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Fatal Zika virus disease in adults: A critical reappraisal of an under-recognized clinical entity

2019; Elsevier BV; Volume: 83; Linguagem: Inglês

10.1016/j.ijid.2019.03.002

1878-3511

Alfonso J. Rodríguez‐Morales, Eduardo Ramírez-Vallejo, Lucia Elena Alvarado-Arnez, Alberto Paniz‐Mondolfi, Lysien I. Zambrano, Albert I. Ko,

Mosquito-borne diseases and control

Zika virus (ZIKV) is a flavivirus that was most likely introduced into Latin America back in 2013 (Rodriguez-Morales, 2015Rodriguez-Morales A.J. Zika: the new arbovirus threat for Latin America.J Infect Dev Ctries. 2015; 9: 684-685Crossref PubMed Scopus (99) Google Scholar), but did not cause identifiable outbreaks until its massive emergence in Brazil in 2015, when it rapidly spread across the Americas and the Caribbean (Weaver et al., 2016Weaver S.C. Costa F. Garcia-Blanco M.A. Ko A.I. Ribeiro G.S. Saade G. et al.Zika virus: history, emergence, biology, and prospects for control.Antiviral Res. 2016; 130: 69-80Crossref PubMed Scopus (474) Google Scholar). The World Health Organization (WHO) declared the ZIKV epidemic a public health emergency of international concern (PHEC) at the height of the pandemic in 2016 (Rodriguez-Morales, 2015Rodriguez-Morales A.J. Zika: the new arbovirus threat for Latin America.J Infect Dev Ctries. 2015; 9: 684-685Crossref PubMed Scopus (99) Google Scholar, Rodriguez-Morales, 2018Rodriguez-Morales A.J. Severe, atypical and fatal cases of Zika virus infection: experience in Colombia.Int J Infect Dis. 2018; 73: 71Abstract Full Text Full Text PDF Google Scholar), after identifying clusters of ZIKV-associated Guillain–Barré syndrome (GBS) (do Rosario et al., 2016do Rosario M.S. de Jesus P.A. Vasilakis N. Farias D.S. Novaes M.A. Rodrigues S.G. et al.Guillain–Barre syndrome after Zika virus infection in Brazil.Am J Trop Med Hyg. 2016; 95: 1157-1160Crossref PubMed Scopus (77) Google Scholar), and more significantly due to its association with outbreaks of microcephaly among newborn infants in which a causal link between ZIKV infection and birth defects was reliably demonstrated (Rasmussen et al., 2016Rasmussen S.A. Jamieson D.J. Honein M.A. Petersen L.R. Zika virus and birth defects—reviewing the evidence for causality.N Engl J Med. 2016; 374: 1981-1987Crossref PubMed Scopus (1336) Google Scholar). The clinical manifestations of congenital ZIKV infection extend beyond microcephaly and comprise a distinct constellation of birth defects and manifestations known as the congenital Zika syndrome (CZS) (Nogueira et al., 2018Nogueira M.L. Nery Junior, N.R.R. Estofolete C.F. Bernardes Terzian A.C. Guimaraes G.F. Zini N. et al.Adverse birth outcomes associated with Zika virus exposure during pregnancy in Sao Jose do Rio Preto, Brazil.Clin Microbiol Infect. 2018; 24: 646-652Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Moore et al., 2017Moore C.A. Staples J.E. Dobyns W.B. Pessoa A. Ventura C.V. Fonseca E.B. et al.Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians.JAMA Pediatr. 2017; 171: 288-295Crossref PubMed Scopus (578) Google Scholar). The ZIKV pandemic in the Americas and Caribbean was known to cause over one million cases and there were reports in which the virus was found to cause severe, life-threatening complications in addition to GBS and CZS, especially among patients with associated comorbidities (Rodriguez-Morales, 2018Rodriguez-Morales A.J. Severe, atypical and fatal cases of Zika virus infection: experience in Colombia.Int J Infect Dis. 2018; 73: 71Abstract Full Text Full Text PDF Google Scholar). From a clinical standpoint, until 2013, ZIKV was generally considered to cause a mild, self-limiting illness, which did not pose a serious public health threat (Rodriguez-Morales, 2015Rodriguez-Morales A.J. Zika: the new arbovirus threat for Latin America.J Infect Dev Ctries. 2015; 9: 684-685Crossref PubMed Scopus (99) Google Scholar, Rodriguez-Morales, 2018Rodriguez-Morales A.J. Severe, atypical and fatal cases of Zika virus infection: experience in Colombia.Int J Infect Dis. 2018; 73: 71Abstract Full Text Full Text PDF Google Scholar, Martinez-Pulgarin et al., 2016Martinez-Pulgarin D.F. Acevedo-Mendoza W.F. Cardona-Ospina J.A. Rodriguez-Morales A.J. Paniz-Mondolfi A.E. A bibliometric analysis of global Zika research.Travel Med Infect Dis. 2016; 14: 55-57Crossref PubMed Scopus (56) Google Scholar). However, it was not until the first non-perinatal death was identified in a 15-year-old girl from northern Colombia in October 2015, (Arzuza-Ortega et al., 2016Arzuza-Ortega L. Polo A. Perez-Tatis G. Lopez-Garcia H. Parra E. Pardo-Herrera L.C. et al.Fatal sickle cell disease and Zika virus infection in girl from colombia.Emerg Infect Dis. 2016; 22: 925-927Crossref PubMed Scopus (76) Google Scholar) that an increasing number of ZIKV-associated fatalities were reported in the literature. The case from Malaysia reported by Rajahram et al., 2019Rajahram G.S. Hale G. Bhatnagar J. Hiu J. Thayan R. William T. et al.Postmortem evidence of disseminated Zika virus infection in an adult patient.Int J Infect Dis. 2019; https://doi.org/10.1016/j.ijid.2019.01.047Abstract Full Text Full Text PDF Scopus (5) Google Scholar in the current issue of the International Journal of Infectious Diseases, confirms that ZIKV infection can result in atypical disease and lead to severe and even fatal outcomes (Rodriguez-Morales, 2018Rodriguez-Morales A.J. Severe, atypical and fatal cases of Zika virus infection: experience in Colombia.Int J Infect Dis. 2018; 73: 71Abstract Full Text Full Text PDF Google Scholar). It also demonstrates, as seen in other studies (Sarmiento-Ospina et al., 2016Sarmiento-Ospina A. Vasquez-Serna H. Jimenez-Canizales C.E. Villamil-Gomez W.E. Rodriguez-Morales A.J. Zika virus associated deaths in Colombia.Lancet Infect Dis. 2016; 16: 523-524Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, Soares et al., 2016Soares C.N. Brasil P. Carrera R.M. Sequeira P. de Filippis A.B. Borges V.A. et al.Fatal encephalitis associated with Zika virus infection in an adult.J Clin Virol. 2016; 83: 63-65Crossref PubMed Scopus (93) Google Scholar, Zonneveld et al., 2016Zonneveld R. Roosblad J. Staveren J.W. Wilschut J.C. Vreden S.G. Codrington J. Three atypical lethal cases associated with acute Zika virus infection in Suriname.IDCases. 2016; 5: 49-53Crossref PubMed Scopus (19) Google Scholar, Azevedo et al., 2016Azevedo R.S. Araujo M.T. Martins Filho A.J. Oliveira C.S. Nunes B.T. Cruz A.C. et al.Zika virus epidemic in Brazil. I. Fatal disease in adults: clinical and laboratorial aspects.J Clin Virol. 2016; 85: 56-64Crossref PubMed Scopus (58) Google Scholar), that this neurotropic virus can disseminate to multiple organs and tissues, in addition to the central nervous system, while inflicting pathological effects. Previous to this report, the majority of fatalities associated with ZIKV infection were almost invariably linked to acute neurological complications (Sarmiento-Ospina et al., 2016Sarmiento-Ospina A. Vasquez-Serna H. Jimenez-Canizales C.E. Villamil-Gomez W.E. Rodriguez-Morales A.J. Zika virus associated deaths in Colombia.Lancet Infect Dis. 2016; 16: 523-524Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, Soares et al., 2016Soares C.N. Brasil P. Carrera R.M. Sequeira P. de Filippis A.B. Borges V.A. et al.Fatal encephalitis associated with Zika virus infection in an adult.J Clin Virol. 2016; 83: 63-65Crossref PubMed Scopus (93) Google Scholar, Azevedo et al., 2016Azevedo R.S. Araujo M.T. Martins Filho A.J. Oliveira C.S. Nunes B.T. Cruz A.C. et al.Zika virus epidemic in Brazil. I. Fatal disease in adults: clinical and laboratorial aspects.J Clin Virol. 2016; 85: 56-64Crossref PubMed Scopus (58) Google Scholar). However, amongst those exceptional fatalities without neurological involvement, the question was raised as to whether ZIKV could cause renal and cardiac involvement, as was observed on autopsy examinations of the case described in this issue. Renal and cardiac complications have been reported in atypical, severe (Villamil-Gomez et al., 2016aVillamil-Gomez W.E. Ramirez-Vallejo E. Cardona-Ospina J.A. Silvera L.A. Rodriguez-Morales A.J. Electrocardiographic alterations in patients with chikungunya fever from Sucre, Colombia: a 42-case series.Travel Med Infect Dis. 2016; 14: 510-512Crossref PubMed Scopus (12) Google Scholar, Alvarez et al., 2017Alvarez M.F. Bolivar-Mejia A. Rodriguez-Morales A.J. Ramirez-Vallejo E. Cardiovascular involvement and manifestations of systemic Chikungunya virus infection: a systematic review.F1000Res. 2017; 6: 390Crossref PubMed Scopus (40) Google Scholar), and fatal cases (Hoz et al., 2015Hoz J.M. Bayona B. Viloria S. Accini J.L. Juan-Vergara H.S. Viasus D. Fatal cases of Chikungunya virus infection in Colombia: diagnostic and treatment challenges.J Clin Virol. 2015; 69: 27-29Crossref PubMed Scopus (49) Google Scholar, Mercado et al., 2018Mercado M. Acosta-Reyes J. Parra E. Guzman L. Beltran M. Gasque P. et al.Renal involvement in fatal cases of Chikungunya virus infection.J Clin Virol. 2018; 103: 16-18Crossref PubMed Scopus (25) Google Scholar) of chikungunya virus (CHIKV) infection. Conversely, cases of ZIKV infection with documented renal or cardiac complications have been reported on rarely and have usually lacked detailed histopathological evaluation as well as molecular confirmation of the presence of viral RNA within the renal or cardiac tissues during routine autopsy of fatal cases (Mercado-Reyes et al., 2019Mercado-Reyes M. Acosta-Reyes J. Navarro-Lechuga E. Corchuelo S. Rico A. Parra E. et al.Dengue, Chikungunya and Zika virus coinfection: results of the national surveillance during the Zika epidemic in Colombia.Epidemiol Infect. 2019; 147: e77Crossref PubMed Scopus (43) Google Scholar). ZIKV infection has previously been reported to cause cardiovascular compromise as a consequence of systemic infection, as revealed by electrocardiographic and echocardiographic alterations (Villamil-Gomez et al., 2018Villamil-Gomez W.E. Ramirez-Vallejo E. Rodriguez-Morales A.J. Cardiac compromise in Zika virus infection.Mayo Clin Proc. 2018; 93: 393-394Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, Schwartzmann et al., 2017Schwartzmann P.V. Ramalho L.N. Neder L. Vilar F.C. Ayub-Ferreira S.M. Romeiro M.F. et al.Zika virus meningoencephalitis in an immunocompromised patient.Mayo Clin Proc. 2017; 92: 460-466Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar), even including venous thromboembolism (in ZIKV and CHIKV infections) (Ramacciotti et al., 2019Ramacciotti E. Agati L.B. Aguiar V.C.R. Wolosker N. Guerra J.C. de Almeida R.P. et al.Zika and Chikungunya virus and risk for venous thromboembolism.Clin Appl Thromb Hemost. 2019; 25Crossref Scopus (37) Google Scholar), as well as demonstrating myocardial inflammation secondary to viral infection (Villamil-Gomez et al., 2018Villamil-Gomez W.E. Ramirez-Vallejo E. Rodriguez-Morales A.J. Cardiac compromise in Zika virus infection.Mayo Clin Proc. 2018; 93: 393-394Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Autopsy examinations of a heart transplant recipient who developed ZIKV infection revealed plasma cell infiltrates in the myocardial tissue, along with perivascular and endovascular damage (Schwartzmann et al., 2017Schwartzmann P.V. Ramalho L.N. Neder L. Vilar F.C. Ayub-Ferreira S.M. Romeiro M.F. et al.Zika virus meningoencephalitis in an immunocompromised patient.Mayo Clin Proc. 2017; 92: 460-466Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Nevertheless, publications in the literature on cardiovascular manifestations in adult patients with ZIKV infection are scarce, and the case report by Rajahram et al., 2019Rajahram G.S. Hale G. Bhatnagar J. Hiu J. Thayan R. William T. et al.Postmortem evidence of disseminated Zika virus infection in an adult patient.Int J Infect Dis. 2019; https://doi.org/10.1016/j.ijid.2019.01.047Abstract Full Text Full Text PDF Scopus (5) Google Scholar is timely in underscoring how this arboviral infection can produce unexpected clinical complications with renal and cardiovascular involvement. Previous reports have suggested an association between cardiovascular complications and ZIKV during the acute phase of the infection (Villamil-Gomez et al., 2018Villamil-Gomez W.E. Ramirez-Vallejo E. Rodriguez-Morales A.J. Cardiac compromise in Zika virus infection.Mayo Clin Proc. 2018; 93: 393-394Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, Li et al., 2016Li X.F. Dong H.L. Huang X.Y. Qiu Y.F. Wang H.J. Deng Y.Q. et al.Characterization of a 2016 clinical isolate of Zika virus in non-human primates.EBioMedicine. 2016; : 170-177Google Scholar, Minhas et al., 2017Minhas A.M. Nayab A. Iyer S. Narmeen M. Fatima K. Khan M.S. et al.Association of Zika virus with myocarditis, heart failure, and arrhythmias: a literature review.Cureus. 2017; 9: e1399PubMed Google Scholar). However, only a limited number of studies have addressed this potential association (Martinez-Pulgarin et al., 2016Martinez-Pulgarin D.F. Acevedo-Mendoza W.F. Cardona-Ospina J.A. Rodriguez-Morales A.J. Paniz-Mondolfi A.E. A bibliometric analysis of global Zika research.Travel Med Infect Dis. 2016; 14: 55-57Crossref PubMed Scopus (56) Google Scholar, Minhas et al., 2017Minhas A.M. Nayab A. Iyer S. Narmeen M. Fatima K. Khan M.S. et al.Association of Zika virus with myocarditis, heart failure, and arrhythmias: a literature review.Cureus. 2017; 9: e1399PubMed Google Scholar). Findings in patients (Abdalla et al., 2018Abdalla L.F. Santos J.H.A. Barreto R.T.J. Souza E.M.E. D'Assuncao F.F. Borges M.A. et al.Atrial fibrillation in a patient with Zika virus infection.Virol J. 2018; 15: 23Crossref PubMed Scopus (15) Google Scholar) and non-human primates (Li et al., 2016Li X.F. Dong H.L. Huang X.Y. Qiu Y.F. Wang H.J. Deng Y.Q. et al.Characterization of a 2016 clinical isolate of Zika virus in non-human primates.EBioMedicine. 2016; : 170-177Google Scholar) have provided evidence that ZIKV has a broad tissue tropism, which includes renal and heart tissues (Rajahram et al., 2019Rajahram G.S. Hale G. Bhatnagar J. Hiu J. Thayan R. William T. et al.Postmortem evidence of disseminated Zika virus infection in an adult patient.Int J Infect Dis. 2019; https://doi.org/10.1016/j.ijid.2019.01.047Abstract Full Text Full Text PDF Scopus (5) Google Scholar, Li et al., 2016Li X.F. Dong H.L. Huang X.Y. Qiu Y.F. Wang H.J. Deng Y.Q. et al.Characterization of a 2016 clinical isolate of Zika virus in non-human primates.EBioMedicine. 2016; : 170-177Google Scholar). Nevertheless, further investigations are needed in order to delineate the underlying pathogenic processes in which ZIKV affects myocardial tissue and to characterize the spectrum of cardiovascular manifestations caused by this emerging arboviral infection (Musso et al., 2018Musso D. Rodriguez-Morales A.J. Levi J.E. Cao-Lormeau V.M. Gubler D.J. Unexpected outbreaks of arbovirus infections: lessons learned from the Pacific and tropical America.Lancet Infect Dis. 2018; 18: e355-e361Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). A review of the literature identified a total of 84 fatal cases of ZIKV infection during the recent pandemic in the Americas (Rodriguez-Morales et al., 2018Rodriguez-Morales A.J. Acevedo-Mendoza W.F. Nasner-Posso K.M. Martínez-Pulgarín D.F. Restrepo-López A. Cardona-Ospina J.A. Postnatal acquired fatal Zika virus infection in the Americas: a systematic review.Int J Infect Dis. 2018; 73: 195Abstract Full Text Full Text PDF Google Scholar). However, few of these reported cases underwent an in-depth tissue assessment and molecular characterization during autopsy, as was performed in the case report by Rajahram et al., 2019Rajahram G.S. Hale G. Bhatnagar J. Hiu J. Thayan R. William T. et al.Postmortem evidence of disseminated Zika virus infection in an adult patient.Int J Infect Dis. 2019; https://doi.org/10.1016/j.ijid.2019.01.047Abstract Full Text Full Text PDF Scopus (5) Google Scholar. It should be emphasized that the pathogenesis of severe ZIKV infection remains poorly understood. In vitro and experimental animal models have provided evidence that antibody-dependent enhancement (ADE) may play a role, but clinical correlates for this phenomenon still need to be confirmed in human ZIKV infection (Ngono and Shresta, 2018Ngono A.E. Shresta S. Immune response to dengue and Zika.Annu Rev Immunol. 2018; 36: 279-308Crossref PubMed Scopus (128) Google Scholar, Andrade et al., 2019Andrade P. Gimblet-Ochieng C. Modirian F. Collins M. Cardenas M. Katzelnick L.C. et al.Impact of pre-existing dengue immunity on human antibody and memory B cell responses to Zika.Nat Commun. 2019; 10: 938Crossref PubMed Scopus (31) Google Scholar). Recent studies suggested that preexisting high antibody titers to dengue virus were associated with a reduced risk of acquiring ZIKV infection and disease. In this sense, the landscape of ZIKV immunity that now exists may affect the risks of future transmission (Rodriguez-Barraquer et al., 2019Rodriguez-Barraquer I. Costa F. Nascimento E.J.M. Nery N.J. Castanha P.M.S. Sacramento G.A. et al.Impact of preexisting dengue immunity on Zika virus emergence in a dengue endemic region.Science. 2019; 363: 607-610Crossref PubMed Scopus (155) Google Scholar). Additionally, cases with arboviral co-infections/co-detection (dengue and chikungunya) have been reported in Colombia and Brazil (Villamil-Gomez et al., 2016bVillamil-Gomez W.E. Rodriguez-Morales A.J. Uribe-Garcia A.M. Gonzalez-Arismendy E. Castellanos J.E. Calvo E.P. et al.Zika, dengue, and chikungunya co-infection in a pregnant woman from Colombia.Int J Infect Dis. 2016; 51: 135-138Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, Sardi et al., 2016Sardi S.I. Somasekar S. Naccache S.N. Bandeira A.C. Tauro L.B. Campos G.S. et al.Coinfections of Zika and Chikungunya viruses in Bahia, Brazil, identified by metagenomic next-generation sequencing.J Clin Microbiol. 2016; 54: 2348-2353Crossref PubMed Scopus (89) Google Scholar), as well as concurrent infections with other microorganisms such as Leptospira (Neaterour et al., 2017Neaterour P. Rivera A. Galloway R.L. Negron M.G. Rivera-Garcia B. Sharp T.M. Fatal Leptospira spp./Zika virus coinfection-Puerto Rico, 2016.Am J Trop Med Hyg. 2017; 97: 1085-1087Google Scholar) and co-infections with other arboviruses (Mercado-Reyes et al., 2019Mercado-Reyes M. Acosta-Reyes J. Navarro-Lechuga E. Corchuelo S. Rico A. Parra E. et al.Dengue, Chikungunya and Zika virus coinfection: results of the national surveillance during the Zika epidemic in Colombia.Epidemiol Infect. 2019; 147: e77Crossref PubMed Scopus (43) Google Scholar). Co-circulation with other arboviruses and ADE pose a challenge for physicians and public health authorities, given the potential to confound and delay diagnosis and possibly influence poorer outcomes in patients with previous exposure to other flaviviruses (Ngono and Shresta, 2018Ngono A.E. Shresta S. Immune response to dengue and Zika.Annu Rev Immunol. 2018; 36: 279-308Crossref PubMed Scopus (128) Google Scholar). As a result, multiple research networks on ZIKV and arboviruses in general have been established, which can leverage protocols, methodologies, and multidisciplinary approaches to inform treatment, prevention, and control strategies. Although recent advances have greatly contributed to our understanding of ZIKV pathogenesis, systemic involvement and the expanding tissue tropism of this virus and its potential relationship to different lineages highlight important aspects for future investigation. Finally, it is worth considering the setting for vaccine development and preparedness for other emerging arboviruses in Latin America and the Asia-Pacific region, such as Ross River, Mayaro, Oropouche, Madariaga, West Nile, and the Venezuelan equine encephalitis and Eastern equine encephalitis viruses. None. All authors report no potential conflicts. All authors have submitted the ICMJE Disclosure Form for Potential Conflicts of Interest. AJRM conceived the idea of the Editorial and performed a review of the literature on the related topic. All authors read the case that is being editorialized. AJRM developed the first draft of the manuscript. All authors consequently contributed to revisions. All authors approved the final version submitted. This article was presented in part at the 18th International Congress of Infectious Diseases (18th ICID) and the XVIII Congress of the Argentine Society for Infectious Diseases (SADI), Buenos Aires, Argentina, March 1–4, 2018 (Conference of A.J. Rodriguez-Morales at Session 48: Zika: Regional Experiences in Neurological Diseases and Severe Cases). The Faculty of Health Sciences of the Universidad Tecnológica de Pereira, the Colombian Association of Infectious Diseases (ACIN) (Coffee-Triangle Region chapter), and the International Society for Infectious Disease (ISID) supported A.J. Rodriguez-Morales in his participation at the ICID/SADI meetings where this article was initially presented.