International Journal of Clinical Trials | January-March 2023 | Vol 10 | Issue 1 Page 56 International Journal of Clinical Trials McVey MJ et al. Int J Clin Trials. 2023 Feb;10(1):56-65 http://www.ijclinicaltrials.com pISSN 2349-3240 | eISSN 2349-3259 Protocol The transfusion-associated dyspnea prospective observation and laboratory assessment study: a protocol for investigating and disambiguating cardiopulmonary and high-grade febrile transfusion reactions in adults Mark J. McVey 1,2,3 , Samia Saeed 4,5 , Reda Siddiqui 4,5 , Chantal Armali 5,6 , Amie Kron 5,6 , Donald R. Branch 5,7,8,9 , Davor Brinc 4,7 , Liying Zhang 5 , Nadine Shehata 5,7,8,10,11 , Katerina Pavenski 5,7,8,12 , Akash Gupta 5,6,7,13 , Yulia Lin 5,6,7 , Lani Lieberman 4,5,7 , Jacob M. Pendergrast 4,5,7,8,11 , Jeannie Callum 5,14 , Christine Cserti-Gazdewich 4,5,7,8,11 * ABSTRACT Background: Cardiorespiratory transfusion reactions drive most transfusion-related morbidity and mortality. Transfusion- associated circulatory overload and transfusion-related acute lung injury have established causes, important impacts, mitigation options, and revised definitions, while non-conforming CRTRs fall into a category known as transfusion-associated dyspnea. Though procedures to investigate high-risk febrile transfusion reactions are typically rooted in detecting incompatibility or bacterial contamination, a common standard for examining CRTRs is lacking. CRTRs are further challenged by charting limitations, confounding (or enhanced susceptibility) by comorbidities, and/or overlapping insults. Deeper profiling of CRTRs could improve categorizations, reveal best-value diagnostics, and decipher the nature of (and/or minimize) reactions coded as TAD. Methods: The primary objective of this multi-center study is to reduce uncertainty in final conclusions drawn on CRTRs (cases), defined by dyspnea with objective disturbances and/or significant hemodynamic insults, with/without fever (±F). HRFTRs (controls) represent higher-grade F (T≥39°C or chills/rigors or lower-grade F (≥38°C by +Δ1°C) with non-respiratory effects). Patients (goal: 200) consent to additional sampling (≤24h post-TR) to identify contributing factors in case/control presentations, and in diagnostic groups (TRALI, TACO±F, TAD). Mechanistic axes of interest are cardiorenal, hemolytic, leukoagglutinating, biolipid, vasoactive, and inflammatory. Secondary goals include elucidation of real-life “insult-multiplicity” in CRTRs, tests of greatest yield, and distinguishing features in TRALI/TACO/TAD. Conclusions: A deep systematic CRTR probe may not only reduce diagnostic uncertainty but frame biomarker performance and pathologic signatures in definition-specific CRTRs. The re-classifiability or biology of TAD may be better understood. High- quality, mechanistic, true-to-quantity hemovigilance better exposes burdens and management options. Trial Registration: The trial is registered with ClinicalTrials.gov. with registry number NCT04267029. Keywords: Transfusion, Hemovigilance, TAD, TACO, TRALI, Fever 1 Department of Anesthesiology and Pain Medicine, 5 Quality in Utilization, Education and Safety in Transfusion (QUEST) Research Program, 7 Department of Laboratory Medicine and Pathobiology, 8 Department of Medicine, Division of Hematology, University of Toronto, Toronto, Canada 2 Department of Anesthesia and Pain Medicine, Hospital for Sick Children, Toronto, Canada 3 Department of Physics, Toronto Metropolitan University, Toronto, Canada 4 Laboratory Medicine Program, 11 Division of Medical Oncology and Hematology, Benign Hematology/Blood Disorders Program, University Health Network, Toronto, Canada 6 Precision Diagnostics and Therapeutics Program, Sunnybrook Health Sciences Centre, Toronto, Canada 9 Centre for Innovation, Canadian Blood Services, at Keenan Research Centre of the Li Ka Shing, Knowledge Institute of St. Michael's Hospital, Toronto, Canada 10 Department of Laboratory Medicine and Pathobiology, Sinai Health, Mount Sinai Hospital, Joseph & Wolf Lebovic Health Complex, Toronto, Canada 12 Department of Laboratory Medicine, St Michael’s Hospital, Unity Health, Toronto, Canada 13 Platelet Immunology Laboratory, Diagnostic Services, Canadian Blood Services, Winnipeg, Canada 14 Department of Pathology and Molecular Medicine, Queen’s University at Kingston Health Sciences Centre, Kingston, Canada Received: 04 October 2022 Accepted: 10 December 2022 *Correspondence: Dr. Christine Cserti-Gazdewich, E-mail: Christine.Cserti@uhn.ca Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: https://dx.doi.org/10.18203/2349-3259.ijct20230051