Zika Virus-Associated Microcephaly and Eye Lesions in the Newborn

Literature Review Zika Virus-Associated Microcephaly and Eye Lesions in the Newborn Gregory Valentine,1 Lucila Marquez,2 and Mohan Pammi3 1 Department of Pediatrics, 2Department of Pediatrics, Section of Infectious Diseases, and 3Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, Texas Corresponding Author: Gregory Valentine, MD, Department of Pediatrics, One Baylor Plaza, MC: BCM320, Houston, TX 77030. E-mail: . Received March 1, 2016; accepted June 1, 2016; electronically published July 11, 2016. On February 1, 2016, Zika virus (ZIKV) was designated as a Public Health Emergency of International Concern by the director of the World Health Organization. Zika virus has spread to numerous countries throughout the Americas, affecting up to an estimated 1.3 million people since the first reports from Brazil in early 2015. Although ZIKV infections are self-limiting, fetal microcephaly and ophthalmic anomalies have been associated with ZIKV infection as a possible result of perinatal transmission. The causal link between maternal ZIKV infection and newborn microcephaly and eye lesions has not been proven beyond doubt and is currently debated. We discuss the possibility of causality by ZIKV using Koch’s postulates and the more appropriate Bradford Hill criteria. In this review, we summarize and consolidate the current literature on newborn microcephaly and eye lesions associated with ZIKV infection and discuss current perspectives and controversies. Key words. global health; microcephaly; neonate; Zika virus. As of February 1, 2016, Zika virus (ZIKV) is now a Public Health Emergency of International Concern [1]. The association of ZIKV with microcephaly and ophthalmic anomalies was first reported with the outbreak in Brazil in 2015 [2–7]. Given the possible association of ZIKV with congenital abnormalities in neonates, the US Centers for Disease Control and Prevention (CDC) recommends that pregnant women should not travel to places with ongoing ZIKV transmission, and male partners of pregnant women should consider refraining from having sex for the duration of the pregnancy if they have traveled or lived in areas where ZIKV has been reported. Zika virus is an arbovirus first isolated from a rhesus monkey in the Zika Forest near Entebbe, Uganda in 1947 [8]. In 1952, Uganda and Tanzania reported the first human cases [9]. From the 1950s to 1980s, ZIKV spread throughout Africa and Southeast (SE) Asia. Until the early 2000s, there were no reported epidemic outbreaks of ZIKV. The first reported epidemic occurred on the island of Yap in the Federated States of Micronesia in 2007 [10], and this was soon followed by another epidemic in French Polynesia (FP) in 2013 [11, 12]. The FP epidemic was the largest in ZIKV history with more than 28 000 infections in the first 4 months of the epidemic. The first cases of Guillain-Barre Syndrome (GBS) associated with ZIKV were reported during the FP outbreak [13]. New ZIKV cases were subsequently found in Cook Island, Easter Island, and New Caldonia [14–16]. The origins of the emerging pandemic began in the northeast regions of Brazil with the first reported cases in May 2015 [17]. Zika virus has since spread throughout Central and South America and the Caribbean, including the US Virgin Islands and Puerto Rico [18–20]. The Virus and Entomology Zika virus is a positive sense, single-stranded ribonucleic acid (RNA) virus of the Flaviviridae family. It is an arbovirus transmitted to humans via the bite of an infected mosquito of the Aedes genus, primarily Aedes aegypti [21]. Aedes polynesiensis, Aedes albopictus, Aedes africanus, and Aedes hensilli have also been considered as vectors for ZIKV [21–23]. Aedes aegypti and A albopictus, found throughout much of the Americas, also transmit chikungunya and dengue viruses that have similar clinical presentations. The ZIKV genome contains 10 794 nucleotides encoding 3419 amino acids [24]. Through genome studies, ZIKV is closest in relation to the Spondweni virus, another flavivirus that is a mosquito-borne pathogen [25–27]. Journal of the Pediatric Infectious Diseases Society, Vol. 5, No. 3, pp. 323–8, 2016. DOI:10.1093/jpids/piw037 © The Author 2016. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: . 324 Valentine et al With the spread of ZIKV initially throughout Africa and SE Asia, genomics of the virus showed separate African and Asian lineages. Genomic testing of ZIKV causing the outbreak on Yap Island in Micronesia found it to be related to the Asian rather than the African lineage [28, 29]. The FP strain seems to be related most closely to the SE Asian strains rather than from the Yap Island outbreak, suggesting introduction into FP independent of the Yap island outbreak. The genome of the ZIKV causing the Brazilian epidemic is closest to that of ZIKV from FP, which suggests the continued eastward spread of the Asian lineage [17]. The potential for ZIKV spread looms large. Mexico, Colombia, and the United States have an estimated 30.5, 23.2, and 22.7 million people, respectively, living in regions that are conducive to the spread of ZIKV by A aegypti and A albopictus [30]. Given the distribution of A aegypti mosquitos, ZIKV has huge potential to spread throughout these countries in the coming months. Diagnostic Testing for Zika Virus Infections Zika virus diagnosis relies mainly upon the detection of ZIKV RNA in body fluid specimens. Reverse-transcriptase polymerase chain reaction (RT-PCR) and viral isolation in blood specimens collected less than 5 days after the onset of symptoms are the reference techniques [31]. The viremic period in humans can be short, potentially from the 3rd to the 5th day after the first occurrence of symptoms. Several studies have found that ZIKV can be isolated for almost 1 week longer in the urine than compared with the serum [32, 33]. Zika virus has also been isolated from the saliva, amniotic fluid, and semen [34, 35]. Reverse-transcriptase PCR has also shown the presence of ZIKV in neuronal tissues [36]. Zika virus serology may also be useful for diagnosis of ZIKV infections, although this may be complicated by cross-reactivity. Zika virus-specific immunoglobulin (Ig) M antibodies can be detected by enzyme-linked immunosorbent assay (ELISA) or immunofluorescence assays after day 5 from the onset of symptoms. The CDC has obtained Emergency Use Authorization from the US Food and Drug Administration (FDA) to use the Zika IgM Antibody Capture ELISA for the detection of IgM antibodies in serum and/or cerebrospinal fluid. It is recommended to test potentially affected individuals as soon as 4 days and up to 12 weeks after potential infection [37]. Antibodies can cross-react with other genetically related viruses such as other members of the Flaviviridae family (ie, Yellow fever, Dengue, West Nile), making serologic tests difficult to interp (...truncated)