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Abstract
Introduction Strongyloides stercoralis is an intestinal helminth ubiquitous in tropical and subtropical regions worldwide. It persists in the human host for a lifetime as a result of autoinfection and if undetected and untreated, can lead to increased morbidity and high mortality in immunocompromised individuals such as the transplant population. Transplant patients, including solid-organ and haematopoietic stem cell transplants (SOT and HSCT, respectively), are at a high risk of hyperinfection and disseminated strongyloidiasis. Unfortunately screening is often not systematically performed. Prevalence estimates of Strongyloides in this high-risk population is not well studied. Through this systematic review, we aim to summarise the descriptive evidence on Strongyloides prevalence in SOT and HSCT patients, including diagnostic and screening practices alongside the cases of hyperinfection, disseminated strongyloidiasis and the mortality rate in this population.
Methods and analyses Through the use of various online library databases, we will conduct a systematic review including relevant literature on the prevalence of Strongyloides in SOT and HSCT patients as well as studies assessing hyperinfection and disseminated strongyloidiasis in this patient population. The Population, Intervention, Comparison, Outcome and Study Design strategy and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be used to determine a final subset of studies for analysis. Quality assessment for case series and case reports will be determined by a modified quality assessment tool developed by the National Heart, Lung, and Blood Institute (NIH), and the CARE guidelines, respectively. We will provide a narrative synthesis of the findings pertaining to the primary and secondary outcomes of interest (prevalence of Strongyloides and mortality rate in transplant population, respectively) alongside the associated 95% CI. Estimates from individual studies will be pooled using a random effects model.
Ethics and dissemination This systematic review does not require formal ethical approval since no primary data will be collected. Findings will be disseminated through a peer-reviewed publication and relevant conferences.
PROSPERO registration number CRD42021269305.
- epidemiology
- tropical medicine
- diagnostic microbiology
- parasitology
- transplant medicine
- epidemiology
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Strengths and limitations of this study
Having searched numerous online databases and with no restriction on dates or languages of publication, we aim to capture the most relevant literature.
The reported Strongyloides prevalence is based on a small number of heterogeneous studies with significant variations in study regions and diagnostic methods used thereby impacting our ability to pool results.
Studies reporting prevalence of Strongyloides in transplant patients are mostly limited to case reports and case series, there by restricting our analyses to these study designs.
Introduction
Strongyloides stercoralis is an intestinal helminth ubiquitous in tropical and subtropical regions worldwide and infects 10%–40% of the population in these countries.1–4 The uncertainty in the global burden of strongyloidiasis stems from the challenges associated with the estimation of its prevalence. Recent estimates of the global prevalence of strongyloidiasis suggest 614 (95% CI 313 to 910) million people are infected.4 The reported prevalence is based on a small number of heterogeneous studies with significant variations in study regions and diagnostic methods used.5–8 Given the low sensitivity of stool-based parasitological and biomolecular methods, prevalence estimates reported in studies using only stool-based techniques is also likely underestimated.9 10 Serological testing appears to be more sensitive with sensitivity ranging from 70% to 95%. However, its specificity is of concern because of cross-reactivity with other helminths, especially in endemic countries with high burden of geohelminthiasis.10
Strongyloides is a unique parasite because it persists in the host throughout its life as a result of autoinfection. Strongyloides is often asymptomatic or causes mild symptoms that involve the gastrointestinal tract, respiratory tract, or the skin in immunocompetent hosts. In contrast, it can cause life-threatening disseminated disease in people with impaired immunity. People taking corticosteroids, coinfected with human T-cell lymphotropic virus-1, with transplant-related immunosuppression, or with haematological malignancies are at highest risk.11 12 The mortality rate of disseminated strongyloidiasis can be as high as 85%.13
In non-endemic countries, foreign born populations account for the majority of cases of strongyloidiasis. A recent systematic review and meta-analysis that summarised prevalence data for strongyloidiasis among migrants originating from endemic countries and migrating to non-endemic countries found that the overall prevalence was 12%.14 This study was limited by a lack of studies involving migrants from several world regions and the fact that diagnostic methods were often left unreported. Migrants, many of whom are from Strongyloides endemic countries, comprise a significant and increasing proportion of the population in most high-income countries such as Canada (21%), Australia (30%), Germany (17%), the UK (14%), Sweden (20%) and the USA(15%).15 The rise of migration and the increasing use of immunosuppressive therapy in many clinical conditions highlights the need for better data to determine the optimal screening and treatment strategy for Strongyloides among immunocompromised migrants.
The prevalence of Strongyloides in solid-organ transplant (SOT) and haematopoietic stem cell transplant (HSCT) patients is not well documented. Moreover, Strongyloides is not systematically screened in at-risk transplant candidates or transplant recipients which can lead to severe hyperinfection and disseminated strongyloidiasis.16–24 The numerous clinical manifestations combined with a lack of awareness may impede accurate diagnosis and contribute to the high mortality rate observed. Cases have been reported in kidney, liver, pancreas, intestine, lung SOT and HSCT. A recent study in Austria, a non-endemic country for Strongyloides, has demonstrated a seroprevalence of 3% among the kidney transplant recipients.25 A study from Malaysia, a country with high endemicity, reported a Strongyloides prevalence of 4.9% in 288 organ transplant recipients using a stool-based technique (formalin-ether concentration) which likely underestimated the prevalence in this high-risk population.26
Given the global burden of strongyloidiasis, increased migration and travel in and from non-endemic countries, increasing recipients of SOT and HSCT as well as high mortality rate of severe strongyloidiasis, it is essential to gather more data on the prevalence of Strongyloides in the transplant population to inform more robust prevalence studies and to determine the best screening strategies. Through this systematic review, we aim to consolidate the descriptive evidence specifically on the prevalence of Strongyloides infection in the SOT and HSCT in non-endemic/low-endemic and in moderate/high-endemic regions and the methods used to diagnose infections (stool-based methods and serology). As a secondary objective, we also aim to summarise the cases of hyperinfection and disseminated strongyloidiasis in the SOT and HSCT patients and consolidate the mortality rate in that population.
Methods and analysis
Search strategy and study selection
This systematic review will be prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).27 The search strategy will be developed with the assistance of a medical librarian and will consist of text words and relevant indexing to identify studies about S. stercoralis infection in SOT and HSCT candidates and recipients. The following databases were searched for relevant studies on 27 July 2021: MEDLINE (via Ovid & via PubMed); The Cochrane CENTRAL Register of Controlled Trials & Cochrane Database of Systematic Reviews (via Wiley); Embase (via Ovid); Africa-Wide Information (via EBSCO); Global Health (via Ovid); Global Index Medicus (via WHO); Scopus (via Elsevier), Latin American and Caribbean Health Sciences Literature (LILACS). Clinical trials registries (clinicaltrials.gov, International Clinical Trials Registry Platform) will also be searched. No restrictions on date and language of publication will be applied in effort to optimise the evidence to be captured. The MEDLINE search strategy will be applied to all databases with appropriate modifications (online supplemental appendix 1). In addition, further studies will be identified in Web of Science and Scopus by carrying out citation searches for the reference lists of included studies. The MEDLINE search strategy will be rerun prior to submission to capture studies published in the intervening time interval. The bibliographic software Rayyan will be used for the purposes of citation management (including deduplication) and storage. The implementation of the search strategy will occur prior to the selection of relevant studies and data extraction as per the PRISMA guidelines.27 Additionally, the Population, Intervention, Comparison, Outcome and Study Design strategy was used to formulate the research question, the inclusion and exclusion criteria and to guide the overall review process (table 1).28
Supplemental material
Population, Intervention, Comparison, Outcome and Study Design (PICOS) strategy and inclusion and exclusion criteria
Table 1 one provides a summary of the studies considered relevant for this review. In our review, we will include all studies that assess the prevalence of Strongyloides in SOT and haematopoitic stem cell transplant candidates and recipients. The included studies may be performed on children (less than 18 years of age) and/or adults who are migrants, travellers and residents of Strongyloides endemic or non-endemic areas. Diagnosis of Strongyloides must be confirmed through either stool-based methods or serology. The primary outcome of interest is the prevalence of strongyloidiasis in SOT and HSCT candidates and recipients. A secondary outcome of interest includes mortality rate of the reported cases of hyperinfection and disseminated strongyloidiasis in this population. Finally, we aim to include a variety of study designs in our review, including case reports, case-series, observational and interventional studies, and conference abstracts.
Screening and data extraction
Titles and abstracts of studies retrieved using the predefined search strategies and those from additional sources (eg, clinical trials registries, Web of Science and Scopus) will be screened independently by two review authors (FN and CQ) to identify studies that meet the inclusion criteria. Inclusion of an article will be re-evaluated among the two reviewers if there is a disagreement. If the disagreement persists, an expert reviewer (SB) will make the final decision. Next, the full text of potential eligible studies will be independently assessed by the two review authors (FN and CQ). All articles that meet all the inclusion criteria will be submitted for data extraction by the two review authors who will read the full text articles. Relevant data from the studies that meet the inclusion criteria will be extracted and incorporated into two separate standard data extraction forms by two reviewers (FN and CQ). These two extraction forms will be merged once complete. Extracted data will include: general and methodological study characteristics and more specific variables including, but not limited to: study design, methods, baseline population characteristics (eg, age, sex, ethnicity), SOT (kidney, liver, heart, lung, intestine, pancreas), HSCT (autologous or allogeneic) number of patients, country of origin, severity of infection (asymptomatic, isolated eosinophilia, mild infection, hyperinfection, disseminated disease), method of diagnosis (stool-based method, serology), specific details on treatment regimen, prevalence, treatment response, mortality rate, authors conclusion and any reported biases. In case any data is unclear or unavailable, the corresponding author for the study may be contacted for further clarification. Prior to full extraction, the reviewers (FN and CQ) will perform a pilot data extraction using a small random sample of the included studies. The expert reviewer (SB) will assess the pilot data extraction for quality control and concordance purposes. Cohen’s kappa (κ) will be calculated based on the initial pilot data extraction to assess inter-reviewer concordance.
Risk of bias and quality assessment
Study quality and risk of bias assessment will be performed by the two review authors (FN and CQ) using modified quality assessment tools. The quality assessment tools for case series and observational studies are a modified adaptation of the study quality assessment tool developed by the National Heart, Lung and Blood Institute, National Institutes of Health (NIH).29 The quality of case reports will be assessed using an adaptation of the CARE guidelines.30 Any uncertainties will be addressed by the expert reviewer (SB).
Descriptive and statistical analysis
A narrative synthesis will be carried out for all studies included in our review. The primary outcome of interest, the prevalence of strongyloidiasis in SOT and HSCT candidates or recipients will be reported along with an estimated 95% CI. The prevalence of Strongyloides will be stratified by type of sample; stool or serum sample. If possible, the prevalence will be further stratified by age (ie, ≤18 years old vs general population), region of origin, study setting, host country, and decade of publication. The second outcome of interest which consists of the mortality rate of severe strongyloidiasis will be reported alongside appropriate 95% CI. Prevalence and mortality rate of severe strongyloidiasis will be presented in the form of proportions (with associated precision) for case reports and case series and in the form of effect sizes (OR, HR, relative risk) for interventional/observational studies. Outcomes reported for SOT and HSCT as well as outcomes from endemic and non-endemic regions among articles with the same study design will be pooled using a random effects model.
Through our comprehensive systematic review, we aim to fill the evidence gap and increase the body of knowledge on the prevalence of Strongyloides in SOT and HSCT and the mortality rate of severe strongyloidiasis in this population by including all of the relevant literature. Not only will this review compile the available evidence, it will also shed light on the need for further, high-quality prevalence studies of strongyloidiasis in the transplant population.
Amendments
In the case of any amendments to the present protocol, specific details and justifications will be provided through PROSPERO prior to the publication of this review.
Patient and public involvement
Patients nor the public were involved in the design, conduct, reporting or dissemination plans of our research.
Ethics and dissemination
This systematic review does not require formal ethical approval since no primary data will be collected. Findings will be disseminated through a peer-reviewed publication and relevant conferences.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors SB and FN designed, drafted and reviewed the initial manuscript while LH, CQ, and ML provided further review. The search strategy was developed and executed by SB, FN and LH. SB planned quality assessment and statistical analyses. All authors approved and contributed to the final written manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.