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      Clinical and Serological Findings of Madariaga and Venezuelan Equine Encephalitis Viral Infections: A Follow-up Study 5 Years After an Outbreak in Panama

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          Abstract

          Background

          Human cases of Madariaga virus (MADV) infection were first detected during an outbreak in 2010 in eastern Panama, where Venezuelan equine encephalitis virus (VEEV) also circulates. Little is known about the long-term consequences of either alphavirus infection.

          Methods

          A follow-up study of the 2010 outbreak was undertaken in 2015. An additional survey was carried out 2 weeks after a separate 2017 alphavirus outbreak in a neighboring population in eastern Panama. Serological studies and statistical analyses were undertaken in both populations.

          Results

          Among the originally alphavirus-seronegative participants (n = 35 of 65), seroconversion was observed at a rate of 14.3% (95% CI, 4.8%–30.3%) for MADV and 8.6% (95% CI, 1.8%–23.1%) for VEEV over 5 years. Among the originally MADV-seropositive participants (n = 14 of 65), VEEV seroconversion occurred in 35.7% (95% CI, 12.8%–64.9%). In the VEEV-seropositive participants (n = 16 of 65), MADV seroconversion occurred in 6.3% (95% CI, 0.2%–30.2%). MADV seroreversion was observed in 14.3% (95% CI, 1.8%–42.8%) of those who were originally seropositive in 2010. VEEV seroconversion in the baseline MADV-seropositive participants was significantly higher than in alphavirus-negative participants. In the population sampled in 2017, MADV and VEEV seroprevalence was 13.2% and 16.8%, respectively. Memory loss, insomnia, irritability, and seizures were reported significantly more frequently in alphavirus-seropositive participants than in seronegative participants.

          Conclusions

          High rates of seroconversion to MADV and VEEV over 5 years suggest frequent circulation of both viruses in Panama. Enhanced susceptibility to VEEV infection may be conferred by MADV infection. We provide evidence of persistent neurologic symptoms up to 5 years following MADV and VEEV exposure.

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          Most cited references31

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          Neurological Sequelae Resulting from Encephalitic Alphavirus Infection

          The recent surge in viral clinical cases and associated neurological deficits have reminded us that viral infections can lead to detrimental, long-term effects, termed sequelae, in survivors. Alphaviruses are enveloped, single-stranded positive-sense RNA viruses in the Togaviridae family. Transmission of alphaviruses between and within species occurs mainly via the bite of an infected mosquito bite, giving alphaviruses a place among arboviruses, or arthropod-borne viruses. Alphaviruses are found throughout the world and typically cause arthralgic or encephalitic disease in infected humans. Originally detected in the 1930s, today the major encephalitic viruses include Venezuelan, Western, and Eastern equine encephalitis viruses (VEEV, WEEV, and EEEV, respectively). VEEV, WEEV, and EEEV are endemic to the Americas and are important human pathogens, leading to thousands of human infections each year. Despite awareness of these viruses for nearly 100 years, we possess little mechanistic understanding regarding the complications (sequelae) that emerge after resolution of acute infection. Neurological sequelae are those complications involving damage to the central nervous system that results in cognitive, sensory, or motor deficits that may also manifest as emotional instability and seizures in the most severe cases. This article serves to provide an overview of clinical cases documented in the past century as well as a summary of the reported neurological sequelae due to VEEV, WEEV, and EEEV infection. We conclude with a treatise on the utility of, and practical considerations for animal models applied to the problem of neurological sequelae of viral encephalopathies in order to decipher mechanisms and interventional strategies.
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            Eastern equine encephalitis in Latin America.

            The eastern equine encephalitis (EEE) and Venezuelan equine encephalitis (VEE) viruses are pathogens that infect humans and horses in the Americas. Outbreaks of neurologic disease in humans and horses were reported in Panama from May through early August 2010. We performed antibody assays and tests to detect viral RNA and isolate the viruses in serum samples from hospitalized patients. Additional cases were identified with enhanced surveillance. A total of 19 patients were hospitalized for encephalitis. Among them, 7 had confirmed EEE, 3 had VEE, and 1 was infected with both viruses; 3 patients died, 1 of whom had confirmed VEE. The clinical findings for patients with EEE included brain lesions, seizures that evolved to status epilepticus, and neurologic sequelae. An additional 99 suspected or probable cases of alphavirus infection were detected during active surveillance. In total, 13 cases were confirmed as EEE, along with 11 cases of VEE and 1 case of dual infection. A total of 50 cases in horses were confirmed as EEE and 8 as VEE; mixed etiologic factors were associated with 11 cases in horses. Phylogenetic analyses of isolates from 2 cases of equine infection with the EEE virus and 1 case of human infection with the VEE virus indicated that the viruses were of enzootic lineages previously identified in Panama rather than new introductions. Cases of EEE in humans in Latin America may be the result of ecologic changes that increased human contact with enzootic transmission cycles, genetic changes in EEE viral strains that resulted in increased human virulence, or an altered host range. (Funded by the National Institutes of Health and the Secretaría Nacional de Ciencia, Tecnología e Innovación, Panama.).
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              Epidemic Venezuelan equine encephalitis in La Guajira, Colombia, 1995.

              In 1995, the first Venezuelan equine encephalitis (VEE) outbreak in Colombia in 22 years caused an estimated 75,000 human cases, 3000 with neurologic complications and 300 fatal, in La Guajira State. Of the state's estimated 50,000 equines, 8% may have died. An epizootic IC virus, probably introduced from Venezuela, was rapidly amplified among unvaccinated equines. Record high rainfall, producing high densities of vector Aedes taeniorhynchus, led to extensive epidemic transmission (30% attack rate) in the four affected municipalities. Native Wayuu Indians, constituting 24% of the state's population, were at increased risk of infection (risk ratio, 3.3; 95% confidence interval, 2.2-5.3). Epidemiologic studies found no evidence of human-to-human transmission. A higher-than-expected number of abortions during the outbreak confirmed a previously suspected abortifacient role of VEE infection. Pesticide applications and a mass equine vaccination program contributed to preventing the outbreak's spread south of La Guajira.
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                Author and article information

                Journal
                Open Forum Infect Dis
                Open Forum Infect Dis
                ofid
                Open Forum Infectious Diseases
                Oxford University Press (US )
                2328-8957
                September 2020
                20 August 2020
                20 August 2020
                : 7
                : 9
                : ofaa359
                Affiliations
                [1 ] Department of Zoology, University of Oxford , Oxford, UK
                [2 ] Department of Research in Virology and Biotechnology, Gorgas Memorial Institute of Health Studies , Panama City, Panama
                [3 ] National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford , Oxford, United Kingdom
                [4 ] Department of Epidemiology, Ministry of Health , Panama, Panama
                [5 ] Clinical Research Unit, Gorgas Memorial Institute of Health Studies , Panama City, Panama
                [6 ] Department of Research in Emerging and Zoonotic Diseases, Gorgas Memorial Institute of Health Studies , Panama City, Panama
                [7 ] Institute for Human Infection and Immunity, Department of Microbiology and Immunology, Department of Pathology, and World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch , Galveston, Texas, USA
                [8 ] MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London , London, UK
                [9 ] Department of Statistics, University of Oxford , Oxford, UK
                [10 ] Division of Infectious Disease and Global Medicine, Department of Medicine, University of Florida , Gainesville, Florida, USA
                Author notes
                Correspondence: Jean-Paul Carrera, Msc, MA, Department of Zoology, University of Oxford, Oxford, OX1 3SY, UK ( jean.carrera@ 123456zoo.ox.ac.uk ).

                Equal contribution

                Author information
                http://orcid.org/0000-0002-1459-2858
                Article
                ofaa359
                10.1093/ofid/ofaa359
                7518370
                33005697
                625b1e02-558e-48cd-b0f4-ef1933454890
                © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 06 May 2020
                : 02 August 2020
                : 13 August 2020
                : 25 September 2020
                Page count
                Pages: 7
                Funding
                Funded by: Ministry of Economy and Finance of Panama;
                Award ID: 1.11.1.3.703.01.55.120
                Funded by: Center for Emerging Viruses and Arboviruses;
                Funded by: National Institutes of Health, DOI 10.13039/100000002;
                Award ID: AI120942
                Funded by: University of Oxford, DOI 10.13039/501100000769;
                Award ID: SFF1920_CB2_MPLS_1293647
                Funded by: Medical Research Council, DOI 10.13039/501100000265;
                Funded by: Department for International Development, DOI 10.13039/501100000278;
                Funded by: European Union, DOI 10.13039/501100000780;
                Categories
                Major Articles
                AcademicSubjects/MED00290

                madariaga virus,neurological sequelae,panama,venezuelan equine encephalitis virus

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