Re-emergence of Oropouche virus as a novel global threat

Highlights

• •Oropouche fever is emerging as a global public health concern.
• •A novel reassortant OROV lineage drives the 2023–2025 outbreak in the Americas.
• •Over 23,000 cases confirmed, with expansion into non-endemic regions.
• •OROV is linked to Guillain–Barré syndrome and congenital anomalies.

Abstract

Oropouche fever is a viral infectious disease caused by the Oropouche virus (OROV), primarily transmitted by the biting midge Culicoides paraensis. Historically considered endemic to the Amazon region, particularly in Brazil, Peru, and Ecuador, Oropouche fever has resulted in an estimated 500,000 recorded infections. However, its true burden has remained largely unknown for over seven decades, serving as a classic example of a neglected tropical disease. In 2024, however, OROV rapidly expanded beyond its traditional Amazonian hotspots, spreading across Brazil and into other parts of South and Central America. Imported cases have also been reported in North America and Europe, underscoring its emergence as an escalating global public health concern. This literature review explores the historical epidemiology of Oropouche fever while shedding light on its rising public health relevance and emerging clinical challenges. The ongoing 2023–2025 outbreak has significantly affected Brazil, Peru, Bolivia, Cuba, and Panama and is linked to a novel reassortant OROV lineage that originated in the Brazilian Amazon. This new lineage has since established transmission chains throughout South and Central America, with international spread likely driven by increased human mobility and air travel. As of early 2025, over 23,000 confirmed cases have been reported worldwide, including five fatalities and clear evidence of viral expansion into previously unaffected regions. Alongside this viral geographic spread, OROV infection is increasingly associated with severe clinical outcomes, including Guillain–Barré syndrome and vertical transmission leading to miscarriage and congenital anomalies. The ongoing outbreak OROV reassortant lineage also demonstrates increased virulence, immune evasion, and enhanced viral fitness, likely contributing to their epidemic potential. Despite advances in surveillance during the current outbreak, critical gaps remain, including the absence of a standardized global lineage classification system, underscoring the urgent need for strengthened genomic surveillance, deeper insights into pathogenesis, expanded vector competence research, and innovative strategies for disease and vector control.

Graphical abstract

1. Introduction

Oropouche fever, a viral infection causing acute febrile illness, is caused by Oropouche virus (OROV) infection. Most individuals infected with OROV become symptomatic after an incubation period of three to ten days, presenting with fever, headache, myalgia, arthralgia, and retro-orbital pain (Martins-Filho et al., 2024). The disease was first reported in 1955 in a forest worker in a village called Vega de Oropouche, near the Oropouche River in Trinidad and Tobago (Cr et al., 1961). In the following decade, OROV was associated with several outbreaks in Pará state, in northern Brazil, within the Amazon Basin region (Pinheiro et al., 1981). The Amazon Basin region, located in northern Brazil, includes the states of Acre, Amapá, Amazonas, Pará, Rondônia, Roraima, and Tocantins, as well as portions of Maranhão and Mato Grosso.

OROV (Orthobunyavirus oropoucheense) is an arthropod-borne virus classified within the order Bunyavirales, family Peribunyaviridae and genus Orthobunyavirus (Home, 2025). OROV belongs to the Simbu serogroup, one of the 18 serogroups within the Orthobunyavirus genus. The virus has a negative-sense, single-stranded linear RNA genome of approximately 13,000 nucleotides in length. Its genome is segmented into three parts: S (small, ∼ 0.7 kb), M (medium, ∼ 4.4 kb), and L (large, ∼ 6.9 kb) (Elliott, 2014). As a segmented virus, OROV is susceptible to reassortment events, the exchange of viral genome segments that can lead to the emergence of novel strains. These events occur when a host cell is co-infected by multiple viruses, allowing for segment exchange and the generation of progeny viruses with new genome combinations (Schwartz, 2025). Reassortment events can also occur between different members of the Simbu serogroup, potentially giving rise to new viral species. This has been observed in the emergence of Perdoes virus (PDEV), which has not yet been isolated in humans, along with (Schwartz, 2025; Tilston-Lunel et al., 2015) Iquitos virus (IQTV) (Aguilar et al., 2011), and Madre de Dios virus (MDDV) (Ladner et al., 2014).

The OROV is a zoonotic arbovirus maintained in nature by two transmission cycles. In the sylvatic cycle, the virus is maintained in vertebrate hosts such as sloths, rodents, non-human primates, and birds, being transmitted mainly by biting midge Culicoides paraensis, although mosquitos (eg. Culex quinquefasciatus) also can transmit the virus. In the urban cycle, the virus spreads from person to person through bites from Culicoides paraensis midge (Pinheiro et al., 1981). The transition from the sylvatic to the urban cycle is primarily attributed to human incursion on forested areas and their proximity to urban environments (Home, 2018). The rainy season, coupled with temperatures between 30 °C and 32 °C and relative humidity levels ranging from 75 % to 85 %, creates optimal ecological conditions for the proliferation of Culicoides paraensis populations (Feitoza et al., 2023). Recent data from ongoing Oropouche fever outbreaks indicate that the rise in viral infections aligns with the seasonal patterns of Culicoides paraensis. These patterns suggest that transmission intensifies during the rainy season, while lower yet sustained transmission persists throughout the dry season (Naveca et al., 2024).

Oropouche fever became endemic in the Brazilian Amazon region in the 1960s, with several epidemics being reported since then (Pinheiro et al., 1981). Over the last seven decades, the disease has been sporadically reported in Brazil and other countries in South America, affecting around 500,000 people until 2022 (Wesselmann et al., 2024). In late 2023, Brazil faced the re-emergence of Oropouche fever, leading to the largest-ever OROV outbreak across the entire country (Scachetti et al., 2025). The virus also spread to South America and the Caribbean, accounting for over 16,000 confirmed infections in 2024 and for the first time has been associated with fatalities (Oropouche, 2025). Along with the current disease outbreak, novel clinical features have been reported, including neurological manifestations (Fernández de et al., 2024), and vertical virus transmission causing miscarriage, stillbirth, and congenital fetal malformations (Ceccarelli et al., 2025).

The co-circulation of other endemic arboviruses, such as dengue, chikungunya and Zika can exacerbate the impact burden of Oropouche fever across the Americas. The incidence of these diseases can overwhelm healthcare systems, further complicating public health responses (Oropouche 2024; de Paiva Barçante and Cherem, 2025; Musso et al., 2018). Beyond arboviruses, endemic regions are also affected by a wide range of other pathogens causing acute febrile illness, including bacteria such as Leptospira spp. (leptospirosis) (Esteves et al., 2025) and parasites like Plasmodium spp. (malaria) (Garcia et al., 2024). These co-circulating pathogens pose a significant diagnostic challenge due to their similar clinical presentations and limited access to specific laboratory diagnostics in many endemic settings (Tam et al., 2016). Furthermore, climate change and human-driven environmental modifications, such as deforestation and urbanization, may facilitate the expansion of OROV transmission (Poongavanan et al., 2025). Given the high risk of its spread within the Americas - and its potential for global dissemination, as observed with the dengue virus (Brem et al., 2023) - strengthening knowledge and surveillance efforts is crucial to enhancing the effectiveness of control and mitigation strategies (Okesanya et al., 2025).

However, there are relatively few studies focusing on the epidemiology, genomics, and zoonotic cycle of OROV, making it challenging to develop effective measures for controlling and mitigating the expansion of the disease. To address these gaps, I conducted a literature review to provide a clearer understanding of the virus's epidemiology, potential reservoirs, and vectors. As of April 1, 2025, I searched PubMed, medRxiv, and bioRxiv using the term "oropouche." The search yielded 359 results in PubMed, 24 in medRxiv, and 67 in bioRxiv. These studies were carefully reviewed to extract data related to the disease epidemiology, symptoms, clinical manifestations, potential hosts and vectors, and viral genomic epidemiology. Additionally, I retrieved data from the GISAID EpiArbo (Wallau, 2023), NCBI Virus (Brister et al., 2015), and NextStrain (Hadfield et al., 2018) tools to enhance the understanding of the current landscape of OROV genomic surveillance. This knowledge is crucial for implementing strategies to manage and mitigate current and future outbreaks of Oropouche fever.

2. History of human Oropouche fever

Oropouche fever disease was first identified in Trinidad and Tobago in 1955. The virus (strain TRVL 9760) was isolated from a febrile forest worker from Vega de Oropouche, a village located three miles north of Sangre Grande. Another strain of OROV was isolated in 1960 from a pool of Coquillettidia venezuelensis mosquitoes collected in Bush Bush Forest, Nariva Swamp, Trinidad and Tobago (Cr et al., 1961). In May 1960, the virus was first isolated in Brazil from the blood of a sloth (Bradypus tridactylus) found in a forested area during the construction of the Belém-Brasilia highway. Additionally, a pool of Aedes serratus mosquitoes from the same area tested positive for the virus (da Rosa et al., 2017).

In 1961, OROV was also detected in Belém, the capital of Pará State in northern Brazil, where a large Oropouche fever epidemic affected an estimated 11,000 individuals. Symptoms reported included headache, fever, muscle and joint pain, back pain, photophobia, diplopia, nausea, and dizziness. Nearly all patients presented with leukopenia, and although attempts to isolate the virus from mosquitoes and animals in the region did not succeed (Patuá, 2025). While OROV was first isolated in Trinidad and Tobago, later phylogenetic analyses suggest that its origin may be traced back to northern Brazil before spreading to Trinidad and Tobago (Vasconcelos et al., 2011).

Between 1961 and 1979, four more Oropouche fever outbreaks were registered in Pará, Brazil, with an estimated occurrence of over 60,000 cases (Pinheiro et al., 1981; Tesh, 1994; LeDuc et al., 1981). The virus was thought to be geographically restricted to the Pará region until the 1980s, when sporadic cases or self-limited outbreaks were reported in other Brazilian states (Amazonas, Maranhão, Goiás, Rondônia) and Panama, with over 100,000 cases documented (Tesh, 1994; Borborema et al., 1982; Vasconcelos et al., 1989). In the 1990s, Oropouche virus was also reported in Peru, including an outbreak that occurred in 1998 (Tesh, 1994; Baisley et al., 1998; da Silva Azevedo, 2025; Castro et al., 2013). During the 2000s, the virus spread further (Tilston-Lunel et al., 2015; da Silva Azevedo, 2025; Terzian et al., 2009; Vasconcelos et al., 2009; Cruz et al., 2009; Mourão et al., 2025), causing infections in Ecuador (Manock et al., 2009; Forshey et al., 2010), Peru (Forshey et al., 2010), Argentina (Pinheiro and Travassos da Rosa, 2004), and Bolivia (Forshey et al., 2010), with more than 500 laboratory-confirmed cases. From 2010 to 2022, Oropouche fever infections were also reported in Haiti (Elbadry et al., 2021) and French Guiana (Gaillet et al., 2021), totaling over 700 laboratory-confirmed cases in that period (Elbadry et al., 2021; Gaillet et al., 2021; Bastos et al., 2014; da Costa et al., 2017; García et al., 2016; Naveca et al., 2018; de Souza Luna et al., 2017; Alva-Urcia et al., 2017; Wise et al., 2018; Silva-Caso et al., 2019; Wise et al., 2020; Martins-Luna et al., 2020; Lmds et al., 2020; Gómez-Camargo et al., 2021; Carvalho et al., 2022; Pavon et al., 2022; Silva et al., 2024; Grisales-Nieto et al., 2024; Ciuoderis et al., 2022; Moreira et al., 2024; Alvarez-Falconi and Ba, 2010; Castro et al., 2013; Pujol and Paniz-Mondolfi, 2024).

After decades of sporadic outbreaks in Brazil and South American countries, a large-scale Oropouche fever outbreak emerged in November 2023 in northern Brazil, particularly in Amazonas and Rondônia states. The outbreak continued into 2024, spreading to 23 of the 27 Brazilian states, with more than 13,700 laboratory-confirmed cases reported (Oropouche, 2025). In 2024, Oropouche fever cases also spread to other South American countries, including Peru, Bolivia, Ecuador, French Guiana, and Colombia, as well as to Central American and Caribbean countries such as Cuba and Panama. Furthermore, imported cases were documented in North America and Europe (Dez 13, 2025; Toledo et al., 2024; Branda et al., 2024; Castilletti et al., 2024; Mancon et al., 2024). As of 2025, the outbreak remains ongoing, with the highest number of new cases still being reported in Brazil, though Cuba and Panama continue to experience rising case numbers (Oropouche, 2025).

The historical epidemiology of Oropouche fever is notably limited. Although some studies estimate that over 500,000 cases occurred before 2020, these estimates are likely underestimated due to the disease's neglected status (da Silva Azevedo, 2025; Martins-Filho et al., 2024). Even in Brazil, where the virus has been considered endemic in the northern region, Oropouche fever was not classified as notifiable, and laboratory diagnosis in public health laboratories was not widely implemented until 2023 (Brasil, 2024). This lack of surveillance and limited epidemiological data have impeded a comprehensive understanding of the disease's occurrence over time and the factors driving new outbreaks.

3. Oropouche virus cycles, hosts and vectors

Oropouche virus is maintained in nature by a sylvatic and an urban cycle, and in both cycles, the virus is transmitted between/to mammals or humans by the biting midge and different mosquito species, especially Culicoides paraensis, the primary OROV vector (Pinheiro et al., 1981; Brasil, 2024). Culicoides is a genus of biting midges in the order Diptera, family Ceratopogonidae, comprising over 1300 species classified into numerous subgenera (Sick et al., 2019). Along that, Culicoides biting midges are among the most abundant hematophagous insects worldwide, found in a wide range of environments, from temperate regions to the tropics (Sick et al., 2019).

In the sylvatic cycle, the virus has different mammals serving as natural reservoir hosts. The virus was isolated first from pale-throated sloth (Bradypus tridactylus) in Pará, Brazil in 1960 (Pinheiro et al., 1981). After, OROV was isolated from Callithrix sp. (Nunes et al., 2005) in 2000, and from Callithrix penicillata in 2012, both non-human primates collected in southeast Brazil (Tilston-Lunel et al., 2015). Most of the available studies investigating OROV in mammals were conducted through the detection of OROV antibodies. Antibodies were detected in Pigeons, Duck (1961), monkeys (1967), rodents, chickens, and wild and domestic birds (1975) (Pinheiro et al., 1981). In 2010, it was also detected in cebus apella, in 2013 from Sapajus spp. and Alouatta caraya, all New World non-human primates (Batista et al., 2012; Batista et al., 2013; Gibrail et al., 2016). In 2024, a study in Brazil detected neutralizing antibodies for OROV in cattle and dogs, suggesting a previous exposure of these domestic animals to OROV and their eventual role in the virus enzootic cycle (Dias et al., 2024).

Besides Culicoides paraensis, other arthropods have been described as potential vectors for OROV in the sylvatic cycle. These vectors include mosquito species Culex quinquefasciatus, Coquillettidia venezuelensis, Mansonia venezuelensis, and Aedes serratus (Pinheiro et al., 1981; LeDuc et al., 1981; da Silva Ferreira et al., 2020; Cardoso et al., 2015). More recently, the OROV S segment was also detected in Limatus durhamii, Aedes albopictus, Ochlerotatus serratus, Psorophora cingulata, and Haemagogus tropicalis (Pereira-Silva et al., 2021; Feitoza et al., 2025). Similarly, OROV was detected in Culicoides insignis in Peru in 2024, evidencing a possible new OROV vector (Requena-Zúñiga et al., 2024). However, a deep understanding about the main vectors playing a central role in the sylvatic cycle is still lacking.

The most plausible pathway linking the sylvatic and urban OROV cycle is attributed to a human bridge, in which OROV enters urban areas through a viremic individual who visits natural environments and then returns to urbanized areas (da Rosa et al., 2017; DA et al., 2016). The urban transmission cycle of OROV is the primary driver of emergence and maintenance of large disease outbreaks in humans. In this cycle, the virus is transmitted between humans by the biting midge Culicoides paraensis. Experimental studies have shown that Culicoides paraensis is a more efficient vector than mosquitoes, as it can transmit OROV to hamsters six to twelve days after feeding on viremic patients (Pinheiro et al., 1981). The transmission efficiency of Culicoides paraensis ranges from 25 % to 83 %, whereas it remains below 5 % for Culex quinquefasciatus, underscoring the importance of Culicoides paraensis as the principal vector of OROV (Pinheiro et al., 1981). Additionally, Culicoides paraenesis exhibits diurnal activity and tends to be most abundant during rainy periods, further supporting its role in facilitating OROV transmission in urban environments (Feitoza et al., 2023).

A study assessing the vector competence of three North American species - Culex tarsalis, Culex quinquefasciatus, and Culicoides sonorensis - for OROV, found that Culex quinquefasciatus was capable of infection, dissemination, and transmission, albeit at relatively low rates. Culicoides sonorensis exhibited high infection and dissemination rates but may possess a salivary gland barrier that limits its ability to transmit the virus (McGregor et al., 2021). More recently, a 2025 study demonstrated a lack of competence for OROV transmission among several vector species from the United States, including Aedes albopictus, Culex quinquefasciatus, Culex pipiens, and Anopheles quadrimaculatus mosquitoes (Payne et al., 2025). While these studies indicate that vectors other than Culicoides paraensis exhibit relatively low vector competence for OROV, it is well established that a species ability of a species to transmit a pathogen is shaped by a combination of factors. These include intrinsic characteristics such as vector competence and the incubation period, as well as extrinsic factors like vector density, host preferences, and life time (Kramer and Ciota, 2015). Despite these insights, there remains a critical need for further research to fully elucidate the role of both known and potentially unknown vectors capable of transmitting OROV. Similarly, the dynamics of OROV transmission across sylvatic and urban environments remain poorly understood, particularly regarding potential reservoir hosts in various biomes and their role in initiating or amplifying Oropouche fever outbreaks. A comprehensive understanding of the complete OROV transmission cycle is essential for identifying at-risk regions and populations, ultimately informing more effective strategies to mitigate the spread and impact of the disease (Tegally et al., 2024).

4. Epidemiology

Historically, most of the surveillance efforts and studies investigating OROV infection in populations before the 2010s used hemagglutination inhibition and enzyme-linked immunosorbent assays (ELISAs) to measure human OROV-specific antibodies. These investigations were primarily seroepidemiological surveys that often tested a limited number of individuals, typically from small and non-representative population samples. As a result, the true incidence of OROV infection during most outbreaks remains largely undetermined (Tesh, 1994; Baisley et al., 1998; da Silva Azevedo, 2025; Manock et al., 2009; Forshey et al., 2010; Gaillet et al., 2021; Silva-Caso et al., 2019; Ciuoderis et al., 2022; Gil-Mora et al., 2022). The first molecular detection tools for identifying Simbu serogroup viruses became available in the early 2000s (Cardoso et al., 2015; Moreli et al., 2002). In 2017, Naveca et al. developed a one-step multiplexed reverse transcription real-time polymerase chain reaction for simultaneous detection of Mayaro, Oropouche, and Oropouche-like viruses. This assay has since become the most widely used molecular diagnostic tool for laboratory surveillance of Oropouche fever (Naveca et al., 2017).

However, due to the neglected nature of Oropouche fever, OROV surveillance remained suboptimal. Few studies have investigated the true extent of OROV circulation, even in Brazil, where the virus is considered endemic in the North region. Most existing research consists of isolated reports of minor outbreaks or sporadic cases, with a notable absence of comprehensive longitudinal studies to monitor OROV transmission over time. As a result, the current understanding of the epidemiological landscape of Oropouche fever remains limited and fragmented. These knowledge gaps significantly hinder the development of accurate risk assessments and the implementation of effective public health strategies to prevent and control the disease (Wesselmann et al., 2024).

Since the first reported cases of Oropouche fever in 1955, it is estimated that over 500,000 human infections have occurred, the majority of which were reported in the Brazilian North Region (Amazon) and Peru. More than thirty outbreaks have been documented in Brazil across multiple decades, with additional outbreaks reported in Peru (1990s, 2000s, 2010s, and 2023), Ecuador (2001, 2016), Haiti (2014), Bolivia (2007, 2022), Colombia (2018, 2020), and French Guiana (2020). Some of these outbreaks reached substantial scales, such as the 1980 outbreak in Amazonas, Brazil, which was estimated to have affected more than 97,000 individuals (Fig. 1) (Borborema et al., 1982).

Fig. 1.

Number of confirmed cases of Oropouche virus infections reported globally until 2022. The data was compiled from studies available on PubMed and were cited throughout the text.

From January to October 2023, Brazil reported 286 cases of Oropouche fever, primarily concentrated in the Amazon and neighboring states. In November 2023, the state of Amazonas experienced a significant surge in cases, with 546 additional cases reported between November and December, bringing the total for 2023 to 832 cases—all confined to the North Region. In 2024, the increase in cases continued in Brazil, with outbreaks reported across all five Brazilian regions and a total of 13,791 cases documented throughout the year, the majority still occurring in the North. As of April 1, 2025, 7320 cases have already been reported. Notably, there has been a geographic shift in case distribution, with increasing concentration in the Southeast and Northeast regions of Brazil (Oropouche, 2025).

Beyond Brazil, Oropouche fever has caused outbreaks in several countries across Latin America and the Caribbean. Since 2024, Peru has reported 1265 cases, followed by Cuba with 638 cases, Bolivia with 356, Panama with 221, and Colombia with 74. Additional cases have been documented in Venezuela (5 cases), Guyana (4), Ecuador (3), and Barbados (2) (Fig. 2). In Brazil, Oropouche cases typically peak annually between November and April. Similarly, the current outbreaks in other countries exhibit seasonal patterns, aligning with their respective warmer and rainier periods. Reported peak transmission periods include March–April 2024 in Bolivia, February–March 2024 in Colombia, May–September 2024 in Cuba, January 2024 in Panama, and January–March 2024 in Peru (PAHO, 2025).

Fig. 2.

Global distribution of confirmed Oropouche fever cases reported between 1954 and 2022 (left) and during the current outbreak from 2023 to 2025 (right). Countries shown in red reported imported cases only during the 2023–2025 Oropouche virus outbreak.

Most OROV infections reported in the current outbreaks have primarily affected individuals aged 20 to 49 years. In Brazil, this age group accounts for 56.9 % of all reported cases. Although the distribution of cases by sex varies slightly across countries, it remains generally balanced. In Brazil, where the largest number of cases has been reported, 52.5 % of infections occurred in males. In contrast, in Cuba, 55 % of the 626 confirmed cases were female (PAHO, 2025; Painel de Monitoramento das Arboviroses 2025). Regarding the ecological characteristics of OROV in current outbreaks, Graff et al. also highlighted that most infections in Brazil have been reported in small municipalities near forested areas or in large urban centers within the Amazon region that are adjacent to such environments. Both forested areas and agricultural landscapes—including banana, cassava, oil palm, cocoa, and rubber plantations—create ideal conditions for the lifecycle of Culicoides paraensis. The urbanization of Culicoides paraensis is facilitated by the close interface between these forested and agricultural areas and urban environments, driving the continued transmission and geographic expansion of OROV (Gräf et al., 2025).

Since 2024, imported cases of OROV have been reported in the USA (109 cases, primarily in Florida) (Morrison et al., 2024), Canada (three cases), and the Cayman Islands (one case) in North America (Oropouche, 2025). Similarly, Europe has experienced multiple introductions of OROV, with notable cases in Italy (nine reported introductions) (Branda et al., 2024; Castilletti et al., 2024; Mancon et al., 2024; Castilletti et al., 2024; Deiana et al., 2024; Barbiero et al., 2025), Spain (nine), France (a group of five women returning from Cuba) (Gourjault et al., 2025), Germany (two), and the Netherlands (one) (Iglói et al., 2025). Most of these reported introduction events in North America and Europe were traced back to Cuba. Importations from Brazil to Italy were also reported (Fig. 3) (Mancon et al., 2024; Huits et al., 2024). The frequency and geographic spread of these importation events—particularly during 2024—highlight the significant global risk of OROV spreading to non-endemic regions, mirroring the ongoing outbreak dynamics in Brazil. High human mobility, coupled with the increasing accessibility of global travel, plays a central role in facilitating the spread of emerging and re-emerging infectious diseases. Furthermore, the geographic expansion of virus-transmitting vectors, driven by climate change, raises concerns about the potential establishment of OROV transmission in new and non-endemic regions (Wesselmann et al., 2024; Cain and Ly, 2024; Portillo et al., 2024; dos Santos et al., 2025; Bermann et al., 2025).

Fig. 3.

Oropouche virus introductions reported in the literature during the ongoing Oropouche fever outbreak. Colored lines represent international introduction events, with each line originating from the presumed source country and pointing toward the destination. Line thickness is proportional to the number of reported introductions.

Before the re-emergence of OROV in late 2023, no fatalities had been attributed to Oropouche fever since the first outbreak in 1960 (Home 2018). As of April 1 2025, five deaths have been confirmed in the current Oropouche fever outbreak. In 2024, Brazil recorded four fatalities. The first case occurred in March 2024 and involved a 24-year-old woman from Bahia, followed by a second case in May 2024, involving a 21-year-old woman from the same state. Neither woman was pregnant or had preexisting comorbidities. Both initially presented with acute symptoms, including fever, headache, retro-orbital pain, and myalgia, which rapidly progressed to severe complications such as intense abdominal pain, bleeding, hypotension, and respiratory failure. The third fatal case involved a 57-year-old man from Paraná in southern Brazil, while the fourth occurred in August 2024, when a 61-year-old woman from Espírito Santo in southeastern Brazil succumbed to the disease (No title, 2025). More recently, in March 2025, Panama confirmed a fatal case of Oropouche fever in an 82-year-old man with a history of hypertension and diabetes mellitus (Minsa redobla vigilancia ante el primer fallecido por el Virus Oropouche, 2025).

Additionally, the co-circulation of OROV with other arboviruses in several countries increases the risk of co-infections with viruses such as dengue, Zika, or chikungunya. These co-infections may result in more severe illness or atypical clinical outcomes (Vogels et al., 2019; Vita et al., 2025). During the current Oropouche fever outbreak, a dengue-OROV co-infection was reported in a case imported from Cuba to Italy in 2024 (Vita et al., 2025; Colavita et al., 2025). A previous case of OROV co-infection was reported in Brazil in 2019, involving an individual who was triple-infected with dengue, chikungunya, and OROV, and presented with neurological manifestations (Pavon et al., 2022).

5. Symptoms and neurological manifestations

In most reported outbreaks to date—including the ongoing ones—affected individuals commonly present with symptoms such as fever, headache, myalgia, arthralgia, and retro-orbital pain. A portion of patients also exhibit nausea, vomiting, and photo-phobia (Naveca et al., 2024; Vasconcelos et al., 1989; da Silva Azevedo, 2025; Vasconcelos et al., 2009; Mourão et al., 2025; Martins-Luna et al., 2020). Other symptoms including cutaneous rash, meningitis, encephalitis, dizziness, anorexia, and other systemic manifestations are also reported at a lower frequency (Pinheiro et al., 1981; da Rosa et al., 2017; Vasconcelos et al., 1989; Vasconcelos et al., 2009; Mourão et al., 2025; Alvarez-Falconi and Ba, 2010). The clinical course often includes an initial phase of intense acute symptoms lasting 2 to 4 days, followed by a period of remission. In cases where symptoms relapse, this typically occurs 7 to 10 days after symptom onset, with gradual recovery over the second week and beyond (Pastula et al., 2024).

In addition to the most common symptoms, several neurological manifestations associated with OROV infection have been reported in Brazil and more recently in other countries. These cases commonly present with neck stiffness, cognitive confusion, and lethargy. The first documented neurological manifestations were reported in an outbreak in Pará, Brazil in 1980, with 22 laboratory-confirmed cases exhibiting symptoms consistent with meningitis or meningismus (vomiting, mild lethargy, diplopia, nystagmus, and disturbances in equilibrium), including neck stiffness was observed in most patients, and cerebrospinal fluid analysis revealed an elevated cell count in 20 of the 22 cases (Pinheiro et al., 1982). OROV infection affecting the central nervous system was also reported in three adult patients (Bastos et al., 2012) from Amazonas, Brazil, in 2012; and in an immunocompetent patient from São Paulo, Brazil who was diagnosed with aseptic meningoencephalitis after OROV infection in 2016 (Vernal et al., 2019). In 2021, two additional neurological cases due to OROV infection were reported in Pará, Brazil where patients presented with seizures (Chiang et al., 2021). Supporting this clinical evidence, experimental animal models have demonstrated OROV tropism for brain cells, reinforcing its potential for neuroinvasion (Rodrigues et al., 2011; Santos et al., 2012).

Recently, alongside the emergence of the Oropouche fever outbreak in Cuba, an association between Oropouche fever and Guillain–Barré syndrome (GBS) has been reported. GBS is an autoimmune disorder affecting the peripheral nervous system and the leading cause of acute neuromuscular paralysis globally (Bellanti and Rinaldi, 2024; Martos-Benítez et al., 2025). In Cuba, the incidence of GBS significantly increased between 2018 and 2024, with a notable surge following the 2024 OROV outbreak. Hospitalizations due to GBS increased from 8.80 cases per million inhabitants in 2018 to 31.43 per million in 2024, suggesting a potential post-infectious etiology linked to OROV. This link has been attributed to the absence of dengue virus detection and a lack of Zika and chikungunya virus circulation in Cuba during the same period (Fernández de et al., 2024; de Armas Fernández et al., 2025; González-Quevedo et al., 2025). However, travel surveillance and genomic analyses uncovered an unreported Zika virus outbreak in 2017 and dengue virus circulation between 2011 and 2022 in Cuba, indicating that other arboviruses may have also been involved in the observed increase in GBS cases (Taylor-Salmon et al., 2024; Grubaugh et al., 2019).

A recent analysis of 38 confirmed Oropouche fever cases during the 2024 outbreak in Matanzas, Cuba, revealed that 29 % of patients developed encephalitis, while 21 % were diagnosed with GBS (Bello-Rodríguez et al., 2025). According to the Pan American Health Organization (PAHO), Cuba reported 626 confirmed cases of Oropouche in 2024, including 119 cases with neurological manifestations associated with OROV infection. These included 78 cases of GBS, 26 cases of encephalitis, and 15 cases of meningoencephalitis. Additionally, two imported OROV cases reported in the United States also presented with neuroinvasive disease. In Brazil, one case of OROV-associated encephalitis was reported during the 2024 outbreak (PAHO, 2025).

6. Vertical transmission

Recent evidence has shown the potential for vertical transmission of OROV, with reports linking the infection to adverse pregnancy outcomes, including miscarriage, stillbirth, and congenital anomalies, including microcephaly. This emerging concern mirrors the pattern observed during the 2015–2016 Zika virus outbreak in the Americas (Fe das et al., 2025; Filho et al., 2024). It is hypothesized that OROV crosses the placental barrier via maternal blood, infects placental cells, and subsequently reaches the fetal circulation. Once in the fetus, the virus may disseminate to the brain and infect neural cells, potentially leading to neurological damage (No title, 2025). During a study conducted in the 1982 outbreak in Amazonas State, Brazil, spontaneous abortion was reported in two of nine pregnant women diagnosed with OROV infection during their second month of gestation (Borborema et al., 1982; Sah et al., 2024).

On May 24, 2024, a pregnant woman in Pernambuco state, northeast Brazil, presented with symptoms of OROV infection during her 30th week of gestation. Molecular testing using RT-PCR confirmed OROV infection in both maternal serum and placental tissue, and by June 6, 2024, fetal death was confirmed. Postmortem analysis detected OROV RNA in multiple fetal organs and tissues, strongly supporting vertical transmission of the virus. The fetus samples were negative for molecular detection of other arboviruses (dengue, Zika, chikungunya, and Mayaro). A second case was reported in the same state in June 2024, involving a woman diagnosed with OROV infection during her sixth week of pregnancy. The patient experienced a miscarriage 21 days after symptom onset, at approximately eight weeks of gestation. However, in this case, fetal tissue samples were not available for further virological analysis (PAHO, 2024).

In July 2024, Ceará state, Brazil reported a case of OROV infection in pregnancy that was associated with a stillbirth at 30th weeks' gestation (Filho et al., 2024), with fetal death twelve days after mother onset of symptoms. Molecular diagnostic testing of maternal blood obtained at the initial evaluation confirmed acute OROV infection; testing negative for dengue, Zika, chikungunya, and Mayaro viruses. Further testing did not identify any additional infections or other conditions that could have caused the stillbirth. Additionally, OROV RNA was detected in multiple fetal samples, including the cerebrospinal fluid, brain, lungs, liver, umbilical cord, and placenta, confirming that vertical transmission had occurred. The histopathological analysis of the fetal tissue was limited due to autolysis, but phylogenetic analysis, incorporating viral sequencing data from the fetus, further confirmed the link between this stillbirth and the ongoing OROV outbreak in Brazil (Filho et al., 2024). In August 2024, a neonate was born with congenital anomalies attributed to OROV vertical transmission (including microcephaly, ventriculomegaly, agenesis of corpus callosum, and joint malformations) in Acre, Brazil. The mother, who was in the 36th week of pregnancy, had present cutaneous eruptions and fever, and was diagnosed with OROV infection right after childbirth. The newborn died 47 days after birth, and postmortem examinations detected OROV RNA in multiple tissues of the newborn (Ministério da Saúde informa caso de anomalia congênita associada à Oropouche, 2025).

Along with that, in June 2024, the Instituto Evandro Chagas in Pará, Brazil, conducted a retrospective study, and four newborns with microcephaly were detected with the presence of IgM class antibodies against OROV in serum samples and cerebrospinal fluid. The samples had also tested negative for dengue, chikungunya, Zika, and West Nile virus (Brasil, 2024). Another case series conducted in Brazil assessed historical cases of newborns with microcephaly, arthrogryposis, and other congenital malformations without a confirmed cause and their mothers for potential OROV congenital infections from 2015 to 2024. The study detected OROV IgM antibodies in six of 68 newborns with microcephaly of unknown cause, negative for Zika virus and other congenital pathogens associated with miscarriage, stillbirth, and congenital malformations. One newborn who died had OROV RNA and antigens in several tissues, including the brain (Nielsen-Saines and Brasil, 2025). Another case series study conducted in Espírito Santo State, Southeast Brazil, in 2024, identified two OROV infections occurring in the first trimester of pregnancy. One case resulted in a spontaneous abortion, while the other led to a live birth with corpus callosum dysgenesis, one of the most common congenital malformations. Among 13 OROV infections detected in the third trimester, OROV RNA was found in the placenta in five cases. One case suggested possible intrapartum transmission, with the neonate presenting clinical manifestations, whereas the remaining cases were asymptomatic. However, no congenital anomalies were observed in third-trimester infections (Cola et al., 2025). These findings collectively underscore the growing body of evidence supporting the teratogenic potential of OROV and highlight the urgent need for enhanced surveillance and research on congenital Oropouche syndrome.

7. Genomic epidemiology

Initial genomic analyses revealed that the 2023–2025 Oropouche fever outbreaks were caused by a novel reassortant OROV lineage, designated OROVBR-2015-2024. Using phylogenetic reconstruction, Naveca et al. demonstrated that the M segment of this lineage clustered within the OROVBR-2009-2018 clade, while the L and S segments grouped with the OROVPE/CO/EC-2008-2021 clade. The OROVBR-2009-2018 clade had circulated in the Brazilian Amazon between 2009 and 2018, whereas the OROVPE/CO/EC-2008-2021 clade was detected in Peru, Colombia, and Ecuador from 2008 to 2021, including during an outbreak in Esmeraldas, Ecuador, in 2016 (Naveca et al., 2024). Both clades probably co-circulated in the Amazonas state, where the OROVBR-2015-2024 clade emerged between 2010 and 2014, from a reassortment event between the two clades, and remained undetected until late 2023. Additionally, Naveca et al. identified six major sub-lineages within OROVBR-2015-2024, each circulating across different northern Brazilian states at various times between 2022 and 2024 (Naveca et al., 2024).

Subsequently, Iani et al. demonstrated that this novel reassortant lineage expanded to other Brazilian regions, establishing local transmission, followed by cross-border movement into Peru (de Melo Iani et al., 2025). This viral expansion within Brazil led to the emergence of two distinct sublineages, one primarily circulating in northern and northeastern regions, and the other associated with the southeastern and southern regions. The study also identified multiple reassortment events among OROV genomes circulating in Brazil in 2024, which may have contributed to the virus’s enhanced adaptability to new ecological niches and hosts, thereby facilitating its broader geographic spread. In parallel, Graff et al. provided evidence that OROV outbreaks in previously non-endemic regions of Brazil resulted from multiple, recurrent long-distance transmission events originating in the Amazon, likely driven by air travel involving infected individuals (Gräf et al., 2025). Also, the emergence of the OROVBR-2015-2024 lineage and its sub-lineages highlights that reassortment plays a significant role in OROV evolution, not only through interactions with other viruses from the Simbu serogroup, as seen in classic reassortants (IQTV, PDEV and MDDV), but also through events occurring within OROV genotypes and lineages themselves (Files et al., 2022). The frequent detection of novel reassortant lineages in recent outbreaks can suggest that these genetic exchanges are ongoing and may accelerate due to intensified viral circulation (Scachetti et al., 2025).

Alongside the circulation of the OROVBR-2015-2024 lineage in Peru in 2024, Olortegui et al. reported that an outbreak in the Iquitos region during late 2023 and early 2024 was associated with the OROVPE/CO/EC-2008-2021 clade (Olortegui et al., 2024). A similar scenario was reported in Colombia in 2024, where the co-circulation of both the OROVBR-2015-2024 and OROVPE/CO/EC-2008-2021 clades was observed. The latter clade was likely introduced into the region from Peru (Fig. 4) (Usuga et al., 2024).

Fig. 4.

Nextstrain global phylogeny of Oropouche virus. The phylogenetic trees represent the evolutionary relationships of Oropouche virus across its three genome segments (M, L, and S). The phylogenetic reconstruction was built, maintained, and made publicly available at Nextstrain (Hadfield et al., 2018; Sagulenko et al., 2018) (https://nextstrain.org/oropouche) by Miguel Paredes and the Nextstrain team. The visualization shown was accessed on April 1, 2025, based on a dataset updated on March 14, 2025, which includes 626 Oropouche virus sequences sourced from GenBank. A full list of sequence contributors is provided in the Supplementary Material. This figure is used under the Creative Commons CC-BY-4.0 license.

So far now, the OROVBR-2015-2024 lineage seems to be established with local transmission chains in Peru, Colombia, Bolivia, and Cuba (Valdez et al., 2024; auspice 2025). In Panama, besides more than two hundred confirmed OROV cases, there are no genome sequences available to identify the virus circulating in the current outbreak in the region. The genome sequences of OROV have been made publicly available through GISAID (Wallau, 2023) and NCBI Virus databases (GeneBank) (Brister et al., 2015), with the majority of these sequences being redundantly present in both platforms. As of April 1, 2025, approximately 1000 complete genome sequences are available; however, significant gaps remain between sequences from the current outbreak and those from earlier periods. These gaps hinder efforts to accurately reconstruct viral transmission dynamics. Moreover, the absence of genomic data from countries currently experiencing OROV outbreaks in the Americas further limits our complete understanding of viral circulation in these regions (Naveca et al., 2024; Gräf et al., 2025).

OROV has been traditionally classified into four distinct genotypes (I, II, III, and IV) based on analysis of the N gene. However, a recent study demonstrated that this classification scheme is insufficient for accurately categorizing novel viral sequences that include all three genome segments (Tilston-Lunel et al., 2015). In the context of the current outbreak, most studies have not adopted a standardized system for lineage or clade classification. To advance a coordinated global genomic surveillance strategy for OROV, there is an urgent need to establish a unified and comprehensive lineage classification system, similar to those recently proposed and implemented for SARS-CoV-2 (Tilston-Lunel et al., 2015), dengue (Hill et al., 2024), and rabies virus (Campbell et al., 2022). Such a framework would enhance the ability to monitor viral evolution, track transmission dynamics, and coordinate public health responses across affected regions.

8. Conclusions

Oropouche fever re-emerged in 2023, causing an unprecedented outbreak that spread beyond its historically endemic regions, reaching previously unaffected countries. Although the virus has circulated in Brazil for the past seven decades, it has often gone undetected due to a lack of surveillance, typical of a neglected disease. The ongoing Oropouche fever outbreak has been accompanied by new neurological manifestations. Along with that, increasing evidence of vertical transmission events, linked to congenital malformations raises significant public health concerns.

Additionally, an exploratory in-vitro analysis showed that the reassortant OROVBR-2015-2024 clade currently circulating in recent outbreaks has phenotypic changes contributing to increased virulence, and the ability to evade antibodies present in the serum of individuals previously infected with the virus, allowing it to persist and continue circulating in northern Brazil, an area where the virus had been endemic for decades. Additionally, the 2023–25 OROV reassortant has an enhanced viral fitness potentially increasing virus transmissibility and leading to epidemic spread of Oropouche fever cases observed in Latin America (Scachetti et al., 2025).

Although Oropouche fever surveillance has been improved in the ongoing outbreak compared to previous viral epidemics, critical gaps remain. Notably, the absence of genomic data from the Caribbean and Central America hampers efforts to understand the virus’s evolution, transmission dynamics, and potential for future outbreaks. The increased human movement across continents, and the expanding invasion of arbovirus vectors into temperate regions, elevate the OROV as a significant global public health threat. These challenges stress the urgent need for enhanced active surveillance, a deeper understanding of pathogenic mechanisms involved in the disease, assessment of vector competence in other species of Culicoides and mosquitoes, as well as a stronger focus on new disease and vector control strategies.

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) [grant numbers 23/2551-0000510-7 and 23/2551-0000852-1], and by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ) [grant number 443757/2023-2].

CRediT authorship contribution statement

Richard Steiner Salvato: Conceptualization, Data curation, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The author declare no competing interests in relation to this study. There were no financial supports or funding sources that could be perceived as influencing the research outcomes or interpretations presented in this manuscript. All authors have contributed to the study and have no conflicts of interest to disclose.

Data availability

No data was used for the research described in the article.