The NEW ENGLAND JOURNAL of MEDICINE Perspective Zika Virus in the Americas — Yet Another Arbovirus Threat Anthony S. Fauci, M.D., and David M. Morens, M.D.​​ he explosive pandemic of Zika virus infection nized “spillover” infections in hu- occurring throughout South America, Central mans, even in highly enzootic areas.2 Its current explosive pan- America, and the Caribbean (see map) and demic reemergence is therefore T 3 potentially threatening the United States is the most truly remarkable. Decades ago, African researchers noted that recent of four unexpected arrivals complex cycles involving verte- aedes-transmitted Zika epizootics of important arthropod-borne viral brates such as mammals or birds inexplicably tended to follow ae- diseases in the Western Hemi- and blood-feeding vectors. Until des-transmitted chikungunya epi- sphere over the past 20 years. It recently, only a few arboviruses zootics and epidemics. An analo- follows dengue, which entered had caused clinically significant gous pattern began in 2013, when this hemisphere stealthily over human diseases, including mos- chikungunya spread pandemical- decades and then more aggres- quito-borne alphaviruses such as ly from west to east, and Zika sively in the 1990s; West Nile vi- chikungunya and flaviviruses such later followed. Zika has now cir- rus, which emerged in 1999; and as dengue and West Nile. The cled the globe, arriving not only chikungunya, which emerged in most historically important of in the Americas but also, in Sep- 2013. Are the successive migra- these is yellow fever virus, the first tember, in the country of Cape tions of these viruses unrelated, recognized viral cause of deadly Verde in West Africa, near its pre- or do they reflect important new epidemic hemorrhagic fever. sumed ancient ancestral home. patterns of disease emergence? Zika, which was discovered in- With the exception of West Furthermore, are there secondary cidentally in Uganda in 1947 in Nile virus, which is predominant- health consequences of this arbo- the course of mosquito and pri- ly spread by culex-species mosqui- virus pandemic that set it apart mate surveillance,1 had until now toes, the arboviruses that recently from others? remained an obscure virus con- reached the Western Hemisphere “Arbovirus” is a descriptive fined to a narrow equatorial belt have been transmitted by aedes term applied to hundreds of pre- running across Africa and into mosquitoes, especially the yellow dominantly RNA viruses that are Asia. The virus circulated pre- fever vector mosquito A. aegypti. transmitted by arthropods, nota- dominantly in wild primates and These viruses started to emerge bly mosquitoes and ticks. Arbo- arboreal mosquitoes such as Aedes millennia ago, when North African viruses are often maintained in africanus and rarely caused recog- villagers began to store water in n engl j med nejm.org 1 The New England Journal of Medicine Downloaded from nejm.org on February 2, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. PERSPECTIVE zika virus in the americas Locally acquired cases or virus isolation Serosurvey data only Countries with Past or Current Evidence of Zika Virus Transmission (as of December 2015). For countries with serosurvey data only, evidence of Zika virus transmission is derived from studies that detected Zika virus anti- bodies in healthy people. Outlined areas, all with locally acquired cases or virus isolation, include Cape Verde, Cook Islands, Easter Island, Federated States of Micronesia, French Polynesia, Martinique, New Caledonia, Puerto Rico, Solomon Islands, and Vanuatu. Data are from the Centers for Disease Control and Prevention (http://www . cdc . gov/​­zika). their dwellings. Arboreal A. aegypti Through early epidemiologic crease in incidence from 2014 to then adapted to deposit their eggs surveillance and human challenge 2015, which some public health in domestic water-containing ves- studies, Zika was characterized officials believe is caused by Zika sels and to feed on humans, as a mild or inapparent dengue- virus infections in pregnant which led to adaptation of arbo- like disease with fever, muscle women. Although no other flavi- real viruses to infect humans. The aches, eye pain, prostration, and virus is known to have terato- yellow fever, dengue, and chikun- maculopapular rash. In more than genic effects, the microcephaly gunya viruses evolved entirely new 60 years of observation, Zika has epidemic has not yet been linked maintenance cycles of human– not been noted to cause hemor- to any other cause, such as in- A. aegypti–human transmission.4 rhagic fever or death. There is in creased diagnosis or reporting, Now, 5000 years later, the worst vitro evidence that Zika virus increased ultrasound examinations effects of this evolutionary cas- mediates antibody-dependent en- of pregnant women, or other in- cade are being seen in the repeat- hancement of infection, a phenom- fectious or environmental agents. ed emergence of arboviruses into enon observed in dengue hemor- Despite the lack of definitive new ecosystems involving humans. rhagic fever; however, the clinical proof of any causal relationship,5 Moreover, arboviruses transmitted significance of that finding is some health authorities in afflict- by different mosquitoes have, in uncertain. ed regions are recommending parallel, adapted to humans’ do- The ongoing pandemic con- that pregnant women take me- mestic animals, such as horses in firms that Zika is predominantly ticulous precautions to avoid the case of Venezuelan equine en- a mild or asymptomatic dengue- mosquito bites and even to delay cephalitis and pigs in the case of like disease. However, data from pregnancy. It is critically impor- Japanese encephalitis virus, or to French Polynesia documented a tant to confirm or dispel a causal vertebrate hosts and non-aedes concomitant epidemic of 73 cases link between Zika infection of mosquitoes found in areas of of Guillain–Barré syndrome and pregnant women and the occur- human habitation, as West Nile other neurologic conditions in rence of microcephaly by doing virus did. The possibility that Zika a population of approximately intensive investigative research, may yet adapt to transmission by 270,000, which may represent including careful case–control and A. albopictus, a much more widely complications of Zika. Of greater other epidemiologic studies as distributed mosquito found in at concern is the explosive Brazilian well as attempts to duplicate this least 32 states in the United epidemic of microcephaly, mani- phenomenon in animal models. States, is cause for concern. fested by an apparent 20-fold in- In a “pure” Zika epidemic, a 2 n engl j med nejm.org The New England Journal of Medicine Downloaded from nejm.org on February 2, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. PERSPECTIVE zika virus in the americas diagnosis can be made reliably not cost-effective, yet vaccine evolve and adapt within ecologic on clinical grounds. Unfortunate- stockpiling followed by rapid niches that are increasingly be- ly, the fact that dengue and chi- deployment may be too slow to ing perturbed by humans. Zika is kungunya, which result in simi- counter sudden explosive epidem- still a pandemic in progress, and lar clinical pictures, have both ics. Although yellow fever has many important questions about been epidemic in the Americas historically been prevented entire- it, such as that of teratogenicity, confounds clinical diagnoses. Spe- ly by aggressive mosquito control, remain to be answered. Yet it has cific tests for dengue and chikun- in the modern era vector control already reinforced one important gunya are not always available, has been problematic because of lesson: in our human-dominated and commercial tests for Zika expense, logistics, public resis- world, urban crowding, constant have not yet been developed. More- tance, and problems posed by international travel, and other over, because Zika is closely relat- inner-city crowding and poor san- human behaviors combined with ed to dengue, serologic samples itation. Among the best preven- human-caused microperturbations may cross-react in tests for either tive measures against Zika virus in ecologic balance can cause in- virus. Gene-detection tests such are house screens, air-condition- numerable slumbering infectious as the polymerase-chain-reaction ing, and removal of yard and agents to emerge unexpectedly. In assay can reliably distinguish the household debris and containers response, we clearly need to up our three viruses, but Zika-specific that provide mosquito-breeding game with broad and integrated tests are not yet widely available. sites, luxuries often unavailable to research that expands understand- The mainstays of management impoverished residents of crowd- ing of the complex ecosystems in are bed rest and supportive care. ed urban locales where such epi- which agents of future pandemics When multiple arboviruses are demics hit hardest. are aggressively evolving. cocirculating, specific viral diag- With its recent appearance in Disclosure forms provided by the authors nosis, if available, can be impor- Puerto Rico, Zika virus forces are available with the full text of this article tant in anticipating, preventing, us to confront a potential new at NEJM.org. and managing complications. For disease-emergence phenomenon: From the National Institute of Allergy and