 2012.</ref>
===Surgical Therapy===
The mainstay of treatment for RVF is medical therapy. Surgery is usually not required in such cases.

==Prevention==
===Primary Prevention===
*Avoiding exposure to infected or unwell livestock.
*Separating and isolating animals with symptoms from the rest of the herd will help in curtailing the spread amongst the animals, which in turn will decrease the risk of transmission of the virus from animals to humans.
*Effective mosquito control is pertinent in reducing transmission to humans.
*Many vaccines have been developed over the course of history, with the major challenge being, formulating a one-shot vaccine for livestock. Few vaccines are undergoing testing to gain approval for use in animals. <ref>Njenga MK, Njagi L, Thumbi SM, et al. Randomized controlled field trial to assess the immunogenicity and safety of rift valley fever clone 13 vaccine in livestock. PLoS neglected tropical diseases. 2015 Mar;9(3):e0003550.</ref>
===Secondary prevention===
There are no established measures for secondary prevention of this disease.


==External links==
*[http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/rvf.htm Official CDC RVF Information Page]
*[http://www.who.int/mediacentre/factsheets/fs207/en/ WHO Rift Valley fever]

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