The Oropouche fever in America: A hidden threat and a possible cause of microcephaly due to vertical transmission

Nathalia Mariana Santos Sansone Matheus Negri Boschiero Luiz Felipe Azevedo Marques Fernando Augusto Lima Marson ^*

• Sao Francisco University, Braganca Paulista, Brazil

Dear Editor, Latin America (LATAM) is facing a severe outbreak of arbovirus, particularly Dengue fever (Boschiero et al., 2023; Sansone et al., 2024a). In addition, the cases of Oropouche fever (OF), a zoonotic disease caused by the Oropouche virus (OROV), are increasing (Sansone et al., 2024b). The OROV is a member of the Bunyaviridae family. Its viral genome is composed of three segments of negative-sense single-stranded ribonucleic acid (RNA). Previous outbreaks described between 2022 and 2024 were associated with viral rearrangements resulting in a reassortant virus, with genomic segments from different previously circulating strains (Azevedo et al., 2024; Moreira et al., 2024). Also, there is a description of a genomic rearrangement between the OROV and the Iquitos virus that is also classified in the Orthobunyavirus oropoucheense species — that included other species: Madre de Dios virus, Oropouche-like virus, and Perdoes virus (Azevedo et al., 2024; Moreira et al., 2024). Transmitted mainly by the Culicoides paraensis midge, OF can also spread through other arthropods such as Aedes serratus, Culex quinquefasciatus, and Coquillettidia venezuelensis (Martins-Filho et al., 2024; Zhang et al., 2024). First identified in Trinidad and Tobago in the 1950s OF is endemic to the Amazon region and extends to umpteen Central and South American countries (Martins-Filho et al., 2024). As of the 18th epidemiological week in 2024, LATAM reported 5193 cases of OF, with Brazil accounting for 4583 cases (88.3%) — Pan American Health Organization. Recent data from the Brazilian Ministry of Health show a dramatic increase to 6976 cases by the 26th epidemiological week, up to 839.5% from 831 cases in 2023 (Figs. 1a, 1b; Fig. 2). According to a recent Brazilian study, the OROV has been detected in all the 26 states from Brazil in 2024, in contrast to 2023 in which most of the cases were reported in Amazon and Cerrado regions. Small and medium municipalities from the non-Amazon region were especially affected, with the frequency of cases 3 to 9 times higher compared to large municipalities (Gräf et al., 2024). Please see the complete data in the Graph Abstract presented in Supplementary Material Presentation 1 and Supplementary Table 1. OF has also spread to non-endemic regions — extra-Amazonian states where autochthonous cases have been reported (Fig. 1c), and factors such as global warming, deforestation, and flooding may exacerbate mosquito-borne disease outbreaks by modulating the life cycle of mosquitoes and spreading their proliferation (Martins-Filho et al., 2024; Sah et al., 2024). Also, it is of utmost importance to screen the viral genomic rearrangements; the arboviruses' viral rearrangements were previously associated with pandemics — human outbreaks. The symptoms of OF symptoms are similar to those of other arboviruses such as dengue and chikungunya, complicating the diagnosis, and routine laboratory tests are scarce (Martins-Filho et al., 2024). Most cases are self-limiting, but serious complications such as meningitis and encephalitis can occur (Martins-Filho et al., 2024).OF can lead to neurological issues such as meningitis and encephalitis (Zhang et al., 2024), but only the Zika virus has been definitively linked to microcephaly through vertical transmission (Vaziri et al., 2022). On July 11th, 2024, the Brazilian Ministry of Health recommended increased surveillance for vertical transmission of the OROV (Nota Técnica no 6/2024-CGARB/DEDT/SVSA/MS — Ministério da Saúde, n.d.). The Evandro Chagas Institute found Immunoglobulin M (IgM) antibodies to the OROV in serum and cerebrospinal fluid samples from four newborns with microcephaly who tested negative for other arboviruses (Dengue, Chikungunya, Zika, and West Nile virus) (Nota Técnica no 15/2024-SVSA/MS — Ministério da Saúde, n.d.). Although the exact link between the OROV and microcephaly is not yet clear, recent findings include a case of fetal death at 30 weeks with the virus detected in fetal organs, suggesting a potential for vertical transmission (Nota Técnica no 15/2024-SVSA/MS — Ministério da Saúde, n.d.).In addition to this discovery, Brazilian researchers traced a recent case series in which they evaluated infants who tested negative for other infectious diseases and congenital malformations, such as microcephaly and arthrogryposis, and their respective mothers for the presence of antibodies against the OROV. A total of 68 samples were collected: 65 from historical cases and three from 2024. Of these, 6 of 68 (8.8%) samples from newborns exhibited a positive immunoglobulin M (IgM) reaction against OROV in the cerebral spinal fluid (6 cases); in addition, 4 cases presented a positive IgM reaction in the serum too. Of the 6 newborn samples with a positive IgM reaction against OROV, one case at age 44 days had an identification of OROV RNA through the real-time-quantitative polymerase chain reaction analysis from cerebral spinal fluid. Moreover, the patient died at 47 days of life and also presented an OROV RNA through the real-time-quantitative polymerase chain reaction from pleural fluid and tissues from the brain, kidney, and lungs. In this particular case, several modifications of the brain macroscopically and microscopically were described, including necrotic and apoptotic changes of neurons, microglia and astrocytes, vacuolization, and tissue atrophy (das Neves Martins et al., 2024). The Brazilian Ministry of Health has recommended intensifying the surveillance of pregnancies and newborns in cases of suspected arbovirus infections. This includes monitoring abortions, fetal deaths, and congenital neurological malformations, and collecting relevant biological samples. For protection, pregnant women should avoid areas prone to insects, use fine mesh screens, wear protective clothing, apply repellent, keep their homes clean, and follow local health guidelines if there are confirmed cases in their area (Oropouche: Cases of mother-to-child transmission under investigation in Brazil - PAHO/WHO | Pan American Health Organization, 2024; Nota Técnica no 15/2024-SVSA/MS — Ministério da Saúde, n.d.).Because it is an emerging arbovirus, in order to deal with the increase in OF cases, it is crucial to control mosquito proliferation and identify mosquito breeding sites (Sansone et al., 2024b). LATAM public health agents and governments should collaborate on health policies to promote OF education for better diagnosis and prevention. These efforts could manage local outbreaks, mitigate individual impact, and protect travelers from endemic areas. Continued research on the link between OF and microcephaly in newborns is also essential to understand their relationship. However, in addition to the measures taken to contain any arbovirus, there is a need for continuous genomic surveillance for the OROV. This is to note possible genomic rearrangements and optimize diagnostic methods. The latter currently still depend on complex machinery, especially in developing countries, thus avoiding underreporting. Finally, as with the Zika virus, there is a need for cohort studies, especially prospective ones, with larger samples, in order to assess the long-term complications for affected individuals and babies who may be born with microcephaly or other complications.