Virology and Virality: Confronting Zika in and Beyond the Emergency Department

Abstract

The Zika virus (ZIKV), obscure to all but virologists and travel-medicine specialists for several decades after its initial discovery in monkeys (Uganda, 1947) and in human beings (Uganda and Tanzania, 1952), is now all too familiar. Although many emergency physicians are unlikely ever to encounter a case, the combination of known risks, unknown variables, and plausible near-future scenarios could make ZIKV something more than just this year's model in a long series of high-profile reportable pathogens. Its outsized share of public attention reflects an unusual combination of apparent benignity in many settings and insidious morbidity in others. After the expansion of the 2015 Brazilian/Latin American outbreak to Miami and other US cities, the Centers for Disease Control and Prevention (CDC) has responded with its customary current and thorough guidelines for physicians,1Centers for Disease Control and Prevention. Zika virus: for healthcare providers. Available at: http://www.cdc.gov/zika/hc-providers/index.html. Accessed August 29, 2016.Google Scholar the media,2Centers for Disease Control and Prevention. Zika virus (digital press kit). Available at: http://www.cdc.gov/media/dpk/2016/dpk-zika-virus.html. Accessed August 29, 2016.Google Scholar and the general public,3Centers for Disease Control and Prevention. Zika virus. Available at: http://www.cdc.gov/zika/index.html. Accessed August 29, 2016.Google Scholar including multiple Clinical Outreach and Communication Activity sessions on the topic. “Their recommendations usually tend to be on the conservative side,” observed Stephen V. Cantrill, MD, an emergency physician formerly at Denver Health Medical Center who cochairs the American College of Emergency Physicians’ (ACEP's) Quality and Patient Safety Committee and serves on the Clinical Policies Committee and the Colorado Governor's Emergency Epidemic Response Committee. “The CDC is the best we've got.” The centers' advice on surveillance, testing, complications, notification, transmission reduction, mosquito control, and other countermeasures, he found, supports cautious optimism that Zika will have limited effects in the United States in the long term. The critical term, as usual, is cautious. “The fact that the virus was being sexually transmitted was a surprise,” acknowledged CDC spokesman Benjamin Haynes. “It was one of those things that we're continuing to learn. Yet the bright side of that is, of the more than 2,700 cases in the United States, a very small handful of those are sexually transmitted. What's most important is that health care providers are looking for the signs and symptoms of Zika. CDC's focused a lot on pregnant women, but just because you're not a woman looking to get pregnant, or a woman who is pregnant, doesn't mean you can't help spread Zika.” (This case count pertains to US states; when US territories are added, the large numbers in Puerto Rico and the Virgin Islands push the total to 14,110 as of August 31, 2016.4Centers for Disease Control and Prevention. Zika virus: case counts in the US. Available at: http://www.cdc.gov/zika/geo/united-states.html. Accessed September 4, 2016.Google Scholar) Viewed alongside other recent outbreaks of viral diseases such as Ebola, chikungunya, and enterovirus D68, ZIKV usually has relatively mild effects. Approximately 80% of infected persons are asymptomatic: “[A] vast majority of people don't even know they have the disease,” Dr. Cantrill reported. For the 1 in 5 cases that become symptomatic (commonly including fever, rash, joint or muscle pain, conjunctivitis, or headache), symptoms last only days or weeks and are treatable with standard measures: rest, hydration, and acetaminophen, although not nonsteroidals until dengue has been ruled out (to prevent hemorrhage). Severer complications, including Guillain-Barré syndrome, have been observed. Although the rarity of that autoimmune condition (1 to 2 cases per 100,000 population, according to the CDC) makes it difficult to quantify the correlation with ZIKV, a recent report from 7 nations, including Brazil's heavily affected Bahia state, establishes a strong association, with a 28% higher incidence in male patients despite an overall 75% higher incidence of ZIKV disease in female patients (perhaps reflecting sex differences in reporting or active health care seeking).5dos Santos T, Rodriguez A, Almiron M, et al. Zika virus and the Guillain-Barré syndrome—case series from seven countries. N Engl J Med. http://dx.doi.org/10.1056/NEJMc1609015.Google Scholar The effects of ZIKV in pregnancy are so disturbing that knowledgeable commentators are comparing this outbreak to the effects of thalidomide and rubella during the 1960s.6Lyon J. Zika: worse than thalidomide? JAMA. http://dx.doi.org/10.1001/jama.2016.11054.Google Scholar Case clusters of microcephaly in areas where Aedes aegypti is endemic have been accompanied by other neurologic effects, including arthrogryposis7van der Linden V. Filho E.L.R. Lins O.G. et al.Congenital Zika syndrome with arthrogryposis: retrospective case series study.BMJ. 2016; 354: i3899Crossref PubMed Scopus (148) Google Scholar (and perhaps further conditions to be reported after this writing), which may amount to a congenital Zika syndrome. Michael J. Burns, MD, clinical professor of emergency medicine and internal medicine/infectious diseases at University of California–Irvine, observed that information about Zika is often “out of date in a week because there's so many new things always being either discovered or new recommendations made every few days. They're even finding now that the Zika virus may not be detected in utero…. The baby may be normal at birth and develop brain abnormalities a few weeks after birth.” There has been speculation about a generation of severely impaired children born during the years of highest vulnerability before an effective vaccine becomes available, with predictable burdens on families, caregivers, and society (Haynes cited estimates that “caring for individuals with microcephaly can possibly cost up to $10 million in their lifetime”). Because sexual transmission, observed in male-to-female, female-to-male,8Davidson A. Slavinski S. Komoto K. et al.Suspected female-to-male sexual transmission of Zika Virus—New York City, 2016.Morb Mortal Wkly Rep. 2016; 65: 716-717Crossref PubMed Scopus (246) Google Scholar and male-to-male9Deckard D.T. Chung W.M. Brooks J.T. et al.Male-to-male sexual transmission of Zika virus—Texas, January 2016.Morb Mortal Wkly Rep. 2016; 65: 372-374Crossref PubMed Scopus (257) Google Scholar directions to date, raises the possibility that unwitting human beings may ultimately become more effective viral vectors than mosquitoes, a researcher writing in the New York Times has labeled ZIKV “the millennials' STD [sexually transmitted disease]”10Folkers K.M. Zika: the millennials’ STD?.New York Times. August 20, 2016; (Available at:) (Accessed August 25, 2016)http://www.nytimes.com/2016/08/21/opinion/sunday/zika-the-millennials-std.htmlGoogle Scholar for its effect on sexual and reproductive decisions. What researchers have observed to date about ZIKV, Dr. Cantrill observed, “demonstrates that we can't really think ahead of Mother Nature.” A possible best-case scenario, involving effective control of the primary vectors A aegypti and the more northward-venturing A albopictus (or even their eradication, as some lay commentators have proposed11Engber D. Let's kill all the mosquitoes.Slate. January 29, 2016; (Available at:) (Accessed August 21, 2016)http://www.slate.com/articles/health_and_science/science/2016/01/zika_carrying_mosquitoes_are_a_global_scourge_and_must_be_stopped.htmlGoogle Scholar), is unlikely, Dr. Cantrill suggested, in part because of these mosquitoes' behavior and habitat: they can breed in tiny amounts of water and often live indoors, where public spraying is unlikely to reach. He quoted a speaker at a National Academy of Medicine Zika conference last February,12National Academy of Medicine. Research priorities to inform public health and medical practice for domestic Zika virus: a workshop. February 16, 2016. Available at: https://nam.edu/event/research-priorities-to-inform-public-health-and-medical-practice-for-domestic-zika-virus-a-workshop/. Accessed August 31, 2016.Google Scholar echoing a widespread sentiment: “We're not going to spray our way out of this one.” The recent detection of ZIKV in surveillance-trap samples of Miami Beach mosquitoes13Florida Department of Agriculture and Consumer Services. Miami-Dade mosquitoes test positive for Zika. Available at: http://www.freshfromflorida.com/News-Events/Press-Releases/2016-Press-Releases/Miami-Dade-Mosquitoes-Test-Positive-for-Zika. Accessed September 1, 2016.Google Scholar 4 weeks after the beginning of a spraying campaign with the organophosphate insecticide Naled14Alvarez L. Belluck P. Spraying begins in Miami to combat the Zika virus.New York Times. August 4, 2016; (Available at: http://www.nytimes.com/2016/08/05/health/spraying-begins-in-miami-to-combat-the-zika-virus.html. Accessed September 1, 2016)Google Scholar bears out this prediction. Human adaptations may determine whether ZIKV becomes a source of tragic but measured morbidity or a permanent, far-flung scourge. Experts believe that emergency physicians can make pivotal contributions to a multispecialty containment effort. “It's an evolving situation and a fast-moving target,” said Kristi L. Koenig, MD, professor of clinical emergency medicine at the University of California at Irvine School of Medicine and member of ACEP’s Infectious Disease Expert Panel who has participated in CDC-ACEP collaborative work on responses to the outbreak. “Zika is just the latest example of one of these emerging infectious diseases where the information is rapidly changing. Emergency physicians are used to making decisions and managing situations with incomplete information.” Incomplete information, indeed, constitutes much of what the public has been receiving. New Jersey governor Chris Christie, playing to xenophobia-tinged fears during the Republican primaries, advocated quarantining travelers from Brazil,15Maron D.F. Why we shouldn't quarantine travelers because of Zika.Sci Am. February 7, 2016; (Available at:) (Accessed September 1, 2016)http://www.scientificamerican.com/article/why-we-shouldn-t-quarantine-travelers-because-of-zika/Google Scholar paying little or no attention to scientific counsel.16Koenig K.L. Quarantine for Zika virus? where is the science?.Disaster Med Public Health Prep. April 1, 2016; (Available at:) (Accessed August 10, 2016)https://www.cambridge.org/core/journals/disaster-medicine-and-public-health-preparedness/article/quarantine-for-zika-virus-where-is-the-science/A81ED950444E743D6347E19BE604B2E0Google Scholar Fearmongering has not been limited to the political realm: the social media images posted by former US women's Olympic soccer goalkeeper Hope Solo, posing with netting and multiple bottles of insect repellent,17Solo H. Twitter post, July 21, 2016. Available at: https://twitter.com/hopesolo/status/756322142128594944/photo/1. Accessed August 29, 2016.Google Scholar sent a worldwide message of prudence shading into paranoia, provoking chants of “Zi-ka!” from insulted Brazilian spectators each time she handled the ball. Elsewhere on the irrationality spectrum, one can find assorted conspiratorialsts attempting to deny the correlation between ZIKV and microcephaly altogether, advancing instead their pet theories implicating vaccines, genetically modified organisms, the mainstream media, or the Illuminati. The comedic value of such ventures into viral memetics (in the cyberspace sense of the term viral) naturally diminishes sharply at the sight of affected children. Seekers of responsibly vetted information can find it through the CDC, the World Health Organization (WHO),18World Health Organization. Zika virus and complications. Available at: http://www.who.int/emergencies/zika-virus/en/. Accessed August 30, 2016.Google Scholar the New England Journal of Medicine's Zika resource page,19The New England Journal of Medicine. Zika virus. Available at: http://www.nejm.org/page/zika-virus. Accessed August 21, 2016.Google Scholar and a similar resource at Medscape,20Medscape. Zika virus resource center. Available at: http://www.medscape.com/resource/zika-virus. Accessed August 24, 2016.Google Scholar which Dr. Burns found particularly timely and practical. An essential concept debunking media-driven overreactions, Dr. Burns emphasized, is that the means of transmission are known and are not casual: “Even health care workers who aren't up on it may think, 'Oh, the patient has Zika, or they were just in an endemic area with no symptoms; they might be contagious to other people, and if they're in the ED [emergency department], they need to be isolated.' And that's not, of course, the case.” The CDC's Haynes offers recommendations that all clinicians, including emergency physicians, can put into practice. Assessment of risk factors and exposures should include relevant travel to areas with ZIKV transmission and sexual exposure to travelers to those areas; all providers should discuss mosquito bite prevention and other preventive measures with persons at risk for mosquito-borne ZIKV transmission. Although Zika may present with fever and rash, many patients may be asymptomatic or minimally symptomatic, highlighting the need for a good travel and exposure history. All clinicians should assess pregnant women for possible ZIKV exposure; if an emergency physician is treating a pregnant woman who does not have an obstetrics provider, this is an important reason to link the patient with obstetric care in addition to routine prenatal assessment and care. Providers should also advise pregnant women about how to prevent sexual transmission during pregnancy and should be able to counsel patients with ZIKV risk factors or exposure on use of contraception to avoid pregnancy. Particular concerns for emergency physicians, Haynes continued, include Guillain-Barré syndrome (rare, but capable of presenting in an emergency fashion and requiring immediate attention) and severe thrombocytopenia, which has been described in a small number of cases and should be considered if clinically correlated. “Like all pregnant women, pregnant women infected with ZIKV may deliver precipitously, including in emergency or first-responder settings, and providers should be prepared for the additional care those infants may require,” he added. “Fever in a returning traveler (especially from malaria-endemic regions) is a medical emergency; emergency department providers should have ZIKV disease in their differential while continuing to evaluate for other infections which might be life threatening. CDC recommends standard precautions in all health care settings to protect both health care personnel and patients from infection with ZIKV, as well as from blood-borne pathogens.” Beyond specifically medical information, physicians in the United States may need to educate or remind concerned patients about basic aspects of A aegypti and A albopictus biology and behavior. Only females feed on humans, they are daytime biters (unlike other familiar mosquito genera), they prefer indoor life, and they are not superbugs: an Aedes mosquito's life span is a week or 2, and it flies no more than 300 to 400 feet from its hatching site. Jorge Rey, PhD, director of the Florida Medical Entomology Laboratory at the University of Florida in Vero Beach, emphasizes “the standard advice: drain/eliminate water-holding containers around the home, use an EPA [Environmental Protection Agency]-approved repellent according to label instructions, and wear protective clothing to avoid mosquito bites.” “We tend to see people coming in with concerns to the emergency department when they have no other access to health care, or not good access to health information,” Dr. Koenig added. “We saw this after anthrax: people coming in wanting Cipro prescriptions. We saw this after…the event in Japan: the horrific earthquake, tsunami, and radiation release, when supposedly the radiation clouds were coming across to the coastline of California and people were asking for the magic iodine pill.” One of the ZIKV outbreak's chief challenges is “how to counsel people who might be concerned about it, especially pregnant women,” Dr. Koenig said, “in understandable, clear terms because this whole art of crisis and emergency risk communications is a science in and of itself…. The public probably doesn't understand that the majority of the cases are asymptomatic. The majority of the public may not understand that well how it's transmitted: in particular, that we're not talking about a mosquito in Florida flying to California.” The top-level question about any form of preparedness, she said, is “prepared for what?”; clarity about specific risks is paramount. Concerns about ZIKV in the blood supply are common, she observed: “If you have a pregnant patient who needs a blood transfusion, you should be prepared to understand the latest information and be able to explain the risks and benefits, just as we do for other types of reactions and infections.” The current risk in the continental United States is low, the CDC reports, and efforts are in place to keep it that way: the Food and Drug Administration issued a guidance document in August identifying ZIKV as a transfusion-transmitted infection and directing all establishments collecting whole blood and blood components to screen for it, citing detection of the virus in blood samples in French Polynesia, Puerto Rico, and Brazil.21Center for Biologics Evaluation and Research; US Food and Drug Administration. Revised recommendations for reducing the risk of Zika virus transmission by blood and blood components: guidance for industry. August 2016. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM518213.pdf. Accessed August 26, 2016.Google Scholar In both public and professional communications about emerging-disease hazards, Dr. Koenig often finds that pithy 3-term phrases offer mnemonic value. The essentials of disaster preparation and surge capacity, for example, are facilities, personnel, and appropriate operating procedures, or “stuff, staff, and structure.” Beginning with a basic public-health-emergency protocol, initially developed for Ebola and modifiable for other diseases, that she calls “isolate/identify/inform,”22Koenig K.L. Identify, isolate, inform: a 3-pronged approach to management of public health emergencies.Disaster Med Public Health Prep. 2015; 9: 86-87Crossref PubMed Scopus (18) Google Scholar she has published a ZIKV-specific iteration23Koenig K.L. Almadhyan A. Burns M.J. Identify-isolate-inform: a tool for initial detection and management of Zika virus patients in the emergency department.West J Emerg Med. 2016; 17: 238-244PubMed Google Scholar that emphasizes identification (travel to endemic areas plus inadequate mosquito bite protection being appropriate grounds for testing) and stipulates that isolating infected persons to prevent contact, droplet, or airborne transmission is unnecessary for this disease. For ED personnel in particular, Dr. Koenig's concept of a preliminary Vital Sign Zero—“a very well-known concept to people who are working in the prehospital environment,” she noted—poses the question: “Before I touch that patient or measure traditional vital signs such as pulse and blood pressure, do I need to make sure that I'm protecting myself and protecting others? Do they have a contagious infectious disease, and how is it contagious?” Answers differ for each pathogen. ZIKV, as an arbovirus, differs from Ebola, in which transmission through contact with bodily fluids requires disease-appropriate personal protective equipment (PPE); from airborne conditions such as tuberculosis; and from droplet-contact hazards such as influenza. “Safety of the care provider,” Dr. Cantrill commented, is “really not an issue with Zika…. You'd do standard things, but it's not to the degree you'd be suiting up in a level C suit to see a patient with Zika.” Overreactions to relatively rare risks, Dr. Koenig pointed out, are not without costs and risks in their own right because they can divert limited resources from causes of more substantial morbidity. The history of other outbreaks is informative. Concerns about inappropriate quarantining, for example, create disincentives for health care workers to travel to eradicate diseases at their source. A 2014 nurses' strike at some Californian hospitals over allegations of inadequate protection represented “a secondary effect of Ebola,” she noted; “whether that was true or not was unclear, but they were concerned they didn't have the proper training and PPE…. I would suspect there was some morbidity and mortality when suddenly 20,000 nurses walked off the job.” During the H1N1 epidemic of 2009, while chairing her hospital's preparedness committee, she observed that the WHO and CDC offered conflicting recommendations about droplet or airborne transmission, and thus about “whether the PPE required was an N95 respirator, which you would need for airborne, like tuberculosis, or a surgical mask, as we've used for any other type of influenza…. We were actually having shortages of N95 respirators, and we believed the science supported the simple surgical masks.” In a different emergency, at the World Trade Center attack site, she saw personnel equipped with respirators but wearing them around their necks: the right stuff, but the wrong structure. Dr. Koenig has come to view a certain recurrent phrase, “out of an abundance of caution,” as troublesome boilerplate that can correlate with resource misallocation and unintended consequences. Maintaining targeted and updated information about each new outbreak, she believes, is the way to prevent caution from edging past abundant to excessive and counterproductive. “Malaria kills far more people than Zika or Ebola or many of these other diseases,” she noted, “but malaria is not in the news.” There is much to discover about ZIKV, even as observations of its effects reach the general media daily and the medical literature nearly as regularly. In the United States, “there is some thought that the whole southern tier may end up with some degree of local transmission,” Dr. Cantrill reported. “We don't know how much it's going to be; we don't know how long it's going to last…. The symptomatic aspect of the disease really lasts days to weeks; we know that it is present in semen for a while longer. We don't know what that while is.” The CDC currently recommends that nonpregnant couples whose male partner has traveled to a ZIKV-endemic area use barrier protection or avoid sex for at least 6 months if that partner has had a ZIKV diagnosis or symptoms, or at least 8 weeks if the partner is asymptomatic. Those living in an endemic area who are asymptomatic should consider such measures as long as ZIKV is found there. On the positive side, Dr. Burns noted, ZIKV circulates for a limited period in blood after infection occurs—the incubation period in CDC guidelines ranges from 3 to 14 days—and does not induce a chronic carrier state. ZIKV appears immunologically straightforward: “The Zika virus, as far as I know, has one major serogroup, and so once you have an active infection, you're probably immune for years if not for life.” This contrasts with dengue, for example, which has 4 distinct serotypes and little or no cross-immunity after recovery from infection by any one type. It also contrasts with fast-mutating viruses such as HIV or hepatitis C: “If you find an effective vaccine, it's likely to keep working.” Accelerated vaccine development against ZIKV,24Mukherjee S. The race for a Zika vaccine.New Yorker. August 22, 2016; (Available at:) (Accessed August 23, 2016)http://www.newyorker.com/magazine/2016/08/22/the-race-for-a-zika-vaccineGoogle Scholar despite congressional refusal to allocate dedicated funds to the effort without political poison pills, creates the possibility that a vaccine, currently undergoing phase 1 clinical trials,25National Institutes of Health. NIH begins testing investigational Zika vaccine in humans. August 3, 2016. Available at: https://www.nih.gov/news-events/news-releases/nih-begins-testing-investigational-zika-vaccine-humans. Accessed September 2, 2016.Google Scholar will be available relatively soon (“probably a year or 2 down the road,” Haynes suggested). Dr. Burns expects a herd-immunity effect in affected regions: “Once, say, 60% of the people get infected in a couple years, they get immune, and they can't be reinfected again. So when the mosquitoes are biting them, they can't be transmitting Zika from that person who’s immune to another person. So I think you're going to find that the incidence is going to decrease markedly in the next year or 2.” The pattern recurs as the population's proportion of nonimmune children crosses a threshold: “this has been seen in other epidemics where they come on every, say, 3 to 5 years, and then they disappear because of herd immunity,” Dr. Burns added. “Until there's a vaccine, it'll be an ongoing problem in all endemic areas.” One recent epidemiologic report estimated that the current ZIKV outbreak will last only about 3 years, according to available surveillance data, likely interventions reducing the vector mosquitos' life span, and modeling of the epidemic's basic reproduction number R0 (with R0 <1 indicating that an epidemic will end), with herd immunity probably delaying a recurrent outbreak.26Ferguson N.M. Cucunubá Z.M. Dorigatti I. et al.Countering the Zika epidemic in Latin America.Science. 2016; 353: 353-354Crossref PubMed Scopus (185) Google Scholar Yet the variables involved are highly contingent. Given a scenario of expanded sexual transmission, affected by the unknown duration of viral persistence in semen and perhaps amplified by climate-change effects pushing the range of A aegypti and A albopictus gradually northward, ZIKV may be something physicians will need to contend with on large geographic and chronologic scales. For now, Dr. Burns expects that emergency physicians will field “a lot of questions from patients who may think they have the Zika virus but don't, because they haven't been to the right areas,” which in the United States, he expects, will chiefly include southeast Texas and south Louisiana, as well as south Florida. Anomalous cases do occur, Dr. Burns said. “There was one case in Utah where an old man transmitted it to his son, who was a caregiver, by body fluid, and it's the only one we know so far. It's likely when they investigate it…that he had a very high viral titer in his blood and body secretions. [The caregiver] got Zika and hadn't traveled out of Utah and probably got it from having body fluids of the patient onto his skin with open abrasions. But it's not likely to be transmitted by kissing and things like that.” Other conceivable viral reservoirs, such as sequestration in ocular fluids as found with Ebola, remain subject to investigation. The causal mechanism linking ZIKV to microcephaly remains obscure, complicated by the apparent finding of microcephaly clusters only after the virus had migrated out of eastern Africa (although reporting conditions there can obscure estimates of morbidity27Nutt C. Zika originated in Africa. Why are we so sure it's harmless there?.Slate. September 2, 2016; (Available at:) (Accessed September 4, 2016)http://www.slate.com/articles/health_and_science/medical_examiner/2016/09/zika_started_in_sub_saharan_africa_and_it_may_be_as_harmful_to_that_region.htmlGoogle Scholar). “It's interesting why microcephaly seems to be much more common in South America than elsewhere because this virus has been in eastern Africa for several decades,” Dr. Burns noted. “It's possibly that it's different mosquitoes there and can only be transmitted between primates in eastern Africa, and not from primates to humans via mosquitoes. Then when it spread to Southeast Asia, [we] didn't seem to see these reports of microcephaly from there until it spread to Yap Island and the Federated States of Micronesia, and then later French Polynesia. And I'm not sure why. Is it because the mosquitoes aren't as good transmitters in different species, or because…people react differently? I don't know.” The sensitivity and specificity of the ZIKV tests28Centers for Disease Control and Prevention. Guidance for US laboratories testing for Zika virus infection. Available at: http://www.cdc.gov/zika/laboratories/lab-guidance.html. Accessed September 4, 2016.Google Scholar approved to date are further critical variables. The real-time reverse transcriptase–polymerase chain reaction test for ZIKV ribonucleic acid in serum or urine, Dr. Burns reported, usually performed by the CDC or state health department laboratories within 14 days of the onset of symptoms, is highly sensitive, with rare false positives. If commercial tests were to emerge, however, he would mistrust their reliability and recommends that practitioners continue to use local public health laboratories. Antibody tests, he added, performed when reverse transcriptase–polymerase chain reaction testing results are negative, “are likely to be truly positive and accurate if it's been at least a few weeks since [infection], but if you test it too early, you may have negative antibody tests. Also, those antibody tests cross-react with related viruses like West Nile, chikungunya, and some other encephalitis viruses, so a positive test for antibodies for Zika may actually be a false positive from an infection from one of those other viruses.” A plaque-reduction neutralization test measuring virus-specific antibody titers, Dr. Cantrill added, can help distinguish the cross-reacting antibodies; still, he summarized, “It's not black and white.” The proposed release in Key Haven, FL, of Oxitec transgenic male A aegypti carrying a gene intended to render a subsequent mosquito generation nonviable has received Food and Drug Administration environmental-assessment approval.29Food and Drug Administration. FDA releases final environmental assessment for genetically engineered mosquito. Available at: http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm490246.htm. Accessed September 4, 2016.Google Scholar The trial awaits a local referendum in November, with opponents of genetically modified organisms arguing that it risks tampering excessively with ecosystemic balance, against proponents pointing out that A aegypti, as one invasive species among hundreds of other nonvector species, has no value to the predation chain that would outweigh the benefits to human health. “That is very intriguing and might be very effective, much more effective than spraying,” Dr. Cantrill commented. “They have demonstrated previously, using this technology, [that they can] decrease the mosquito population by 90%…. There's always unintended consequences, but this is something that is not completely new.” The stream of Zika-related news indicates that no overview at this stage of the outbreak can be more than a snapshot; comprehensive views will require historical perspective. Any single day is likely to include reassuring reports and disturbing ones, eg, the news that no laboratory-confirmed cases have been associated to date with the Rio de Janeiro Olympics30World Health Organization. Zika situation report. August 25, 2016. Available at: http://www.who.int/emergencies/zika-virus/situation-report/25-august-2016/en/. Accessed August 29, 2016.Google Scholar counterbalanced by a case of sexual transmission in a site without endemic arthropod vectors from a man who had traveled to an affected region but was asymptomatic.31Brooks RB, Carlos MP, Myers RA, et al. Likely sexual transmission of Zika virus from a man with no symptoms of infection—Maryland, 2016. Morb Mortal Wkly Rep. http://dx.doi.org/10.15585/mmwr.mm6534e2.Google Scholar Too many instances like the latter, and ZIKV's basic reproduction number just might surprise experts and pass the threshold of containability. The front lines of this outbreak, like outbreaks past and undoubtedly those to come, range from distant sites where emerging pathogens lurk—doing literally untold damage to populations who are both medically underserved and largely invisible to the media—all the way to the developed world's offices and EDs, where physicians wield uncertain, ever-shifting information as a tool that just might tip the balance in the right direction.