https://orcid.org/0000-0001-7200-4770
Figures
Abstract
Background
Zika virus (ZIKV) has generated global interest in the last five years mostly due to its resurgence in the Americas between 2015 and 2016. It was previously thought to be a self-limiting infection causing febrile illness in less than one quarter of those infected. However, a rise in birth defects amongst children born to infected pregnant women, as well as increases in neurological manifestations in adults has been demonstrated. We systemically reviewed the literature to understand clinical manifestations and health outcomes in adults globally.
Methods
This review was registered prospectively with PROPSERO (CRD 42018096558). We systematically searched for studies in six databases from inception to the end of September 2020. There were no language restrictions. Critical appraisal was completed using the Joanna Briggs Institute Critical Appraisal Tools.
Findings
We identified 73 studies globally that reported clinical outcomes in ZIKV-infected adults, of which 55 studies were from the Americas. For further analysis, we considered studies that met 70% of critical appraisal criteria and described subjects with confirmed ZIKV. The most common symptoms included: exanthema (5,456/6,129; 89%), arthralgia (3,809/6,093; 63%), fever (3,787/6,124; 62%), conjunctivitis (2,738/3,283; 45%), myalgia (2,498/5,192; 48%), headache (2,165/4,722; 46%), and diarrhea (337/2,622; 13%). 36/14,335 (0.3%) of infected cases developed neurologic sequelae, of which 75% were Guillain-Barré Syndrome (GBS). Several subjects reported recovery from peak of neurological complications, though some endured chronic disability. Mortality was rare (0.1%) and hospitalization (11%) was often associated with co-morbidities or GBS.
Conclusions
The ZIKV literature in adults was predominantly from the Americas. The most common systemic symptoms were exanthema, fever, arthralgia, and conjunctivitis; GBS was the most prevalent neurological complication. Future ZIKV studies are warranted with standardization of testing and case definitions, consistent co-infection testing, reporting of laboratory abnormalities, separation of adult and pediatric outcomes, and assessing for causation between ZIKV and neurological sequelae.
Author summary
Interest in Zika virus (ZIKV) has increased in the last decade due to its emergence and rapid spread in the Americas. In this review, we examine ZIKV clinical manifestations and sequelae in adults. Among studies reporting subjects with confirmed ZIKV and critical appraisal scores of at least 70%, symptoms reported include exanthema, fever, arthralgia, conjunctivitis, myalgia, headache, and diarrhea. Neurological sequelae in this group occurred in 0.3% of subjects, of which 75% were Guillain-Barré Syndrome (GBS). Recovery from GBS was variable: some patients returned to health and others endured chronic disability. Mortality was rare (0.1%). Hospitalization (11%) was often associated co-morbidities or GBS; this percentage perhaps reflects studies in which all reported subjects were hospitalized. Synthesizing reported data is challenging given the wide range of case definitions and ZIKV testing practices.
Citation: Halani S, Tombindo PE, O’Reilly R, Miranda RN, Erdman LK, Whitehead C, et al. (2021) Clinical manifestations and health outcomes associated with Zika virus infections in adults: A systematic review. PLoS Negl Trop Dis 15(7): e0009516. https://doi.org/10.1371/journal.pntd.0009516
Editor: Pedro F. C. Vasconcelos, Instituto Evandro Chagas, BRAZIL
Received: July 7, 2020; Accepted: May 28, 2021; Published: July 12, 2021
Copyright: © 2021 Halani 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 manuscript and its Supporting Information files.
Funding: Funding was provided by the Canadian Institutes of Health Research—Team grant—FRN149784. (https://cihr-irsc.gc.ca/e/193.html) This research was supported, in part, by a Canada Research Chair in Economics of Infectious Diseases held by BS (CRC-950-232429, https://www.chairs-chaires.gc.ca/home-accueil-eng.aspx) 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.
Introduction
Zika virus (ZIKV) was first identified in sentinel rhesus macaque monkeys in 1947 in Uganda, with the first report of human disease in 1952[1,2]. The virus has two dominant lineages, historically found in Africa and South-East Asia [3,4]. ZIKV is a single-stranded RNA virus, belonging to the flavivirus genus, which is a part of the Flaviviridae family of viruses [5–7]. There is overlap in terms of epidemiology and transmission cycles between ZIKV and other vector-borne diseases, in particular dengue and chikungunya [8]. Most Aedes mosquitoes are capable of carrying and transferring ZIKV, with Aedes aegypti and Aedes albopictus being recognized as the main vectors in human transmission [2,7]. Pregnancy, blood transfusions and sexual transmission are confirmed as other routes of transmission [3,9–14].
ZIKV has generated substantial global interest in the last five years mostly due to its recent re-emergence and rapid spread in the Americas between 2015 and 2016[15–17]. Prior to 2015 no infections were reported in the Americas [18]. Previously thought to be a self-limiting infection causing febrile illness in 20% of those infected, new concerns have arisen due the sharp rise in birth defects amongst children born to infected pregnant women [19–21] ZIKV has also been associated with long-term neurological sequelae in adults [22]. This systematic review synthesizes the existing literature on clinical manifestations and sequelae of ZIKV infection specifically in adults. Knowledge generated from this review will aid in informing when to test for ZIKV and will provide information regarding the risk of clinical outcomes and prognosis with ZIKV infection in adults.
Methods
Protocol and registration
We report this systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [23]. We registered the study protocol on PROSPERO, a database of registered systematic reviews (Registration number: CRD42018096558, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=96558) in May 2018.
Information sources
We systematically searched for relevant studies in MEDLINE (Ovid), Embase (Ovid), PubMed, CINAHL (EBSCO), LILACS (Literatura Latino-americana e do Caribe em Ciências da Saúde) and WHO’s ICTRP clinical trials registries database.
Search strategy
An information specialist with expertise in systematic reviews designed and carried out the search following the methodology of a Cochrane systematic review [24,25]. Our broad search was composed of "Zika Virus" or "Zika Virus Infection" controlled vocabulary (MeSH) and corresponding natural language terms. There were no language restrictions. We initially searched for studies published from inception through to April 2018 and then updated the search to include studies until September 15 2020. Full search strategy can be accessed in S1 Text.
Eligibility criteria
The following studies were included: observational studies (cross-sectional, case-control and cohort studies), indexed reports, and case reports and case series reporting with at least 10 participants that reported on health outcomes for adults (≥18 years). Randomized controlled trials (RCT) investigating the outcomes of interest were also included; those that focused on treatment safety and efficacy were not. References reporting on the effects of ZIKV in fetuses, and not the pregnant mother, were excluded from the review, as were any studies focusing on children (<18 years old). Studies that reported on adult outcomes but also included children, and in which the data could not be separated, were included, while stating the mixed population in the Results. We excluded publications such as editorials, letters and news articles, and animal studies. Abstracts and conference proceedings were excluded.
Study selection, data collection, synthesis
Two reviewers independently screened titles and abstracts of identified records followed by reviewing the full text against inclusion/exclusion criteria using DistillerSR (Evidence Partners, Ottawa, Canada). Discrepancies were resolved through consensus or consultation with a third reviewer or the larger research team.
Data was then extracted on a pre-designed, pilot-tested data extraction form on Microsoft Excel including study characteristics, subject demographics characteristics, ZIKV signs and symptoms, and clinical outcomes, including descriptive statistics and measures of association. Study type was also determined by the two reviewers and classification was performed in keeping with literature by Dekker and colleagues and reference textbook by Fletcher and colleagues [26,27]. Discrepancies in data extraction were resolved through consensus or consultation with a third reviewer.
We descriptively summarized the results using frequencies, percentages, and ranges. We did not perform a meta-analysis given the heterogeneity of the studies included.
Risk of bias assessment
We critically appraised included studies using the Joanna Briggs Institute Critical Appraisal Tools [28]. Each reviewer scored the studies and a third reviewer was consulted in the case of disagreement. In assessing whether outcomes were measured in a standard, valid, and reliable way, standard criteria were used as a benchmark; for example the Brighton criteria for Guillain Barré Syndrome (GBS) [29,30]. To calculate the total percent criteria met, we removed criteria that were found to be “not applicable” from the denominator.
Results
Here we outlined the results of our study selection, study characteristics, subject demographics, risk of bias assessment, data on case definitions, health outcomes and further analyses (travel-associated cases, co-infections, comorbidities and pre-existing conditions, and laboratory manifestations).
Results of study selection
Through the database search, 15,956 articles were identified and 12,068 deduplicated titles and abstracts were screened against eligibility criteria, of which 837 were selected for full-text review. Of these 837 articles, 499 pertained to pregnant women and/or children only and were excluded. Another 265 studies were excluded mainly because they were case reports or case series with fewer than ten participants, conference abstracts, or letters to the editor. Seventy-three studies reported on adult populations and were included in the review. (Fig 1)
PRISMA Flow Diagram illustrating identification, screening, eligibility, and inclusion of articles related to adult health outcomes with ZIKV.
Study characteristics
Of the 73 included studies, there were eight (11%) case-control studies, 13 (18%) case series, 13 (18%) cohort studies, and 39 (53%) cross-sectional studies. Forty one studies were from the Latin America and the Caribbean, 14 from the USA and Canada, eight from Europe, four from Asia, three from Oceania, two from India, and one from the Middle East. Forty four studies were conducted using public health reporting and/or surveillance data, while others collected data from hospitals, healthcare centers, travel centers, or clinics. (S1 Fig and S1 Table)
From all studies, the total number of ZIKV-infected patients reported was 309,649 including suspected, probable, and confirmed cases. Sample size ranges and medians were: case-control studies had a median of 46 subjects (range: 18 to 6,117 subjects), case series had a median of 20 subjects (range: 10 to 37,878 subjects), cohort studies had a median of 101 subjects (range: 17 to 7,722 subjects), and cross-sectional studies had a median of 948 subjects (range: 34 to 108,087 subjects).
Subject demographics
Of the 49 studies that reported the median age for all subjects in the study, the median age ranged from 20 to 61 years. From 61 studies in which the number of female subjects with ZIKV were reported, there were 114,800 females out of 188,391 infected subjects (61%). Twenty one studies reported cases of ZIKV associated with travel, and 37 studies included pregnant women in their study subjects. (Table 1)
Risk of bias in individual studies
Sixty-three studies met at least 70% of critical appraisal criteria (all eight case-control studies, 10 of 13 case series, 11 of 13 cohort studies, and 34 of 39 cross-sectional studies) when assessed using the Joanna Briggs Institute (JBI) critical appraisal tool. Further details on how the critical appraisal tool was utilized and study classification can be found in S3 Text.
ZIKV case definitions
Clinical case definitions of ZIKV infection varied widely between studies, and are listed in S5. Many definitions required fever and/or rash for inclusion, such as the widely used Pan-American Health Organization (PAHO) definition. Sometimes, other cardinal symptoms associated with ZIKV infection (e.g., conjunctivitis, arthralgias) qualified as independent inclusion criteria. Number of symptoms required for eligibility ranged from 1–4. Other studies included patients based on a complication of ZIKV infection, most commonly neurological sequelae or specifically GBS.
Forty of 73 (55%) studies included some form of confirmatory testing (in any or all subjects) that met at least one criterion of the World Health Organization (WHO) criteria for ‘confirmed’ ZIKV infection [104]. The two main methods were RT-PCR of serum and/or urine, and positive serum ZIKV IgM with positive viral neutralization testing (Table A in S5 Text)
In the percentages calculated in the subsequent section on health outcomes (and in Table 2), we included only studies that met at least 70% of the critical appraisal criteria. We reported on a subset of subjects with ‘confirmed’ ZIKV infection either by strict WHO definition or similar to this definition as assessed by the authors of the current systematic review. Studies in which the definition of ZIKV infection was similar to the WHO definition of ‘probable’ or ‘suspected’ ZIKV were included separately (Table 3). S4 Text and S2 Fig outline more detail to the approach taken to present the data based on diagnosis or type of testing for ZIKV. S5 Text includes clinical and laboratory criteria for confirmed ZIKV cases by the authors of the primary articles (relevant to Table 2 of manuscript), and the case definitions of ZIKV by authors of primary articles included in Table 3 of the manuscript.
ZIKV health outcomes
There were 17,764 subjects identified with confirmed ZIKV infection with confirmatory testing broadly consistent with WHO criteria.
ZIKV symptomatology, complications, Hospitalizations, and mortality
Symptoms from most common to least common included: exanthema (5,456/6,129; 89%), arthralgia (3,809/6,093; 63%), fever (3,787/6,124; 62%), conjunctivitis (2,738/6,021; 45%), myalgia (2,498/5,192; 48%), headache (2,165/4,722; 46%), and diarrhea (337/2,622; 13%). (Table 2 and Fig 2A) Other reported symptoms and signs from all the studies (beyond those reported in Table 2) included nausea and/or vomiting, lymphadenopathy, pharyngitis, swelling, eye pain, hepatosplenomegaly, and anorexia [52,113].
Many studies had missing data on symptoms, ranging from minor to considerable. This was often related to data collection from patient records in studies with surveillance designs.
Among 27 studies that reported on neurological complications in subjects with laboratory-confirmed ZIKV infection, there were 197 subjects identified with neurological sequelae among 14,496 subjects (1.4%), of which 180 cases were GBS (91%). (Brasil et al. (2016) and Webster-Kerr et al. (2017) were excluded from the analysis as it was unclear if ZIKV was confirmed in the neurological cases [69,92].) Other neurological complications among this cohort included transverse myelitis (2 cases), encephalitis (5 cases), chronic inflammatory demyelinating polyneuropathy (1 case), meningitis (1 case), and other neurological syndromes (8 cases). (Fig 2B)
We considered that 1.4% may be an overestimate for the neurological complication rate given the presence of case-control studies or case series that focused on neurological sequelae. After exclusion of these studies [32,36,42,45,47,53,109], 20 studies remained. Among these, neurological complications occurred in 36 of 14,335 confirmed ZIKV cases (0.3%), of which 27 cases were GBS (75%).
(A) Symptomatology of adults and (B) Neurological syndromes in adults with confirmed ZIKV (similar to WHO criteria) and meeting at least 70% of critical appraisal criteria. CIDP: Chronic inflammatory demyelinating polyneuropathy, GBS: Guillain-Barré Syndrome.
Other neurological manifestations (beyond those reported in Table 2) from the studies include convulsions and optic neuropathy and in particular studies, were reported as distinct neurologic sequelae [82,89].
In terms of hospitalizations, 347 of 3,167 subjects with ZIKV were admitted (11%). This included studies that only recruited hospitalized patients. There were 14 deaths among the 14,202 subjects with ZIKV for whom death was one of the reported outcomes (0.1%). The causes of four of the deaths that we report here were shock and coagulopathy in a patient with vascular comorbidity, hospital-acquired pneumonia, cerebral edema and brainstem herniation in a patient with encephalitis, and septic shock [53,91,109]. In the study by Mercado-Reyes et al., the fatal cases reported are those with co-infection: histopathology on one subject with CHIKV-ZIKV showed tubule-interstitial nephritis, and changes related to systemic inflammatory response syndrome (SIRS), a second case endured multi-organ failure, and a third the histopathology demonstrated acute demyelinating polyneuropathy, pneumonia, and SIRS findings in the liver and spleen.[97] The cause of death for the remaining seven subjects were not reported in the primary studies.
Guillain-barré syndrome disease incidence and risk factors
Several studies using population-level data reported increases in GBS incidence during the ZIKV epidemic, suggesting a role for ZIKV in GBS pathophysiology. According to Anaya et al. (2017), the incidence of GBS increased 4.41-fold in Cúcuta, Colombia compared to the pre-ZIKV outbreak period [105]. In the Dirlikov et al. study in Puerto Rico, the incidence of GBS in 2016 was 3.5 subjects per 100,000 population, which is 2.1 times greater than the approximate yearly incidence of 1.7 subjects per 100,000[43].
Case-control studies have attempted to characterize GBS in the context of ZIKV infection. Anaya et al. (2017) compared ZIKV-positive subjects with GBS (cases) to ZIKV-positive subjects without GBS (controls) in Cúcuta, Colombia, and reported that lower socioeconomic class or an increased number of previous infections (such as Mycoplasma pneumoniae) were two factors associated with increased risk of developing GBS [105]. Dirlikov et al. in 2018 compared 71 subjects diagnosed with GBS with ZIKV and 36 subjects with GBS but without ZIKV in Puerto Rico, and illustrated that subjects with ZIKV more commonly described symptoms of arthralgia and rash than those without ZIKV (arthralgia: 13/71 vs. 1/36 p = 0.03; rash: 36/71 vs. 3/36; p < 0.001) [43]. However, the median duration of seven days from preceding illness to the onset of neurological disease did not differ between the two groups [114]. The Miller Fisher Syndrome, a variant of GBS comprised of a triad of symptoms (ataxia, areflexia, ophthalmoplegia), was present in one subject in each of three studies (Table 4) [42,45,53].
Other studies did not detect an association between ZIKV and GBS. Geurts van Kessel et al. compared GBS cases with healthy controls in Bangladesh and found that the presence of neutralizing antibodies against ZIKV was not significantly increased in GBS cases (odds ratio of 2.23, P = 0.14) [33].
Guillain-barré syndrome disease outcomes
We report separately the GBS disease progression and outcomes from the subjects across eight studies with confirmed ZIKV (Table 4) and the GBS disease trajectory from subjects across four studies with probable or suspected ZIKV (Table 5).
In subjects with confirmed ZIKV, the median number of days from illness onset to onset of neurological symptoms ranged from five to ten days. On electromyography studies, the acute inflammatory demyelinating polyneuropathy subtype (AIDP) was present in 45 of 91 cases (49%) and the acute motor axonal neuropathy (AMAN) subtype was present in 50 of 132 cases tested (38%). Among the probable and suspected cases of ZIKV with GBS for whom electrophysiologic data was available, 88 of 129 (68%) tested subjects presented with the AIDP subtype, while 50 of 132 (38%) tested subjects exhibited the AMAN subtype. (Table 5)
Among this group of confirmed ZIKV and GBS cases, the median length of hospital stay ranged from eight to 31 days. Forty three of 96 cases (45%) were admitted to the intensive care unit (ICU) and the mortality rate among 115 cases of GBS and confirmed ZIKV was 3% (four deaths). The causes of two of these deaths in cases of GBS were septic shock and hospital-acquired pneumonia [53,109]. Respiratory failure and/or mechanical ventilation was reported in 30 of 106 cases of GBS and ZIKV (28%).
Disability and physical function were assessed among studies that reported on GBS using various scoring tools including the GBS disability score, Hughes’ functional scale, or modified Rankin scale score [115–118]. In Chang et al. in northern Colombia, 60% (nine of 15) of their subjects with GBS and ZIKV had completely recovered at the one-year mark, and 40% had remaining disability[42]. In contrast, Lynch et al. (2019) in their study in Colombia noted two of eight subjects with GBS and ZIKV had full recovery whereas five of eight subjects had persistent sequelae including weakness, tremors of the face, and sensory deficits [45]. In the Anaya et al., study in Cúcuta, Colombia, dysautonomia predicted poor outcomes, such as resulting disability, in ZIKV-positive GBS cases [105].
Dirlikov et al. in 2018 also noted that subjects with ZIKV and GBS more commonly had difficulty swallowing, paresthesias and weakness of the face, and shortness of breath compared to those with GBS without ZIKV [114]. Also more commonly patients with ZIKV and GBS were admitted to ICU and required ventilatory support than those without ZIKV (ICU admission: 47/71 vs. 16/36 p = 0.03; mechanical ventilation 22/71 vs. 4/36 p = 0.02) [114]. Dirlikov et al. also reported that at six months, it was more common that GBS patients with ZIKV had persistent facial disability compared to those without ZIKV infection [114]. Dirlikov et al. also reported on operative procedures that were required as a result of ZIKV infection included tracheostomy and gastrotomy tube placement [43].
Further findings
The subsequent sections highlight travel-associated cases, co-infections with ZIKV, the implications of pre-existing health conditions, and pertinent laboratory manifestations of ZIKV.
Travel-associated cases
Armstrong et al. (2016) reported that among 115 residents of the United States of America with laboratory-confirmed ZIKV infection, 37% had traveled to Central America, 33% to the Caribbean, and 21% to South America with only 6% to Southeast Asia and the Pacific Islands and 2% within North America [66]. Meltzer et al. (2019) described a cohort of Israeli travelers and among the 30 ZIKV-positive cases, 23 of 30 (77%) had traveled to the Americas and 7 of 30 (23%) had traveled to Asia [57]. Of note, in the latter study, there were 248 symptomatic travelers from a total of 1,188 returning Israeli travelers that were tested for ZIKV and only 28 of these 248 (11%) symptomatic travelers were ZIKV-positive [57]. Other travel-related studies demonstrated similar percentages to that summarized here in terms of destinations [78,119].
Co-Infections
Geurts van Kessel et al. describe cases of GBS and ZIKV-positivity with Campylobacter jejuni co-infection (9 of 18 subjects) in Bangladesh. [33] All of the subjects with C. jejuni co-infection had an isolated motor presentation of GBS as opposed to the ZIKV-associated GBS cases (without evidence of C. jejuni co-infection) in which 6 of 9 cases had a sensory-motor presentation of GBS [109].
Azeredo et al. in 2018 recruited patients in Brazil with suspected arboviral infection in the acute stage with fever, rash, and two other symptoms from a predefined list as well as suspected Zika and dengue cases [120]. Dengue virus (DENV)/ZIKV coinfection occurred in 18 of 134 subjects (13.4%), whereby testing was done using reverse-transcriptase polymerase chain reaction (RT-PCR); DENV mono-infection occurred in 38% and ZIKV mono-infection in 13·4% of cases [120]. Seven subjects had Chikungunya virus (CHIKV) IgM indicating recent infection [120]. To compare symptomatology, the cases that were ZIKV positive consistently reported exanthema and pruritis whereas the DENV-positive subjects often had anorexia, dizziness, vomiting, and prostration [120].
Comorbidities and pre-existing conditions
Schirmer et al. reported that co-morbidities, including connective tissue disease, dementia, and congestive heart failure in United States Veterans with ZIKV infection were associated with an increased risk of hospitalization [89]. In a cohort study of 101 subjects with human immunodeficiency virus (HIV) infection in Brazil, Calvet et al. measured the CD4+ count and HIV viral loads before ZIKV infection and two months after ZIKV infection and no significant differences were observed [52].
Laboratory abnormalities in ZIKV
The synthesis of laboratory abnormalities was limited by the variability in reporting. Thrombocytopenia in patients with ZIKV was described in detail by Van Dyne and colleague [48]. Their study in Puerto Rico consisted of 47 subjects with ZIKV-associated thrombocytopenia without another etiology among 37,878 subjects with ZIKV infection (0.1%) [48]. Twelve of these subjects had severe thrombocytopenia (platelet count less than 20 x 109/L or platelet count less than 50 x 109/L and clinical management in keeping with a diagnosis of immune thrombocytopenic purpura) and 35 had non-severe thrombocytopenia (platelet count less than 100 x 109/L that did not meet criteria for severe thrombocytopenia) [48]. Of the subjects with severe thrombocytopenia, all were hospitalized, 33% were admitted to an ICU setting, and mortality was 8% [48].
In the study by Azeredo et al. in Brazil comparing various arboviruses, ZIKV and DENV mono-infections presented with overall lower leukocyte counts compared to cases with no arboviral infections; however, only ZIKV mono-infected subjects show statistically significantly decreased lymphocyte counts compared to non-infected cases [120].
Discussion
We identified 73 studies globally that reported clinical outcomes in ZIKV-infected adults. Forty of the studies were from the Americas, consistent with the predominance of ZIKV in these countries during the recent epidemic. Travel-associated studies also demonstrated a similar trend in terms of destinations. Of the studies with subjects with confirmed ZIKV and that met at least 70% of critical appraisal criteria, exanthema (5,456/6,129; 89%) and arthralgia (3,809/6,093; 63%) were two common presenting symptoms and 0.3% of infected cases developed neurologic sequelae, of which 83% were GBS. Several subjects reported recovery from peak of GBS or neurological symptoms; however, some endured chronic disability. Mortality was uncommon, and certain co-morbidities such as heart failure and dementia, as well as complications including GBS and thrombocytopenia, were associated with a greater risk of hospitalization [89].
The frequency of clinical signs and symptoms found by this review, and in particular the high proportions of subjects with fever and rash, is influenced by the clinical case definitions used in the primary studies. Many clinical case definitions of suspected ZIKV infection–especially those developed early in the epidemic–were based on the presence of fever and/or rash with or without additional symptoms. Subsequently, studies have demonstrated that ZIKV infection can occur in the absence of such “cardinal symptoms” and can be minimally symptomatic, and in fact asymptomatic ZIKV infection has long been recognized. Thus, there is bias in the known spectrum of ZIKV clinical features. It should be noted that many studies had considerable missing clinical data due to their retrospective data collection methods, which could have affected estimates. Also important to consider is the integrity of clinical data, which is subject to inaccuracies related to self-reporting and variation in measurement and definitions (e.g., fever).
In this review, there was epidemiologic data supporting an association between adult ZIKV infections and neurological complications, namely GBS, given the mirroring of the trends of these two diseases [32,35,43,49,70,121]. After excluding studies that intentionally enriched for patients with neurological complications, we calculated a risk of neurological sequelae in ZIKV infection of 0.3%. This number remains subject to bias: some of the studies were case series rather than population-based studies, and our requirement for laboratory confirmation of ZIKV infection may have inflated this number as there may be more aggressive testing of severe ZIKV disease. Other systematic reviews and meta-analyses have generated variable estimates. A systematic review and meta-analysis including studies from nine countries until November 2017 showed that 1.23% of ZIKV infections could progress to GBS. [122] Capasso et al. conducted a systematic review and meta-analysis of the GBS incidence rates before and during the ZIKV epidemic and demonstrated that GBS increased 2.6 times during ZIKV over background rates [123]. A meta-analysis of thirty-four studies showed that ZIKV prevalence in GBS was 2.4 to 25 times greater than anticipated, although trends in GBS cases did not mirror fluctuations in ZIKV diagnoses during outbreaks [124]. Specifically regarding subtypes of GBS, the acute inflammatory demyelinating polyneuropathy (AIDP) subtype, classically thought to be related to slowed or decreased conduction speed, was more common among ZIKV-infected subjects than the acute motor axonal neuropathy (AMAN) subtype related to the disintegration of neuronal axons [125]. This has been illustrated by a review by Uncini et al. [126], and is consistent with a meta-analysis of GBS and ZIKV in which the frequency of the AIDP electrophysiologic subtype was 62% followed by 16% [127]. Our data from the probable and suspected ZIKV cases supports this point of AIDP being the more common subtype than AMAN, although ZIKV was not confirmed in these subjects.
Mortality rate in this review was 0.4%. We compare this with a mean case fatality rate of 0.02% from ZIKV illustrated in a systematic review of ZIKV in the Americas. [128] In subjects with confirmed ZIKV and GBS, admission rate to the ICU was 50% and mortality rate was 3%. Consistent with our findings, Leonhard et al. report in all cases, 49% admission rate to ICU and a mortality rate of 1%. [127]
There was significant variability in usage and type of confirmatory testing for ZIKV infection. Given the potential non-specificity of symptoms and overlap with other flaviviruses, other infections, and non-infectious etiologies, subjects with unconfirmed ZIKV infection were not included in our higher-level analysis. Thus, we may have missed true cases of ZIKV infection and potentially biased the spectrum of disease. We are cognizant that access to confirmatory testing and standardization of testing and case definitions is related to a number of factors, including geographical and site-specific resources and/or where samples could be tested. Some studies compared the results of applying different classification systems to the data to articulate this point [92].
Our systematic review has several limitations. First, the heterogeneity of results was one of the barriers to meta-analyses. This heterogeneity is likely related to multiple factors including the aforementioned variation in clinical case definitions and confirmatory testing.
Second, testing for co-infections and reporting of laboratory abnormalities was heterogenous across studies. The symptoms of ZIKV may mimic those of other arboviruses, which underscores the importance of delineating a mono-infection from co-infection with another arbovirus and from cross-reactivity in serologic testing. In several studies, enzyme-linked immunosorbent assay (ELISA) IgM results for other arboviruses were IgM or IgG positive [33,41,44]. However, the interpretation of these results requires other more definitive methodologies. Schirmer et al. used an appropriate testing algorithm, in which specimens where ZIKV RT-PCR was negative or not done, specimens were further tested with IgM ELISAs for ZIKV and if positive, equivocal or inconclusive, they were subjected to plaque reduction neutralization testing (PRNT) for the suspected virus or viruses [89]. We did not summarize data on co-infections versus cross-reactivity given the challenges with consistent testing algorithms. Biochemical abnormalities are potentially overestimated or underestimated as well. For instance, in the study by Van Dyne et al. that described ZIKV-associated thrombocytopenia, 28% of the charts of patients that reported thrombocytopenia were available for review [48]. In future studies, consistent co-infection testing and surveillance for laboratory abnormalities will be required to accurately estimate the incidences of these outcomes.
Third, categorization of studies into study type (cross-sectional, cohort, case series, case-control) was challenging. Some of the studies were re-categorized by the systematic review authors compared to how the studies self-described. For example, we re-labelled studies that were described as prevalence as cross-sectional studies if they reported on both exposures and outcomes but did not have features of cohort studies, case-control studies, or case series [71]. This was in keeping with the description of analytical cross-sectional studies as described by Alexander et al [129]. One of the included studies used a mixed-methods approach, thus for classification purposes we chose the dominant study type to report in our systematic review [105].
Fourth, the description of GBS disease progression and outcomes, including admission to ICU and mechanical ventilation, are highly dependent on geographic location and available hospital resources [130]. Moreover, comorbidities play a role in hospitalization and death and can positively or negatively influence the likelihood of receiving ZIKV diagnosis and we recognize the complex interplay of these factors on the total numbers [56,89,91]. We recognize also that the percentage of hospitalization in ZIKV patients reported in our study (16%) may be inflated by the inclusion of case series of hospitalized patients.
Finally, some studies had mixed populations including adults, children, and congenital cases. We defined the adult population as 18 years of age and older, but some studies defined the adult age group differently, and pediatric cases could not be separated for reporting. Children and congenital cases were removed from final counts when possible, or indicated where this was not possible [57,69,75–77,80,84,88,105,107].
The strengths of our systematic review are the thorough and comprehensive search strategy employed, including studies until September 2020, the use of broad keywords of “Zika virus” and “Zika infection,” and the lack of language restrictions which allowed us to include as many studies as possible. After exclusion criteria and removing children and CZS-based studies, there was a large body of literature to extract data from. Several studies have reported on the virology, testing, and differential diagnoses for ZIKV; however, to our knowledge this is the first systematic review to synthesize the epidemiology, symptomatology and outcomes of adult ZIKV infection globally [131–133]. This study contributes both to the body of clinical epidemiology literature of ZIKV and to that of travel medicine. Our results have depicted the geographic distribution of cases as well as those that are travel-related, and highlighted risk factors for developing complications and hospitalization associated with ZIKV infection.
Supporting information
S1 Table. Study Type Classifications.
Included in this supplement is a table categorizing each study by study type (‘case-control,’ ‘case series,’ ‘cross-sectional,’ or ‘cohort’) and further sub-categorizing each study into ‘surveillance,’ ‘public health-based,’ or ‘other’ (hospital-based, single-center). CDC = Centre for Disease Control, GBS = Guillain-Barré Syndrome, ICU = intensive care unit, INS = Instituto Nacional de Salud (in Colombia), US = United States WHO = World Health Organization
https://doi.org/10.1371/journal.pntd.0009516.s002
(DOCX)
S1 Fig. Classification of Included Studies in the Systematic Review.
(A) Classified by study-type (classified by authors of systematic review), (B) Classified by geographic location of subjects and (C) Classified by involvement in public health reporting or surveillance versus other (purely hospital-based, healthcare center-based, population-based, travel-clinic based).
https://doi.org/10.1371/journal.pntd.0009516.s003
(TIF)
S2 Fig. Diagrammatic Representation of Distribution of Primary Studies.
This figure depicts the grouping of primary studies into tables within our manuscript based on ZIKV testing methodologies and details included within each primary study.
https://doi.org/10.1371/journal.pntd.0009516.s004
(TIF)
S1 Text. Full Search Strategy for Systematic Review.
Included here the search strategy and review process with details on the searches performed from five of the included databases.
https://doi.org/10.1371/journal.pntd.0009516.s005
(DOCX)
S2 Text. PROSPERO protocol CRD 42018096558 used for this study.
Protocol amendment has been submitted to include three authors on the protocol.
https://doi.org/10.1371/journal.pntd.0009516.s006
(PDF)
S3 Text. Joanna Briggs Institute (JBI) Critical Appraisal Tool and ZIKV Adult Population Results.
S3A. Table JBI Critical Appraisal Tool Questionnaire for Case-Control Studies Applied to ZIKV Systematic Review. S3B Table. JBI Critical Appraisal Tool Questionnaire for Case Series Applied to ZIKV Systematic Review. S3C Table. JBI Critical Appraisal Tool Questionnaire for Cohort Studies Applied to ZIKV Systematic Review. S3D Table. JBI Critical Appraisal Tool Questionnaire for Cross-Sectional Studies Applied to ZIKV Systematic Review. Note: Causation cannot be inferred from cross-sectional studies, though if no statistical analysis was performed, a point was subtracted from the critical appraisal for the particular study.
https://doi.org/10.1371/journal.pntd.0009516.s007
(DOCX)
S4 Text. Summary of Data Processing for Adult ZIKV Clinical Manifestations and Health Outcomes.
https://doi.org/10.1371/journal.pntd.0009516.s008
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S5 Text. ZIKV Case Definitions by Authors of Primary Articles.
S5A Table–Clinical and laboratory criteria for Confirmed ZIKV Case by Authors from Primary Articles Included in Table 2 in Manuscript. DENV = Dengue Virus, PAHO = Pan American Health Organization, PRNT = Plaque Reduction Neutralization Test, RT-PCR = Reverse Transcriptase-Polymerase Chain Reaction, RNA = Ribonucleic Acid, VNT = Virus Neutralization Test, WHO = World Health Organization. S5B Table–Case Definitions of ZIKV by Authors of Primary Articles Included in Table 3 in Manuscript. DENV = Dengue Virus, ECDC = European Center for Disease Control Clinical Case Definition = ZIKV infection defined as maculopapular rash with or without fever, and painful joints or muscles or non-purulent conjunctivitis, GBS = Guillain Barré Syndrome, ELISA = Enzyme-Linked Immunosorbent Assay, INS = National Health Institute, PAHO = Pan American Health Organization[45], PCR = polymerase chain reaction, RNA = Ribonucleic Acid, RT-PCR = Reverse Transcriptase-Polymerase Chain Reaction, rRT-PCR = Real-time Reverse Transcriptase-Polymerase Chain Reaction, VNT = Virus Neutralization Test, ZIKV = Zika Virus, ZVD = Zika Virus Disease.
https://doi.org/10.1371/journal.pntd.0009516.s009
(DOCX)
References
- 1. Wikan N, Smith DR. Zika virus: History of a newly emerging arbovirus. The Lancet Infectious Diseases. 2016;16: E119–126. pmid:27282424
- 2. Abushouk AI, Negida A, Ahmed H. An updated review of Zika virus. Journal of Clinical Virology. 2016;84: 53–58. pmid:27721110
- 3. Simonin Y, Loustalot F, Desmetz C, Foulongne V, Constant O, Fournier-Wirth C, et al. Zika Virus Strains Potentially Display Different Infectious Profiles in Human Neural Cells. EBioMedicine. 2016;12: 161–169. pmid:27688094
- 4. Lanciotti RS, Kosoy OL, Laven JJ, Velez JO, Lambert AJ, Johnson AJ, et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerging Infectious Diseases. 2008;14: 1232–9. pmid:18680646
- 5. Song BH, Yun SI, Woolley M, Lee YM. Zika virus: History, epidemiology, transmission, and clinical presentation. Journal of Neuroimmunology. 2017. pmid:28285789
- 6. Faye O, Freire CCM, Iamarino A, Faye O, de Oliveira JVC, Diallo M, et al. Molecular Evolution of Zika Virus during Its Emergence in the 20th Century. PLoS Neglected Tropical Diseases. 2014;8: e2636. pmid:24421913
- 7. Chang C, Ortiz K, Ansari A, Gershwin ME. The Zika outbreak of the 21st century. Journal of Autoimmunity. 2016;68: 1–13. pmid:26925496
- 8. Patterson J, Sammon M, Garg M. Dengue, zika and chikungunya: Emerging arboviruses in the new world. Western Journal of Emergency Medicine. 2016;17: 671–679. pmid:27833670
- 9. Conway MJ, Colpitts TM, Fikrig E. Role of the Vector in Arbovirus Transmission. Annual Review of Virology. 2014;1: 71–88. pmid:26958715
- 10. Holtzman M, Golden WC, Sheffield JS. Zika Virus Infection in the Pregnant Woman. Clinical Obstetrics and Gynecology. 2018;61: 177–185. pmid:29319591
- 11. Foy BD, Kobylinski KC, Foy JLC, Blitvich BJ, da Rosa AT, Haddow AD, et al. Probable Non-Vector-borne Transmission of Zika Virus, Colorado, USA. Emerging Infectious Diseases. 2011;17: 880–2. pmid:21529401
- 12. D’Ortenzio E, Matheron S, Yazdanpanah Y. Evidence of sexual transmission of Zika Virus. New England Journal of Medicine. 2016;374: 2195–8. pmid:27074370
- 13. Trew Deckard D, Chung WM, Brooks JT, Smith JC, Woldai S, Hennessey M, et al. Male-to-male sexual transmission of Zika virus—Texas, January 2016. Morbidity and Mortality Weekly Report. 2016;65: 372–4. pmid:27078057
- 14. Motta IJF, Spencer BR, Da Silva SGC, Arruda MB, Dobbin JA, Gonzaga YBM, et al. Evidence for transmission of zika virus by platelet transfusion. New England Journal of Medicine. 2016;375: 1101–3. pmid:27532622
- 15. Campos GS, Bandeira AC, Sardi SI. Zika virus outbreak, Bahia, Brazil. Emerging Infectious Diseases. 2015;21: 1885–6. pmid:26401719
- 16. Hennessey M, Fischer M, Staples JE. Zika virus spreads to new areas—Region of the Americas, May 2015–January 2016. Morbidity and Mortality Weekly Report. 2016;65: 55–8. pmid:26820163
- 17. Heukelbach J, Alencar CH, Kelvin AA, de Oliveira WK, de Góes Cavalcanti LP. Zika virus outbreak in Brazil. Journal of Infection in Developing Countries. 2016;10: 116–20. pmid:26927450
- 18. Posen HJ, Keystone JS, Gubbay JB, Morris SK. Epidemiology of Zika virus, 1947–2007. BMJ Global Health. 2016;1: e000087. pmid:28588942
- 19.
Qureshi AI, editor. Psychological and Social Aspects of Zika Virus Disease. 1st ed. Zika Virus Disease: From Origin To Outbreak. 1st ed. Academic Press; 2018. pp. 143–153. https://doi.org/10.1016/b978-0-12-812365-2.00013–5
- 20.
CDC. Congenital Zika Syndrome & Other Birth Defects. In: Centers for Disease Control [Internet]. 2018 [cited 31 Jan 2019]. Available: https://www.cdc.gov/pregnancy/zika/testing-follow-up/zika-syndrome-birth-defects.html.
- 21. Zorrilla CD, Rivera-Viñas JI, Pujols A de la V, García-García I, Rabionet SE, Mosquera AM. The Zika virus infection in pregnancy: Review and implications for research and care of women and infants in affected areas. Puerto Rico Health Sciences Journal. 2018;37: S66–S72. pmid:30576580
- 22. Muñoz LS, Parra B, Pardo CA. Neurological Implications of Zika Virus Infection in Adults. Journal of Infectious Diseases. 2017. pmid:29267923
- 23. Moher D, Liberati A, Tetzlaff J, Altman DG, Altman D, Antes G, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Medicine. 2009;6: e1000097. pmid:19621072
- 24. Lefebvre C, Glanville J, Briscoe S, Littlewood A, Marshall C, Metzendorf M-I, et al. Part 2: Core methods, Chapter 4: Searching for and selecting studies. Higgins J, Thomas J, editors. In: Cochrane Handbook for Systematic Reviews of Interventions [Internet]. Version 6. 2019 [cited 31 Jan 2019].
- 25.
Tufanaru C, Munn Z, Aromataris E, Campbell J, Hopp L. Joanna Briggs Institute Reviewer’s Manual. Aromataris E, Munn Z, editors. In: Joanna Briggs Institute Reviewer’s Manual [Internet]. The Joanna Briggs Institute; 2017 [cited 31 Jan 2019]. Available: https://reviewersmanual.joannabriggs.org/.
- 26.
Fletcher RH, Fletcher SW, Wagner EH. Chapter 10: Studying Cases. Third Edit. In: Satterfield TS, editor. Clinical Epidemiology: The Essentials: Third Edition. Third Edit. Philadelphia: Williams & Wilkins; 2003. pp. 208–227. https://doi.org/10.1249/01.mss.0000225390.15178.6b
- 27. Dekkers OM, Egger M, Altman DG, Vandenbroucke JP. Distinguishing case series from cohort studies. Annals of Internal Medicine. 2012;3: 37–40. pmid:22213493
- 28.
Joanna Briggs Institute, The University of Adelaide. Critical Appraisal Tools. [cited 31 Jan 2019]. Available: https://joannabriggs.org/ebp/critical_appraisal_tools.
- 29. Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Annals of Neurology. 1990;27 Suppl: S21–4. pmid:2194422
- 30. Fokke C, Van Den Berg B, Drenthen J, Walgaard C, Van Doorn PA, Jacobs BC. Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria. Brain. 2014;137(Pt 1): 33–43. pmid:24163275
- 31. Anaya JM, Rodríguez Y, Monsalve DM, Vega D, Ojeda E, González-Bravo D, et al. A comprehensive analysis and immunobiology of autoimmune neurological syndromes during the Zika virus outbreak in Cúcuta, Colombia. Journal of Autoimmunity. 2017;77: 123–138. pmid:28062188
- 32. Cao-Lormeau VM, Blake A, Mons S, Lastère S, Roche C, Vanhomwegen J, et al. Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: A case-control study. The Lancet. 2016;387: 1531–1539. pmid:26948433
- 33. GeurtsvanKessel CH, Islam Z, Islam MB, Kamga S, Papri N, van de Vijver DAMC, et al. Zika virus and Guillain–Barré syndrome in Bangladesh. Annals of Clinical and Translational Neurology. 2018;5: 606–615. pmid:29761123
- 34. Salinas JL, Walteros DM, Styczynski A, Garzón F, Quijada H, Bravo E, et al. Zika virus disease-associated Guillain-Barré syndrome—Barranquilla, Colombia 2015–2016. Journal of the Neurological Sciences. 2017;381: 272–277. pmid:28991697
- 35. Styczynski AR, Malta JMAS, Krow-Lucal ER, Percio J, Nóbrega ME, Vargas A, et al. Increased rates of Guillain-Barré syndrome associated with Zika virus outbreak in the Salvador metropolitan area, Brazil. PLoS Neglected Tropical Diseases. 2017;11: 1–13. pmid:28854206
- 36. Gongora-Rivera F, Grijalva I, Infante-Valenzuela A, Camara-Lemarroy C, Garza-Gonzalez E, Paredes-Cruz M, et al. Zika Virus infection and Guillain-Barre syndrome in Northeastern Mexico: A case-control study. PloS one. 2020;15: e0230132. https://doi.org/10.1371/journal.pone.0230132 pmid:32214354
- 37. Rivera-Correa J, de Siqueira IC, Mota S, do Rosario MS, Pereira de Jesus PA, Alcantara LCJ, et al. Anti-ganglioside antibodies in patients with Zika virus infection-associated Guillain-Barre Syndrome in Brazil. PLoS neglected tropical diseases. 2019;13: e0007695. https://doi.org/10.1371/journal.pntd.0007695 pmid:31527907
- 38. Kozak RA, Goneau LW, DeLima C, Varsaneux O, Eshaghi A, Kristjanson E, et al. Presence of Flavivirus Antibodies Does Not Lead to a Greater Number of Symptoms in a Small Cohort of Canadian Travelers Infected with Zika Virus. Viruses. 2020;12. https://doi.org/10.3390/v12020140 pmid:31991674
- 39. Acevedo N, Waggoner J, Rodriguez M, Rivera L, Landivar J, Pinsky B, et al. Zika virus, chikungunya virus, and dengue virus in cerebrospinal fluid from adults with neurological manifestations, Guayaquil, Ecuador. Frontiers in Microbiology. 2017;8: 1–6. pmid:28197127
- 40. Arias A, Torres-Tobar L, Hernández G, Paipilla D, Palacios E, Torres Y, et al. Guillain-Barré syndrome in patients with a recent history of Zika in Cúcuta, Colombia: A descriptive case series of 19 patients from December 2015 to March 2016. Journal of Critical Care. 2017;37: 19–23. pmid:27610587
- 41. Baskar D, Amalnath D, Mandal J, Dhodapkar R, Vanathi K. Antibodies to Zika virus, Campylobacter jejuni and gangliosides in Guillain-Barre syndrome: A prospective single-center study from southern India. Neurology India. 2018;66: 1324–1331. pmid:30232998
- 42. Chang AY, Lynch R, Martins K, Encinales L, Cadena Bonfanti A, Pacheco N, et al. Long-term clinical outcomes of Zika-associated Guillain-Barré syndrome. Emerging Microbes and Infections. 2018;7: 4–7. pmid:29323108
- 43. Dirlikov E, Major CG, Medina NA, Lugo-Robles R, Matos D, Muñoz-Jordan JL, et al. Clinical features of Guillain-Barré syndrome with vs without zika virus infection, Puerto Rico, 2016. JAMA Neurology. 2018;75: 1089–1097. pmid:29799940
- 44. Duijster JW, Goorhuis A, van Genderen PJJ, 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: 797–802. pmid:27209175
- 45. Lynch RM, Mantus G, Encinales L, Pacheco N, Li G, Porras A, et al. Augmented zika and dengue neutralizing antibodies are associated with guillain-Barré syndrome. Journal of Infectious Diseases. 2019;219: 26–30. pmid:30113672
- 46. Sebastián UU, Ricardo AVA, Alvarez BC, Cubides A, Luna AF, Arroyo-Parejo M, et al. Zika virus-induced neurological critical illness in Latin America: Severe Guillain-Barre Syndrome and encephalitis. Journal of Critical Care. 2017;42: 275–281. pmid:28806562
- 47. Uncini A, González-Bravo DC, Acosta-Ampudia YY, Ojeda EC, Rodríguez Y, Monsalve DM, et al. Clinical and nerve conduction features in Guillain−Barré syndrome associated with Zika virus infection in Cúcuta, Colombia. European Journal of Neurology. 2018;25: 644–650. pmid:29266602
- 48. Van Dyne EA, Neaterour P, Rivera A, Bello-Pagan M, Adams L, Munoz-Jordan J, et al. Incidence and outcome of severe and nonsevere thrombocytopenia associated with zika virus infection-Puerto Rico, 2016. Open Forum Infectious Diseases. 2019;6: 1–9. pmid:30631791
- 49. Watrin L, Ghawché F, Larre P, Neau JP, Mathis S, Fournier E. Guillain-Barré Syndrome (42 Cases) Occurring during a Zika Virus Outbreak in French Polynesia. Medicine (United States). 2016;95: 1–8. pmid:27057874
- 50. Chaumont H, Roze E, Tressieres B, Lazarini F, Lannuzel A. Central nervous system infections in a tropical area: influence of emerging and rare infections. European journal of neurology. 2020;27: 2242–2249. https://doi.org/10.1111/ene.14422 pmid:32602577
- 51. Lannuzel A, Fergé J-L, Lobjois Q, Signate A, Rozé B, Tressières B, et al. Long-term outcome in neuroZika: When biological diagnosis matters. Neurology. 2019;92: e2406–e2420. pmid:31028126
- 52. Calvet GA, Brasil P, Siqueira AMH, Zogbi HE, Gonçalves BDS, Santos ADS, et al. Zika virus infection and differential diagnosis in a cohort of HIV-infected patients. Journal of Acquired Immune Deficiency Syndromes. 2018;79: 237–243. pmid:29912006
- 53. Da Silva IRF, Frontera JA, De Filippis AMB, Do Nascimento OJM. Neurologic complications associated with the Zika virus in Brazilian adults. JAMA Neurology. 2017;74: 1190–1198. pmid:28806453
- 54. de Laval F, d’Aubigny H, Mathéus S, Labrousse T, Ensargueix AL, Lorenzi EM, et al. Evolution of symptoms and quality of life during Zika virus infection: A 1-year prospective cohort study. Journal of Clinical Virology. 2018;109: 57–62. pmid:30523784
- 55. Kam YW, Leite JA, Lum FM, Tan JJL, Lee B, Judice CC, et al. Specific biomarkers associated with neurological complications and congenital central nervous system abnormalities from Zika virus-infected patients in Brazil. Journal of Infectious Diseases. 2017;216: 172–181. pmid:28838147
- 56. Lozier MJ, Burke RM, Lopez J, Acevedo V, Amador M, Read JS, et al. Differences in prevalence of symptomatic zika virus infection, by age and sex—puerto rico, 2016. Journal of Infectious Diseases. 2018;217: 1678–1689. pmid:29216376
- 57. Meltzer E, Lustig Y, Schwartz E. Zika Virus in Israeli travelers: Emergence of Asia as a major source of infection. American Journal of Tropical Medicine and Hygiene. 2019;100: 178–182. pmid:30426920
- 58. Ng DHL, Ho HJ, Chow A, Wong J, Kyaw WM, Tan A, et al. Correlation of clinical illness with viremia in Zika virus disease during an outbreak in Singapore. BMC Infectious Diseases. 2018;18. pmid:29310571
- 59. Sokal A, D’Ortenzio E, Houhou-Fidouh N, Brichler S, Dorchies J, Cabras O, et al. Zika virus infection: report of the first imported cases in a Paris travel centre. Journal of travel medicine. 2016;24: 1–4. pmid:28679155
- 60. Vega FLR, Bezerra JMT, Said RF de C, Gama Neto AN da, Cotrim EC, Mendez D, et al. Emergence of chikungunya and Zika in a municipality endemic to dengue, Santa Luzia, MG, Brazil, 2015–2017. Revista da Sociedade Brasileira de Medicina Tropical. 2019;52: e20180347. https://doi.org/10.1590/0037-8682-0347-2018 pmid:30652797
- 61. Petridou C, Simpson A, Charlett A, Lyall H, Dhesi Z, Aarons E. Zika virus infection in travellers returning to the United Kingdom during the period of the outbreak in the Americas (2016–17): A retrospective analysis. Travel Medicine & Infectious Disease. 2019;29: 21–27. pmid:30853504
- 62. Hunsberger S, Ortega-Villa AM, Powers JH 3rd, Rincon Leon HA, Caballero Sosa S, Ruiz Hernandez E, et al. Patterns of signs, symptoms, and laboratory values associated with Zika, dengue, and undefined acute illnesses in a dengue endemic region: Secondary analysis of a prospective cohort study in southern Mexico. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases. 2020;98: 241–249. https://doi.org/10.1016/j.ijid.2020.06.071
- 63. Crespillo-Andujar C, Diaz-Menendez M, Trigo E, Arsuaga M, de la Calle F, Lago M, et al. Characteristics of Zika virus infection among international travelers: A prospective study from a Spanish referral unit. Garcia J Martinez-Sanchez N Rodriguez R Herrero B Lopez F Bartha JL Elorza MD Lafuente MC Hortelano MG M-BE, editor. Travel medicine and infectious disease. 2020;33: 101543. https://doi.org/10.1016/j.tmaid.2019.101543 pmid:31805400
- 64. el Sahly HM, Gorchakov R, Lai L, Natrajan MS, Patel SM, Atmar RL, et al. Clinical, Virologic, and Immunologic Characteristics of Zika Virus Infection in a Cohort of US Patients: Prolonged RNA Detection in Whole Blood. Open forum infectious diseases. 2019;6: ofy352. https://doi.org/10.1093/ofid/ofy352
- 65. Adams Laura; Bello-Pagan Melissa; Lozier Matthew; Ryff KR; et al. Update: Ongoing Zika Virus Transmission—Puerto Rico, November 1, Epidemiologic Surveillance. 2016;65: 774–779. pmid:27490087
- 66. Armstrong P, Hennessey M, Adams M, Cherry C, Chiu S, Harrist A, et al. Armstrong 2016 mm6511e1 Zika travel cases. 2016;65: 286–289.
- 67. Azeredo EL, dos Santos FB, Barbosa LS, Souza TMA, Badolato-Corrêa J, Sánchez-Arcila JC, et al. Clinical and Laboratory Profile of Zika and Dengue Infected Patients: Lessons Learned From the Co-circulation of Dengue, Zika and Chikungunya in Brazil. PLoS Currents. 2018;10. pmid:29588874
- 68. Boggild AK, Geduld J, Libman M, Yansouni CP, McCarthy AE, Hajek J, et al. Surveillance report of Zika virus among Canadian travellers returning from the Americas. Cmaj. 2017;189: E334–E340. pmid:28280063
- 69. Brasil P, Calvet GA, Siqueira AM, Wakimoto M, de Sequeira PC, Nobre A, et al. Zika Virus Outbreak in Rio de Janeiro, Brazil: Clinical Characterization, Epidemiological and Virological Aspects. PLoS Neglected Tropical Diseases. 2016;10: 1–13. pmid:27070912
- 70. Brenciaglia M, Noël TP, Fields PJ, Bidaisee S, Myers TE, Nelson WM, et al. Clinical, Serological, and Molecular Observations from a Case Series Study during the Asian Lineage Zika Virus Outbreak in Grenada during 2016. Canadian Journal of Infectious Diseases and Medical Microbiology. 2018;2018: 1–9. pmid:29623138
- 71. da Silva Brito KG 1, dos Santos EB 1, dos Santos Maia Lucas L 1, Orsini Marco 2, 3 Fiorelli R2, Teixeira Silmar, 4 Ayres C 4, Correia Luan, 4 Bastos Victor Hugo 4, et al. Prevalence of neurological complications associated with Zika virus in a brazilian metropolis. 2018;10: 111–117. pmid:30232131
- 72. Daudens-Vaysse E, Ledrans M, Gay N, Ardillon V, Cassadou S, Najioullah F, et al. Zika emergence in the French Territories of America and description of first confirmed cases of Zika virus infection on Martinique, November 2015 to February 2016. Eurosurveillance. 2016;21. pmid:27447300
- 73. Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. New England Journal of Medicine. 2009;360: 2536–2543. pmid:19516034
- 74. Francis L, Hunte S-A, Valadere AM, Polson-Edwards K, Asin-Oostburg V, Hospedales CJ. Zika virus outbreak in 19 English- and Dutch-speaking Caribbean countries and territories, 2015–2016. Revista Panamericana de Salud Pública. 2018;42. pmid:31093148
- 75. Hall V, Walke 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. Morbidity and Mortality Weekly Report. 2018;67: 265–269. pmid:29518067
- 76. Hamer DH, Barbre KA, Chen LH, Grobusch MP, Schlagenhauf P, Goorhuis A, et al. Travel-associated Zika virus disease acquired in the americas through February 2016: A GeoSentinel analysis. Annals of Internal Medicine. 2017;166: 99–108. pmid:27893080
- 77. 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 Diseases. 2017;17: 813–821. pmid:28527892
- 78. Huits R, Maniewski U, Van Den Bossche D, Lotgering E, Tsoumanis A, Cnops L, et al. A cross-sectional analysis of Zika virus infection in symptomatic and asymptomatic non-pregnant travellers: Experience of a European reference center during the outbreak in the Americas. Travel Medicine and Infectious Disease. 2019;27: 107–114. pmid:30205195
- 79. Jimenez Corona ME, de la Garza Barroso AL, Rodriguez Martínez JC, Luna Guzmán NI, Ruiz Matus C, Díaz Quiñonez JA, et al. Clinical and Epidemiological Characterization of Laboratory-Confirmed Authoctonous Cases of Zika Virus Disease in Mexico. PLoS Currents. 2016;8: ecurrents.outbreaks.a2fe1b3d6d71e24ad2b5afe9828240. pmid:27158557
- 80. Journel I, Andrécy LL, Metellus D, Pierre JS, Faublas RM, Juin S, et al. Transmission of Zika virus—Haiti, October 12, 2015–September 10, 2016. Morbidity and Mortality Weekly Report. 2017;66: 172–176. pmid:28207688
- 81. Lee CT, Vora NM, Bajwa W, Boyd L, Harper S, Kass D, et al. Zika virus surveillance and preparedness-new york city, 2015–2016. Morbidity and Mortality Weekly Report. 2016;65: 629–634. https://doi.org/10.15585/mmwr.mm6524e3 pmid:27337505
- 82. Malta JMAS, Vargas A, Leite PLE, Percio J, Coelho GE, Ferraro AHA, et al. Síndrome de Guillain-Barré e outras manifestações neurológicas possivelmente relacionadas à infecção pelo vírus Zika em municípios da Bahia, 2015. Epidemiologia e servicos de saude: revista do Sistema Unico de Saude do Brasil. 2017;26: 9–18. pmid:28226004
- 83. McGibbon E, Moy M, Vora NM, Dupuis A, Fine A, Kulas K, et al. Epidemiological characteristics and laboratory findings of zika virus cases in New York city, January 1, 2016-June 30, 2017. Vector-Borne and Zoonotic Diseases. 2018;18: 382–389. pmid:29742003
- 84. Méndez N, Oviedo-Pastrana M, Mattar S, Caicedo-Castro I, Arrieta G. Zika virus disease, microcephaly and Guillain-Barré syndrome in Colombia: Epidemiological situation during 21 months of the Zika virus outbreak, 2015–2017. Archives of Public Health. 2017;75: 1–11. pmid:28074128
- 85. Millet JP, Montalvo T, Bueno-Marí R, Romero-Tamarit A, Prats-Uribe A, Fernández L, et al. Imported zika virus in a European city: How to prevent local transmission? Frontiers in Microbiology. 2017;8: 1–13. pmid:28197127
- 86. Parra B, Lizarazo J, Jiménez-Arango JA, Zea-Vera AF, González-Manrique G, Vargas J, et al. Guillain-Barré syndrome associated with Zika virus infection in Colombia. New England Journal of Medicine. 2016;375: 1513–1523. pmid:27705091
- 87. Rozé B, Najioullah F, Fergé JL, Dorléans F, Apetse K, Barnay JL, et al. Guillain-Barré Syndrome Associated with Zika Virus Infection in Martinique in 2016: A Prospective Study. Clinical Infectious Diseases. 2017;65: 1462–1468. pmid:29020245
- 88. Ryan SJ, Carlson CJ, Stewart-Ibarra AM, Borbor-Cordova MJ, Romero MM, Cox SA, et al. Outbreak of zika virus infections, Dominica, 2016. Emerging Infectious Diseases. 2017;23: 1926–1927. pmid:29048289
- 89. Schirmer PL, Wendelboe A, Lucero-Obusan CA, Ryono RA, Winters MA, Oda G, et al. Zika virus infection in the Veterans Health Administration (VHA), 2015–2016. PLoS Neglected Tropical Diseases. 2018;12: 2015–2016. pmid:29795560
- 90. Thomas DL, Sharp TM, Torres J, Amstrong PA. Local Transmission of Zika Virus—Puerto Rico,. Morbidity and Mortality Weekly Report. 2016;65: 154–159. pmid:26890470
- 91. Vroon P, Roosblad J, Poese F, Wilschut J, Codrington J, Vreden S, et al. Severity of acute Zika virus infection: A prospective emergency room surveillance study during the 2015–2016 outbreak in Suriname. IDCases. 2017;10: 117–121. pmid:29147641
- 92. Webster-Kerr K, Christie C, Grant A, Chin D, Burrowes H, Clarke K, et al. Emergence of Zika Virus Epidemic and the National Response in Jamaica. West Indian Medical Journal. 2017;65: 24–26. pmid:28375542
- 93. Grajales-Muniz C, Borja-Aburto VH, Cabrera-Gaytan DA, Rojas-Mendoza T, Arriaga-Nieto L, Vallejos-Paras A. Zika virus: Epidemiological surveillance of the Mexican Institute of Social Security. PloS one. 2019;14: e0212114. https://doi.org/10.1371/journal.pone.0212114 pmid:30742671
- 94. Valle J, Eick SM, Fairley JK, Waggoner JJ, Goodman RA, Rosenberg E, et al. Evaluation of Patients for Zika Virus Infection in a Travel Clinic in the Southeast United States, 2016. Southern Medical Journal. 2019;112: 45–51. pmid:30608632
- 95. Fernández Martínez B, Martínez Sánchez E v, Díaz García O, Gómez Barroso D, Sierra Moros MJ, Cano Portero R. Zika virus disease in Spain. Surveillance results and epidemiology on reported cases, 2015–2017. Medicina clinica. 2019;153: 6–12. pmid:30797578
- 96. Silva MMO, Tauro LB, Kikuti M, Anjos RO, Santos VC, Goncalves TSF, et al. Concomitant Transmission of Dengue, Chikungunya, and Zika Viruses in Brazil: Clinical and Epidemiological Findings from Surveillance for Acute Febrile Illness. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2019;69: 1353–1359. https://doi.org/10.1093/cid/ciy1083
- 97. Mercado-Reyes M, Acosta-Reyes J, Navarro-Lechuga E, Corchuelo S, Rico A, Parra E, et al. Dengue, chikungunya and zika virus coinfection: results of the national surveillance during the zika epidemic in Colombia. Epidemiology & Infection. 2019;147: e77–e77. pmid:30869010
- 98. Guanche Garcell H, Gutierrez Garcia F, Ramirez Nodal M, Ruiz Lozano A, Perez Diaz CR, Gonzalez Valdes A, et al. Clinical relevance of Zika symptoms in the context of a Zika Dengue epidemic. Journal of infection and public health. 2020;13: 173–176. https://doi.org/10.1016/j.jiph.2019.07.006 pmid:31399372
- 99. del Carpio-Orantes L, Moreno-Aldama N, Sánchez-Díaz J. Clinical characterization of dengue, chikungunya and Zika during 2016 in Veracruz, Mexico. Medicina Interna de Mexico. 2020;36: 147–152.
- 100. Castaneda-Martinez F, Valdespino-Padilla M. Characterization of Zika outbreak in rightful owner of IMSS in Lazaro Cardenas, Michoacan, 2016. Medicina Interna de Mexico. 2020;36: 50–58.
- 101. Sharma R, Agarwal M, Gupta M, Singh R, Mahavar S, Sharma R, et al. Clinicodemographic profiling of zika outbreak in Jaipur, Rajasthan. Indian Journal of Medical Specialities. 2019;10: 184–189.
- 102. Vazquez C, de la Fuente AG, Villalba S, Torales J, Gamarra ML, Ortega MJ, et al. Retrospective detection of Zika virus transmission in Paraguay—January to December 2016. Weekly Epidemiological Record. 2019;94: 161–165. Available: http://myaccess.library.utoronto.ca/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=rzh&AN=135622635&site=ehost-live.
- 103. Phan LT, Luong QC, Do THH, Chiu CH, Cao TM, Nguyen TTTTV, et al. Findings and lessons from establishing Zika virus surveillance in southern Viet Nam, 2016. Western Pacific surveillance and response journal: WPSAR. 2019;10: 22–30. https://doi.org/10.5365/wpsar.2018.9.2.014 pmid:31720051
- 104.
World Health Organization. Zika virus disease. [cited 31 Jan 2019]. Available: https://www.who.int/csr/disease/zika/case-definition/en/.
- 105. Anaya JM, Rodríguez Y, Monsalve DM, Vega D, Ojeda E, González-Bravo D, et al. A comprehensive analysis and immunobiology of autoimmune neurological syndromes during the Zika virus outbreak in Cúcuta, Colombia. Journal of Autoimmunity. 2017;77: 123–138. pmid:28062188
- 106. Jimenez Corona ME, De la Garza Barroso AL, Rodriguez Martínez JC, Luna Guzmán NI, Ruiz Matus C, Díaz Quiñonez JA, et al. Clinical and Epidemiological Characterization of Laboratory-Confirmed Authoctonous Cases of Zika Virus Disease in Mexico. PLoS Currents. 2016;8: ecurrents.outbreaks.a2fe1b3d6d71e24ad2b5afe9828240. pmid:27158557
- 107. Francis L, Hunte S-A, Valadere AM, Polson-Edwards K, Asin-Oostburg V, Hospedales CJ. Zika virus outbreak in 19 English- and Dutch-speaking Caribbean countries and territories, 2015–2016. International Journal of Infectious Diseases. 2018;73: 183.
- 108. Daudens-Vaysse E, Ledrans M, Gay N, Ardillon V, Cassadou S, Najioullah F, et al. Zika emergence in the French territories of america and description of first confirmed cases of Zika virus infection on Martinique, November 2015 to February 2016. Eurosurveillance. 2016;21: 1–6. pmid:27447300
- 109. GeurtsvanKessel CH, Islam Z, Islam MB, Kamga S, Papri N, van de Vijver DAMC, et al. Zika virus and Guillain–Barré syndrome in Bangladesh. Annals of Clinical and Translational Neurology. 2018;5: 606–615. pmid:29761123
- 110. McGibbon E, Moy M, Vora NM, Dupuis A, Fine A, Kulas K, et al. Epidemiological characteristics and laboratory findings of zika virus cases in New York city, January 1, 2016-June 30, 2017. Vector-Borne and Zoonotic Diseases. 2018;18: 382–389. pmid:29742003
- 111. Roehrig JT, Hombach J, Barrett ADT. Guidelines for plaque-reduction neutralization testing of human antibodies to dengue viruses. Viral Immunology. 2008;21: 123–32. pmid:18476771
- 112.
Pan American Health Organization. Zika Resources: Case Definitions. 2016 [cited 23 Aug 2019]. Available: https://www.paho.org/hq/index.php?option=com_content&view=article&id=11117:zika-resources-case-definitions&Itemid=41532&lang=en.
- 113. de Laval F, d’Aubigny H, Mathéus S, Labrousse T, Ensargueix AL, Lorenzi EM, et al. Evolution of symptoms and quality of life during Zika virus infection: A 1-year prospective cohort study. Journal of Clinical Virology. 2018;109: 57–62. pmid:30523784
- 114. Dirlikov E, Major CG, Medina NA, Lugo-Robles R, Matos D, Muñoz-Jordan JL, et al. Clinical features of Guillain-Barré syndrome with vs without zika virus infection, Puerto Rico, 2016. JAMA Neurology. 2018;75: 1089–1097. pmid:29799940
- 115. van Koningsveld R, Steyerberg EW, Hughes RA, Swan A V., van Doorn PA, Jacobs BC. A clinical prognostic scoring system for Guillain-Barré syndrome. Lancet Neurology. 2007;6: 589–94. pmid:17537676
- 116. Huybrechts KF, Caro JJ, Xenakis JJ, Vemmos KN. The prognostic value of the modified Rankin scale score for long-term survival after first-ever stroke: Results from the Athens stroke registry. Cerebrovascular Diseases. 2008;26: 381–7. pmid:18753743
- 117. Hughes RAC, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial of prednisolone in acute polyneuropathy. The Lancet. 1978;2: 750–3. pmid:80682
- 118. Matsushita M, Kitoh H, Itomi K, Kitakoji T, Iwata K, Mishima K, et al. Orthopaedic manifestations and diagnostic clues in children with Guillain-Barré syndrome. Journal of Children’s Orthopaedics. 2013;7: 177–182. pmid:23755090
- 119. Boggild AK, Geduld J, Libman M, Yansouni CP, McCarthy AE, Hajek J, et al. Surveillance report of Zika virus among Canadian travellers returning from the Americas. Cmaj. 2017;189: E334–E340. pmid:28280063
- 120. Azeredo EL, dos Santos FB, Barbosa LS, Souza TMA, Badolato-Corrêa J, Sánchez-Arcila JC, et al. Clinical and Laboratory Profile of Zika and Dengue Infected Patients: Lessons Learned From the Co-circulation of Dengue, Zika and Chikungunya in Brazil. PLoS Currents. 2018;10: ecurrents.outbreaks.0bf6aeb4d30824de63c4d5d745b217. pmid:29588874
- 121. Simon O, Acket B, Forfait C, Girault D, Gourinat AC, Millon P, et al. Zika virus outbreak in New Caledonia and Guillain-Barré syndrome: a case-control study. Journal of NeuroVirology. 2018;24: 362–368. pmid:29594985
- 122. Barbi L, Coelho AVC, Alencar LCA de, Crovella S. Prevalence of Guillain-Barré syndrome among Zika virus infected cases: a systematic review and meta-analysis. Brazilian Journal of Infectious Diseases. 2018. pmid:29545017
- 123. Capasso A, Ompad DC, Vieira DL, Wilder-Smith A, Tozan Y. Incidence of Guillain-BarréSyndrome (GBS) in Latin America and the Caribbean before and during the 2015–2016 Zika virus epidemic: A systematic review and meta-analysis. PLoS Neglected Tropical Diseases. 2019;13. pmid:31449532
- 124. Bautista LE. Zika virus infection and risk of Guillain-Barré syndrome: A meta-analysis. Journal of the Neurological Sciences. 2019;403: 99–105. pmid:31255970
- 125. Uncini A, Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: Where do we stand? Clinical Neurophysiology. 2018;129: 2586–93. pmid:30419502
- 126. Uncini A, Shahrizaila N, Kuwabara S. Zika virus infection and Guillain-Barré syndrome: A review focused on clinical and electrophysiological subtypes. Journal of Neurology, Neurosurgery and Psychiatry. 2017;88: 266–271. pmid:27799296
- 127. Leonhard SE, Bresani-Salvi CC, Lyra Batista JD, Cunha S, Jacobs BC, Ferreira MLB, et al. Guillain-barré syndrome related to zika virus infection: A systematic review and meta-analysis of the clinical and electrophysiological phenotype. PLoS Neglected Tropical Diseases. 2020;14: 1–24. pmid:32339199
- 128. Cardona-Ospina JA, Henao-SanMartin V, Acevedo-Mendoza WF, Nasner-Posso KM, Martínez-Pulgarín DF, Restrepo-López A, et al. Fatal Zika virus infection in the Americas: A systematic review. International Journal of Infectious Diseases. 2019;88: 49–59. pmid:31499212
- 129. Alexander L, Lopes B, Richhetti-Masterson K, Yeatts K. Cross-Sectional Studies. In: ERIC Notebook Section Edition. UNC CH Department of Epidemiology [Internet]. [cited 31 Jan 2019]. Available: https://sph.unc.edu/files/2015/07/nciph-ERIC8-rev.pdf.
- 130. Adhikari NKJ, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. The Lancet. 2010;376: 1339–1346. pmid:20934212
- 131. Jamali Moghadam SR, Bayrami S, Jamali Moghadam S, Golrokhi R, Golsoorat Pahlaviani F, SeyedAlinaghi SA. Zika virus: A review of literature. Asian Pacific Journal of Tropical Biomedicine. 2016;6: 989–94.
- 132. Noorbakhsh F, Abdolmohammadi K, Fatahi Y, Dalili H, Rasoolinejad M, Rezaei F, et al. Zika virus infection, basic and clinical aspects: A review article. Iranian Journal of Public Health. 2019;48: 20–31. pmid:30847308
- 133. Agumadu VC, Ramphul K. Zika Virus: A Review of Literature. Cureus. 2018;10: e3025. pmid:30254814