Oropouche fever

Oropouche fever
Midges (Culicoides sp.) are the main vectors which spread the Oropouche virus to humans.
Specialty	Infectious diseases
Symptoms	Fever (~100%), headache (70–80%), arthralgia, myalgia, nausea, vomiting, dizziness, photophobia, rash
Complications	Meningoencephalitis
Usual onset	3–8 days
Duration	2–7 days
Causes	Oropouche virus (OROV)
Diagnostic method	Clinical, laboratory (PCR)
Differential diagnosis	Dengue, Chikungunya, Zika, yellow fever, malaria
Treatment	Symptomatic; none specific

Oropouche fever is a tropical viral infection transmitted by biting midges and mosquitoes from the blood of sloths to humans. This disease is named after the region where it was first discovered and isolated at the Trinidad Regional Virus Laboratory in 1955, by the Oropouche River in Trinidad and Tobago.^[1] Oropouche fever is caused by a specific arbovirus, the Oropouche virus (OROV), of the Bunyaviridae family.

Large epidemics are common and very swift, one of the earliest and largest having occurred at the city of Belém, in the Brazilian Amazon state of Pará, with 11,000 recorded cases. In the Brazilian Amazon, oropouche is the second most frequent viral disease, after dengue fever. Several epidemics have generated more than 263,000 cases, of which half occurred in the period from 1978 to 1980.^[2] It is estimated that more than half a million cases have occurred since in Brazil alone, with most having gone undiagnosed or misdiagnosed due to limited availability of laboratory methods for diagnosis (which are expensive and time-consuming), the clinical similarity of Oropouche fever to other more prevalent arboviral illnesses, and the fact that in many cases there may be co-infection with other similar mosquito-borne viruses.^[3]

The signs and symptoms of Oropouche fever are similar to those of dengue, Chikungunya, and Zika.^[4] Symptoms typically begin 3 to 8 days after infection. Fever, headache, and muscle and joint pains are most common; a skin rash, unusual sensitivity to light, and nausea and vomiting may also occur. Most cases are self-limited, with recovery in 2 to 7 days. In severe illness, however, the central nervous system may be affected, with symptoms of meningitis and encephalitis, and a tendency to excessive bleeding has been reported in up to 15% of cases.^[4]

Oropouche has been recognized as among the most neglected of tropical diseases and as an emerging infectious disease: little is known about its epidemiology, pathogenesis, and natural history; it has potential for spread throughout the Western Hemisphere and, climate conditions permitting, to other continents as well; and there is no specific treatment or vaccine.^[4][5]

Oropouche fever is characterized as an acute febrile illness, meaning that it begins with a sudden onset of a fever followed by severe clinical symptoms.^[6] It typically takes 4 to 8 days from the incubation period to first start noticing signs of infection, beginning from the bite of the infected mosquito or midge.^[7]

Fevers are the most common symptom, occurring in nearly all cases, with temperatures as high as 40 °C (104 °F). Other symptoms include chills, headache, muscle and joint pain (myalgia and arthralgia), dizziness, photophobia, nausea, vomiting, joint pains, epigastric pain, and rashes.^[8] As in dengue, a skin rash resembling rubella, conjunctival injection, and pain behind the eyes may occur.^[7] The initial febrile episode typically resolves within 7 days, but it is very common to have a reoccurrence of these symptoms with a lesser intensity.^[7] Studies have shown this typically happens in about 60% of cases.^[7] Fatigue and weakness may also persist for up to a month after infection.^[6][4]

In serious cases, particularly in large outbreaks, the central nervous system may be affected with symptoms of meningitis and encephalitis, including severe headache, dizziness, neck stiffness, double vision, darting of the eyes, uncoordinated movements, and evidence of viral infection in the cerebrospinal fluid (CSF).^[4] A tendency to abnormal bleeding has been reported in up to 15% of cases.^[4]

Oropouche orthobunyavirus
Virus classification
(unranked):	Virus
Realm:	Riboviria
Kingdom:	Orthornavirae
Phylum:	Negarnaviricota
Class:	Ellioviricetes
Order:	Bunyavirales
Family:	Peribunyaviridae
Genus:	Orthobunyavirus
Species:	Oropouche orthobunyavirus

The oropouche virus is an emerging infectious agent that causes the illness oropouche fever.^[9] This virus is an arbovirus and is transmitted among sloths, marsupials, primates, and birds through the mosquitoes Aedes serratus and Culex quinquefasciatus.^[3] The oropouche virus has evolved to an urban cycle infecting humans though midges as its main transporting vector.^[3]

OROV was first described in Trinidad in 1955 when the prototype strain was isolated from the blood of a febrile human patient and from Coquillettidia venezuelensis mosquitoes.^[1] In Brazil, OROV was first described in 1960 when it was isolated from a three-toed sloth (Bradypus tridactylus) and Ochlerotatus serratus mosquitoes captured nearby during the construction of the Belém-Brasilia Highway.^[1] The oropouche virus is responsible for causing massive, explosive outbreaks in Latin American countries, making oropouche fever the second most common arboviral infection seen in Brazil.^[10] So far the only reported cases of Oropouche fever have been in Brazil, Panama, Peru, Bolivia, Colombia, Cuba, and Trinidad and Tobago.^[7][11]

ORO fever occurs mainly during the rainy seasons because there is an increase in breeding sites in the vector populations.^[7] There has also been reports of the oropouche epidemics during the dry season but this is most likely due to the high population density of mosquitoes from the past rainy season.^[7] Moreover, during the dry season there is a deceased chance of outbreaks which decreases the amount of midges this is because the amount of outbreaks is related to the number of human population that has not yet been exposed to this virus.^[7]

Oropouche fever is caused by the oropouche virus (OROV) that belongs to the Peribunyaviridae family of arboviruses.^[7] This virus is a single-stranded, negative sense RNA virus which is the cause of this disease.^[8] There are no specific ultrastructural studies of the oropouche virus in human tissues that have been recorded to this date.^[7] It is likely that this viral agent shares similar morphological characteristics with other members of the Orthobunyavirus genus.^[7] Members of the Orthobunyavirus genus have a three part, single-stranded, negative sense RNA genome of small (S), medium (M) and large (L) RNA segments.^[7] These segments function to encode nucleocapsids, glycoproteins and the RNA polymerase in that sequential order.^[7] Through phylogenetic analysis of nucleocapsid genes in different oropouche virus strains, it has been revealed that there are three unique genotypes (I, II, III) that are currently spreading through Central and South America.^[7]

Reassortment is said to be one of the most important mechanisms in explaining the viral biodiversity in orthobunyaviruses.^[7] This occurs when two genetically related viruses infect the same cell at the same time forming a progeny virus and this virus holds various components of genetic L, M and S segments from the two parental viruses.^[7] In reassortment, the S and L segments are the ones that are usually exchanged between species further, the S segment, that is coded by the nucleocapsid protein, and the L polymerase function together to create a replication of the viral genome. Due to this, one segment will restrict the molecular evolution of another segment and this is said to be inherited as a pair.^[7] On the contrary, the M segment codes for viral glycoproteins and these could be more prone to mutations due to a higher selective pressure in their coding region because these proteins are major host range determinants.^[7]

There is not a significant amount of information regarding the natural pathogenesis of OROV infections. It is known that within 2–4 days from the initial onset of systematic symptoms in humans, the presence of this virus is detected in the blood. In some cases this virus has also been recovered from the cerebrospinal fluid, but the route of invasion to the central nervous system (CNS) remains unclear.^[7] In one study of three patients with oropouche meningoencephalitis confirmed by reverse transcription-polymerase chain reaction, two of the patients had underlying conditions that can affect the CNS and immune system (one had HIV/AIDS) and the third had neurocysticercosis; the authors thus theorized that CNS invasion by OROV can be facilitated by preexisting damage to the blood-brain barrier.^[10]

To further elucidate the pathogenesis of OROV, experimental studies using murine models have been performed.^[12]

BALB/c neonate mice were treated with this virus subcutaneously and presented clinical symptoms five days after inoculation.^[7] The mice revealed a high concentration of the replicating virus in the brain along with inflammation of the meninges and apoptosis of neurons without encephalitis,^[7] which is inflammation of the brain due to an infection.^[7] These findings confirmed the neurotropism of this virus, which means that this virus is capable of infecting nerve cells. Immunohistochemistry was used to reveal how this virus had access to the central nervous system.^[7] The findings indicated that the OROV infection starts from the posterior parts of the brain and progresses toward the forebrain.^[7] The oropouche virus spreads through the neural routes during early stages of the infection, reaching the spinal cord and traveling upward to the brain through brainstem with little inflammation.^[7] As the infection progresses, the virus crosses the blood-brain barrier and spreads to the brain parenchyma leading to severe manifestations of encephalitis.^[7]

Laboratory diagnosis of the oropouche infection is done through classic and molecular virology techniques.^[7] These include:

1. Virus isolation attempt in new born mice and cell culture (Vero Cells)^[7]
2. Serological assay methods, such as HI (hemagglutination inhibition), NT (neutralization test), and CF (complement fixation test) tests and in-house-enzyme linked immunosorbent assay for total immunoglobulin, IgM, and IgG detection using convalescent sera^[7][9] (this obtained from recovered patients and is rich in antibodies against the infectious agent)
3. Reverse transcription polymerase chain reaction (RT-PCR) and real time RT-PCR for genome detection in acute samples (sera, blood, and viscera of infected animals)^[7]

Clinical diagnosis of oropouche fever is challenging due to the nonspecific nature of the disease; in many cases, it can be confused with dengue fever or other arboviral illnesses.^[9]

Oropouche fever occurs in outbreaks, so the chances of one contracting it after being exposed to areas with midges or mosquitoes is rare.^[8] Prevention strategies include reducing the breeding of midges through source reduction (removal and modification of breeding sites) and reducing contact between midges and people. This can be accomplished by reducing the number of natural and artificial water-filled habitats in which the midge larvae grow.^[8]

There is no vaccine.^[4][5]

As for other arboviral diseases, there is no cure or specific therapy for Oropouche fever; only symptomatic treatment (such as analgesics for pain relief and fluids to prevent and treat dehydration) is recommended.^[13][14] Aspirin is not a recommended choice of drug because it can reduce blood clotting and may aggravate the hemorrhagic effects and prolong recovery time.^{[citation needed]} Ribavirin is ineffective and is not recommended.^[4][5]

The infection is usually self-limited and complications are rare. Illness usually lasts for about a week, although in extreme cases can be prolonged^[1] and aches and fatigue can persist for several weeks.^[6] Patients usually recover fully with no long-term ill-effects. There had been no recorded fatalities resulting from oropouche fever until 2024, when two deaths were confirmed in the Brazilian state of Bahia.^[15][16]