Recent Zika virus (ZIKV) outbreaks in the Pacific and the Americas have highlighted clinically significant congenital neurological abnormalities resulting from ZIKV infection in pregnancy. However, little is known about ZIKV infections in children and adolescents, a group that is potentially vulnerable to ZIKV neurovirulence.
We conducted a systematic review on the clinical presentation and complications of children and adolescents aged 0 to 18 years with a robust diagnosis of ZIKV infection. We searched PubMed, Web of Science, LILACs, and EMBASE until 13 February 2020 and screened reference lists of eligible articles. We assessed the studies’ risk of bias using pre-specified criteria.
Our review collated the evidence from 2543 pediatric ZIKV cases representing 17 countries and territories, identified in 1 cohort study, 9 case series and 22 case reports. The most commonly observed signs and symptoms of ZIKV infection in children and adolescents were mild and included fever, rash, conjunctivitis and arthralgia. The frequency of neurological complications was reported only in the largest case series (identified in 1.0% of cases) and in an additional 14 children identified from hospital-based surveillance studies and case reports. ZIKV-related mortality was primarily accompanied by co-morbidity and was reported in one case series (<0.5% of cases) and three case reports. One death was attributed to complications of Guillain-Barré Syndrome secondary to ZIKV infection.
Conclusions and relevance
Based on the current evidence, the clinical presentation of ZIKV infection in children and adolescents appears to be primarily mild and similar to the presentation in adults, with rare instances of severe complications and/or mortality. However, reliable estimation of the risks of ZIKV complications in these age groups is limited by the scarcity and quality of published data. Additional prospective studies are needed to improve understanding of the relative frequency of the signs, symptoms, and complications associated with pediatric ZIKV infections and to investigate any potential effects of early life ZIKV exposure on neurodevelopment.
Although the number of Zika virus (ZIKV) cases has declined following the 2015–2016 outbreak in the Americas, ZIKV remains a public health concern due to the potentially severe consequences of in utero exposure to the virus. While there is an increasing understanding of the effects of prenatal congenital ZIKV infection, less is known regarding the potential consequences of postnatal non-congenital ZIKV infection in children and adolescents. As this age group may also be vulnerable to the adverse effects of ZIKV on the nervous system, a better understanding of ZIKV infection in this population is needed. This knowledge may help to inform the case definition for ZIKV disease in children and elucidate whether children and adolescents should be included in strategies and measures for prevention of ZIKV infection, which are currently aimed primarily at pregnant women. After a review of the existing literature, the authors found that ZIKV infection in children and adolescents appears to be similar to adults and primarily mild, with little evidence of severe neurological consequences. Further research using prospective methods and neurodevelopmental assessments is warranted.
Citation: Ramond A, Lobkowicz L, Clemente NS, Vaughan A, Turchi MD, Wilder-Smith A, et al. (2020) Postnatal symptomatic Zika virus infections in children and adolescents: A systematic review. PLoS Negl Trop Dis 14(10): e0008612. https://doi.org/10.1371/journal.pntd.0008612
Editor: Remi N. Charrel, Aix-Marseille Universite, FRANCE
Received: August 7, 2019; Accepted: July 17, 2020; Published: October 2, 2020
Copyright: © 2020 Ramond et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This project was funded by the Wellcome Trust & UK DFID (205377/Z/16/Z) Authors funded: AR, EBB, NSC https://wellcome.ac.uk/funding and ZikaPLAN (European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 734584). https://ec.europa.eu/programmes/horizon2020/en Authors funded: LL, NSC, AV, MDT, AWS, EBB The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Following the introduction of the arthropod-borne flavivirus Zika (ZIKV) into Brazil in 2013 , ZIKV spread rapidly across the Americas, facilitated by global air travel , and autochthonous transmission of ZIKV has now been reported in 84 countries and territories worldwide . After the explosive 2015–2016 outbreak in the Americas, a rapid decline in cases was observed from 2017 onwards ; however smaller clusters, often uncovered by travelers [5–8], continue to be detected beyond the Americas, in Asia [9–13] and Africa [14, 15].
Valuable progress has been achieved in recent years in terms of understanding the transmission and clinical presentation of ZIKV infections in adults and congenitally infected neonates. Although around 29–82% of ZIKV infections in the general population have been reported to be asymptomatic , the most frequently reported signs and symptoms include rash, fever, arthralgia, and conjunctivitis [3, 17]. Evidence has shown that ZIKV is also neurotropic, with approximately 5–10% of congenital ZIKV infections leading to neurologic anomalies in neonates [18–24]. A specific constellation of structural abnormalities and functional disabilities is now recognized as Congenital Zika Syndrome (ICD-10 P35.4). The definition includes five unique features (i.e., severe microcephaly, subcortical calcifications, macular scarring and pigmentary retinal mottling, congenital contractures, and early hypertonia), which are used to distinguish congenital ZIKV infection from other congenital infections [25, 26]. Another severe neurological complication which has been linked with ZIKV infection is the severe autoimmune polyneuropathy known as Guillain-Barré Syndrome (GBS) [27, 28].
While the presentation of ZIKV infection in adults is well-defined, there is limited information on the spectrum of clinical manifestations of ZIKV infections in children and adolescents (defined here as 0–18 years). This is an important gap to address as this age group comprises a substantial fraction of all ZIKV infections. Reports on the proportion of children and adolescents among ZIKV cases range from 10% in the U.S. (January—December 2016)  to 24% in Colombia (August 2015—April 2016)  and 31% in the state of Pernambuco in Brazil (November 2015—October 2016) . Reports on the proportion of symptomatic ZIKV infections in children and adolescents range from 41% in Nicaragua  to 70% in French Polynesia . Further, given the importance of brain development in childhood and adolescence, and the neurovirulence of ZIKV, children may be more susceptible to the adverse neurological consequences of ZIKV infection .
To our knowledge, no systematic review to date has examined the existing literature on the clinical presentation of ZIKV infections in children and adolescents. This study aims to give an overview of the spectrum of clinical manifestations of postnatal ZIKV infections in children and adolescents (0–18 years) and to highlight existing knowledge gaps for the scientific community to stimulate further research.
Search strategy and selection criteria
We conducted this systematic review following a pre-defined research protocol registered in the PROSPERO database (CRD42019119260), in accordance with PRISMA guidelines (S1 Table) . To identify studies reporting on postnatal ZIKV infection in children, we performed a comprehensive literature search, with no date or language restrictions, using four databases (PubMed, Web of Science, LILACs, and EMBASE) from 1956 to 13 February 2020. A broad search strategy was used to identify studies reporting on postnatal ZIKV infection in children. The search strategy utilized Medical Subject Headings and keywords, including English, French, Spanish and Portuguese translations, relating to ZIKV and pediatric populations (S1 Methods). No date or language restrictions were applied.
Study selection and data extraction
Eligible studies included cohort, cross-sectional, case series, and case report studies reporting on symptoms of postnatal ZIKV infection in children, aged 0 to 18 years of age, with a robust confirmation of ZIKV infection (i.e., laboratory confirmation by molecular (reverse transcription polymerase chain reaction [RT-PCR]) or serologic test (Immunoglobulin (Ig) M and G enzyme-linked immunosorbent assays [ELISAs], antibody hemagglutination assay, plaque reduction neutralization test [PRNT], or Council of State and Territorial Epidemiologists [CSTE] criteria ). Studies reporting on symptoms of congenital ZIKV infection or with evidence of a co-infection were excluded from the review. Three reviewers (AR, LL, and AV) screened identified studies for eligibility in duplicate; any discrepancies were resolved by a third reviewer (EBB and NSC). References of eligible studies were also screened to identify additional potentially relevant studies. Three reviewers (AR, LL, and AV) performed the data extraction independently and cross-verified the results for accuracy and consistency. Extracted data included information on: study author, study location, year, number of ZIKV cases, population source, ZIKV diagnostic testing, and differential diagnostic testing. Outcomes of interest extracted were the frequency of rash, fever, conjunctivitis (i.e., inclusive of other signs of conjunctival involvement, such as conjunctival hyperemia), arthralgia, myalgia, and headache and other signs and symptoms of ZIKV infection [3, 17]. For case reports, additional information on patient complications and co-morbidities were extracted where available. A world map indicating the location of studies was created using Tableau Desktop 2019.2.2.
Two reviewers independently assessed study quality. The cohort study was assessed using the Oxford Centre for Evidence-based Medicine (OCEBM) Levels of Evidence, March 2009, which range from level 1 (highest) to 5 (lowest level of evidence) . The case series and case reports were evaluated using the study quality criteria proposed by Murad and colleagues (2018) . Overall risk of study bias was based primarily on the assessment of participant exposure (i.e., ZIKV diagnosis) and outcomes (i.e., ZIKV signs, symptoms, and complications).
Our search returned a total of 9440 records, of which 2825 were duplicates and were removed (S1 Fig). After screening 6614 individual records, we removed 6394 by title or abstract. We assessed 220 full text articles for eligibility, of which 188 were not included due to: study design (reviews or commentary articles, n = 32; conference abstracts, n = 12), study outcome (no information on clinical signs, symptoms, or complications, n = 53), study sample (different target population, n = 56), and exposure ascertainment (lack of robust ZIKV confirmation, n = 6). We excluded an additional 30 studies, in which cases had congenital ZIKV infections (n = 23) or known co-existing infections with other pathogens (n = 7). We identified one additional full text article from the reference review of eligible articles. This resulted in 32 final full text articles included in the systematic review (i.e., 1 cohort, 9 case series and 22 case reports).
Cohort and case series studies
Ten studies, including a total of 2503 cases and conducted across 7 countries and territories (Colombia, Guadeloupe, Panama, Puerto Rico, Singapore, Nicaragua and the United States of America, Fig 1), reported on the presence of ZIKV symptoms in a pediatric study population or sub-group (Table 1). Only one investigation characterized the clinical presentation of pediatric ZIKV cases in a prospective cohort study . In eight studies, children and adolescent ZIKV cases were identified using ZIKV surveillance systems [40–47]. In five of these studies, data were obtained from national or county level surveillance systems [40, 41, 43, 45, 48], while passive surveillance and hospital-based surveillance systems were respectively used in the three remaining studies [44, 46, 47]. In the final case series, possible ZIKV cases were identified using physician reports . According to the OCEBM Levels of Evidence, the one cohort study was graded Level 1b. Within the case series, the study quality varied, reflecting differences in population sampling and study design, with one case series rated good , five of the case series rated fair [41, 42, 44, 45, 49], and three studies rated poor [40, 43, 46] (S2 Table).
For studies reporting on travel-associated infections, the country of infection was reported as location of study. Dark red indicates the countries with the greatest representation of case reports. Size of blue circle indicates the number of cohort and case series studies within a given country.
In all but one study, confirmatory testing for ZIKV was performed if cases presented with at least one common sign or symptom of ZIKV infection. In the remaining study, confirmatory testing was performed if cases presented with signs of encephalitis . Confirmation of ZIKV infections was performed exclusively using laboratory assays in all except one study , which made use of a variety of patient records to ascertain ZIKV diagnosis based on CSTE criteria. These records included clinician reporting, laboratory reporting, death certificates, birth certificates and electronic medical records [36, 40]. Four studies, from Guadeloupe, the United States of America, and Colombia reported testing for concomitant infection by other arboviruses (dengue +/- chikungunya) [43, 45, 47, 49], although the testing method used was only reported in three studies [43, 45, 47].
Of the ten studies, nine [39–42, 44, 46, 47, 49] reported on the presence of common signs and symptoms of ZIKV infections , while the remaining study reported only on the presence of neurological disorders . The most frequently reported ZIKV symptoms among confirmed pediatric ZIKV cases were rash (prevalence range: 29–100%), fever (55–99%), conjunctivital involvement (11–64%), arthralgia (14–48%), myalgia (6–57%), and headache (21–50%) (Table 1). Upper respiratory tract symptoms were reported in four studies (21–38% of cases), and gastro-intestinal symptoms were reported in four studies (2–29% of cases).
Neurological signs were not commonly detected in pediatric ZIKV patients. Only three out of seven population-based studies reporting on the presence or absence of neurological complications reported the presence of neurological signs [43, 46, 47]. One case series using retrospective surveillance system data from a children’s hospital in Panama, identified 2 RT-PCR-confirmed ZIKV infections among 12 GBS cases . In a second hospital-based case series of pediatric encephalitis cases in Colombia, six cases had confirmed ZIKV mono-infections . The median duration of encephalitis was five days, and additional reported symptoms included reduced responsiveness to analgesics, dehydration due to intense vomiting, and seizures in two patients. Neither of these two studies provided estimates of the frequency of the neurological complications among the general population of pediatric ZIKV cases [46, 47]. In the third and largest case series, a 2015–2016 Colombian study, 18,576 postnatal pediatric ZIKV cases were reported, of whom 1207 children had a laboratory-confirmed diagnosis of ZIKV infection . Among the 18,576 possible cases of ZIKV, 96 cases with neurological conditions were reported, including 66 cases of polyneuropathy of which 40 cases had GBS, 17 cases of viral encephalitis, eight cases of demyelinating diseases, four cases of inflammatory diseases of the central nervous system, and one case classified as other neurological disorder.
Among the 1207 laboratory-confirmed cases, 1% (12/1207 cases) developed neurological complications, the details of which were not provided. Further, no information was available regarding any evaluation of neurodevelopment in these cases. Additionally, of the 40 ZIKV cases with a reported diagnosis of GBS, confirmatory laboratory testing appeared to be available for only two fatal cases (one case was positive for ZIKV, the other negative).
The same study also provided the only reports of mortality in pediatric ZIKV patients among case series. Study authors reported the death of six patients with confirmed ZIKV infection in their cohort (an estimated 0.5% of confirmed ZIKV cases) . Further investigation into cause of death, which was available for three patients, revealed that, for two patients, death was attributed to acute myeloid leukemia and bacterial meningitis, respectively. For the final patient, death was attributed to complications of GBS, secondary to ZIKV infection.
Three studies investigated the prevalence of ZIKV signs and symptoms by age. The first study, led by Read and colleagues in Puerto Rico in 2016, presented the details of ZIKV-associated signs and symptoms in age groups <1y, 1-4y, 5-9y and 10-18y (S2 Fig) . Objective clinical signs (fever, rash and erythema) were present among cases at a similarly high prevalence across age groups, whereas subjective symptoms such as headache, eye pain, arthralgia, myalgia and bone pain were three to nine times more prevalent in the oldest age group compared to the youngest age groups (10-18y vs. <1y or 1-4y). The prevalence of conjunctivitis as a symptom of ZIKV infection also appeared to increase with age, whereas the prevalence of cough appeared to decrease. Irritability was a symptom primarily prevalent in younger participants, with reported irritability among 56% of participants aged <1y, compared to 17 to 23% among other age groups. However, these age trends were only reported to be statistically significant for headache and irritability (p-value<0.05).
In the second study, a surveillance-based study in 10 states in the United States of America by Lindsey and colleagues, the details of ZIKV-associated signs and symptoms in children were presented in age groups 1-11y and 12-17y and compared to the frequency in adults (S3 Fig) . Patent signs, such as rash and conjunctivitis, were present among cases at a similarly high prevalence between the two age groups, whereas fever, arthralgia and myalgia were more common in older children (12-17y) than younger children (1-11y) (p-value<0.05 for all). Arthralgia, arthritis, edema, and myalgia were less common in children overall compared to adults (p-value<0.05 for all). None of the children in this study were reported to experience neurological complications.
In the third study, a cohort study based in Nicaragua, Burger-Calderon and colleagues also noted that the clinical presentation of Zika virus infection differed across pediatric ages . Among the 556 participants with confirmed ZIKV disease, older cases presented more frequently with arthralgia, myalgia, and headache. Of note, identification of cases based on the WHO and PAHO case definitions alone would have led to missed diagnoses of more than two-thirds of laboratory-confirmed symptomatic ZIKV infections in this cohort. However, the sensitivity of both the WHO and the PAHO case definitions increased with age (11% to 56% and 6% to 37%, respectively).
Twenty-two case reports from across 12 countries and territories described 40 pediatric cases of ZIKV (Fig 1, Table 2). Eleven cases (28%) were aged between 6 months and 5 years, 8 cases (20%) were aged 6 to 10 years, 19 cases (48%) were between 11 and 16 years, and 2 cases (5%) were less than 15 years but with an unspecified age. ZIKV infection was laboratory-confirmed by RT-PCR in 88% of cases (n = 35), and serology in 28% of cases (n = 11). Thirty-five cases (88%) underwent further testing for potential co-infections. Overall, the quality of the case reports varied from good (59% of studies) to poor (27% of studies) based on the Murad, et al., criteria (S3 Table) .
Individual symptoms of ZIKV infection were reported for 38 of the 40 patients. One study reported only on complications of ZIKV infection (i.e., hepatomegaly, thrombocytopenia, anemic shock) , and the remaining study reported only that the infection was asymptomatic . The most common reported symptom was fever, which was present in 92% of reports (33/36 cases) mentioning presence or absence of fever in pediatric ZIKV cases (Table 2). Other common symptoms included rash (84%, 27/32 cases), conjunctivital involvement (54%, 13/24 cases), headache (52%, 12/23 cases), myalgia (42%, 8/19 cases), and arthralgia (24%, 4/17 cases). Upper respiratory tract symptoms were also present in 68% of cases (13/19) and GI symptoms in 83% of cases (10/12). Neurological complications were reported in 18% of cases (6/34) with information on the presence of neurologic signs. These included one case of acute myelitis , one case of encephalitis , one case of peripheral neuropathy , one case of left middle cerebral artery infarct with right hemiparesis , one case of seizures and diffuse neurological manifestations , and one case of Alice in Wonderland Syndrome .
Outcomes of ZIKV infection were available in 31 case reports. The majority of patients (74%, 23 cases) experienced a full recovery following ZIKV infection. As reported earlier, six cases suffered from neurological complications [52–57] and an additional three cases (ages 2, 15, and 16y) were reported to have died [50, 58, 59]. For all three fatal cases, there was evidence or likelihood of underlying co-morbidity (acute leukemia, sickle cell disease, Evans syndrome). Five of the six cases with neurological complications suffered from impaired motor function. Two cases (ages 13 and 15y) regained the ability to walk after two weeks and one month respectively [52, 54], one case was discharged from the hospital with mild gait difficulty , one case (age 10 mo) who had suffered from a stroke recovered partial motor function after 3 months , and the last case (age 2y) who suffered from encephalitis had major motor sequelae in all four limbs after three months . No assessment of potential consequences on neurodevelopment was reported for any of the cases.
This review, which collated the evidence from 2543 pediatric ZIKV cases across 1 cohort study, 9 case series, and 22 case reports, summarizes the existing knowledge on the presentation and complications of symptomatic postnatal ZIKV infection in children and adolescents.
While the rates of symptomatic ZIKV infection in the general population have been studied extensively , there is limited information available regarding the proportion of symptomatic ZIKV infection in pediatric populations. Reliable estimates of the rate of asymptomatic ZIKV in pediatric populations are limited. The majority of investigations studying ZIKV infection in adolescent and pediatric populations use the presentation of ZIKV-like symptoms as a prerequisite for performing diagnostic testing, which precludes inclusion of asymptomatic ZIKV cases. Estimates of the prevalence of symptoms vary significantly between studies, from approximately 7% in Miami-Dade county (USA)  to 41% in Nicaragua  and 71% in French Polynesia . Despite a lack of reliable estimates of the rates of symptomatic ZIKV infection in pediatric populations, findings from this review suggest that when symptomatic, pediatric ZIKV infection is primarily mild, with little evidence of severe complications or adverse outcomes. Unsurprisingly, the signs most commonly reported in pediatric cases, fever and rash, were also most frequently used to identify potential ZIKV cases. Findings from three studies describing symptoms by age suggested similar frequencies of signs, such as fever, rash and conjunctivitis across age groups, but lower frequencies of subjective pain-related symptoms, such as arthralgia and myalgia, in younger age groups, which is likely due to the difficulty of accurately identifying such self-reported symptoms in young children [39, 44, 45]. There was little evidence of severe outcomes among ZIKV patients, with only four studies (one case series  and three case reports [50, 58, 59]) reporting deaths among pediatric ZIKV patients. Further, for the majority of these events, there was evidence of underlying medical conditions (i.e., leukemia, sickle cell disease, and bacterial meningitis). With regards to the single population-based study reporting on ZIKV-associated mortality, the number of deaths reported in this study must be interpreted with caution as it is unclear whether confirmatory diagnosis of ZIKV infection was prioritized in deceased cases, potentially inflating the proportion of ZIKV-associated death. There was also limited evidence available regarding the prevalence and presentation of neurological complications of ZIKV infection, which is unsurprising given the rarity of these events and the small number of cases in population-based studies. Only the largest case series reported the presence of neurological complications, which were present in 1% of pediatric cases with a confirmed ZIKV diagnosis . Cases of ZIKV-associated GBS were also reported in this study; however, details of GBS diagnosis and laboratory confirmation of ZIKV diagnosis were not available for all cases, limiting the reliability of the information.
Evaluating the rates and presentation of neurological complications in children and adolescents is of particular importance given the neurotropism of ZIKV and the vulnerability of young brains in development . The strongest evidence for the neurotropic activity of ZIKV arises from prenatal exposure to the virus, which can lead to Congenital Zika Syndrome, one of the most severe manifestations being microcephaly . Additional manifestations associated with congenital ZIKV infection that have been identified to date include epilepsy, motor abnormalities and bladder dysfunction [60, 61]. While the exact mechanism for the neurotropic activity of ZIKV remains unclear, a suggested mechanism is through the virus’s ability to halt the proliferation of neural progenitor cells and possibly induce cell death [62, 63]. Early postnatal ZIKV infection in rhesus macaques has also been shown to affect neurodevelopment, suggesting that ZIKV infection in infants may have potential long-term consequences . However, no studies to date have assessed the potential consequences of non-congenital ZIKV infection on neurodevelopment in human children.
Based on the findings of the studies reported in this systematic review, the neurological consequences of postnatal exposure appear to be less severe compared to prenatal exposure to ZIKV. Studies showed little evidence of neurological complications in children and adolescents. However, an accurate assessment of the range and frequency of ZIKV-associated complications is limited by the paucity of data in this age group, and particularly in infants. Of note, among the six children with neurological complications, sequelae appeared to be more severe in the two youngest cases (≤2 years) [53, 55]. The two cases, of which one experienced an infarct and the other encephalitis, had not fully recovered from the neurological sequelae after three months [53, 55].
Beyond its effects on the central nervous system, ZIKV may also indirectly affect the peripheral nervous system through induced parainfective or post-infective autoimmune response [65, 66]. Increased numbers of GBS patients in ZIKV-endemic zones suggest that the virus may contribute to the pathogenesis of GBS. Using data on GBS and ZIKV cases from 11 locations between 2007 and 2017, a recent paper derived an estimate of 2 GBS cases per 10,000 ZIKV infections . In conducting this review, we found little published evidence regarding the prevalence of GBS in pediatric ZIKV cases. Only two case series identified possible ZIKV-associated GBS cases in their study populations, but both were limited by the lack of information regarding confirmatory ZIKV diagnostic tests in these cases [43, 46].
There are strengths and limitations to this review. In order to include as many relevant studies as possible, we have used a broad search strategy and included French, Spanish and Portuguese terms given the geographical distribution of ZIKV. For the majority of cases, diagnosis of ZIKV infection was based on RT-PCR, the most reliable method of ZIKV diagnosis in regions with active flavivirus circulation. We have included both observational studies and case reports to provide a full summary of the existing evidence regarding postnatal ZIKV infections, but we note that the overall evidence base is limited as only one investigation was a cohort study with prospective ascertainment of infections. In addition, publication biases (i.e., systematic differences between published and unpublished evidence) remain a concern. First, observational studies without significant findings may be less represented in the appraised literature. Second, although useful for describing more severe and rare complications which would otherwise require large sample sizes to detect, case reports are typically biased towards unusual or severe disease presentations.
It is also important to note that the varying case definitions used to identify possible ZIKV cases in each study may limit the representativeness and exhaustiveness of the signs and symptoms reported in this review. In particular, studies focusing on identifying cases with rash , or fever  may have overreported these symptoms, leading to an overestimation of their prevalence in pediatric populations. Studies using a broader case definition and populations identified using cohort or national or county level surveillance data are likely to be more representative of symptomatic pediatric ZIKV infection. However, growing evidence suggests that standard case definitions, such as the PAHO and WHO definitions, have low sensitivity in pediatric populations and could lead especially to under-representation of the youngest children with ZIKV disease [39, 44, 45]. Furthermore, the signs and symptoms described in these studies may not be exhaustive, as atypical symptomatic ZIKV cases are unlikely to have been identified using routine surveillance systems.
The small sample sizes in the majority of case series, also limits our ability to assess the risk of ZIKV complications (in particular GBS) and mortality in children and adolescents given the low frequency of these outcomes, and incomplete ZIKV testing in studies reporting on these outcomes. Of particular note, despite Brazil being the epicenter of the 2015–2017 ZIKV outbreak , as laboratory confirmation of ZIKV infection was prioritized for pregnant women , no population-based pediatric studies with laboratory confirmation of ZIKV were available from Brazil.
While reliable diagnosis of ZIKV infection is often hampered by the limited availability of laboratory tests and the reliance on presentation of ZIKV-like symptoms, the majority of studies included in this review used RT-PCR. While RT-PCR is the most specific method for identifying acute ZIKV infection, the test has limited sensitivity and may misclassify ZIKV cases as false negatives, especially in patients with symptom onset more than 10 days before testing. Of note, two case reports relied exclusively on single serologic tests for confirmatory diagnosis (IgM and antibody hemagglutination) [54, 70], which have the potential to cross-react with other flaviviruses . However, in both case reports, cases tested negative for dengue virus infection, which increases the confidence in the reliability of ZIKV diagnosis for these cases. Additionally, two case series reported on both laboratory-confirmed and probable ZIKV cases, hence the findings from these studies are less reliable. However, we note that in the study by Lindsey and colleagues (2020), only 11% of cases were probable, with the remaining 78% positive for ZIKV by RT-PCR and 11% by IgM with PRNT confirmation .
An important consideration when seeking to distinguish between non-congenital and congenital ZIKV infection is the age-range of the study population. This distinction is particularly difficult within the first month of life and is complicated by a lack of knowledge regarding viral persistence in congenitally infected neonates [22, 72]. However, there is only one study in this review which may have included children under one month old, as the age distribution of the 25 infants included in the study was not provided .
Due to increased urbanization and ecological shifts associated with climate change, the geographic distribution of key arthropod vectors (i.e., Aedes Aegypti, Aedes Albopictus) is expanding, putting new populations at risk of arbovirus infections [73, 74]. A better understanding of the short and long-term clinical consequences of ZIKV and other neurotropic arboviruses, including Dengue, Chikungunya, West Nile, and Japanese Encephalitis viruses [75–77], is essential to help establish appropriate control and prevention measures. Based on the evidence summarized in this review, we have proposed a list of outstanding questions as priorities for future research on ZIKV infections in children and adolescents:
- What is the full spectrum of clinical presentations associated with pediatric ZIKV infections? What factors (e.g., age, sex, prior flavivirus infection) influence the severity of ZIKV disease?
- What are the risks and spectrum of neurological complications associated with postnatal ZIKV infection in children and adolescents? Are neurological complications of ZIKV infection more severe in younger children? What is the risk of ZIKV-associated GBS in children and adolescents?
- What is the impact of non-congenital ZIKV infections, especially those in the first 1000 days of life, on pediatric neurodevelopment?
In conclusion, the available evidence identified in this review suggests that the presentation of ZIKV infection is primarily mild in children and adolescents, which may limit case ascertainment using standard clinical case definitions for ZIKV disease. Prospective follow-up of pediatric ZIKV cases using data linkage may help elucidate the long-term impacts of postnatal ZIKV infection in children and adolescents.
S1 Methods. Literature search strategy: Search terms for each database used on 13 February 2020.
S2 Fig. Prevalence of ZIKV-related signs and symptoms by age group reported by Read, et al., 2018 4.
- 1. Albuquerque M, Souza WV, Araujo TVB, Braga MC, Miranda Filho DB, Ximenes RAA, et al. The microcephaly epidemic and Zika virus: building knowledge in epidemiology. Cad Saude Publica. 2018;34(10):e00069018. Epub 2018/10/18. pmid:30328996.
- 2. Quam MB, Wilder-Smith A. Estimated global exportations of Zika virus infections via travellers from Brazil from 2014 to 2015. J Travel Med. 2016;23(6). Epub 2016/09/08. pmid:27601533.
- 3. WHO. Zika virus disease, Interim case definition. 2016;WHO/ZIKV/SUR/16.1.
- 4. O'Reilly KM, Lowe R, Edmunds WJ, Mayaud P, Kucharski A, Eggo RM, et al. Projecting the end of the Zika virus epidemic in Latin America: a modelling analysis. BMC Med. 2018;16(1):180. Epub 2018/10/05. pmid:30285863; PubMed Central PMCID: PMC6169075.
- 5. Katanami Y, Kutsuna S, Taniguchi S, Tajima S, Takaya S, Yamamoto K, et al. Detection of Zika virus in a traveller from Vietnam to Japan. J Travel Med. 2017;24(5). Epub 2017/05/13. pmid:28498965.
- 6. Wang G, Zheng W, Zhu S, Wu Z, Lam TT, Tong Y, et al. A cluster of Zika virus infection among travellers returning to China from Samoa: a case tracing study. J Travel Med. 2018;25(1). Epub 2018/05/03. pmid:29718403.
- 7. Wilder-Smith A, Chang CR, Leong WY. Zika in travellers 1947–2017: a systematic review. J Travel Med. 2018;25(1). Epub 2018/07/18. pmid:30016469.
- 8. Angelo KM, Stoney RJ, Brun-Cottan G, Leder K, Grobusch MP, Hochberg N, et al. Zika among international travelers presenting to GeoSentinel sites, 2012–2019: implications for clinical practice. J Travel Med. 2020. Epub 2020/04/25. pmid:32330261.
- 9. Meltzer E, Lustig Y, Schwartz E. Zika Virus in Israeli Travelers: Emergence of Asia as a Major Source of Infection. The American journal of tropical medicine and hygiene. 2019;100(1):178–82. Epub 2018/11/15. pmid:30426920; PubMed Central PMCID: PMC6335930.
- 10. Watts AG, Huber C, Bogoch II, Brady OJ, Kraemer MUG, Khan K. Potential Zika virus spread within and beyond India. J Travel Med. 2018;25(1). Epub 2018/11/27. pmid:30476232.
- 11. World Health Organization. Zika virus infection: India. 2018.
- 12. Biswas A, Kodan P, Gupta N, Soneja M, Baruah K, Sharma KK, et al. Zika outbreak in India in 2018. J Travel Med. 2020. Epub 2020/02/12. pmid:32044958.
- 13. Leshem E, Lustig Y, Brosh-Nissimov T, Paran Y, Schwartz E. Incidence of laboratory-confirmed Zika in Israeli travelers to Thailand: 2016–2019. J Travel Med. 2019;26(7). Epub 2019/08/14. pmid:31407788.
- 14. Musso D, Lanteri MC. Emergence of Zika virus: where does it come from and where is it going to? The Lancet Infectious diseases. 2017;17(3):255. Epub 2017/03/01. pmid:28244380.
- 15. Sassetti M, Ze-Ze L, Franco J, Cunha JD, Gomes A, Tome A, et al. First case of confirmed congenital Zika syndrome in continental Africa. Trans R Soc Trop Med Hyg. 2018;112(10):458–62. Epub 2018/07/28. pmid:30053235.
- 16. Haby M M PM, Elias V, Reveizc L. Prevalence of asymptomatic Zika virus infection: a systematic review. Bullitain World Health Organization. 2018. http://dx.doi.org/10.2471/BLT.17.201541.
- 17. World Health Organization. Zika virus: Factsheet. 2018. https://www.who.int/en/news-room/fact-sheets/detail/zika-virus.
- 18. Brasil P, Pereira JP Jr., Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, et al. Zika Virus Infection in Pregnant Women in Rio de Janeiro. N Engl J Med. 2016;375(24):2321–34. Epub 2016/03/05. pmid:26943629; PubMed Central PMCID: PMC5323261.
- 19. Hoen B, Schaub B, Funk AL, Ardillon V, Boullard M, Cabie A, et al. Pregnancy Outcomes after ZIKV Infection in French Territories in the Americas. N Engl J Med. 2018;378(11):985–94. Epub 2018/03/15. pmid:29539287.
- 20. Nogueira ML, Nery Junior NRR, Estofolete CF, Bernardes Terzian AC, Guimaraes GF, Zini N, et al. Adverse birth outcomes associated with Zika virus exposure during pregnancy in Sao Jose do Rio Preto, Brazil. Clin Microbiol Infect. 2018;24(6):646–52. Epub 2017/11/15. pmid:29133154.
- 21. Noronha L, Zanluca C, Azevedo ML, Luz KG, Santos CN. Zika virus damages the human placental barrier and presents marked fetal neurotropism. Memorias do Instituto Oswaldo Cruz. 2016;111(5):287–93. Epub 2016/05/05. pmid:27143490; PubMed Central PMCID: PMC4878297.
- 22. Pomar L, Vouga M, Lambert V, Pomar C, Hcini N, Jolivet A, et al. Maternal-fetal transmission and adverse perinatal outcomes in pregnant women infected with Zika virus: prospective cohort study in French Guiana. BMJ. 2018;363:k4431. Epub 2018/11/02. pmid:30381296.
- 23. Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, et al. Vital Signs: Update on Zika Virus-Associated Birth Defects and Evaluation of All U.S. Infants with Congenital Zika Virus Exposure—U.S. Zika Pregnancy Registry, 2016. MMWR Morb Mortal Wkly Rep. 2017;66(13):366–73. Epub 2017/04/07. pmid:28384133; PubMed Central PMCID: PMC5657905.
- 24. Shapiro-Mendoza CK, Rice ME, Galang RR, Fulton AC, VanMaldeghem K, Prado MV, et al. Pregnancy Outcomes After Maternal Zika Virus Infection During Pregnancy—U.S. Territories, January 1, 2016-April 25, 2017. MMWR Morb Mortal Wkly Rep. 2017;66(23):615–21. Epub 2017/06/16. pmid:28617773; PubMed Central PMCID: PMC5657842.
- 25. Moore CA, Staples JE, Dobyns WB, Pessoa A, Ventura CV, Fonseca EB, et al. Characterizing the Pattern of Anomalies in Congenital Zika Syndrome for Pediatric Clinicians. JAMA Pediatr. 2017;171(3):288–95. Epub 2016/11/05. pmid:27812690; PubMed Central PMCID: PMC5561417.
- 26. Pomar L, Lambert V, Madec Y, Vouga M, Pomar C, Matheus S, et al. Placental infection by Zika virus in French Guiana. Ultrasound in obstetrics & gynecology: the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2019. Epub 2019/11/28. pmid:31773804.
- 27. Cao-Lormeau VM, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet. 2016;387(10027):1531–9. Epub 2016/03/08. pmid:26948433; PubMed Central PMCID: PMC5444521.
- 28. WHO. Guillain-Barré syndrome—Colombia and Venezuela. 2016.
- 29. Hall V, Walker WL, Lindsey NP, Lehman JA, Kolsin J, Landry K, et al. Update: Noncongenital Zika Virus Disease Cases—50 U.S. States and the District of Columbia, 2016. MMWR Morbidity and mortality weekly report. 2018;67(9):265–9. Epub 2018/03/09. pmid:29518067; PubMed Central PMCID: PMC5844284.
- 30. Pacheco O, Beltran M, Nelson CA, Valencia D, Tolosa N, Farr SL, et al. Zika Virus Disease in Colombia—Preliminary Report. N Engl J Med. 2016. Epub 2016/06/16. pmid:27305043.
- 31. Brito CA, Brito CC, Oliveira AC, Rocha M, Atanasio C, Asfora C, et al. Zika in Pernambuco: rewriting the first outbreak. Revista da Sociedade Brasileira de Medicina Tropical. 2016;49(5):553–8. Epub 2016/11/05. pmid:27812648.
- 32. Gordon A, Gresh L, Ojeda S, Katzelnick LC, Sanchez N, Mercado JC, et al. Prior dengue virus infection and risk of Zika: A pediatric cohort in Nicaragua. PLoS medicine. 2019;16(1):e1002726. Epub 2019/01/23. pmid:30668565; PubMed Central PMCID: PMC6342296.
- 33. Aubry M, Teissier A, Huart M, Merceron S, Vanhomwegen J, Roche C, et al. Zika Virus Seroprevalence, French Polynesia, 2014–2015. Emerg Infect Dis. 2017;23(4):669–72. Epub 2017/01/14. pmid:28084987; PubMed Central PMCID: PMC5367400.
- 34. Lenroot RK, Giedd JN. Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev. 2006;30(6):718–29. Epub 2006/08/05. pmid:16887188.
- 35. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. Epub 2009/07/23. pmid:19622552; PubMed Central PMCID: PMC2714672.
- 36. CSTE. Zika Virus Disease and Zika Virus Infection Without Disease, Including Congenital Infections Case Definitions and Addition to the Nationally Notifiable Diseases List. In: Prevention CfDCa, editor. Atlanta, USA: CSTE; 2016.
- 37. Phillips B et al. Oxford Centre for Evidence-based Medicine—Levels of Evidence (March 2009).http://www.cebm.net/index.aspx?o=1025. 2009.
- 38. Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med. 2018;23(2):60–3. Epub 2018/02/09. pmid:29420178; PubMed Central PMCID: PMC6234235.
- 39. Burger-Calderon R, Carrillo FB, Gresh L, Ojeda S, Sanchez N, Plazaola M, et al. Age-dependent manifestations and case definitions of paediatric Zika: a prospective cohort study. The Lancet Infectious Diseases. 2020;20(3):371–80. pmid:31870907
- 40. Goodman AB, Dziuban EJ, Powell K, Bitsko RH, Langley G, Lindsey N, et al. Characteristics of Children Aged <18 Years with Zika Virus Disease Acquired Postnatally—U.S. States, January 2015-July 2016. MMWR Morbidity and mortality weekly report. 2016;65(39):1082–5. Epub 2016/10/07. pmid:27711041.
- 41. Griffin I, Zhang G, Fernandez D, Cordero C, Logue T, White SL, et al. Epidemiology of Pediatric Zika Virus Infections. Pediatrics. 2017;140(6). Epub 2017/11/03. pmid:29093135.
- 42. Ho ZJM, Hapuarachchi HC, Barkham T, Chow A, Ng LC, Lee JMV, et al. Outbreak of Zika virus infection in Singapore: an epidemiological, entomological, virological, and clinical analysis. The Lancet Infectious Diseases2017.
- 43. Tolosa N, Tinker SC, Pacheco O, Valencia D, Botero DS, Tong VT, et al. Zika Virus Disease in Children in Colombia, August 2015 to May 2016. Paediatric and perinatal epidemiology. 2017;31(6):537–45. WOS:000415371900008. pmid:28806479
- 44. Read JS, Torres-Velasquez B, Lorenzi O, Rivera Sanchez A, Torres-Torres S, Rivera LV, et al. Symptomatic Zika Virus Infection in Infants, Children, and Adolescents Living in Puerto Rico. JAMA Pediatr. 2018;172(7):686–93. Epub 2018/05/31. pmid:29813148; PubMed Central PMCID: PMC6137503.
- 45. Lindsey NP, Porse CC, Potts E, Hyun J, Sandhu K, Schiffman E, et al. Postnatally Acquired Zika Virus Disease Among Children, United States, 2016–2017. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2020;70(2):227–31. pmid:30855072.
- 46. Cano M, Esquivel R. Infección por virus Zika en el Hospital del Niño "Dr José Renán Esquivel" (Panamá): Revisión de casos de desde su introducción en Latinoamérica. Pediátr Panamá. 2018;47(3):15–9.
- 47. Salgado DM, Vega R, Rodríguez JA, Niño Á, Rodríguez R, Ortiz Á, et al. Clinical, laboratory and immune aspects of Zika virus-associated encephalitis in children. International Journal of Infectious Diseases. 2020;90:104–10. pmid:31678190
- 48. Darbellay J, Cox B, Lai K, Delgado-Ortega M, Wheler C, Wilson D, et al. Zika Virus Causes Persistent Infection in Porcine Conceptuses and may Impair Health in Offspring. EBioMedicine. 2017;25:73–86. Epub 2017/11/04. pmid:29097124; PubMed Central PMCID: PMC5704061.
- 49. Cordel N, Birembaux X, Chaumont H, Delion F, Chosidow O, Tressieres B, et al. Main Characteristics of Zika Virus Exanthema in Guadeloupe. JAMA dermatology. 2017;153(4):326–8. Epub 2017/02/28. pmid:28241170.
- 50. Sarmiento-Ospina A, Vasquez-Serna H, Jimenez-Canizales CE, Villamil-Gomez WE, Rodriguez-Morales AJ. Zika virus associated deaths in Colombia. The Lancet Infectious diseases. 2016;16(5):523–4. Epub 2016/04/14. pmid:27068488.
- 51. Lednicky J, De Rochars VMB, El Badry M, Loeb J, Telisma T, Chavannes S, et al. Zika Virus Outbreak in Haiti in 2014: Molecular and Clinical Data. Plos Neglected Tropical Diseases. 2016;10(4). WOS:000375376700089. pmid:27111294
- 52. Mecharles S, Herrmann C, Poullain P, Tran TH, Deschamps N, Mathon G, et al. Acute myelitis due to Zika virus infection. Lancet. 2016;387(10026):1481. Epub 2016/03/08. pmid:26946926.
- 53. Brito Ferreira ML, Antunes de Brito CA, Moreira AJP, de Morais Machado MI, Henriques-Souza A, Cordeiro MT, et al. Guillain-Barre Syndrome, Acute Disseminated Encephalomyelitis and Encephalitis Associated with Zika Virus Infection in Brazil: Detection of Viral RNA and Isolation of Virus during Late Infection. The American journal of tropical medicine and hygiene. 2017;97(5):1405–9. Epub 2017/11/16. pmid:29140242; PubMed Central PMCID: PMC5817749.
- 54. Cleto TL, de Araujo LF, Capuano KG, Rego Ramos A, Prata-Barbosa A. Peripheral Neuropathy Associated With Zika Virus Infection. Pediatr Neurol. 2016;65:e1–e2. Epub 2016/10/13. pmid:27729183.
- 55. Landais A, Césaire A, Fernandez M, Breurec S, Herrmann C, Delion F, et al. ZIKA vasculitis: A new cause of stroke in children? 2017.
- 56. Marinho PES, Alvarenga PPM, Lima MT, de Souza Andrade A, Candiani TMS, Crispim APC, et al. Central and peripheral nervous system involvement in Zika virus infection in a child. J Neurovirol. 2019;25(6):893–6. Epub 2019/06/22. pmid:31222674.
- 57. Paniz-Mondolfi AE, Giraldo J, Rodriguez-Morales AJ, Pacheco O, Lombo-Lucero GY, Plaza JD, et al. Alice in Wonderland syndrome: a novel neurological presentation of Zika virus infection. J Neurovirol. 2018;24(5):660–3. Epub 2018/08/15. pmid:30105501.
- 58. Arzuza-Ortega L, Polo A, Perez-Tatis G, Lopez-Garcia H, Parra E, Pardo-Herrera LC, et al. Fatal Sickle Cell Disease and Zika Virus Infection in Girl from Colombia. Emerg Infect Dis. 2016;22(5):925–7. Epub 2016/04/19. pmid:27089120; PubMed Central PMCID: PMC4861530.
- 59. Azevedo RSS, Araujo MT, Martins Filho AJ, Oliveira CS, Nunes BTD, Cruz ACR, et al. Zika virus epidemic in Brazil. I. Fatal disease in adults: Clinical and laboratorial aspects. Journal of Clinical Virology. 2016;85:56–64. pmid:27835759
- 60. Pessoa A, van der Linden V, Yeargin-Allsopp M, Carvalho M, Ribeiro EM, Van Naarden Braun K, et al. Motor Abnormalities and Epilepsy in Infants and Children With Evidence of Congenital Zika Virus Infection. Pediatrics. 2018;141(Suppl 2):S167–S79. Epub 2018/02/14. pmid:29437050.
- 61. Costa Monteiro LM, Cruz GNO, Fontes JM, Saad Salles TRD, Boechat MCB, Monteiro AC, et al. Neurogenic bladder findings in patients with Congenital Zika Syndrome: A novel condition. PLoS One. 2018;13(3):e0193514. Epub 2018/03/02. pmid:29494684; PubMed Central PMCID: PMC5832242.
- 62. Tang BL. Zika virus as a causative agent for primary microencephaly: the evidence so far. Arch Microbiol. 2016;198(7):595–601. Epub 2016/07/15. pmid:27412681.
- 63. Koppolu V, Shantha Raju T. Zika virus outbreak: a review of neurological complications, diagnosis, and treatment options. J Neurovirol. 2018;24(3):255–72. Epub 2018/02/15. pmid:29441490.
- 64. Mavigner M, Raper J, Kovacs-Balint Z, Gumber S, O'Neal JT, Bhaumik SK, et al. Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques. Sci Transl Med. 2018;10(435). Epub 2018/04/06. pmid:29618564; PubMed Central PMCID: PMC6186170.
- 65. Mehta R, Soares CN, Medialdea-Carrera R, Ellul M, da Silva MTT, Rosala-Hallas A, et al. The spectrum of neurological disease associated with Zika and chikungunya viruses in adults in Rio de Janeiro, Brazil: A case series. PLoS neglected tropical diseases. 2018;12(2):e0006212. Epub 2018/02/13. pmid:29432457; PubMed Central PMCID: PMC5837186.
- 66. Wilder-Smith A, Gubler DJ, Weaver SC, Monath TP, Heymann DL, Scott TW. Epidemic arboviral diseases: priorities for research and public health. Lancet Infect Dis. 2017;17(3):e101–e6. Epub 2016/12/25. pmid:28011234.
- 67. Mier YT-RL, Delorey MJ, Sejvar JJ, Johansson MA. Guillain-Barre syndrome risk among individuals infected with Zika virus: a multi-country assessment. BMC Med. 2018;16(1):67. Epub 2018/05/16. pmid:29759069; PubMed Central PMCID: PMC5952697.
- 68. Lowe R, Barcellos C, Brasil P, Cruz OG, Honorio NA, Kuper H, et al. The Zika Virus Epidemic in Brazil: From Discovery to Future Implications. Int J Environ Res Public Health. 2018;15(1). Epub 2018/01/10. pmid:29315224; PubMed Central PMCID: PMC5800195.
- 69. Procedimentos a serem adotados para a vigilância da Febre do vírus Zika no Brasil. In: Saúde Md, editor. Brasilia: Secretaria de Vigilância em Saúde; 2016.
- 70. J. G. OLSONI TGK, SUHANDIMAN* AND TRIWIBOWO* Zika virus, a cause of fever in Central Java, Indonesia TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE,; 1981
- 71. Zimmerman MG, Quicke KM, O'Neal JT, Arora N, Machiah D, Priyamvada L, et al. Cross-Reactive Dengue Virus Antibodies Augment Zika Virus Infection of Human Placental Macrophages. Cell Host Microbe. 2018;24(5):731–42 e6. Epub 2018/11/16. pmid:30439342.
- 72. Besnard M, Dub T, Gerardin P. Outcomes for 2 Children after Peripartum Acquisition of Zika Virus Infection, French Polynesia, 2013–2014. Emerg Infect Dis. 2017;23(8):1421–3. Epub 2017/05/18. pmid:28514228; PubMed Central PMCID: PMC5547815.
- 73. Kraemer MUG, Reiner RC Jr., Brady OJ, Messina JP, Gilbert M, Pigott DM, et al. Past and future spread of the arbovirus vectors Aedes aegypti and Aedes albopictus. Nat Microbiol. 2019. Epub 2019/03/06. pmid:30833735.
- 74. Liu-Helmersson J, Quam M, Wilder-Smith A, Stenlund H, Ebi K, Massad E, et al. Climate Change and Aedes Vectors: 21st Century Projections for Dengue Transmission in Europe. EBioMedicine. 2016;7:267–77. Epub 2016/06/21. pmid:27322480; PubMed Central PMCID: PMC4909611.
- 75. Mehta R, Gerardin P, de Brito CAA, Soares CN, Ferreira MLB, Solomon T. The neurological complications of chikungunya virus: A systematic review. Rev Med Virol. 2018;28(3):e1978. Epub 2018/04/20. pmid:29671914; PubMed Central PMCID: PMC5969245.
- 76. Carod-Artal FJ, Wichmann O, Farrar J, Gascon J. Neurological complications of dengue virus infection. Lancet Neurol. 2013;12(9):906–19. Epub 2013/08/21. pmid:23948177.
- 77. Solomon T, Mallewa M. Dengue and other emerging flaviviruses. The Journal of infection. 2001;42(2):104–15. Epub 2001/09/05. pmid:11531316.
- 78. Peralta-Aros C, García-Nieto V. Does Zika virus infection induce prolonged remissions in children with idiopathic nephrotic syndrome? Pediatr Nephrol. 2017;32(5):897–900. pmid:28175986
- 79. Heang V, Yasuda CY, Sovann L, Haddow AD, da Rosa APT, Tesh RB, et al. Zika virus infection, Cambodia, 2010. Emerging Infectious Diseases. 2012;18(2):349–51. pmid:22305269
- 80. Wu D, Sun J, Zhong H, Guan D, Zhang H, Tan Q, et al. A family cluster of imported ZIKV cases: Viremia period may be longer than previously reported. The Journal of infection. 2016;73(3):300–3. Epub 2016/07/05. pmid:27373766.
- 81. Yin Y, Xu Y, Su L, Zhu X, Chen M, Zhu W, et al. Epidemiologic investigation of a family cluster of imported ZIKV cases in Guangdong, China: probable human-to-human transmission. Emerging microbes & infections. 2016;5(9):e100. Epub 2016/09/08. pmid:27599469; PubMed Central PMCID: PMC5113051.
- 82. Duijster JW, Goorhuis A, van Genderen PJ, Visser LG, Koopmans MP, Reimerink JH, et al. Zika virus infection in 18 travellers returning from Surinam and the Dominican Republic, The Netherlands, November 2015-March 2016. Infection. 2016;44(6):797–802. Epub 2016/05/23. pmid:27209175; PubMed Central PMCID: PMC5121170.
- 83. Slavov S, Matsuno A, Yamamoto A, Otaguiri K, Cervi M, Covas D, et al. Zika virus infection in a pediatric patient with acute gastrointestinal involvement. Pediatric Reports. 2017;9(4):7341. pmid:29383222
- 84. Florescu SA, Cotar AI, Popescu CP, Ceianu CS, Zaharia M, Vancea G, et al. First Two Imported Cases of Zika Virus Infections in Romania. Vector borne and zoonotic diseases (Larchmont, NY). 2017;17(5):354–7. Epub 2017/04/25. pmid:28437183.
- 85. Olson JG, Ksiazek TG, Suhandiman, Triwibowo. Zika virus, a cause of fever in Central Java, Indonesia. Trans R Soc Trop Med Hyg. 1981;75(3):389–93. Epub 1981/01/01. pmid:6275577.
- 86. Alejo-Cancho I, Torner N, Oliveira I, Martínez A, Muñoz J, Jane M, et al. Twenty-four cases of imported zika virus infections diagnosed by molecular methods. Diagn Microbiol Infect Dis. 2016;86(2):160–2. pmid:27492132
- 87. Alera MT, Hermann L, Tac-An IA, Klungthong C, Rutvisuttinunt W, Manasatienkij W, et al. Zika virus infection, Philippines, 2012. Emerg Infect Dis. 2015;21(4):722–4. Epub 2015/03/27. pmid:25811410; PubMed Central PMCID: PMC4378478.
- 88. Boyer Chammard T, Schepers K, Breurec S, Messiaen T, Destrem AL, Mahevas M, et al. Severe Thrombocytopenia after Zika Virus Infection, Guadeloupe, 2016. Emerg Infect Dis. 2017;23(4):696–8. Epub 2016/12/21. pmid:27997330; PubMed Central PMCID: PMC5367410.