Oropouche virus fever

Approximately 70 years ago, it was believed that the age-old battle between humans and infectious diseases was nearing its end, with victory in sight for humanity. However, in recent decades, this outlook has proven to be utopian.¹ During this time, emerging infectious diseases such as Nipah, Zika, Chikungunya, Ebola fever, and coronavirus disease 2019 have been reported, while some other infectious diseases have re-emerged or continue to re-emerge periodically, such as Dengue and influenza virus, to mention just a few viral examples. In this context, the World Health Organization considers the Oropouche virus (OROV) to be a pathogen of priority concern in epidemic and pandemic preparedness and research, although it currently classifies it as low risk.²

Among arboviruses, OROV is considered endemic in regions of Central and South America. This virus is responsible for Oropouche fever, a neglected disease that often causes mild and self-limiting symptoms³. Its clinical presentation is considered indistinguishable from infections caused by other arboviruses with which it shares an ecological niche, as well as from other microorganisms responsible for acute febrile illness.^3,4 OROV possesses characteristics that enable ongoing transmission in endemic areas; these include the diversity of reservoirs and the range of vectors capable of transmitting the virus. Moreover, it is transmitted undiagnosed in some Amazonian regions of Peru and other countries with limited healthcare systems, due to its clinical similarity to other arboviral infections and shortcomings in epidemiological surveillance. These conditions make the spread of OROV a potential public health concern in the future.⁴

The causative agent of Oropouche fever belongs to the family Peribunyaviridae, genus Orthobunyavirus, species oropoucheense, serogroup Simbu. Its genome consists of three single-stranded negative-sense RNA segments: small (S), medium (M) and large (L). This characteristic of its genetic material allows it to perform gene rearrangements, which is an evolutionary mechanism that has the ability to generate a new recombinant virus. In addition, this mechanism drives the genetic diversity and divergence of the virus, which facilitates its dissemination by enhancing its transmission and influencing the severity of the disease.⁵

Thus, in South America, three OROV reassortants have been identified, namely Iquitos virus (IQTV), Madre de Dios virus (MDDV), and Perdões virus (PDEV), although the latter has not yet been isolated in humans.⁶ Due to limited arboviral surveillance across the Americas, it is likely that the number of OROV reassortants is underestimated⁶. The traditional classification of OROV, based on analysis of the N gene, comprises four distinct genotypes (I, II, III and IV). However, this scheme has been shown to be insufficient for accurately categorising new viral sequences based on all three segments of the viral genome.⁷ It is important to note that, to date, no standardised and comprehensive system has been adopted for the classification of lineages or clades, such as exists for other viruses like dengue.⁷ Despite this, recent outbreaks have been reported to be caused by the new lineage OROVBR-2015-2024, which has established local transmission chains in Brazil, Peru, Cuba, Colombia and Bolivia.⁸

Since its detection in 1955 in Trinidad and Tobago, cases of Oropouche fever have been reported in Central and South America, with incidence increasing over recent decades. As of February 2025, OROV infection has been documented in both human and non-human hosts from rural or forested areas in 11 countries within the Americas region, with the highest number of cases reported in Brazil, Peru, Ecuador, Argentina, Bolivia, Panama, Colombia, and Venezuela, indicating a wide geographical spread.^5,9 The first occurrences in densely populated urban areas were reported in northeastern Brazil in 2016,¹⁰ where up to 36% of individuals have tested positive.¹¹ Similarly, outbreaks with high attack rates have been recorded, such as in French Guiana in 2020, where OROV was identified in 43% (41/95) of individuals studied.¹² Data from other South American countries, such as Brazil, also indicate evidence of exposure to OROV, with neutralising antibodies detected in 10.24% of patients.¹³

Transmission of the virus occurs through an enzootic cycle involving non-human primates and other wild mammals. Both urban and sylvatic transmission cycles have been described. In the sylvatic cycle, the vectors responsible for transmission include Aedes and Culex mosquitoes (such as Coquillettidia venezuelensis in Trinidad, Ochlerotatus serratus, and Culex quinquefasciatus in Brazil). In the urban cycle, the primary vector is Culicoides paraensis, commonly known as the 'midge'.¹¹ Urban transmission, amplified by human activity, raises concerns regarding the potential for global dissemination due to the high number of Culicoides species that may be capable of transmitting the virus. Likewise, it is also known that Culex tarsalis and Culicoides sonorensis may possess the ability to transmit OROV. However, the clinical and epidemiological implications of these findings remain unclear.^5,11

Alongside the increase in cases reported in endemic regions of South and Central America in recent years, the European Centre for Disease Prevention and Control (ECDC) confirmed the first imported cases of OROV infection in Europe, with 19 cases identified across Spain, Germany, and Italy. These cases involved patients who had recently travelled to Cuba and Brazil.¹⁴ Similarly, the US Centers for Disease Control and Prevention (CDC) confirmed 21 cases of OROV infection in the United States in patients who had recently travelled to Cuba.¹⁵ In addition to these reports, which stem from human migration, there is the impact of climate change – a global phenomenon – the expansion of arthropod vectors, and the identification of potential animal reservoirs. This scenario supports the likely spread of OROV beyond South and Central America in the near future.¹⁶ For this reason, the ECDC rates the risk of contracting OROV disease as moderate for EU and US citizens travelling to countries where active transmission occurs, and low for contracting the disease otherwise.¹⁴

The available evidence on clinical presentation and sequelae of infection comes from studies with methodological limitations, so morbidity and mortality may be underestimated. As of April 2025, the Pan American Health Organisation has already reported 5 deaths directly caused by the virus in Brazil and Panama.^17,18 In the vast majority of cases this infection has a mild clinical presentation and is self-limiting. The incubation period varies from 2 to 10 days, followed by fever, headache, arthralgia, myalgia, nausea, vomiting, chills and photophobia. Other signs and symptoms reported in different studies include rash, retroocular pain, haemorrhages and central nervous system involvement.^3,4 Recovery is usually complete and without sequelae, although persistent myalgia and asthenia lasting more than 30 days have been reported.^5,9 The disease may recur 1–4 weeks after the fever has subsided; this occurs in about 60% of cases. The mechanisms responsible and the factors that may trigger relapsing disease are not yet understood.¹⁹ Moreover, the incidence of asymptomatic infections is difficult to estimate in the absence of passive surveillance studies. Regarding associated complications, the risk of vertical transmission and the possibility of foetal damage with OROV IgM identified in live newborns with microcephaly of unknown cause is reported.^18,20 The Pan American Health Organization risk assessment of August 2024 reports one foetal death and three miscarriages possibly related to OROV in Brazil.¹⁸ Cases of Guillain-Barré syndrome related to this viral infection have also been reported.⁵

So far, no coinfections of OROV with reassortant viruses have been reported. However, coinfections with Dengue, Zika, and Chikungunya viruses have been described. The impact of these coinfections on disease morbidity and mortality remains unclear.^5,13

The pathogenesis of OROV is poorly understood. Although the immune response against OROV has not been extensively studied, it has been demonstrated that host innate immunity, particularly the production of interferons and pro-inflammatory cytokines, plays a crucial role in controlling and resolving OROV infection. At the onset of viral infection, a signalling cascade is activated that results in the production of cytokines; interferons are critical in containing viral replication. Furthermore, the virus can modulate the host immune response by interfering with cytokine production or signalling, or by inhibiting immune cell function via microRNA-mediated mechanisms. It can also evade the immune system by forming immune complexes.¹⁶

Due to the wide range of microorganisms responsible for acute febrile illness, diagnosing OROV based solely on clinical features is not feasible. For this reason, in settings without access to laboratory testing, patients are at risk of being undiagnosed, misdiagnosed, or untreated, and outbreaks may go unrecognised. Laboratory identification of the causative agent relies on three diagnostic criteria: a positive reverse transcription polymerase chain reaction (rt-PCR), detection of specific IgM, or seroconversion in paired samples. Viral culture and cell isolation are also used for research and diagnostic purposes.⁵ Currently, there are no validated immunochromatographic tests available for point-of-care use to benefit affected populations.¹⁸

At present, no specific antiviral treatment has been developed for OROV. Studies using ribavirin and mycophenolate in animal models have proven ineffective. Interferon-alpha may restrict viral replication in murine models when administered prior to or shortly after disease onset; however, the clinical relevance of this finding remains undetermined.⁵ Management of confirmed infection is based on supportive care according to disease severity. Initial clinical management should include rest, frequent fluid intake, and the use of analgesics and antipyretics. Patients presenting with severe clinical manifestations should be hospitalised for individualised supportive treatment.⁹

Regarding disease control and prevention, regions that have borne the burden of OROV due to the frequency of outbreaks have initiated and promoted efforts to better understand the factors that determine disease onset and severity, transmission routes, and the clinico-epidemiological characteristics of affected populations.⁹ Currently, there are no licensed vaccines or antiviral medications available to prevent OROV infection or to treat the underlying cause in individuals with Oropouche fever. However, research is ongoing into vaccine candidates based on chimeric viruses, as well as studies using bioinformatic methods to predict new epitope candidates for vaccine design.⁵ In this context, it is recommended that travellers to affected areas use insect repellents containing N,N-diethyl-m-toluamide or icaridin and sleep under mosquito nets. Pregnant women should reconsider non-essential travel to areas with a high risk of Oropouche virus transmission.¹⁸

Therefore, OROV represents an emerging threat with the potential for global spread, driven by factors such as human migration, climate change, and the virus's and its vectors' adaptability. Although it generally causes mild disease, the potential for complications and its rapid spread justifies the need for more rigorous epidemiological surveillance, a comprehensive public health approach, and international collaborative efforts to control it. While it is impossible to predict the potential spread of a microorganism with certainty, this virus should be on the radar of virologists and public health agencies. As with past epidemics and pandemics, it should not be underestimated from the outset, as what we do not know is the most feared and also the most likely.

Ethical considerations

No ethical approval or informed consent was required as no patient data were used and no experiments of any kind were performed.

Funding

The authors declare that they have not received any funding for the preparation of this manuscript.