Emergence of Oropouche virus among international travelers: A growing concern in non-endemic areas

Abstract

Introduction

Oropouche fever is an emerging disease caused by an arthropod-borne virus, Oropouche virus. This virus is mainly circulating in Central and South America. In 2024 they have been reported an ongoing outbreak.

Methods

For this study, travelers returning from endemic areas with dengue-like symptoms and negative results for dengue from March to October 2024, were tested for Oropouche through RT-PCR.

Results

Among 43 patients tested, we detected an imported case of Oropouche fever imported from Cuba in a traveler presenting biphasic fever and neurological symptoms. The virus was detected by RT-PCR in urine samples collected more than one month after the onset of symptoms, suggesting prolonged viral shedding and expanding the diagnostic period for molecular confirmation of the infection.

Conclusion

Although only few cases have been yet reported in European travelers, the expansion of the virus in the Americas supports laboratory preparedness and clinical awareness.

Resumen

Introducción

La fiebre de Oropouche es una enfermedad emergente causada por un virus Oropouche transmitido por artrópodos. Este virus circula principalmente en América Central y del Sur. En 2024 se ha informado de un brote en curso.

Métodos

Se realizó la de detección de Oropouche mediante RT-PCR a viajeros que regresaron de áreas endémicas con síntomas similares al dengue y resultados negativos para dengue entre marzo y octubre de 2024.

Resultados

De los 43 pacientes examinados, detectamos un caso de fiebre de Oropouche importado de Cuba en un viajero que presentaba fiebre bifásica y síntomas neurológicos. El virus se detectó mediante RT-PCR en muestras de orina recogidas más de un mes después del inicio de los síntomas, lo que sugiere una diseminación viral prolongada y amplía el período de diagnóstico para la confirmación molecular de la infección.

Conclusión

Aunque solo se han notificado unos pocos casos en viajeros europeos, la expansión del virus en las Américas respalda la necesidad de una buena preparación del laboratorio y una buena conciencia clínica.

Introduction

Although Oropouche virus (OROV) has been circulating in Central and South America for the last decade, only in 2024, more than 10,000 confirmed cases of Oropouche fever have been reported in different countries of the Americas, mainly Brazil, Peru, Cuba, Bolivia and Colombia.¹ The first two imported cases in Europe were detected in Italy in May and June, 2024 in travelers returning from Cuba.² Since then, several cases in non-endemic regions have been reported.^1,3 A high level of suspicion in travelers returning from these areas is crucial, since there have been fatal cases reported, as well as vertical transmission with derived fetal malformations.⁴ However, surveillance of OROV infections in travelers with dengue-like symptoms is not regularly performed and clinical and microbiological information in this population is still scarce.^2,5

In the present study, we aimed to detect all imported cases of OROV disease in travelers returning from endemic areas visiting the International Traveler's Health Clinic (Hospital Clinic in Barcelona) from March to October 2024 and to describe its detailed clinical and microbiological presentation.

Methods

From March to October 2024, travelers returning from Central and South America with a dengue-like symptoms and negative results for dengue, Chikungunya and Zika viruses were screened for OROV. Samples collected for OROV detection included serum, urine and saliva. All samples were extracted using a semi-automated system (magLEAD 12gC, Precision System Science Co, Ltd, Matsudo, Japan) and were tested with a multiplex reverse transcription real-time reverse transcription PCR (RT-PCR) for simultaneous detection of OROV and Mayaro virus.⁶

Detailed information regarding the clinical presentation and blood test results, was collected from patients diagnosed with OROV. In patients with positive results, serial samples were collected in order to determine the usefulness of molecular detection and viral shedding in different samples.

Finally, we conducted a narrative literature review to describe the clinical presentation, laboratory and microbiological characteristics of OROV cases in non-endemic areas.

Results

OROV screening in travelers with dengue-like symptoms

From March to October 2024 a total of 43 patients returning from Colombia (n = 8), Brazil (n = 12), Cuba (n = 8), Argentina (n = 13), Peru (n = 5), Panama (n = 3), Republica Dominicana (n = 1) and Bolivia (n = 3) were tested by OROV RT-PCR in serum and/or urine samples. Twenty-one (49%) of patients were women and the median age was 43. Among the 43 patients tested by OROV RT-PCR in serum and/or urine samples, one (2%) resulted positive. No positive cases for Mayaro virus were detected.

Case description

A traveler in his late fifties, with previous medical history of hypertension and diabetes, visited friends and relatives in Cuba from June 3 to June 23, 2024. Four days after arriving to Cuba, he suffered high fever, arthralgia, myalgia, malaise, headache and diarrhea. The symptoms resolved spontaneously after one week, with the exception of the arthralgia, that persisted for a few more days. One day after his arrival to Spain, on June 25, the patient developed fever again, as well as the general symptoms previously described, except for diarrhea. He also experienced tactile allodynia and hyperalgesia on the left side of the body. No skin rash was observed and the remaining physical examination was unremarkable.

Blood tests revealed slightly elevation of transaminases but no cytopenias. A dengue rapid diagnostic test for non-structural protein 1 (NS1) antigen and dengue-specific immunoglobulin IgM and IgG antibodies was negative (SD BIOLINE Dengue Duo (Standard Diagnostic Inc, Kyongii-Do, Korea).⁷ RT-PCR (LightMix Modular Dengue, TIB Molbiol, Berlin, Germany) as well as IgM and IgG antibodies against dengue, Zika and Chikungunya viruses in serum samples also resulted negative (Dengue IgG Indirect ELISA and IgM Capture ELISA, Panbio, Abbott Diagnostics Korea Inc. Gyeonggi-do, Korea; Zika Virus ELISA IgG and IgM, EUROIMMUN Medizinische Labordiagnostika AG, Lübeck, Germany; Chikungunya Virclia IgG and IgM Monotest, VIRCELL SL, Granada, Spain). The second episode of fever lasted for ten days. After three more days of tactile allodynia, the patient completely recovered.

OROV molecular detection and viral shedding

From this positive patient initial serum and urine samples were collected 24 days after the first onset of symptoms in Cuba (when the patient was still symptomatic). Additional serum, urine and saliva samples were collected at day 34 days after the onset of symptoms (6 days after the complete resolution of fever).

OROV RNA was detected in the first and second urine samples with quantification cycle (Cq) values of 30 and 33, respectively. Serum and saliva samples tested negative.

OROV cases in non-endemic regions

The number of reported cases in non-endemic areas is very scarce: so far, 19 in Europe (Spain (12), Italy (5), and Germany (2)³) and 21 in the US. Almost all of them had travelled to Cuba. For those with clinical information reported, the most common symptoms matched those in endemic areas. Of note, two patients (both from Europe) reported neurological symptoms, and three patients from the US and one from Spain showed a biphasic evolution.

Table 1 summarizes the clinical and microbiological presentation of the OROV cases reported in non-endemic countries.

Table 1.

Characteristics of cases reported in non-endemic areas.^1–4

	USA (n = 21)	Italy (n = 2)	Spain (n = 1)
Age group, years
• 0–19	2 (10)	0	0
• 20–39	5 (24)	1 (50)	0
• 40–59	10 (48)	1 (50)	1 (100)
• ≥60	4 (19)	0	0
Sex, female	10 (48)	NR	0
Travel destination, Cuba	21 (100)	2 (100)	1 (100)
Symptoms
Dengue-like symptoms
• Fever	20 (95)	2 (100)	1 (100)
• Myalgia	18 (86)	0	1 (100)
• Arthralgia	12 (57)	1 (50)	1 (100)
• Headache	16 (76)	2 (100)	1 (100)
• Retroorbital pain	5 (24)	2 (100)	0
• Nausea/vomiting	6 (29)	2 (100)	0
• Abdominal pain	6 (29)	NR	0
• Rash	6 (29)	0	0
• Bleeding^a	1 (5)	1 (50)	0
Other general symptoms
• Fatigue/malaise	13 (62)	2 (100)	1 (100)
• Diarrhea	10 (48)	2 (100)	1 (100)
Neurological symptoms^b	NR	1 (50)	1 (100)
Biphasic evolution	3 (14)	0	1 (100)
Blood test abnormalities
• Elevated CRP	NR	2 (100)	0
• Elevated transaminases	NR	1 (50)	1 (100)
• Leucopenia	NR	1 (50)	0
• Lymphopenia	NR	1 (50)	0
• Thrombocytopenia	NR	0	0
Microbiological findings (for diagnosis of OROV)
Molecular detection	14 (67)^c	2 (100)	1 (100)
• Positive RT-PCR blood	14 (67)	2 (100)	0
• Positive RT-PCR urine	Not performed	1 (50)	1 (100)
PRNT90	8 (38)^c	Not performed	Not performed

CRP: C-reactive protein; NR: not reported; PRNT₉₀: 90% plaque reduction neutralization test; RT-PCR: real-time reverse transcription polymerase chain reaction.

a

Bleeding: mucosal bleeding (n = 1), petechiae (n = 1).

b

Neurological symptoms: paresis of left arm (n = 1), tactile allodynia and hyperalgesia on the left side of the body (n = 1).

c

One patient with positive RT-PCR and positive PRNT₉₀.

Discussion

Significant circulation of OROV has been reported in Brazil, Colombia, Ecuador, French Guiana, Panama, Peru, and Trinidad and Tobago for the last decades.¹ The identification of this case, along with the two previously reported in Italy,² and other cases in Europe and North America,^1,3,5 highlights the increasing spread of OROV in endemic areas.⁸ This fact and the recent reports on fatal cases and potential vertical transmission of OROV underscores the need for heightened clinical awareness and the availability of diagnostic tools for surveillance of OROV in travelers returning from OROV endemic areas.

The non-specific clinical presentation, a scarce knowledge of the disease, and a limited availability of reliable diagnostic tools are some of the challenges in diagnosing OROV infections.⁹ In areas where co-infection with other arbovirus for which we have better diagnostic tests is endemic, the challenge complicates even further.¹⁰ In this context, a high level of clinical suspicion is crucial. However, comprehensive insights into the disease's clinical course remain limited. Our case presented acute febrile illness after an incubation period of 4 days, which is within the typical 3–8-day range for OROV infection.⁹ The patient exhibited two well differentiated symptomatic periods, which we suggest could be a biphasic presentation, with tactile allodynia and hyperalgesia during the second phase.

In Oropouche fever, symptom recurrence has been reported in approximately 60–70% of cases. Although these recurrences are more common within the first 10 days after the initial onset of symptoms, they can occur up to 3 weeks later.⁹ In non-endemic regions, biphasic presentation has been reported only in 3 out of 20 (15%) US travelers.⁵ In our case OROV infection couldn’t be confirmed during the initial symptoms and, therefore, the possibility of two different infections causing the symptoms of the patient cannot be completely ruled out. However, the recurrence of nearly identical symptoms in both phases (except for the neurological symptoms), the compatible times of each phase and the time period between the two phases, and the absence of detectable OROV in serum during the second febrile episode strongly suggest a biphasic course of Oropouche fever.⁹

Neurotropism is a common characteristic among several arboviruses such as Japanese encephalitis virus, tick-borne encephalitis virus, Zika virus and West-Nile virus, among others.^11,12 Neurological manifestations in OROV infections include headache, dizziness, lethargy, diplopia, nystagmus, ataxia, meningitis, encephalitis and focal neurological symptoms.^2,9 They have been mainly reported during large outbreaks in endemic areas but also in travelers.^2,9 Interestingly, OROV neuroinvasion of the central nervous system has been observed in animal models even without neurological symptoms, highlighting the significant neurotropism of OROV.¹³ Finally, although biphasic fever and neurological symptoms have been previously described^2,5 in other arboviral diseases, they are rarely reported in travelers with dengue-like illnesses and might help raising the clinical suspicion of OROV infection.¹⁴ Further studies allowing a better characterization of the clinical presentation of OROV infections compared to other arboviral infections are crucial to confirm these hypotheses.

Little is known about the performance of molecular diagnostic tests from clinical samples for OROV. The virus can be detected in serum, urine and cerebrospinal fluid.⁹ To our knowledge, positive RT-PCR tests in urine had been reported only up to 19 days after the onset of symptoms, in a traveler returning from Cuba.¹⁵ Thus, our case represents the first report detecting OROV RNA in urine more than 4 weeks after the onset of symptoms. Prolonged shedding in urine has also been reported in other arboviruses such as dengue and Zika viruses.^16,17 Larger studies should be performed to ascertain whether urine may represent a relevant diagnostic sample for OROV infections.

Our report, along with the other OROV imported cases reported, highlights the importance of being aware of OROV disease in travelers returning from areas with current circulation of OROV with dengue-like symptoms but with negative diagnostic tests for dengue, especially when presenting with biphasic fever or neurological symptoms. Viral detection of OROV in urine could be a useful tool for the diagnosis of OROV infection at late stages of the disease.

Ethical statement

The patient signed an informed consent allowing the collection and analysis of additional clinical samples and the publication of the case. The study was designed in compliance with Good Clinical Practice and following the Declaration of Helsinki.

Funding

The ISGlobal authors acknowledge support from the grant number CEX2023-0001290-S funded by MCIN/AEI/10.13039/501100011033, and support from the Generalitat de Catalunya through the CERCA Program, CIBER-Consorcio Centro de Investigación Biomédica en Red (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea and support from the Generalitat de Catalunya through the CERCA Program.

Conflicts of interest

None declared.