A severe neurological disorder, Guillain-Barré syndrome (GBS) is the leading cause of acute flaccid paralysis. Enhanced surveillance of GBS in Latin America and the Caribbean (LAC) following the 2015–2016 Zika virus (ZIKV) epidemic presents an opportunity to estimate, for the first time, the regional incidence of GBS. For this systematic review and meta-analysis, we searched nine scientific databases and grey literature from January 1,1980 to October 1,2018. Sources with primary data on incident GBS cases in LAC within a well-defined population and timeframe, published in English, Spanish, Portuguese, or French, were included. We calculated the annual GBS incidence rates (IRs) and 95% confidence intervals (CIs) for each source based on published data. Following an assessment of heterogeneity, we used random-effects meta-analysis to calculate the pooled annual IR of GBS. The study is registered with PROSPERO, number CRD42018086659. Of the 6568 initial citation hits, 31 were eligible for inclusion. Background annual GBS IRs in Latin America ranged from 0. 40 in Brazil to 2. 12/100,000 in Chile. The pooled annual IR in the Caribbean was 1. 64 (95% CI 1. 29–2. 12, I2<0. 01, p = 0. 44). During the ZIKV epidemic, GBS IRs ranged from 0. 62 in Mexico to 9. 35/100,000 in Martinique. GBS increased 2. 6 (95% CI 2. 3–2. 9) times during ZIKV and 1. 9 (95% CI 1. 1–3. 4) times during chikungunya outbreaks over background rates. A limitation of this review is that the studies included employed different methodologies to find and ascertain cases of GBS, which could contribute to IR heterogeneity. In addition, it is important to consider that data on GBS are lacking for many countries in the region. Background IRs of GBS appear to peak during arboviral disease outbreaks. The current review contributes to an understanding of the epidemiology of GBS in the LAC region, which can inform healthcare system planning and preparedness, particularly during arboviral epidemics. Registered with PROSPERO: CRD42018086659.
A rare but severe autoimmune neuropathy, Guillain-Barré syndrome (GBS) is the most common type of acute flaccid paralysis (AFP) [1]. Often preceded by infections such as Campylobacter jejuni, about 25% of patients require mechanical ventilation [2]. Prognosis varies greatly based on GBS type and urgent care availability [2–5]. Many patients report residual deficits, including pain, limited mobility, and fatigue, years after disease onset [4,6–8]. Mortality rates range from 3−7% [3,9], although they can be higher in settings with limited access to intensive care [10,11]. In 2008, the total annual cost of GBS in the U. S. alone was estimated at $1. 7 billion (95% CI $1. 6 to 1. 9 billion) [12]. The median global incidence rate (IR) of GBS was estimated at 1. 10 per 100,000 person-years (range, 0. 81–1. 89) [13]. However, this estimate was based on data from studies conducted in Europe and North America [13]. Worldwide, there are large variations in the incidence of GBS, ranging from 0. 38 (95% CI 0. 25–0. 56) to 2. 53 (95% CI 1. 87–3. 56) per 100,000, with most studies reporting annual IRs between 1. 1 and 1. 8 per 100,000 [14]. Prior to the 2015–2016 Zika virus (ZIKV) epidemic in Latin America and the Caribbean (LAC), there were few published studies on the incidence of GBS in the region, with an exception among children. As part of polio eradication efforts, AFP in children under 15 years of age has been a notifiable event in all LAC countries since the 1980s [15–17]. Using polio eradication surveillance data, in 2010, Landaverde et al. estimated 0. 82 cases of GBS per 100,000 among children under 15 years of age (range, 0. 72–0. 90) [18]. ZIKV is an enveloped positive-strand RNA member of the Flavivirus genus in the Flaviviridae family. Other flaviviruses include dengue, yellow fever, West Nile virus and Japanese encephalitis virus, many of which are associated with neurological disease. Like these viruses, ZIKV is principally transmitted by a mosquito bite and is thus described as an arthropod-borne virus or ‘arbovirus’. Its primary vector is the Aedes aegypti mosquito, which transmits the virus between humans and is widespread in tropical regions [19]. ZIKV is known to be neurotropic; infection halts proliferation of neural progenitor cells and may induce cell death, leading to ZIKV-related microcephaly [20]. Beyond congenital Zika syndrome, direct viral invasion as well as a parainfective or postinfective autoimmune response may contribute to GBS pathogenesis [21,22]. An association between GBS and ZIKV was first established in a case-control study in French Polynesia [23]. During the 2015–2016 ZIKV epidemic, many countries in LAC reported increases in GBS cases, particularly in the beginning of 2016 [24,25]. In 2016, the World Health Organization (WHO) concluded that ZIKV infection was a plausible trigger for GBS [26]. The chikungunya (CHIKV) [27,28] and dengue (DENV) viruses [29], two other arboviruses that are endemic in parts of the LAC region, have also been investigated as possible GBS antecedent infectious agents. Enhanced GBS surveillance [30] and increased research present a unique opportunity to assess the background IR of GBS in the LAC region in the aftermath of recent arboviral epidemics. This review aims to assess the background population-wide incidence of GBS in Latin America and the Caribbean through a synthesis of observational studies. For the purposes of this study, “background incidence” refers to the rates reported during time periods with no arboviral epidemic. To our knowledge this is the first systematic review on GBS in this region. A secondary aim of this review is to ascertain the incidence of GBS during arboviral disease outbreaks.
Our protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA-P) guidelines and the Meta-analyses of Observational Studies in Epidemiology (MOOSE) Checklist (see S1 and S2 Files) [31]. We developed the search word criteria by reviewing PubMed MeSH and Embase Emtree subject headings and keywords. We searched nine electronic databases. Our full search terms are provided in the appendix. We conducted a grey literature search on OpenGrey and OAIster and hand-searched relevant journals and the bulletins of ministries of health cited in bibliographic references of the articles selected for full-text review (see S3 File). We also reviewed the references of all included articles. Inclusion criteria were peer-reviewed and government publications that presented primary data on incident GBS cases in LAC within a well-defined population and timeframe and that were published in English, Spanish, Portuguese, or French between January 1,1980 to October 1,2018. The search timeframe was decided upon to update the worldwide review by McGrogan [14] from 1980 to 2008. Review papers were excluded. After removing duplicates, two authors (AC, DLV) independently screened articles by title and abstract based on the inclusion criteria and agreed on those for full-text review. A standard extraction form was developed and tested for reliability. Disagreements were resolved by these two reviewers. One author (AC) extracted the following items from the included articles onto the extraction form: study design, country, region, data collection year (s), population size, age, sex, GBS type, GBS diagnostic criteria, incident cases, statistical measures, and circulating arboviral diseases (ZIKV, DENV, or CHIKV). Three other authors (DLV, DCO, YT) extracted data from 30% of the records for quality control. All data were standardized to annual mean IR by dividing the number of GBS cases reported by the number of weeks of data capture and multiplying the result by 52 weeks. The result was entered as annual GBS cases into the software program, and together with the base population, was used to calculate the annual IR per 100,000 persons. When necessary, we attempted to contact the authors to obtain clarifying information. Three authors (AC, DCO, YT) assessed studies for risk of bias using a tool developed for prevalence studies [32]. To reduce publication bias [33], we searched the grey literature, institutional websites, and conference abstracts. The study protocol was registered with PROSPERO (CRD42018086659, available at https: //www. crd. york. ac. uk/prospero/display_record. php? RecordID=86659). We performed the meta-analysis using the metaprop command in Stata version 15 (College Station, Texas, USA). Annualized GBS cases and population sizes were entered for every selected study. Given high heterogeneity, we performed sub-group analyses by: geography (Latin America versus the Caribbean; Southern Cone, Central and North America, and the Caribbean); time (before and during an epidemic outbreak); population (all and under 15 years of age); and case ascertainment (administrative data using ICD codes only and medical record review). Double arcsine transformation and random-effects models were used to calculate pooled IR estimates of GBS [34].
Among the studies in Latin America that reported background GBS IRs in all ages, the highest were reported in Chile (2. 12 per 100,000; 95% CI 1. 90–2. 36) [44] and Argentina (2. 06 per 100,000; 95% CI 0. 43–6. 03) [39], and the lowest in Brazil (0. 40 per 100,000; 95% CI 0. 20–0. 71) [42] (Fig 2). High heterogeneity in Latin America and in other subgroup analyses precluded us from pooling the proportions. The pooled annual IR in the Caribbean was 1. 64 per 100,000 (95% CI 1. 29–2. 12, I2 = 0. 00, p = 0. 44) (Fig 3). There were large annual fluctuations in GBS IRs in any given geographic location. In Chile, over a 12-year period, IRs ranged from 1. 61 per 100,000 (n = 250 cases) in 2001 to 2. 35 per 100,000 (n = 402 cases) in 2010 [44]. Over a 14-year period, Dourado et al. [42] reported a range of 0. 12 to 0. 66 per 100,000 in Rio Grande do Norte, Brazil. Another multi-year study from Brazil estimated mean annual IRs of 0. 4 per 100,000 (range, 0. 3–0. 6) [43]. In the Caribbean island of Aruba, over an 11-year period, Suryapranata et al. reported a range of 1 to 11 cases of GBS, the latter occurring during an outbreak of C. jejuni (IRs ranged 1. 0–10. 37 per 100,000). There was less fluctuation in IRs in Argentina, ranging from 0. 56 per 100,000 in 2011 to 0. 76 per 100,000 in 2010 over a 7-year period [40]. However, the IR of GBS among members of a private health maintenance organization in Buenos Aires averaged 1. 99 per 100,000 over an 8-year period [39]. Of the studies reporting background IRs in children under 15, the lowest rates were in Brazil at 0. 40 per 100,000 [18], followed by Paraguay at 0. 72 per 100,000 [45], and the highest rates in El Salvador at 3. 86 per 100,000 [18], Chile at 1. 63 per 100,000 [18], and Honduras at 1. 37 per 100,000 [37]. The age-specific distribution of GBS in the pediatric population varied widely across countries. Two multi-country studies found the highest GBS IR in the 1−4 age group: Olivé et al. reported that 47% of the GBS cases were in children 1−4 years of age [35] and Silveira et al. reported an average IR of 0. 86 per 100,000 (95% CI 0. 78–0. 89) in this age group as compared to 0. 52 per 100,000 (95% CI 0. 49–0. 53) among 5−14 year-olds [36]. In Paraguay, the IRs ranged from 1. 7 per 100,000 among 1−4 year-olds to 0. 1 per 100,000 among 10−14 year-olds [45]. In Brazil, a similar trend was reported, with 40% of the cases reported in children under 5 [41]. However, in Chile the IRs were higher among 5−9 year-old children (2. 23 per 100,000) than among 0−4 year−olds (2. 17 per 100,000) [44]. GBS distribution by age in the general population did not follow a consistent pattern across countries. In Chile, the IR showed a bimodal distribution with a peak in the youngest ages (2. 23 per 100,000 in 5−9 year-olds), and increased from 1. 22 per 100,000 among 20−29 year-olds to 4. 30 per 100,000 among 70−79 years-olds [44]. In São Paulo, Brazil, GBS was most common among 15−40 year-olds (0. 15 per 100,000), and the IR was lowest in the over 60 (0. 60 per 100,000) and under 15 (0. 80 per 100,000) age groups [43]. In Rio Grande do Norte, Brazil, half of the cases were recorded among under 20 years-olds [42]. In Argentina, 37% of the GBS cases were reported in children under 14 years of age [40]. Reporting of higher IRs among children might be due to higher case detection resulting from vaccination safety and polio eradication surveillance efforts. Studies consistently found a higher burden of GBS among males. In studies of children 15 years of age and younger, the highest male-to-female ratio was documented in El Salvador (1. 8: 1) [35] and the lowest in Brazil (1. 2: 1) [41] and Honduras 1. 3: 1 [37]. Among all ages, the highest male-to-female ratio was documented in Aruba (2. 3: 1) [46], followed by Argentina (1. 6: 1) [40], and the lowest in Brazil (1. 3: 1) [42]. We found that 17 studies reported the GBS IR during arboviral disease outbreaks in seven countries; 14 during the 2015–2016 ZIKV epidemic, one during the 2014 CHIKV outbreak in the French West Indies, and 1 during DENV, CHIKV and ZIKV outbreaks in Martinique (See Fig 4). The IR in the French West Indies during the 2014 CHIKV epidemic was 3. 45 per 100,000 persons [27], representing a two-fold increase from 1. 77 per 100,000 during 2011–2013 (p = 0. 006) [27]. The IR in Martinique increased by 4. 4 times to 9. 35 per 100,000 during the ZIKV epidemic from a mean annual IR of 2. 12 per 100,000 during 2006–2015 [Incidence rate ratio (IRR) (2016 vs. 2006–2015) = 4. 52; 95% CI 2. 80–7. 64] [62]. In Puerto Rico, the IR increased by 2. 1 times during the ZIKV epidemic from 1. 7 to 3. 5 per 100,000 [IRR (2016 vs. 2012–2015) = 2. 06; 95% CI 1. 51–2. 85] [48,63]. In South America, there was substantial heterogeneity in the GBS IRs during the 2015−2016 ZIKV epidemic for the population as a whole, ranging from 7. 63 per 100,000 in Barranquilla, Colombia [58], to 0. 71 per 100,000 in the Brazilian state of Piauí [54]. In a multi-year study, Barcellos et al. reported a 2. 7 (IRR (2015–2016 vs. 2008–2015) = 2. 7; 95% CI 2. 38–3. 07) increase in the rate of GBS hospitalizations in Brazil’s Northeast region during the peak of the ZIKV epidemic as compared to the mean rate in the eight years preceding the epidemic [60]. In Colombia, Machado et al. reported over a two-fold increase in GBS diagnoses during the peak of the ZIKV epidemic as compared to baseline rates (IRR (2016 vs. 2014–2015) = 2. 29; 95% CI 1. 69–3. 14) [61]. In Veracruz, Mexico, del Carpio Orantes reported a GBS IR of 0. 62 per 100,000 during the ZIKV epidemic in 2016 [49]. We performed sub-group analyses by case-ascertainment (i. e. , administrative data based on ICD codes only versus both administrative data and medical record review) to assess if the IR heterogeneity was due to this factor. We found significant within-group heterogeneity but not between-group heterogeneity, indicating that case ascertainment did not significantly bias the IRs. This held true when we performed a region-wide analysis, and when we analyzed Latin American and the Caribbean sub-regions separately (See S1 Fig).
Data on GBS, both historical and current, are lacking for many countries in the region. With the exception of studies using AFP data, most are recent and from ZIKV-affected countries, and baseline data are often lacking. Publication bias in favor of significant results may have limited the availability of studies that found no association between arboviral epidemics and GBS. On the other hand, ZIKV’s high public visibility most likely led to increased scientific research and publications on GBS as well as surveillance (i. e. , detection) bias, particularly in countries affected by the emerging arbovirus. Few studies reported data from Central America and Mexico. Therefore, estimates for this sub-region have a high risk of bias. All but two studies reported effect sizes for the outcome of interest. However, we addressed this limitation by calculating 95% confidence intervals for all studies. Methodological differences in case finding limit comparability across studies. The specificity and sensitivity of administrative data varies by setting [48,77]. Rates of GBS based on administrative records or passive surveillance systems, without medical record review, may be prone to over-reporting [48] and under-reporting [35,78], respectively. We opted to include surveillance and administrative data because of the paucity of data available. The high cost of capture-recapture methods to compare sensitivity of case identification and ascertainment methods of a rare syndrome limits the feasibility of such studies to assess GBS incidence nationwide. Several researchers have accepted the use of administrative data as a viable low-cost option to assess background GBS IRs [40,44]. A limitation of this review is that studies employed different methodologies to ascertain GBS cases. Diagnosing GBS is complex and based on clinical observation and electrophysiological studies. Specialists who can properly diagnose GBS may be unavailable in resource-limited settings. Natural annual variations in incidence may be masked or exacerbated by imperfect case identification. A strength of this research is that all included studies are population based. In addition, many of the studies are multi-year in duration, with a mean of 7. 2 years for studies that analyzed background GBS IRs. This gives us a robust estimate of GBS incidence that balances out natural fluctuations in annual IRs. Another strength is the application of a thorough search methodology and inclusion of most languages spoken in LAC. Inclusion of ministry of health bulletins data served to balance publication bias. Some of the included studies were not carried out with the sole purpose of measuring GBS IRs. While the studies that focused on IR calculations tended to adjust the rates based on population age structures, others did not. This introduces a source of variability. Some studies reported incidence by person-years and others as annual incidence. We addressed this issue by calculating all IRs. Since GBS is triggered by a variety of antecedent infections, baseline incidence of GBS is critical for detecting and monitoring infectious disease outbreaks. The LAC region has been a pioneer in monitoring of GBS in children over the last 30 years [16]. Countries such as Colombia and Brazil have monitored GBS as part of DENV eradication programs [57,79]. The ZIKV epidemic and the reported increases in GBS in the Americas have made GBS a notifiable condition in many countries. As the ZIKV epidemic has spread beyond the Americas [80–82], it is important that those countries are particularly prepared for GBS surveillance and management. Enhanced surveillance and increased research have provided us with new data to assess GBS incidence in this region. Because of its severity and lethality in the absence of adequate care, investments are needed to provide information on GBS to populations at-risk and to build healthcare providers’ capacity to diagnose GBS and follow appropriate care protocols [83,84]. GBS poses an additional burden to health care systems, particularly in resource-limited settings.
A severe neurological disorder, Guillain-Barré syndrome (GBS) is the leading cause of acute flaccid paralysis. This is the first systematic review on GBS incidence in Latin America and the Caribbean before and during arboviral disease outbreaks. There is a large sub-regional and annual fluctuation in the incidence of GBS. Background annual GBS incidence rates (IRs) in Latin America ranged from 0. 40 in Brazil to 2. 12/100,000 in Chile. The pooled annual IR in the Caribbean was 1. 64 (95% CI 1. 29–2. 12, I2<0. 01, p = 0. 44). During the ZIKV epidemic, GBS IRs ranged from 0. 62 in Mexico to 9. 35/100,000 in Martinique. GBS increased 2. 6 times during ZIKV and 1. 9 times during chikungunya outbreaks over background rates. GBS is a costly disease, which can result in long-term disability and high mortality rates in resource constrained healthcare settings. Because GBS can be triggered by arboviral infections, baseline incidence of GBS is critical for detecting neglected tropical disease outbreaks. The current review contributes to an understanding of the epidemiology of GBS in the LAC region, which can inform healthcare system planning and preparedness.
medicine and health sciences
pathology and laboratory medicine
chikungunya infection
pathogens
immunology
geographical locations
microbiology
tropical diseases
viruses
north america
clinical medicine
rna viruses
neglected tropical diseases
caribbean
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south america
medical microbiology
microbial pathogens
arboviral infections
guillain-barre syndrome
brazil
people and places
diagnostic medicine
colombia
clinical immunology
flaviviruses
viral pathogens
autoimmune diseases
biology and life sciences
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zika virus
Incidence of Guillain-Barré Syndrome (GBS) in Latin America and the Caribbean before and during the 2015–2016 Zika virus epidemic: A systematic review and meta-analysis