Infectious disease screening before leukapheresis and its impact on clinical management in CAR-T cell therapy candidates in tropical and middle-income countries: a scoping review

BACKGROUND AND RATIONALE Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of relapsed/refractory hematological malignancies, including diffuse large B-cell lymphoma, acute lymphoblastic leukemia, multiple myeloma, and follicular lymphoma. As access to CAR-T therapy expands to low- and middle-income countries (LMICs) and tropical regions, a critical and largely unaddressed challenge emerges: the management of endemic infectious diseases in candidates undergoing leukapheresis. In tropical and endemic settings, a substantial proportion of CAR-T candidates may harbor latent or chronic infections — including Human T-Lymphotropic Virus types 1 and 2 (HTLV-1/2), Trypanosoma cruzi (Chagas disease), Mycobacterium tuberculosis (latent TB), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, syphilis, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Toxoplasma gondii — that may reactivate under the profound immunosuppression induced by lymphodepletion and CAR-T therapy. Despite this recognized risk, no validated, evidence-based pre-leukapheresis serological screening protocol specific to CAR-T candidates in endemic settings exists. Current institutional practices extrapolate from solid organ transplantation and hematopoietic stem cell transplantation (HSCT) guidelines, which were developed for different immunosuppressive contexts and populations. HTLV-1 is endemic in Brazil, Japan, the Caribbean, and parts of Africa, with Brazil bearing the world's largest absolute burden of infected individuals. Chagas disease affects an estimated 6–7 million people in Latin America. Tuberculosis remains a leading infectious cause of death globally, with disproportionate burden in LMICs. These pathogens are largely absent from CAR-T screening guidelines developed in high-income countries, creating a significant equity and safety gap for patients treated in endemic regions. PURPOSE This scoping review aims to systematically map the existing evidence on pre-leukapheresis infectious disease screening in CAR-T therapy candidates, with a focus on endemic and tropical pathogens. Specifically, the review will: 1. Map the serological and microbiological screening panels used before leukapheresis for CAR-T therapy across published studies, institutional protocols, and clinical guidelines. 2. Describe the seroprevalence of endemic pathogens (HTLV-1/2, Trypanosoma cruzi, latent M. tuberculosis, HBV, HCV, HIV, syphilis/VDRL, CMV, EBV, Toxoplasma gondii) among CAR-T candidates in tropical and middle-income countries. 3. Identify how positive serological findings modify clinical management decisions, including prophylaxis initiation, pre-CAR-T treatment, procedure delay, or patient exclusion. 4. Identify critical evidence gaps and provide the foundation for developing a standardized, geography-adapted pre-leukapheresis infectious screening protocol. FRAMEWORK (PCC) - Population: Adult and pediatric patients with hematological malignancies who are candidates for CAR-T cell therapy, regardless of CAR-T product or target antigen. - Concept: Pre-leukapheresis serological and microbiological infectious disease screening and its impact on clinical management decisions before CAR-T infusion. - Context: Tropical regions, endemic areas, and low- and middle-income countries, with particular focus on Latin America, sub-Saharan Africa, Southeast Asia, and other settings with high burden of endemic infectious diseases. ELIGIBILITY CRITERIA Inclusion: - Study designs: clinical trials, prospective and retrospective cohort studies, case series (≥3 patients), cross-sectional studies, clinical guidelines, position papers, consensus statements, and systematic reviews. - Studies reporting pre-leukapheresis or pre-CAR-T infectious screening data, seroprevalence estimates, or management decisions based on infectious screening results. - Languages: English, Spanish, Portuguese, and French. - No date restriction. Exclusion: - Studies focused exclusively on post-CAR-T infectious complications without reporting pre-treatment screening data. - Single case reports. - Studies in which CAR-T therapy is not the primary therapeutic modality under investigation. - Conference abstracts without accessible full text. SEARCH STRATEGY Nine electronic databases will be searched: PubMed/MEDLINE, Embase, Web of Science, Scopus, LILACS, SciELO, Cochrane Library, ClinicalTrials.gov, and WHO ICTRP. Grey literature will include congress proceedings from EBMT, ASH, ASTCT, and SOHO (2017–present). No date restriction will be applied. The search strategy will be developed and peer-reviewed according to the PRESS (Peer Review of Electronic Search Strategies) checklist. SCREENING AND DATA EXTRACTION Two independent reviewers will perform title/abstract and full-text screening using Rayyan software. Disagreements will be resolved by a third reviewer. Inter-rater reliability will be assessed using Cohen's kappa coefficient, with a target of ≥0.61 before commencing full screening. Data will be extracted using a standardized, pilot-tested form covering: study design, country and region, CAR-T product, target antigen, screening pathogens assessed, seroprevalence per pathogen, and documented clinical management changes triggered by positive screening results. REPORTING Results will be reported in full accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR) checklist (Tricco et al., Ann Intern Med, 2018). A PRISMA-ScR flow diagram will document the number of records identified, screened, and included at each stage. EXPECTED OUTCOMES 1. A comprehensive, evidence-based map of pre-leukapheresis infectious screening practices in CAR-T programs worldwide, with emphasis on endemic settings. 2. Seroprevalence estimates for key pathogens (HTLV-1/2, Trypanosoma cruzi, latent TB, HBV, HCV, HIV, CMV, EBV, toxoplasmosis, syphilis) in CAR-T candidates from tropical and middle-income countries. 3. A comparative table of institutional screening protocols across countries and healthcare systems. 4. A clinical decision algorithm for managing endemic pathogen seropositivity before CAR-T leukapheresis. 5. A formal research gaps agenda to guide future prospective studies and international collaborations in this underexplored field.