Transfusion Associated Dyspnea Profiling (TADPOL)

Transfusion-Associated Dyspnea: Prospective Observational and Laboratory Assessment

Transfusion reactions are defined as harms occurring during or after blood transfusion, with new heart/lung stress (eg. troubled breathing) regarded as cardiorespiratory transfusion reactions (CRTRs). CRTRs are among the most important, as the leading cause of transfusion-related harm and death. Though there are distinct classifications for these events, real life cases often don't fall neatly into a given category, with outliers regarded as "transfusion associated dyspnea (TAD)". It is unknown what TAD is -- whether it has a unique root cause, is a milder version of other known CRTRs, or is a blend of events. The purpose of this study is to better understand TAD and CRTRs by profiling them through a detailed medical history and more intensive laboratory assessment. This review of CRTRs may improve the quality/validity of final conclusions reported in the health record and to hemovigilance bodies, and uncover the nature of TAD and/or minimize CRTRs defaulting to the TAD category. Our enhanced understanding will advance diagnostic, treatment, and prevention efforts.

Study Overview

• Status: Completed
• Conditions: Transfusion Reaction
• Intervention / Treatment: Diagnostic test: TADPOL battery (deep clinicolaboratory profile)

Detailed Description

"Transfusion-Associated Dyspnea: Prospective Observation and Laboratory Assessment" (TADPOL) aims to improve the diagnosis and characterization of cardiorespiratory transfusion reaction (CRTR) patients ("cases"), as compared with high risk febrile transfusion reaction (HRFTR) patients ("controls"), by applying a standardized and intensive clinicolaboratory profiling tool.

CRTR, in contrast with HRFTR, are more difficult to diagnose and manage. Patients are often sick with (or prone to) pathologies that resemble reactions (eg. congestive heart failure [CHF] vs transfusion associated circulatory overload [TACO]), and/or experience more than one transfusion-associated disturbance at a time.

CRTRs are also the most disruptive, distressing, and disposition-escalating events for patients at an individual level, and are disproportionately accountable for transfusion associated deaths at the collective level in national hemovigilance systems. The cardinal CRTRs range from TACO (most commonly) to allergic bronchospasm to transfusion related acute lung injury (TRALI).

Inaccurate classification may undercount certain phenomena (when criteria fail to be met by confounding conditions), and/or overcount others (when including all possibilities-of-relevance in hemovigilance).

These uncertainties beget gaps (or excesses) in patient care and in donor/product-associated decision-making.

HYPOTHESES: The TADPOL CRF and laboratory profiling effort will improve the yields of confident (more certain), accurate (better-grounded), and thorough (multi-event-sensitive) diagnoses in CRTR patients.

Most cases of TAD are likely to be re-classified as milder versions (or overlaps) of possible CRTR states (± the underlying condition), while the remainder may exhibit a signature resembling FNHTR (FTR controls).

Precise case-mapping should yield useful personalized information, while aggregated findings from each disturbance pathway - as they are distributed in each conventional reaction category - can validate the utility of markers being explored in reaction investigation algorithms.

The TADPOL bioarchive and anonymized dataset will also be assets for explorations of novel indicators and patterns.

• Study Type: Observational
• Enrollment (Actual): 151

Contacts and Locations

• Study Contact: Name: Samia Saeed, BSc; Phone Number: 2892 416-340-4800; Email: Samia.Saeed@uhn.ca
• Study Contact Backup: Name: Omar Florez; Phone Number: 8116 416-340-4800

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5G 2C4
      • University Health Network

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients at 4 university-affiliated teaching hospitals who have received a blood transfusion, and experienced a suspected acute transfusion reaction

Description

Inclusion Criteria:

• Age ≥ 18 years
• Transfusion of blood products (components or derivatives) with an available pre-transfusion group & screen specimen
• Referred to the blood transfusion laboratory for review of a suspected acute transfusion reaction (occurring within 24 hours of completing transfusion), and either exhibiting a cardiorespiratory disturbance (CRTR: cases) or a high-risk febrile disturbance (HRFTR: controls)

Exclusion Criteria:

• Pregnant females
• Massive hemorrhage entailing >20 implicated products in the 24h period before the acute transfusion reaction's onset
• Previous enrolment in the same designation (ie- an individual with RTR will not re-enroll if having another RTR, but may re-enrol if having FTR)
• Expected to discharge home or die sooner than specimen acquisition
• Withdrawal of consent at any time

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cases: CRTR (cardiorespiratory transfusion reaction); Respiratory/cardiovascular disturbances after transfusion (>/=2 of respiratory distress, pulmonary edema, cardiovascular system changes, fluid shifts, cardiac strain indicators), with or without accompanying (or pre-existing) fever	Diagnostic test: TADPOL battery (deep clinicolaboratory profile); profile dimensions: hemolytic; allergic; cardiorenal; inflammatory; leukoagglutinating; exploratory bioarchive
Controls: HRFTR (high risk febrile transfusion reactions); Post-transfusion fevers requiring laboratory investigation (Tmax>/=39C, or lesser deflections if accompanied by chills/rigors), without respiratory features (hypoxia or dyspnea)	Diagnostic test: TADPOL battery (deep clinicolaboratory profile); profile dimensions: hemolytic; allergic; cardiorenal; inflammatory; leukoagglutinating; exploratory bioarchive

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CERTAINTY	Improve certainty in final cardiorespiratory transfusion reaction event classifications (by reduction in the number of cases otherwise achieving no better than "possible" provisional conclusions), from the expected base ambiguity rate of 60%, down to 30%.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
COMPLEXITY	Determine the frequency of multi-domain disturbances (ie- "overlap") in cardiorespiratory transfusion reaction referrals	2 years
PATHOGENESIS FOOTPRINTING	Statistically characterize concordance of established and potential criteria in TRALI, TACO, allergic bronchospasm, and TAD	2 years

Collaborators and Investigators

• Sponsor: Toronto Transfusion Medicine Collaborative
• Collaborators: University Health Network, Toronto; Sunnybrook Health Sciences Centre; Unity Health Toronto; MOUNT SINAI HOSPITAL; Canadian Blood Services
• Investigators: Principal Investigator: Christine M Csert-Gazdewich, MD, Universith Health Network

Publications and helpful links

General Publications

• McVey MJ, Cohen R, Arsenault V, Escorcia A, Tasmin F, Pendergrast J, Lieberman L, Lin Y, Callum J, Cserti-Gazdewich C. Frequency and timing of all-cause deaths in visits involving suspected transfusion reactions, and the significance of cardiopulmonary disturbances. Vox Sang. 2021 Sep;116(8):898-909. doi: 10.1111/vox.13086. Epub 2021 Feb 26.
• Callum JL, Cohen R, Cressman AM, Strauss R, Armali C, Lin Y, Pendergrast J, Lieberman L, Scales DC, Skeate R, Ross H, Cserti-Gazdewich C. Cardiac stress biomarkers after red blood cell transfusion in patients at risk for transfusion-associated circulatory overload: a prospective observational study. Transfusion. 2018 Sep;58(9):2139-2148. doi: 10.1111/trf.14820.
• Cohen R, Escorcia A, Tasmin F, Lima A, Lin Y, Lieberman L, Pendergrast J, Callum J, Cserti-Gazdewich C. Feeling the burn: the significant burden of febrile nonhemolytic transfusion reactions. Transfusion. 2017 Jul;57(7):1674-1683. doi: 10.1111/trf.14099. Epub 2017 Mar 28.
• Parmar N, Pendergrast J, Lieberman L, Lin Y, Callum J, Cserti-Gazdewich C. The association of fever with transfusion-associated circulatory overload. Vox Sang. 2017 Jan;112(1):70-78. doi: 10.1111/vox.12473. Epub 2016 Dec 21.

Helpful Links

• TADPOL Protocol paper

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Actual): October 4, 2022
• Study Completion (Actual): December 22, 2022

Study Registration Dates

• First Submitted: February 7, 2020
• First Submitted That Met QC Criteria: February 10, 2020
• First Posted (Actual): February 12, 2020

Study Record Updates

• Last Update Posted (Actual): May 3, 2023
• Last Update Submitted That Met QC Criteria: April 28, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Allergic Reaction; TACO (transfusion associated circulatory overload); TRALI (transfusion related acute lung injury); FNHTR (febrile non-hemolytic transfusion reaction); TAD (transfusion associated dyspnea)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Respiration Disorders; Hematologic Diseases; Signs and Symptoms, Respiratory; Dyspnea; Transfusion Reaction
• Other Study ID Numbers: TADPOL_v0.7

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No