https://orcid.org/0000-0003-0496-9508
Figures
Abstract
Background
Neglected tropical diseases (NTDs) are increasingly encountered in nonendemic settings due to migration, international travel, and global mobility. Their clinical management is often challenging: evidence from endemic regions is limited or not directly applicable, and healthcare providers are frequently unfamiliar with their diagnosis and treatment. Consequently, there is substantial heterogeneity in diagnostic workup, therapeutic choices, and follow-up strategies, which may affect patient outcomes and complicate guideline development. Given the sporadic presentation of these diseases across individual centers and the overall low caseload in nonendemic settings, conducting randomized controlled trials to define optimal strategies is largely unfeasible. To address these gaps, we designed Tropistry, a modular, multicenter registry that integrates harmonized data collection with embedded expert-informed clinical guidance.
Methods
Tropistry is an ambispective, multicenter registry planned for implementation across Belgian and European sites. Its modular structure will allow the sequential integration of disease-specific components, initially focusing on acute schistosomiasis and cutaneous/mucocutaneous leishmaniasis (CL/MCL), selected for their sporadic occurrence, clinical complexity, and lack of standardized management. Data will be collected through REDCap-based electronic case report forms aligned with up-to-date, evidence-based recommendations to ensure harmonized and comparable data collection. Embedded expert-informed guidance will support clinicians unfamiliar with these diseases, complemented by expedited access to ITM experts via TROPmail and aggregated feedback through an interactive R Shiny-based dashboard. A structured evaluation framework will assess feasibility, usability, data quality, user engagement, and treatment adherence to ensure the platform’s utility and validity.
Expected impact
By centralizing harmonized data on diagnostic and therapeutic practices, Tropistry aims to address critical knowledge gaps in managing NTDs in nonendemic settings. For the initial targeted conditions, it will help clarify optimal strategies, such as the combination of corticosteroids and praziquantel for acute schistosomiasis and best practices for therapy and follow-up in CL/MCL. Beyond data collection, Tropistry will provide embedded expert-informed guidance, interactive dashboards, and direct access to ITM experts to support clinicians and promote standardized care. Its modular design will enable expansion to other challenging NTDs, while the built-in evaluation framework ensures continuous assessment and optimization of feasibility, usability, and clinical utility. Ultimately, Tropistry seeks to strengthen collaboration between reference centers and non-specialized facilities and generate robust real-world evidence to inform clinical practice, guideline development, and future trials.
Citation: Bea-Serrano C, Alcedo S, Berens-Riha N, van Henten S, van Griensven J, Van Den Broucke S, et al. (2025) Tropistry: A registry-based modular platform to improve care of neglected tropical diseases in nonendemic settings—Study protocol with two targeted conditions: acute schistosomiasis and cutaneous/mucocutaneous leishmaniasis. PLoS One 20(10): e0335032. https://doi.org/10.1371/journal.pone.0335032
Editor: Peter Mbugua Njogu, University of Nairobi Faculty of Health Sciences, KENYA
Received: August 28, 2025; Accepted: October 4, 2025; Published: October 30, 2025
Copyright: © 2025 Bea-Serrano 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: No datasets were generated or analyzsed during the current study. All relevant data from this study will be made available upon study completion.
Funding: This work was supported by institutional funding from the Institute of Tropical Medicine, Antwerp, within its reference duties for the care of tropical diseases in Belgium, under a convention with the Institut National d’assurance Maladie-Invalidité (https://www.inami.fgov.be/fr). CBS is supported by a Río Hortega contract (CM23/00282) funded by the Instituto de Salud Carlos III (https://www.isciii.es/en/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Neglected tropical diseases (NTDs) represent a substantial global health burden, particularly in low-resource tropical regions [1]. However, globalization has recently blurred traditional geographic boundaries, and NTDs are now increasingly reported in nonendemic countries as a result of the growing trend in travel and migration as well as climate change [2–4]. In 2024, international travel exceeded 1.4 billion trips, nearly returning to pre-pandemic levels [5], while 4.3 million new migrants entered Europe in 2023 [6]. In parallel with evolving ecology, vector-borne NTDs are progressively spreading to previously unaffected temperate areas, including parts of central Europe [7]. In Southern Europe, leishmaniasis, historically endemic, has shown notable epidemiological shifts, including urban outbreaks and the emergence of new animal reservoirs [8]. West Nile virus disease, though a more recent arrival, has become established with recurrent seasonal transmission in countries such as Spain and Italy [9]. In contrast, diseases like dengue and schistosomiasis—previously unseen in Europe as locally transmitted infections—have begun to emerge through sporadic autochthonous outbreaks, typically following imported cases and transient environmental conditions conducive to transmission [10,11]. Consequently, clinicians in nonendemic settings are increasingly confronted with conditions they are not familiar with, and for which standardized management protocols are often lacking [12,13].
The clinical management of NTDs in nonendemic regions implies multiple challenges. Cases typically arise sporadically—either isolated or in small, unpredictable clusters [14]. Patients—often travelers or recently arrived migrants—may present with atypical or non-classical clinical features [15]. Care is frequently fragmented, as most first-line providers lack training in these diseases, leading to delayed referrals to specialized clinics. Moreover, there is substantial heterogeneity in diagnostic and treatment practices not only between these referral institutions [12,16,17] but also among providers within the same center [18]. In the absence of widely available or disseminated guidelines, clinical decisions are often guided by individual physician experience, local preferences or site-specific treatment availability [12,16]. While European healthcare systems may have access to advanced diagnostics and supportive therapies, they often lack clinical protocols tailored to nonendemic facilities or in-country approved drugs for NTDs [12,15,16,18–20], and may also be inaccessible to marginalized populations, including undocumented migrants.
The lack of context-specific evidence remains a key limitation for optimal NTD care in nonendemic areas [12,15,20]. Conducting high-quality research in resource-limited endemic settings is extremely challenging [21,22], and data generated may not be fully applicable to other environments [15]. In nonendemic areas, the low and scattered caseload makes randomized controlled trials (RCTs) largely impractical when there is no pre-established scientific collaboration. Small sample sizes across multiple centers and countries reduce statistical power and increase susceptibility to bias [23]. Additionally, heterogeneity in case definitions, therapeutic protocols, and outcome measurements may lead to major inconsistencies and complicate data analysis and knowledge synthesis. Table 1 summarizes the key barriers to generating high-quality clinical evidence on NTDs in nonendemic settings.
Furthermore, the absence of comprehensive clinical datasets—including treatment outcomes, safety profiles, and long-term follow-up—can hinder regulatory approval and reimbursement for essential therapies for NTDs within European health systems [17,27,28]. This contributes to persistent inequities in access to adequate care for the affected populations.
In this complex and evolving context, observational registries may offer a viable alternative to, or a preliminary step before, randomized trials for generating sufficient evidence on treatment effectiveness, safety, and practice variability regarding NTDs. Building high-quality datasets through collaborative networks implies some minimal harmonization of case definitions, clinical practices, and outcome measures across sites, laying the groundwork for future trials whenever necessary and feasible. With these considerations, a panel of experts at the Institute of Tropical Medicine (ITM), Antwerp, the national reference center for tropical diseases in Belgium, has developed a treatment registry, called Tropistry, aimed at addressing critical knowledge gaps in the clinical management of NTDs in Belgium and other nonendemic countries in Europe. It is designed as a flexible, modular and bidirectional platform that, on the one hand, allows physicians confronted with selected NTDs collecting systematic and structured clinical data to be further analyzed by ITM experts. On the other hand, provides them embedded state-of-the-art guidance and expedited additional support through email/phone if necessary.
Several regional and international initiatives already exist with similar purposes. Networks of reference travel clinics and tropical medicine institutes have substantially contributed to syndromic monitoring, geographical mapping and epidemiological trends of tropical diseases imported to Europe and other nonendemic regions [14,17,25,30]. As the primary focus is on epidemiological surveillance and outbreak detection, there is no collection of detailed clinical data on treatment regimens and outcomes that could support harmonized clinical decision-making. GeoSentinel is the most established global network that specifically monitors travel-related infections, through enhanced diagnostic reporting [14,31,32]. However, it has limited collection of clinical data and lacks information on treatment and outcome. TropNet is a European network that also contributes to surveillance and sharing of expertise on tropical diseases but does not currently collect systematic data on treatment practices and longitudinal outcomes [17]. The LeishMan network focuses on epidemiological surveillance and expert diagnosis of leishmaniasis across Europe [16], but the description of the clinical cases does not provide in-depth information that could immediately impact its optimal management in terms of treatment and follow-up. The European Register of Cystic Echinococcosis (ERCE) aims at collecting data on management according disease staging, but limitations in completeness and consistency have restricted its ability to inform clinical practice or support comparative analyses [30]. Finally, the Chagas nonendemic cohort (ChaNoE) project was recently launched in Spain to harmonize diagnostic and follow-up protocols for Chagas disease and support biobanking and multicenter collaboration [19].
Despite these valuable efforts, there remains a need for a unified and harmonized platform at national and European level that can capture robust real-life data and support non-expert clinicians in the management of NTDs. Here we describe the objectives and methodology of such an initiative, called Tropistry. We provide the protocols for two NTDs we plan to target in the registry initially, i.e., acute schistosomiasis and cutaneous/mucocutaneous leishmaniasis (CL/MCL).
Generic objectives of Tropistry
The primary objectives of Tropistry are threefold: (1) to establish a harmonized modular registry that contributes generating high-quality real-world evidence about treatment practices and outcomes of several relevant NTDs in Belgium; (2) to provide state-of-the-art and individualized guidance for clinicians less familiar with these conditions; and (3) to evaluate Tropistry’s implementation, including its feasibility in routine practice, usability for clinicians, data quality, and influence on treatment adherence across participating sites. The general purpose of this project is to optimize clinical care and inform guideline development and future trials.
The secondary objectives include:
- Description of variability in diagnostic, therapeutic and follow-up practices in Belgian and other European health facilities
- Evaluation of treatment effectiveness and monitoring of adverse events in routine care
- Provision and regular update of expert-informed guidance embedded within data collection tool
- Identification of deviations from recommended treatment and analysis of underlying reasons
- Identification of factors linked to favorable outcomes, relapse, or complications for the different NTDs under study
- Generation of evidence for regulatory bodies when randomized trials are not feasible
Tropistry aims to address most of the current gaps of similar registries, by bridging more directly empirical care and structured evidence generation. Its dual role as both a research platform and a clinical decision-support tool distinguishes it from existing initiatives. While it was initially purposed for NTD care in Belgium, further expansion to, and collaboration with, other similar European facilities is being considered.
Materials and methods
Design and implementation of Tropistry
Tropistry is a pragmatic, flexible, modular, ambispective, bidirectional multicenter registry designed to capture real-world data and to provide expert guidance on NTD care in nonendemic settings. Both retrospective and prospective cases may be included, with eligibility starting from January 2020 to capture recent case management, especially following the post-pandemic resurgence of travel and migration. Sites may adopt retrospective, prospective, or hybrid enrollment, depending on local capacity and regulation. The conceptual framework is presented in Fig 1, where the initial two disease modules are mentioned (acute schistosomiasis and CL/MCL; see below).
As mentioned, Tropistry is currently hosted at ITM, Antwerp, Belgium, as part of ITM’s national reference duties. Belgian academic hospitals and referral centers, as well as other European centers, are invited to join to both provide field data and benefit from updated guidance. Standardized General Data Protection Regulation (GDPR)-compliant REDCap-based case report forms (CRFs) are designed for each targeted disease within specific modules, and generic expert guidance is embedded in the data collection tool. A R Shiny-based dashboard aggregating relevant epidemiological and clinical data from all participating institutions is accessible to all partners in this project. No study-specific interventions are required: clinical decisions remain entirely at the discretion of treating physicians, who are free to follow the guidance or request additional support.
Study population and enrollment
Eligible participants include patients of any age diagnosed with one of the target diseases, based on predefined case definitions and managed at a participating site. Depending on the disease under study only confirmed and probable cases will be included. Patients participating in other studies may also be enrolled. While no formal sample size has been calculated due to the exploratory nature of this study, a target of at least 100 patients per disease module is set before meaningful preliminary analysis is undertaken. Exclusion criteria are minimal: patients without sufficient diagnostic information or consent (written, oral, or opt-out per local policy) are excluded. Sites operating under opt-out consent policies must ensure proper notification. Each site designates a trained clinician and a backup coinvestigator responsible for enrollment and REDCap data entry. Patients can be included at any point in their clinical course, though early inclusion is encouraged to facilitate follow-up and benefit from embedded tools. Patients will be managed according to the local routine care or the suggested guidance, and no financial compensation is considered.
Data collection and core variables
Data is collected using REDCap-based disease-specific CRFs. Centers enter pseudonymized information at baseline and, when feasible, during follow-up or at discharge. The core dataset includes:
- Demographics (e.g., age group, sex, comorbidities)
- Epidemiologic history (e.g., travel, migration, exposure)
- Clinical data (e.g., symptoms, physical findings, laboratory results such as eosinophil cell count or C-Reactive Protein values)
- Specific and supporting diagnostics (e.g., PCR, microscopy, serology, imaging)
- Treatment details (e.g., drug names, doses, durations, sequences)
- Outcomes (e.g., clinical resolution, lesion healing, microbiological clearance)
- Adverse events and complications as documented in the medical record
While follow-up intervals may vary, standardized timepoints and outcome definitions are recommended to support comparability. Regular internal quality checks by the REDCap software and query resolution procedures via the coordinating group at ITM will help ensure data reliability.
Statistical analysis
Descriptive statistics will summarize baseline characteristics, diagnostic methods, treatments, and outcomes. Categorical variables will be reported as frequencies and percentages; continuous variables as means with standard deviations or medians with interquartile ranges, as appropriate. Time-to-event outcomes (cure, relapse, death, adverse event) will be analyzed using Kaplan–Meier and Cox models. Associations between treatments and outcomes will be assessed using univariate and multivariable regression, adjusting for potential confounders such as age, immune status, or disease severity. Analyses will be performed using validated statistical software and will be supported by a statistician to ensure methodological rigor.
Evaluation of utility and validity
The implementation of Tropistry will be evaluated across several dimensions to ensure its utility and validity. We will monitor the number of participating centers, patient recruitment rates, and the integration of the registry into routine workflows to assess feasibility. Usability will be explored through periodic surveys and interviews with clinicians, focusing on data entry processes, clarity of embedded guidance, and practicality during patient care. Data quality will be maintained using REDCap’s validation rules, audit logs, and regular data audits, complemented by targeted manual reviews from the coordinating team. User engagement will be tracked via metrics such as data entry frequency, completeness of follow-up records, and interaction with support tools like TROPmail and the interactive dashboard. Finally, treatment practices across sites will be compared with Tropistry’s expert-informed recommendations, and feedback will be provided to participating centers to promote harmonization and continuous quality improvement.
Ethical considerations and governance
Tropistry was approved by the ITM Institutional Review Board (Ref: 1704/24; 18 November 2024), with local approval required at each participating site. The registry adheres to the Declaration of Helsinki, Good Clinical Practice, and relevant data protection regulations. Informed consent is obtained per local policy. As approved by the ITM IRB, inclusion criteria include oral consent to participate (in sites with an institutional opt-out strategy, with notification in the medical file), or a signed informed consent (possibly provided by a legal representative) in other sites (see Supporting Information S1 Protocol). All data are pseudonymized before REDCap entry, with identifiers stored securely and locally. REDCap provides secure access, audit trails, and regular backups to ensure data integrity. Requests for secondary data use must be submitted to the Tropistry Scientific Committee and are reviewed based on scientific merit and alignment with registry goals. The Scientific Committee is initially composed of ITM experts and will be progressively expanded to include representatives from other participating institutions as the initiative grows. In case of scientific publications, all contributors will be appropriately recognized using a group authorship model (e.g., “and the Tropistry Group”). At least one representative from each main contributing center will be included as a named author. The definition of a main contributing center will vary by disease module, based on the actual number of cases contributed in relation to the overall dataset. Aggregate, de-identified findings will be shared via an interactive dashboard based on R Shiny App to promote transparency and provide timely feedback to participating centers.
Inclusivity in global research
Additional information regarding the ethical, cultural, and scientific considerations specific to inclusivity in global research is included in the Supporting Information (S1 Checklist)
The case for two challenging NTDs: Acute schistosomiasis and cutaneous/mucocutaneous leishmaniasis
The registry initially focuses on two NTDs that have very distinct epidemiology and clinical presentation but share therapeutic challenges and key barriers to generating clinical evidence in nonendemic settings, as summarized in Fig 2. The full protocol including both initial conditions has been approved in 2024 by the ITM Institutional Review Board and is available as S1 Protocol. The full list of variables included in the REDCap-based CRFs for both modules is provided as Supporting Information (S1 and S2 Files).
Created in BioRender. Bea, C. (2025) https://BioRender.com/oucx7kk.
Acute schistosomiasis
Background and rationale.
Acute schistosomiasis (historically called Katayama syndrome when symptomatic) is a rare, often unrecognized hypersensitivity reaction that typically develops 3–12 weeks after freshwater exposure to Schistosoma cercariae in endemic areas, predominantly in sub-Saharan Africa. It frequently affects young travelers or family groups in clusters [18,33]. Clinical presentation—fever, cough, myalgia, headache—with eosinophilia is nonspecific and may mimic other tropical infections, often delaying diagnosis. Standard diagnostic tools such as microscopy and serology have poor sensitivity in the early phase with positivity rates below 70% even when combined [34]. Although promising, molecular (e.g., polymerase chain reaction [PCR]) and antigen-based assays (e.g., circulating anodic antigen [CAA]) remain largely unavailable outside reference centers [35,36]. Treatment practices are heterogeneous and not standardized. Praziquantel is commonly used but has limited efficacy against juvenile worms [37]. Corticosteroids are frequently added to modulate inflammation, but optimal timing, dosage, and duration remain uncertain, with no evidence-based consensus across expert networks [12]. This diagnostic and therapeutic ambiguity underscores the pressing need for innovative ways to generate evidence.
Methods and guidance.
Composite case definitions for Tropistry rely on recent consensus criteria (Table 2) [33]. Cases are classified as confirmed, probable, or possible based on exposure history, clinical presentation, and diagnostics (e.g., serology, microscopy, antigen detection, or PCR). Only confirmed and probable cases are to be included. Data collection follows the generic flow described above, with recommended reassessments taking place, ideally, at 6–12 weeks post-treatment and, when feasible, again at one year. Standardized outcome definitions (Table 3) enable cross-site comparison. As already highlighted, brief embedded guidance supports clinical decisions. In Tropistry, the recommended treatment is based on a recent publication of a prospective clinical study that favored short-course therapy for acute schistosomiasis, in terms of safety and effectiveness [38]. The guidance will be updated as new evidence emerges.
Cutaneous and mucocutaneous leishmaniasis
Background and rationale.
CL/MCL has become one of the most frequently reported travel-acquired infections. Hundreds of cases have been documented in returning travelers through GeoSentinel [14], and the disease is now increasingly diagnosed in nonendemic countries like Belgium [39]. In some regions such as Southern Europe, the epidemiological picture is even blurred by autochthonous cases [40], and there is even a theoretical risk of secondary local transmission where competent vectors are present [7]. In addition, conflict-driven migration, such as that caused by the Syrian civil war, has triggered a major CL outbreak, prompting global concern [41]. Clinical management of CL/MCL is hindered by significant heterogeneity in Leishmania species, clinical presentations, treatment options, and outcomes [16]. Leishmaniasis is traditionally divided into Old World and New World forms based on species and geographic distribution. Old World species (e.g., L. infantum, L. major, L. tropica) are found in Southern Europe, Asia, and Africa, causing substantial skin morbidity. New World species—mainly from the Viannia subgenus, including L. (V.) braziliensis and L. (V.) guyanensis—are endemic to Central and South America and more often associated with mucosal complications. Both CL and MCL can result in disfiguring scars and even mutilation, particularly when facial areas are affected, leading to significant psychosocial consequences [42]. Treatment decisions are often empirical and based on limited evidence. Therapies may be topical, systemic, or combined, with choices influenced by species, lesion severity, anatomical location, and host factors [25,43,44]. However, no universally accepted treatment algorithm exists, and therapeutic responses may be variable [39]. Systematic reviews consistently report wide variability in therapeutic criteria, outcome definitions, and study designs, with most trials being small, fragmented, and methodologically limited [29]. While harmonized trial methodologies have been proposed and collaborative groups have made progress in standardizing eligibility and outcome criteria [45–47], high-quality, generalizable evidence remains lacking. Repeated calls have emphasized the need for a coordinated, multicenter platform trial to evaluate CL/MCL treatments, particularly among international travelers [24].
Methods and guidance.
CL/MCL is defined by compatible skin or mucosal lesions with parasitological confirmation. Cases with characteristic features and relevant exposure but no laboratory confirmation may be enrolled as “clinically compatible” and flagged accordingly. The CRF records in detail lesion characteristics (number, size, location), species identification (if available), host immune status, and mucosal involvement (baseline and follow-up). To address classification inconsistencies across guidelines, Tropistry uses in Belgium a harmonized “complex CL” definition proposed by Vandeputte et al. [39], that incorporates IDSA and LeishMan criteria to make them congruent (Table 4). This does not prevent, however, the inherent heterogeneity of the current criteria of complex CL (from small lesion with esthetical impact to underlying immunosuppression or relapse/non-response). Treatment fields capture drug regimen, route, dosage, and duration. Outcome assessment is recommended at standardized timepoints at Day 42, 90, and 180 [45,47]. Long-term sequelae (e.g., scarring, pigmentary changes) are assessed using LeishCOM_LCL domains [46] (Table 5). When feasible, clinical photographs are uploaded via a secure REDCap module, with proper consent. Embedded guidance in this module focuses on species-specific therapeutic decisions.
Study status and timeline.
Following ethical approval within our institution in 2024, the REDCap CRF for the acute schistosomiasis module have been finalized in May 2025. Subsequently, 15 retrospective cases from the ITM travel clinic have been included in June 2025. Several Belgian academic hospitals have expressed interest in participating in this module. There is also an ongoing dialogue about this initiative with the TropNet consortium, which welcomed this project and considers to expand inclusions in several of its member tropical/travel institutions as well. Inclusions in the CL/MCL module have started at ITM, at the time of writing, but will be initially restricted to Belgian centers as the numbers are much larger than for the first module, before consideration any expansion in complementarity to the Leishman consortium. Continuous enrollment will follow, without a fixed end date. Data analysis will proceed on a rolling basis. Key findings on treatment practices and outcomes will be summarized periodically and shared through the interactive web dashboard, conference presentations, and peer-reviewed publications to inform guidelines and support patient care.
Discussion
In nonendemic settings, the low incidence and clinical heterogeneity of NTDs limit the feasibility of RCTs to inform treatment decision, limiting the generation of robust, practice-oriented evidence. Tropistry was developed as a pragmatic response to this gap, initially for improving care in Belgium. By combining expert-informed guidance with standardized definitions and harmonized follow-up protocols, the registry enables consistent and detailed observational documentation of treatment practices and outcomes, which can reach satisfactory evidence. Its modular and adaptable design supports real-world evidence generation across diverse clinical settings and evolving healthcare needs. This section highlights key features of the platform and its potential contributions to clinical research, care harmonization, and health policy.
Modular design and scalable expansion
Tropistry is constructed around modules that each correspond to target diseases. This allows data collection tailored to the scientific needs, as knowledge gaps may be very different according to the disease under consideration (diagnosis, staging, treatment, follow-up). It is also designed for scalable expansion. New modules—for example, for neurocysticercosis or disseminated strongyloidiasis—could be proposed by participating sites and reviewed by the Scientific Committee. All modules follow a consistent structure: harmonized case definitions, tailored CRFs, and context-specific guidance. Participating centers are supported with onboarding materials, standard case examples, and access to technical and clinical coordination.
Evaluation of platform utility and validity
To ensure that Tropistry fulfills its intended role, we have embedded a formal evaluation component within the study design. This approach allows us to measure the platform’s feasibility, user experience, data quality, and impact on clinical practice in real time, using the results to refine the registry as needed. Including these evaluation measures is expected to strengthen the protocol by providing accountability and opportunities for continuous improvement. Similar registry-based initiatives have highlighted the importance of such evaluation; for example, the recent ChaNoE cohort protocol explicitly aimed to standardize and validate follow-up and treatment criteria to facilitate consistent, high-quality data collection [19]. By integrating utility and validity assessments into Tropistry, we align with these best practices and add an extra layer of rigor to our platform’s implementation.
Regulatory alignment and design rationale
Tropistry aligns with the European Medicines Agency (EMA) Guideline on Registry-Based Studies [26], incorporating core elements such as predefined objectives, disease-specific core datasets, and quality assurance through REDCap’s audit-enabled infrastructure. Its ambispective, modular structure supports long-term follow-up and pharmacovigilance, including documentation of serious adverse events. Although not currently intended for regulatory submission, it is designed with the methodological rigor required for future engagement with regulatory and health technology assessment (HTA) bodies—particularly for NTDs lacking formal trial data. Its design ensures utility for research, clinical care, and policy dialogue, and may trigger innovative research questions based on unusual observations for example.
Embedded clinical guidance and real-time expert support
Tropistry integrates clinical algorithms and decision-support prompts directly within the CRF, delivers individualized treatment recommendations as data is entered, and offers real-time expert consultation. To our knowledge, this is the first initiative to combine these capabilities: clinicians entering case data receive tailored, up-to-date guidance within the CRF, and can immediately contact ITM experts via TROPmail or phone for case-specific advice. This combined model transforms the registry from a passive data collection tool into an active clinical support system, enhancing quality of care, promoting standardization, and facilitating continuous learning within and across centers.
Interactive dashboard for dissemination and engagement
A key innovation is Tropistry’s interactive web-based dashboard, which provides participating sites with regularly updated summaries of epidemiological trends, treatment patterns, outcomes, and adverse events. These updates —generated from secure data exports—support transparency, enable clinical benchmarking, and promote feedback loops across sites. By offering aggregate visualizations without individual identifiers, the dashboard enhances accessibility and aligns with best practices in registry-based research.
Care harmonization and equitable drug access
Tropistry may help reduce disparities in NTD management by documenting treatment practices across varied European settings. Access to essential therapies such as miltefosine for CL/MCL or praziquantel for schistosomiasis remains uneven due to national differences in reimbursement, availability, and importation procedures [27]. These barriers can result in delayed or unaffordable care, particularly outside specialized centers. As recently highlighted in a call for urgent action on the praziquantel shortage in Europe, access to essential NTD treatments cannot be taken for granted [49]. Initiatives like Tropistry are needed to generate evidence that supports harmonized strategies, informs regulatory and reimbursement decisions, and enables professional societies to advocate effectively for sustainable access to key therapies. In some systems, such data already influence reimbursement decisions for rare diseases [50,51].
Strengths and limitations
Tropistry has several design strengths supporting its scalability and relevance: a modular structure for adding new disease-specific components; a clinical focus on diagnosis, treatment, and outcomes; an embedded expert guidance to promote standardized care; an interactive dashboard for timely data visualization; broad inclusion criteria that reflect real-world scenarios; consensus-based definitions for case classification and outcomes; and flexibility to accommodate local practices without compromising standardization; and incorporation of a built-in evaluation framework to monitor its feasibility, user engagement, data quality, and impact on clinical practice, enabling iterative improvements. By aligning with EMA-endorsed principles [26], Tropistry offers a pragmatic and adaptable platform with utility for clinical, regulatory, and public health applications. Compared to RCTs, it immediately captures broader variability in real-world care and treatment response, helping identify unmet needs and inform new research priorities [52].
Nonetheless, the platform faces limitations common to observational studies. Causal inference is not possible, and residual confounding must be considered. Data completeness may vary—especially for retrospective cases—due to site-specific workflows and diagnostic variation. In conditions with prolonged or stepwise recovery, outcome assessment may be delayed or incomplete, particularly where follow-up capacity is limited. More importantly, data quality largely depends on sustained clinician engagement, which may fluctuate over time without dedicated support. As it is about NTDs, no strong financial incentives can be expected for participating institutions. The major drivers would be scientific curiosity and the willingness to contribute to evidence-based clinical decision-making, while the main reward would be shared authorship in quality manuscript and policy briefs. Finally, selection bias is also likely in early phases, as initial participation will involve Belgian referral centers and travel/tropical clinics affiliated to TropNet. Although broader expansion is planned, early data may overrepresent specialized care settings. Widening participation will be key to enhancing representativeness and impact.
Conclusion
Tropistry is a pragmatic, expert-driven registry designed to address persistent and apparently insolvable evidence gaps in the management of NTDs in nonendemic settings. Through standardized data collection, embedded clinical guidance, and robust governance, it provides a scalable framework to improve patient care, inform policy, and generate real-world evidence for rare and complex tropical infections. Continued expansion across diverse healthcare settings will be essential to realizing its full potential.
Supporting information
S1 File. Acute Schistosomiasis module REDCap-based CRF.
https://doi.org/10.1371/journal.pone.0335032.s002
(PDF)
S2 File. Cutaneous and mucocutaneous leishmaniasis module REDCap-based CRF.
https://doi.org/10.1371/journal.pone.0335032.s003
(PDF)
Acknowledgments
The acute schistosomiasis module has been developed in collaboration with the TropNet Schisto Task Force. We thank the Clinical Trials Unit at the ITM for their valuable support in the development of the R Shiny application used for the Tropistry dashboard.
References
- 1.
World Health Organization. Ending the neglect to attain the Sustainable Development Goals: a road map for neglected tropical diseases 2021–2030. 2020.
- 2. Hotez PJ. The rise of neglected tropical diseases in the “new Texas”. PLoS Negl Trop Dis. 2018;12(1):e0005581. pmid:29346369
- 3. Franco JR, Cecchi G, Priotto G, Paone M, Kadima Ebeja A, Simarro PP, et al. Human African trypanosomiasis cases diagnosed in non-endemic countries (2011-2020). PLoS Negl Trop Dis. 2022;16(11):e0010885. pmid:36342910
- 4. Guido G, Frallonardo L, Cotugno S, De Vita E, Patti G, De Santis L, et al. Prevalence of neglected tropical diseases among migrants living in Europe: A systematic review and meta-analysis. Travel Med Infect Dis. 2025;64:102823. pmid:39983935
- 5.
World Tourism Organization. UN Tourism. World Tourism Barometer 2025. UNWTO World Tourism Barometer; 2025;23.
- 6.
Migration to and from the EU - Statistics Explained - Eurostat. [cited 20 May 2025]. Available from: https://ec.europa.eu/eurostat/statistics-explained/index.php?title=Migration_to_and_from_the_EU
- 7. Tidman R, Abela-Ridder B, de Castañeda RR. The impact of climate change on neglected tropical diseases: a systematic review. Trans R Soc Trop Med Hyg. 2021;115(2):147–68. pmid:33508094
- 8. González E, Molina R, Jiménez M. Rabbit trypanosome detection in Phlebotomus perniciosus sand flies from the leishmaniasis outbreak in Madrid, Spain. Acta Trop. 2018;187:201–6. pmid:30107150
- 9. Lara M, Casimiro-Soriguer CS, Pedrosa-Corral I, Gómez-Camarasa C, Lorusso N, Navarro-Marí JM, et al. First autochthonous transmission of West Nile virus (WNV) lineage 2 to humans in Spain. One Health. 2025;20:101036. pmid:40276693
- 10. Cattaneo P, Salvador E, Manica M, Barzon L, Castilletti C, Di Gennaro F, et al. Transmission of autochthonous Aedes-borne arboviruses and related public health challenges in Europe 2007-2023: a systematic review and secondary analysis. Lancet Reg Health Eur. 2025;51:101231. pmid:40213502
- 11. Salas-Coronas J, Bargues MD, Lozano-Serrano AB, Artigas P, Martínez-Ortí A, Mas-Coma S, et al. Evidence of autochthonous transmission of urinary schistosomiasis in Almeria (southeast Spain): An outbreak analysis. Travel Med Infect Dis. 2021;44:102165. pmid:34555514
- 12. Tamarozzi F, Mazzi C, Antinori S, Arsuaga M, Becker SL, Bocanegra C, et al. Landscape of guidance documents used at TropNet and GeoSentinel centres for the clinical management of schistosomiasis outside endemic areas: A systematic appraisal. Travel Med Infect Dis. 2025;64:102822. pmid:39983934
- 13. Pérez-Arellano JL, Górgolas-Hernández-Mora M, Salvador F, Carranza-Rodríguez C, Ramírez-Olivencia G, Martín-Echeverría E, et al. Executive summary of imported infectious diseases after returning from foreign travel: Consensus document of the Spanish Society for Infectious Diseases and Clinical Microbiology (SEIMC). Enferm Infecc Microbiol Clin. 2017;36(3):187–93. pmid:28396090
- 14. Boggild AK, Caumes E, Grobusch MP, Schwartz E, Hynes NA, Libman M, et al. Cutaneous and mucocutaneous leishmaniasis in travellers and migrants: a 20-year GeoSentinel Surveillance Network analysis. J Travel Med. 2019;26(8):taz055. pmid:31553455
- 15. Norman FF, Pérez de Ayala A, Pérez-Molina J-A, Monge-Maillo B, Zamarrón P, López-Vélez R. Neglected tropical diseases outside the tropics. PLoS Negl Trop Dis. 2010;4(7):e762. pmid:20668546
- 16. Guery R, Walker SL, Harms G, Neumayr A, Van Thiel P, Gangneux J-P, et al. Clinical diversity and treatment results in Tegumentary Leishmaniasis: A European clinical report in 459 patients. PLoS Negl Trop Dis. 2021;15(10):e0009863. pmid:34644288
- 17. Gobbi F, Bottieau E, Bouchaud O, Buonfrate D, Salvador F, Rojo-Marcos G, et al. Comparison of different drug regimens for the treatment of loiasis-A TropNet retrospective study. PLoS Negl Trop Dis. 2018;12(11):e0006917. pmid:30383753
- 18. Salvador F, Bocanegra C, Treviño B, Sulleiro E, Sánchez-Montalvá A, Serre-Delcor N, et al. Imported schistosomiasis in travelers: Experience from a referral tropical medicine unit in Barcelona, Spain. Travel Med Infect Dis. 2024;60:102742. pmid:38996855
- 19. Bosch-Nicolau P, Herrero-Martínez JM, Arsuaga M, Chamorro-Tojeiro S, Carrillo I, Bea-Serrano C, et al. The Chagas non-endemic (ChaNoE) cohort: Aims and study protocol. PLoS One. 2025;20(4):e0320637. pmid:40233055
- 20. Casulli A, Antinori S, Bartoloni A, D’Amelio S, Gabrielli AF, Gazzoli G, et al. Neglected Tropical Diseases in Italy: introducing IN-NTD, the Italian network for NTDs. Parasitology. 2023;150(12):1082–8. pmid:37264942
- 21. Ravinetto R, Alirol E, Mahendradhata Y, Rijal S, Lutumba P, Sacko M, et al. Clinical Research in Neglected Tropical Diseases: The Challenge of Implementing Good Clinical (Laboratory) Practices. PLoS Negl Trop Dis. 2016;10(11):e0004654. pmid:27812089
- 22. El-Safi S, Chappuis F, Boelaert M. The Challenges of Conducting Clinical Research on Neglected Tropical Diseases in Remote Endemic Areas in Sudan. PLoS Negl Trop Dis. 2016;10(11):e0004736. pmid:27812094
- 23. Hilgers R-D, Heussen N. Methodological approaches for generating robust evidence from trials in rare diseases. Z Evid Fortbild Qual Gesundheitswes. 2024;189:66–72.
- 24. Vandeputte M, van Henten S, van Griensven J, Bottieau E. Which trial do we need? A collaborative platform trial for cutaneous leishmaniasis amongst international travellers. Clin Microbiol Infect. 2023;29(10):1237–40. pmid:37230249
- 25. Glans H, Dotevall L, Van der Auwera G, Bart A, Blum J, Buffet P, et al. Treatment outcome of imported cutaneous leishmaniasis among travelers and migrants infected with Leishmania major and Leishmania tropica: a retrospective study in European centers 2013 to 2019. Int J Infect Dis. 2022;122:375–81. pmid:35728749
- 26.
Medicines Agency E. Committee for Human Medicinal Products (CHMP) Guideline on registry-based studies Draft sent to the EU Regulatory Network for consultation including EMA committees, Patients’ and Consumers’ Working Party and Healthcare Professionals’ Working Party. 2021 [cited 25 Apr 2025]. Available from: www.ema.europa.eu/contact
- 27. Calleri G, Angheben A, Albonico M. Neglected tropical diseases in Europe: rare diseases and orphan drugs? Infection. 2019;47(1):3–5. pmid:30390200
- 28.
Hulstaert F, Pouppez C, Primus-de Jong C, Harkin Trinity College Dublin K, Neyt M. Evidence gaps for drugs and medical devices at market entry in Europe and potential solutions. Health Services Research (HSR). Brussels: Belgian Health Care Knowledge Centre (KCE); KCE Reports. 2021;347. Available from: www.kce.fgov.be
- 29. López-Carvajal L, Vélez I, Arbeláez MP, Olliaro P. Eligibility criteria and outcome measures adopted in clinical trials of treatments of cutaneous leishmaniasis: systematic literature review covering the period 1991-2015. Trop Med Int Health. 2018;23(5):448–75. pmid:29524291
- 30. Rossi P, Tamarozzi F, Galati F, Akhan O, Cretu CM, Vutova K, et al. The European Register of Cystic Echinococcosis, ERCE: state-of-the-art five years after its launch. Parasit Vectors. 2020;13(1):236. pmid:32381109
- 31. Duvignaud A, Stoney RJ, Angelo KM, Chen LH, Cattaneo P, Motta L, et al. Epidemiology of travel-associated dengue from 2007 to 2022: A GeoSentinel analysis. J Travel Med. 2024;31(7):taae089. pmid:38951998
- 32. Guagliardo SAJ, Smith T, Hamer DH, Huits R, Kozarsky P, Libman M, et al. Analysis of Monkeypox Virus Exposures and Lesions by Anatomic Site. Emerg Infect Dis. 2024;30(11):2381–4. pmid:39365696
- 33. Tamarozzi F, Mazzi C, Antinori S, Arsuaga M, Becker SL, Bottieau E, et al. Consensus definitions in imported human schistosomiasis: a GeoSentinel and TropNet Delphi study. Lancet Infect Dis. 2024;24(10):e627–37. pmid:38467128
- 34. Bottieau E, Clerinx J, de Vega MR, Van den Enden E, Colebunders R, Van Esbroeck M, et al. Imported Katayama fever: clinical and biological features at presentation and during treatment. J Infect. 2006;52(5):339–45. pmid:16169593
- 35. Cnops L, Huyse T, Maniewski U, Soentjens P, Bottieau E, Van Esbroeck M, et al. Acute Schistosomiasis With a Schistosoma mattheei × Schistosoma haematobium Hybrid Species in a Cluster of 34 Travelers Infected in South Africa. Clin Infect Dis. 2021;72(10):1693–8. pmid:32215659
- 36. Stothard JR, Webster BL. Acute Schistosomiasis: Which Molecular Diagnostic Test Is Best and Why. Clin Infect Dis. 2021;72(10):1699–700. pmid:32215645
- 37. Wang X, Yu D, Li C, Zhan T, Zhang T, Ma H, et al. In vitro and in vivo activities of DW-3-15, a commercial praziquantel derivative, against Schistosoma japonicum. Parasit Vectors. 2019;12(1):199. pmid:31053083
- 38. Clerinx J, Maniewski U, Van Den Broucke S, Soentjens P, Cnops L, Van Esbroeck M, et al. Acute schistosomiasis in travellers: outcomes of a short-course therapy. J Travel Med. 2025;32(6):taaf065. pmid:40607759
- 39. Vandeputte M, van Henten S, van Griensven J, Huits R, Van Esbroeck M, Van der Auwera G, et al. Epidemiology, clinical pattern and impact of species-specific molecular diagnosis on management of leishmaniasis in Belgium, 2010-2018: A retrospective study. Travel Med Infect Dis. 2020;38:101885. pmid:32977026
- 40.
Centro Nacional de Epidemiología I de SCIC. Informe epidemiológico sobre la situación de la leishmaniasis en España, 2023. Madrid; 2024 Jul. Available from: https://cne.isciii.es/documents/d/cne/informe_renave_leishmania-2023-1
- 41. Abbara A, González-Sanz M, AlKharrat A, Khalife M, Elferruh Y, Almhawish N, et al. Leishmaniasis in Syria - A call for action of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study Groups for Infections in Travellers and Migrants (ESGITM) and for Clinical Parasitology (ESGCP). Travel Med Infect Dis. 2025;66:102849. pmid:40185351
- 42. Bennis I, Thys S, Filali H, De Brouwere V, Sahibi H, Boelaert M. Psychosocial impact of scars due to cutaneous leishmaniasis on high school students in Errachidia province, Morocco. Infect Dis Poverty. 2017;6(1):46. pmid:28385151
- 43. van Griensven J, Gadisa E, Aseffa A, Hailu A, Beshah AM, Diro E. Treatment of Cutaneous Leishmaniasis Caused by Leishmania aethiopica: A Systematic Review. PLoS Negl Trop Dis. 2016;10(3):e0004495. pmid:26938448
- 44. Blum J, Buffet P, Visser L, Harms G, Bailey MS, Caumes E, et al. LeishMan recommendations for treatment of cutaneous and mucosal leishmaniasis in travelers, 2014. J Travel Med. 2014;21(2):116–29. pmid:24745041
- 45. Olliaro P, Vaillant M, Arana B, Grogl M, Modabber F, Magill A, et al. Methodology of clinical trials aimed at assessing interventions for cutaneous leishmaniasis. PLoS Negl Trop Dis. 2013;7(3):e2130. pmid:23556016
- 46. Ranasinghe S, Senarathne S, Somaratne V, Lacey CJN, Jayakody S, Wickramasinghe A, et al. Development of a Core Outcome Measure Instrument; “LeishCOM_LCL”, for Localised Cutaneous Leishmaniasis. PLoS Negl Trop Dis. 2024;18(8):e0012393. pmid:39208389
- 47. Olliaro P, Grogl M, Boni M, Carvalho EM, Chebli H, Cisse M, et al. Harmonized clinical trial methodologies for localized cutaneous leishmaniasis and potential for extensive network with capacities for clinical evaluation. PLoS Negl Trop Dis. 2018;12(1):e0006141. pmid:29329311
- 48. Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, et al. Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Am Soc Trop Med Hygc. 2017;96(1):24–45.
- 49. Lindner AK, Popescu C, Perez-Molina JA, Díaz-Menéndez M, Rothe C, Asgeirsson H, et al. Shortage of praziquantel in Europe: a clarion call for urgent action. New Microbes New Infect. 2025;66:101613. pmid:40776986
- 50. Prilla S, Groeneveld S, Pacurariu A, Restrepo-Méndez MC, Verpillat P, Torre C, et al. Real-World Evidence to Support EU Regulatory Decision Making-Results From a Pilot of Regulatory Use Cases. Clin Pharmacol Ther. 2024;116(5):1188–97. pmid:38962830
- 51. Innes GK, Smith KA, Kuzucan A, Li J, Rivera D, Panagiotou OA, et al. Real-World Evidence in New Drug and Biologics License Application Approvals During Fiscal Years 2020–2022. Clin Pharmacol Ther. 2025;118(1):85–9. pmid:40276902
- 52.
Gliklich RE, Leavy MB, Dreyer NA. Registries for Evaluating Patient Outcomes: A User’s Guide. 4th edition. AHRQ Publication No. 19(20)EHC020; 2020 Sep.