Zika virus and microcephaly: why is this situation a PHEIC?

In April 2007, an outbreak of illness characterized by rash, arthralgia, and conjunctivitis was reported on Yap Island in the Federated States of Micronesia. Serum samples from patients in the acute phase of illness contained RNA of Zika virus (ZIKV), a flavivirus in the same family as yellow fever, dengue, West Nile, and Japanese encephalitis viruses. These findings show that ZIKV has spread outside its usual geographic range ( 1 , 2 ). Sixty years earlier, on April 18, 1947, fever developed in a rhesus monkey that had been placed in a cage on a tree platform in the Zika Forest of Uganda ( 3 ). The monkey, Rhesus 766, was a sentinel animal in the Rockefeller Foundation’s program for research on jungle yellow fever. Two days later, Rhesus 766, still febrile, was brought to the Foundation’s laboratory at Entebbe and its serum was inoculated into mice. After 10 days all mice that were inoculated intracerebrally were sick, and a filterable transmissible agent, later named Zika virus, was isolated from the mouse brains. In early 1948, ZIKV was also isolated from Aedes africanus mosquitoes trapped in the same forest ( 4 ). Serologic studies indicated that humans could also be infected ( 5 ). Transmission of ZIKV by artificially fed Ae. aegypti mosquitoes to mice and a monkey in a laboratory was reported in 1956 ( 6 ). ZIKV was isolated from humans in Nigeria during studies conducted in 1968 and during 1971–1975; in 1 study, 40% of the persons tested had neutralizing antibody to ZIKV ( 7 – 9 ). Human isolates were obtained from febrile children 10 months, 2 years (2 cases), and 3 years of age, all without other clinical details described, and from a 10 year-old boy with fever, headache, and body pains ( 7 , 8 ). From 1951 through 1981, serologic evidence of human ZIKV infection was reported from other African countries such as Uganda, Tanzania, Egypt, Central African Republic, Sierra Leone ( 10 ), and Gabon, and in parts of Asia including India, Malaysia, the Philippines, Thailand, Vietnam, and Indonesia ( 10 – 14 ). In additional investigations, the virus was isolated from Ae. aegypti mosquitoes in Malaysia, a human in Senegal, and mosquitoes in Côte d’Ivoire ( 15 – 17 ). In 1981 Olson et al. reported 7 people with serologic evidence of ZIKV illness in Indonesia ( 11 ). A subsequent serologic study indicated that 9/71 (13%) human volunteers in Lombok, Indonesia, had neutralizing antibody to ZIKV ( 18 ). The outbreak on Yap Island in 2007 shows that ZIKV illness has been detected outside of Africa and Asia (Figure 1). Figure 1 Approximate known distribution of Zika virus, 1947–2007. Red circle represents Yap Island. Yellow indicates human serologic evidence; red indicates virus isolated from humans; green represents mosquito isolates. Dynamics of Transmission ZIKV has been isolated from Ae. africanus, Ae. apicoargenteus, Ae. luteocephalus, Ae. aegypti, Ae vitattus, and Ae. furcifer mosquitoes ( 9 , 15 , 17 , 19 ). Ae. hensilii was the predominant mosquito species present on Yap during the ZIKV disease outbreak in 2007, but investigators were unable to detect ZIKV in any mosquitoes on the island during the outbreak ( 2 ). Dick noted that Ae. africanus mosquitoes, which were abundant and infected with ZIKV in the Zika Forest, were not likely to enter monkey cages such as the one containing Rhesus 766 ( 5 ) raising the doubt that the monkey might have acquired ZIKV from some other mosquito species or through some other mechanism. During the studies of yellow fever in the Zika Forest, investigators had to begin tethering monkeys in trees because caged monkeys did not acquire yellow fever virus when the virus was present in mosquitoes ( 5 ). Thus, despite finding ZIKV in Ae. Africanus mosquitoes, Dick was not sure whether or not these mosquitoes were actually the vector for enzootic ZIKV transmission to monkeys. Boorman and Porterfield subsequently demonstrated transmission of ZIKV to mice and monkeys by Ae. aegypti in a laboratory ( 6 ). Virus content in the mosquitoes was high on the day of artificial feeding, dropped to undetectable levels through day 10 after feeding, had increased by day 15, and remained high from days 20 through 60 ( 6 ). Their study suggests that the extrinsic incubation period for ZIKV in mosquitoes is ≈10 days. The authors cautioned that their results did not conclusively demonstrate that Ae. aegypti mosquitoes could transmit ZIKV at lower levels of viremia than what might occur among host animals in natural settings. Nevertheless, their results, along with the viral isolations from wild mosquitoes and monkeys and the phylogenetic proximity of ZIKV to other mosquito-borne flaviviruses, make it reasonable to conclude that ZIKV is transmitted through mosquito bites. There is to date no solid evidence of nonprimate reservoirs of ZIKV, but 1 study did find antibody to ZIKV in rodents ( 20 ). Further laboratory, field, and epidemiologic studies would be useful to better define vector competence for ZIKV, to determine if there are any other arthropod vectors or reservoir hosts, and to evaluate the possibility of congenital infection or transmission through blood transfusion. Virology and Pathogenesis ZIKV is an RNA virus containing 10,794 nucleotides encoding 3,419 amino acids. It is closely related to Spondweni virus; the 2 viruses are the only members of their clade within the mosquito-borne cluster of flaviviruses (Figure 2) ( 1 , 21 , 22 ). The next nearest relatives include Ilheus, Rocio, and St. Louis encephalitis viruses; yellow fever virus is the prototype of the family, which also includes dengue, Japanese encephalitis, and West Nile viruses ( 1 , 21 ). Studies in the Zika Forest suggested that ZIKV infection blunted the viremia caused by yellow fever virus in monkeys but did not block transmission of yellow fever virus ( 19 , 23 ). Figure 2 Phylogenetic relationship of Zika virus to other flaviviruses based on nucleic acid sequence of nonstructural viral protein 5, with permission from Dr Robert Lanciotti ( 1 ). Enc, encephalitis; ME, meningoencephalitis. Information regarding pathogenesis of ZIKV is scarce but mosquito-borne flaviviruses are thought to replicate initially in dendritic cells near the site of inoculation then spread to lymph nodes and the bloodstream ( 24 ). Although flaviviral replication is thought to occur in cellular cytoplasm, 1 study suggested that ZIKV antigens could be found in infected cell nuclei ( 25 ). To date, infectious ZIKV has been detected in human blood as early as the day of illness onset; viral nucleic acid has been detected as late as 11 days after onset ( 1 , 26 ). The virus was isolated from the serum of a monkey 9 days after experimental inoculation ( 5 ). ZIKV is killed by potassium permanganate, ether, and temperatures >60°C, but it is not effectively neutralized with 10% ethanol ( 5 ). Clinical Manifestations The first well-documented report of human ZIKV disease was in 1964 when Simpson described his own occupationally acquired ZIKV illness at age 28 ( 27 ). It began with mild headache. The next day, a maculopapular rash covered his face, neck, trunk, and upper arms, and spread to his palms and soles. Transient fever, malaise, and back pain developed. By the evening of the second day of illness he was afebrile, the rash was fading, and he felt better. By day three, he felt well and had only the rash, which disappeared over the next 2 days. ZIKV was isolated from serum collected while he was febrile. In 1973, Filipe et al. reported laboratory-acquired ZIKV illness in a man with acute onset of fever, headache, and joint pain but no rash ( 26 ). ZIKV was isolated from serum collected on the first day of symptoms; the man’s illness resolved in ≈1 week. Of the 7 ZIKV case-patients in Indonesia described by Olson et al. all had fever, but they were detected by hospital-based surveillance for febrile illness ( 11 ). Other manifestations included anorexia, diarrhea, constipation, abdominal pain, and dizziness. One patient had conjunctivitis but none had rash. The outbreak on Yap Island was characterized by rash, conjunctivitis, and arthralgia ( 1 , 2 ). Other less frequent manifestations included myalgia, headache, retroorbital pain, edema, and vomiting ( 2 ). Diagnosis Diagnostic tests for ZIKV infection include PCR tests on acute-phase serum samples, which detect viral RNA, and other tests to detect specific antibody against ZIKV in serum. An ELISA has been developed at the Arboviral Diagnostic and Reference Laboratory of the Centers for Disease Control and Prevention (Ft. Collins, CO, USA) to detect immunoglobulin (Ig) M to ZIKV ( 1 ). In the samples from Yap Island, cross-reactive results in sera from convalescent-phase patients occurred more frequently among patients with evidence of previous flavivirus infections than among those with apparent primary ZIKV infections ( 1 , 2 ). Cross-reactivity was more frequently noted with dengue virus than with yellow fever, Japanese encephalitis, Murray Valley encephalitis, or West Nile viruses, but there were too few samples tested to derive robust estimates of the sensitivity and specificity of the ELISA. IgM was detectable as early as 3 days after onset of illness in some persons; 1 person with evidence of previous flavivirus infection had not developed IgM at day 5 but did have it by day 8 ( 1 ). Neutralizing antibody developed as early as 5 days after illness onset. The plaque reduction neutralization assay generally has improved specificity over immunoassays, but may still yield cross-reactive results in secondary flavivirus infections. PCR tests can be conducted on samples obtained less than 10 days after illness onset; 1 patient from Yap Island still had detectable viral RNA on day 11 ( 1 ). In general, diagnostic testing for flavivirus infections should include an acute-phase serum sample collected as early as possible after onset of illness and a second sample collected 2 to 3 weeks after the first. Public Health Implications Because the virus has spread outside Africa and Asia, ZIKV should be considered an emerging pathogen. Fortunately, ZIKV illness to date has been mild and self-limited, but before West Nile virus caused large outbreaks of neuroinvasive disease in Romania and in North America, it was also considered to be a relatively innocuous pathogen ( 28 ). The discovery of ZIKV on the physically isolated community of Yap Island is testimony to the potential for travel or commerce to spread the virus across large distances. A medical volunteer who was on Yap Island during the ZIKV disease outbreak became ill and was likely viremic with ZIKV after her return to the United States ( 2 ). The competence of mosquitoes in the Americas for ZIKV is not known and this question should be addressed. Spread of ZIKV across the Pacific could be difficult to detect because of the cross-reactivity of diagnostic flavivirus antibody assays. ZIKV disease could easily be confused with dengue and might contribute to illness during dengue outbreaks. Recognition of the spread of ZIKV and of the impact of ZIKV on human health will require collaboration between clinicians, public health officials, and high-quality reference laboratories. Given that the epidemiology of ZIKV transmission on Yap Island appeared to be similar to that of dengue, strategies for prevention and control of ZIKV disease should include promoting the use of insect repellent and interventions to reduce the abundance of potential mosquito vectors. Officials responsible for public health surveillance in the Pacific region and the United States should be alert to the potential spread of ZIKV and keep in mind the possible diagnostic confusion between ZIKV illness and dengue.

Zika fever, considered as an emerging disease of arboviral origin, because of its expanding geographic area, is known as a benign infection usually presenting as an influenza-like illness with cutaneous rash. So far, Zika virus infection has never led to hospitalisation. We describe the first case of Guillain-Barré syndrome (GBS) occurring immediately after a Zika virus infection, during the current Zika and type 1 and 3 dengue fever co-epidemics in French Polynesia.

David L. Heymann 
Executive Director, Communicable Diseases, World Health Organization, Geneva, Switzerland The international response to the severe acute respiratory syndrome (SARS) outbreak, from March to July 2003, tested the assumption that a new and emerging infection–one that had not yet demonstrated its full epidemiologic potential but was spreading from person to person and continent to continent–could be prevented from becoming endemic. Within 4 months after the first global alert about the new disease, all known chains of transmission had been interrupted in an outbreak that affected 27 countries on all continents. Most public health experts and scientists believe that the question of whether SARS has become endemic can only be answered after at least 12 months of postoutbreak surveillance. The SARS experience, however, made one lesson clear early in its course: inadequate surveillance and response capacity in a single country can endanger national populations and the public health security of the entire world. As long as national capacities are weak, international mechanisms for outbreak alert and response will be needed as a global safety net that protects other countries when one nation’s surveillance and response systems fail. During the last decade of the 20th century, several outbreaks, including cholera in Latin America, pneumonic plague in India, and Ebola hemorrhagic fever in the Democratic Republic of the Congo, caused great international concern ( 1 – 3 ). These events demonstrated the consequences that delayed national recognition and response to outbreaks could have: illness and death of national populations including health workers, potential spread to other countries, and significant disruptions of travel and trade. These outbreaks also emphasized the need for a global surveillance and response mechanism. The Global Outbreak Alert and Response Network (GOARN), set up in 1997 and formalized in 2000, was one major response to this need (World Health Organization [WHO], unpub. data and 4 ). Though the network, which now has 120 partners throughout the world, currently identifies and responds to more than 50 outbreaks in developing countries each year, the SARS outbreak was the first time that GOARN identified and responded to an outbreak that was rapidly spreading internationally. One of the partners in GOARN is the WHO Global Influenza Surveillance Network, which was established in 1947 to guide the annual composition of vaccines and provide an early alert to variants that might signal the start of a pandemic of rapidly evolving influenza viruses. This network was placed on alert in late November, when the Canadian Global Public Health Intelligence Network (GPHIN), also a partner in GOARN, picked up media reports of an influenza outbreak in mainland China ( 5 ). Simultaneously, another GOARN partner, the U.S. Global Emerging Infections Surveillance and Response System (GEIS), became aware of similar reports about a severe outbreak, with influenza B the suspected cause, in Beijing and Guangzhou. As GOARN continued to receive reports about influenza outbreaks in China, WHO requested information from Chinese authorities on December 5 and 11. On December 12, WHO received a detailed report on data collected at Chinese influenza surveillance sites, indicating that investigation of 23 influenza virus isolates had confirmed type B strains in all but one and that the number of cases was consistent with the seasonal pattern in previous years. The information was reassuring and an indication that the influenza surveillance system was working well. Although information is incomplete, retrospective case identification by Chinese and GOARN epidemiologists since May 2003 suggests that two respiratory disease outbreaks occurred in Guangdong Province in late November 2002: influenza and what now appears to have been a first wave of SARS cases—an atypical pneumonia that was characterized by small, seemingly unrelated clusters of cases scattered over several municipalities in Guangdong, with low-level transmission to healthcare workers ( 6 ). This first wave of atypical pneumonia appears to have continued until a second wave of disease with amplified transmission to health workers began occurring during the first 10 days of February (WHO, unpub. data). On February 10, 2003, the WHO office in Beijing received an email message describing an infectious disease in Guangdong Province said to have caused more than 100 deaths. On February 11, the Guangzhou Bureau of Health reported to the press more than 100 cases of an infectious atypical pneumonia outbreak that had been spreading in the city for more than 1 month. That same day, the Chinese Ministry of Health officially reported to WHO 300 cases and 5 deaths in an outbreak of acute respiratory syndrome, and the next day reported that the outbreak dated back to November 16, 2002, that influenza virus had not yet been isolated, and that the outbreak was coming under control ( 7 ). When the reports of a severe respiratory disease were received by WHO on February 11, 2003, a new strain of influenza virus was the most feared potential cause, and the WHO Global Influenza Network was again alerted. Concern grew on February 20, when the network received reports from Hong Kong authorities confirming the detection of A(H5N1) avian influenza virus in two persons, and WHO activated its influenza pandemic preparedness plans ( 8 ). During that same week, laboratories of the WHO Global Influenza Surveillance Network began analyzing specimens from a patient with severe atypical pneumonia hospitalized in Hanoi after travel to Hong Kong. Concurrently, GOARN response teams in Vietnam and Hong Kong began collecting clinical and epidemiologic information about the patient and a growing number of others with similar symptoms. As more specimens entered the network laboratories, influenza viruses were ruled out as the causative agent. WHO made its first global alert on March 12, followed by a second, on March 15, when more than 150 suspected new cases had been reported from several geographic areas, including Hong Kong, Singapore, Vietnam and Canada ( 9 , 10 ). With the second alert, WHO provided a case definition and name, thus beginning a coordinated global outbreak response that brought heightened vigilance everywhere and intense control efforts. GOARN linked some of the world’s best laboratory scientists, clinicians, and epidemiologists electronically, in virtual networks that provided rapid knowledge about the causative agent, mode of transmission, and other epidemiologic features ( 11 ). This real-time information made it possible for WHO to provide specific guidance to health workers on clinical management and protective measures to prevent further nosocomial spread. It also made possible recommendations to international travelers to curtail international spread. Recommendations were at first nonspecific, urging international travelers to have a high level of suspicion if they had traveled to or from areas where the outbreak was occurring. But as more information became available, airports were asked to screen passengers for history of contact with SARS and for persons with current illness that fit the SARS case definition. Finally, when these recommendations did not completely stop international spread, passengers themselves were asked to avoid travel to areas where contact tracing was unable to link all cases to known chains of transmission ( 12 ). Within 4 months, transmission of SARS had been interrupted at all sites, and on July 5, 2003, the SARS outbreak was declared contained ( 13 ). As many times occurs with emerging and reemerging infectious diseases, national surveillance mechanisms failed to identify and respond to the emerging outbreak of SARS early enough to prevent its toll of sickness, death, and international spread ( 14 ). In May 2003, ministers of health from the 192 member countries of WHO expressed their deep concern about the impact of SARS and its implications for future outbreaks, which were considered inevitable. In two resolutions, they called for increased national capacity development for surveillance and response and endorsed the ways in which GOARN obtained information about SARS and supported containment efforts ( 15 , 16 ). The resolutions stressed the need for countries to give more attention, with WHO support, to the strengthening of national surveillance and response capacity, and encouraged WHO to continue to strengthen GOARN, its safety net for global alert and response. As SARS so amply demonstrated, protection against the threat of emerging and epidemic-prone diseases requires strong defense systems at national as well as international levels.