Epidemiology of Zika Virus Infection

Abstract

Long known to be endemic in Africa and Southeast Asia and a rare cause of acute febrile illness, Zika virus (ZIKAV) arose from obscurity when an Asian genotype ZIKAV caused an outbreak of mild febrile illness in 2007 in Yap State, Federated States of Micronesia. Subsequent viral spread in the Pacific led to a large outbreak in French Polynesia commencing in 2013. After its recognition in the Americas through March 2017, the Pan American Health Organization has received reports of >750000 suspected and laboratory-confirmed cases of autochthonous ZIKAV transmission. Outbreaks in most countries in the Americas peaked in early to mid-2016. Increased surveillance in several Southeast Asian counties has led to increased case recognition, including an outbreak in Singapore, and the first reports of birth defects linked to ZIKAV in the region. As of April 2017, the World Health Organization reported 84 countries or territories with current or previous ZIKAV transmission.

Zika virus (ZIKAV) is a flavivirus transmitted to humans primarily by Aedes (Stegomyia subgenus) mosquitoes. Other documented modes of transmission include sexual, intrauterine, perinatal, laboratory exposure, and probably blood transfusion [1–6]. Most ZIKAV infections are asymptomatic [7]. When clinical illness occurs, it is generally mild with characteristic clinical symptoms of maculopapular rash, fever, arthralgia, and/or nonpurulent conjunctivitis. However, ZIKAV infection during pregnancy can cause adverse outcomes, such as fetal loss, congenital microcephaly, or other serious brain anomalies [1]. Guillain-Barré syndrome (GBS), and rare cases of encephalopathy, meningoencephalitis, myelitis, uveitis, paresthesia, and severe thrombocytopenia have also been reported after ZIKAV infection [8–14].

ZIKAV was first isolated in 1947 in the Zika Forest of Uganda from a sentinel rhesus monkey that was part of a yellow fever research study [15]. Before 2007, only sporadic human disease cases were reported from countries in Africa and southeast Asia [4, 16–18]. In 2007, the first documented ZIKAV disease outbreak was reported in Yap State, Federated States of Micronesia [7]. In 2013, an outbreak began in French Polynesia, and the virus subsequently spread to other Pacific islands [18]. In May 2015, ZIKAV transmission was reported in Brazil and was subsequently detected through much of the Americas. Cumulatively, as of March 2017, a total of 84 countries or territories globally had reported autochthonous mosquito-borne ZIKAV transmission, including 61 countries or territories with new introduction of ZIKAV since January 2015 (Figure 1) [19].

ZIKAV IN THE AMERICAS

In May 2015, Brazil reported confirmed autochthonous mosquito-borne ZIKAV transmission [20]. Confirmation of ZIKAV presence followed testing of samples collected earlier in 2015 from patients with febrile rash illnesses in northeastern Brazil, although retrospective phylogenetic and molecular clock analyses have suggested that introduction of the virus into Brazil may have occurred as early as 2013 [21–23]. In October 2015, Colombia reported confirmation of local mosquito-borne ZIKAV transmission, and transmission was subsequently reported from much of South America, Central America, the Caribbean, and parts of North America [24]. Retrospectively, circulation of ZIKAV in Haiti as early as December 2014 was demonstrated [25]. As of April 2017, autochthonous mosquito-borne ZIKAV transmission has been confirmed in 49 countries or territories in the Americas [19, 26]. The only countries that have not reported mosquito-borne transmission are Bermuda, Canada, and Uruguay; continental Chile also has not reported mosquito-borne ZIKAV disease cases, but transmission was reported on Easter Island, a territory of Chile, in 2014 [27].

From January 2015 through March 2017, a total of 754460 suspected and laboratory-confirmed autochthonous cases of ZIKAV disease had been reported to the Pan American Health Organization from countries and territories in the Americas [28], 27% of which were laboratory confirmed. The largest number of suspected and confirmed cases were reported from Brazil (346475 cases; 46%) followed by Colombia (107206; 14%), and Venezuela (62200; 8%) (Table 1). Overall by region, South America accounted for 70% of reported cases, the Caribbean 21%, Central America 9%, and North America 1%. Incidence rates were highest in the Caribbean countries and territories, with Saint Barthelemy reporting the highest rate, 10510 cases per 100000 population (Table 2). Although the strength of surveillance systems and the timing of introduction of ZIKAV into countries probably affected these national figures, making comparisons difficult, large and explosive outbreaks clearly occurred in many countries and territories, probably due to introduction of the virus into immunologically naive populations and widespread presence of vectors. During this period, 20 deaths among patients with ZIKAV disease (excluding those with GBS or congenital ZIKAV infection) were reported in the Americas, for a case fatality rate of <0.003%.

Reported ZIKAV disease case numbers in the Americas peaked in February 2016 (Figure 2). However, disease incidence peaked at variable times in different countries and subregions. In the South America region, incidence peaked in February 2016 and subsequently declined [24, 26]. In the Central America region, incidence peaked in January 2016 and initially declined, although a secondary smaller peak occurred in mid-2016. Incidence in the Caribbean region gradually increased during 2016, peaking in mid-2016, later than in the South and Central American regions. In the North America region, incidence rates have remained low; most cases in this region are reported from Mexico, which reports only laboratory-confirmed cases. Although the reported incidence was low in all regions in early 2017, there have been occasional increases in reporting from some countries. The large outbreaks observed in 2016 are unlikely to be seen in 2017 because herd immunity will probably reduce transmission in many areas, but localized outbreaks are likely to continue as the virus is introduced into new areas and susceptible populations are exposed. Based on transmission patterns for other Aedes mosquito-borne diseases, such as dengue and chikungunya virus disease, ZIKAV transmission will be interrupted in some areas, particularly in small island nations, but the disease is likely to become endemic in some countries of the Americas [29].

In late 2015, the Brazilian Ministry of Health reported an unusual increase in congenital microcephaly cases suspected to be associated with ZIKAV infection during pregnancy. In addition, concerns regarding a possible association between ZIKAV infection and GBS had been raised by investigators in Brazil and French Polynesia [30–32]. This ultimately led to the declaration by the World Health Organization of a Public Health Emergency of International Concern in February 2016 [33]. As of March 2017, 24 countries and territories in the Americas had reported 2767 confirmed cases of microcephaly or central nervous system malformations associated with ZIKAV infection during pregnancy. Twenty-two countries and territories had reported ≥1 ZIKAV-associated GBS case, including 15 that reported an increase in GBS incidence compared with baseline rates [26].

ZIKAV IN STATES AND TERRITORIES OF THE UNITED STATES

ZIKAV Disease in Travelers From US States

From 2007–2014, 14 ZIKAV disease cases were identified among US travelers, based on testing performed at the Centers for Disease Control and Prevention (CDC) [34]. These cases included 12 with travel to Pacific Island countries or territories and 2 with travel to Africa [34, 35]. ZIKAV disease was formally added to the United States nationally notifiable condition list in February 2016 [36]. Cases are reported to the CDC by health departments using a standard case definition [37].

Based on preliminary data, US states and the District of Columbia reported 4937 cases of laboratory-confirmed ZIKAV disease among returning overseas travelers from January 2015 to April 2017. Overall, 3181 (64%) reported cases were in female travelers, although the higher percentage of reported cases in female compared with male travelers might reflect care-seeking behavior arising from concerns about ZIKAV infection during pregnancy. The median age among reported case patients was 38 years (range, 11 months to 89 years), with 79% aged 20–59 years. The number of traveler cases peaked in July 2016 (Figure 3). The most frequently reported travel destinations were countries and territories in the Caribbean (2384 cases; 48%), followed by Central America (797; 16%), North America (519; 11%), South America (202; 4%), Pacific Islands (14; <1%), and Asia (11; <1%); the reported location of travel included >1 subregion for 18 persons (<1%) and was unspecified for 992 (20%). Forty-six cases of ZIKAV disease acquired through sexual transmission from returning travelers were also reported.

ZIKAV in the Continental United States

Local transmission of ZIKAV in the continental United States has been identified in 2 states, Florida and Texas. In Florida, 4 ZIKAV disease cases in persons with no recent travel history were identified in residents of 2 counties in July 2016 [38]. Further investigation revealed that 2 of these case patients were employees at workplaces in close geographic proximity in Miami–Dade County, and epidemiologic and laboratory investigations of the worksites and surrounding neighborhood ultimately identified additional persons with evidence of recent ZIKAV infection, with likely exposure from late June onward. As a result, a 2.6-km² (1–square mile) zone of possible active ZIKAV transmission in the Wynwood area in Miami–Dade County, encompassing an approximately 6-block area, was designated in August 2016. This zone remained in place for approximately 7 weeks until it was lifted in September after 45 days with no evidence of active ZIKAV transmission.

Active transmission was also identified in 2 additional small areas of Miami–Dade County. In August, an approximately 4-km² (1.5–square mile) section in the Miami Beach area was designated as having active transmission, and this was expanded to an approximately 12-km² (4.5–square mile) area in September. In October, a 2.6-km² (1–square mile) active transmission area also was designated in the Little River area in Miami–Dade County. An intensive public health response was implemented in all areas with active transmission, including mosquito control by ground-based and aerial adulticide and larvicide applications, and this probably helped control the outbreaks [38].

As of December 2016, no areas of Florida were considered to have ongoing, active mosquito-borne transmission of ZIKAV [39]. Sporadic cases of presumed local mosquito-borne ZIKAV infection were reported during 2016 from 3 additional Florida counties, but detailed investigations did not provide evidence of sustained multiperson local transmission of ZIKAV [39]. A total of 287 locally acquired ZIKAV infections in Florida had been reported by April 2017. Most were identified and reported during 2016, although there have been some reports in 2017 of persons with asymptomatic infections probably acquired during 2016. Among these 287 ZIKAV infections, 217 were reported to the CDC as symptomatic ZIKAV disease cases.

In Texas, the first case of local mosquito-borne ZIKAV disease was reported in Brownsville in November 2016 [40]. Brownsville borders Tamaulipas state, Mexico, where confirmed ZIKAV disease cases had been reported [41]. An additional 5 ZIKAV disease cases were subsequently reported from the Brownsville area [42]. All 6 case patients lived in close geographic proximity.

ZIKAV Disease in US Territories

ZIKAV outbreaks have occurred in 3 US territories, Puerto Rico, the US Virgin Islands, and American Samoa. From January 2015 through April 2017, there were 36432 laboratory-confirmed ZIKAV disease cases acquired through presumed local mosquito-borne transmission in these US territories reported to the CDC, and 143 cases in travelers returning from other affected areas. Among the 36432 locally acquired cases, 22684 (62%) were in female patients. The median age of reported case patients was 32 years (range, <1 month to 100 years), and 76% were aged <50 years.

In December 2015, Puerto Rico became the first US territory to report autochthonous transmission of ZIKAV, after initiation of ZIKAV disease surveillance and subsequent identification of a patient with symptom onset in November [43]. The number of reported cases remained relatively low through April 2016, then increased quickly and peaked in August. Cases then steadily declined with low-level transmission continuing into 2017. Transmission appeared to begin in the heavily populated eastern area of the island and subsequently spread, with cases reported in residents of all 78 municipalities [43, 44]. As of April 2017, a total of 35280 cases of presumed local mosquito-borne transmission had been reported to the CDC.

In April 2016, ZIKAV screening of blood donations was implemented in Puerto Rico. Modeling of screening data suggested a 13% island-wide cumulative incidence of ZIKAV infection from April through mid-August [45]. Serosurveys before and after a 2014 outbreak in Puerto Rico of chikungunya virus disease, another arbovirus transmitted by Aedes aegypti mosquitoes, estimated that about 23% of blood donors in Puerto Rico had acquired chikungunya virus infections [46]. Based on an estimated cumulative incidence of ZIKAV infection of almost 13% by mid-August, 2016, and recognizing that transmission continued thereafter, it is conceivable that about 20%‒25% of the Puerto Rico population was infected with ZIKAV during 2016, similar to the 2014 chikungunya infection rate.

In the US Virgin Islands, the first patient with laboratory-confirmed ZIKAV disease had symptom onset in January 2016. As of April 2017, a total of 1020 cases of presumed local mosquito-borne transmission had been reported to the CDC, with 85% of all cases having symptom onset between July and November 2016. From January to December 2016 in American Samoa, 132 cases acquired through presumed local mosquito-borne transmission were reported to the CDC. The last ZIKAV disease case detected by means of real-time reverse transcription–polymerase chain reaction occurred in a patient with symptom onset in June 2016. Although serologically confirmed cases continued to be reported, serologic cross-reactivity between ZIKAV and other flaviviruses (eg, dengue virus) circulating in American Samoa, and the possible long duration of anti-ZIKAV immunoglobulin M antibody positivity, meant that serological diagnoses were considered too nonspecific to indicate ongoing ZIKAV transmission. Without evidence of any additional reverse-transcription polymerase chain reaction–positive cases, despite enhanced surveillance for and testing of patients with compatible symptoms, the outbreak in American Samoa was considered interrupted in October 2016 [47].

ZIKAV IN AFRICA, ASIA, AND THE PACIFIC

Until 2015, only sporadic ZIKAV disease cases were reported from Africa, likely a result of the nonspecific clinical presentation of disease with symptoms similar to those of other infectious diseases, limited availability of testing, and the potential for misdiagnosis based on flavivirus cross-reactivity in diagnostic tests. Despite this lack of case reporting, it is clear there was ongoing ZIKAV circulation in parts of Africa, suggested by detection of human cases on retrospective testing of patient cohorts, reports of infection in travelers, and detection of virus in mosquito surveys [35, 48–51]. Two African countries reported local ZIKAV transmission for the first time in 2016; Guinea Bissau reported its first case of ZIKAV disease, and 2 cases of infection acquired in Angola were reported, 1 in a resident and 1 in a traveler [52, 53]. Since its emergence in the Americas, ZIKAV also has also been reintroduced to Africa. In October 2015, Cabo Verde reported a ZIKAV disease outbreak [54]. Sequencing of the virus confirmed it was the Asian genotype, the first time this genotype had been detected in Africa. As of May 2016, there had been 7557 suspected ZIKAV disease cases reported from Cabo Verde [55]. Three cases of microcephaly had been reported.

In Asia, occasional cases in residents and travelers and small outbreaks had been reported in the decades after recognition of ZIKAV transmission in the region during the 1950s [17, 56–64]. However improved awareness of and surveillance for ZIKAV disease since the outbreak in the Americas have resulted in increased detection and reporting in the region. Retrospective testing of samples in Bangladesh, Cambodia, and Lao People’s Democratic Republic identified previously unrecognized patients with ZIKAV disease from the last 5‒10 years [53, 64–66]. Thailand substantially enhanced surveillance during 2016 and reported a considerable increase in ZIKAV disease cases, as well as 2 cases of congenital Zika syndrome, the first such cases in the South-East Asia Region [67]. In November 2016, Vietnam became the second country in Southeast Asia to report a case of microcephaly potentially linked with ZIKAV [67]. Singapore had not previously reported ZIKAV disease, but the Ministry of Health reported the first local outbreak there in August 2016, and several small clusters and sporadic cases have been reported into 2017 [68–70].

In the Pacific region, soon after the recognition of the ZIKAV disease in French Polynesia in 2013, outbreaks were reported in New Caledonia and Cook Islands beginning in early 2014, and subsequently in Vanuatu, the Solomon Islands, Samoa, and Fiji in early to mid-2015 [18, 71]. In Papua New Guinea, retrospectively tested samples from patients who had presented with febrile illness during outbreaks of malaria and dengue in 2015 also indicated the presence of ZIKAV there during the same period [72]. Cases have subsequently been reported in several other countries and territories in the Pacific Ocean (Tonga, Kosrae State–Federated States of Micronesia, Marshall Islands, Palau, and as described above, American Samoa) [53].

CONCLUSIONS

For many decades ZIKAV infection was considered a mild disease, but recent years have shown its potential for a variety of severe outcomes and elevated the virus’s importance to that of a global public health priority. The complete global burden of ZIKAV disease is difficult to accurately determine. Because disease is often clinically mild, patients might not seek medical care. Among those who do, the clinical picture might be mistaken for another illness with similar presentation (eg, dengue or chikungunya virus disease), testing might not be available or requested, and diagnosed cases might not be reported. Congenital, neurological, or other adverse outcomes might not be recognized as being ZIKAV associated. Conversely, given the considerable attention currently being given to ZIKAV, reporting might overestimate the true disease incidence as cases due to other causes may be attributed to ZIKAV infection in the absence of laboratory testing.

In November 2016, recognizing that research had confirmed the link between ZIKAV infection and microcephaly, the World Health Organization declared that ZIKAV and associated complications no longer represent a public health emergency of international concern but are rather an enduring public health challenge best managed through long-term coordinated action [73]. Sustained attention to ZIKAV will be needed, because there is still much to understand about its epidemiology and natural history.

Notes

Acknowledgments. The authors wish to acknowledge Jennifer Lehman for her assistance with mapping and provision of data.

Financial support. This work was supported by the CDC.

Disclaimer. The findings and conclusions in this review are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Supplement sponsorship. This work is part of a supplement sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Presented in part: Interim Zika surveillance data have been presented at numerous meetings, including IDSA's IDWeek, New Orleans, 26–30 October 2016.

References