Receiver Operating Characteristics of NT-Probnp in the Transfusion Associated Dyspnea: Prospective Observation & Laboratory Assessment (TADPOL) Study of Cardiorespiratory Versus Febrile Presentation Archetypes

BACKGROUND: B-type natriuretic peptide (BNP) is a hormone secreted in response to volume-related ventricular stretch, and as a biomarker is both diagnostic and prognostic in heart failure. Elevation in BNP or its equimolar N-terminal prohormone fragment (NT-proBNP, noteworthy for its longer half-life) qualifies as a criterion in ISBT-IHN-AABB guidelines for the diagnosis of transfusion-associated circulatory overload (TACO). However, real-life range comparisons in TACO vs. non-respiratory transfusion reactions (TR) are lacking. In the Transfusion Associated Dyspnea-Prospective Observation and Laboratory Assessment (TADPOL) study of acute TRs requiring laboratory investigation (cardiorespiratory events +/- fever [CRTR+/-F] vs. standalone high-risk fevers [HRFTR]), patients consented to NT-proBNP testing as part of a multi-dimensional assessment of presentation archetypes and final diagnoses (e.g., TACO, transfusion-associated dyspnea [TAD], febrile non-hemolytic TR [FNHTR]). METHODS: Blood samples were collected within 24h of reaction onset from patients enrolled across 6 centers in the study's first 134 weeks. NT-proBNP (ng/L) was quantified by chemiluminescence immunoassay (Roche Diagnostics) in real-time (3 sites) or by batched testing (3 sites); reference cut-off values to rule in a cardiac cause for dyspnea in the acute care setting were >450 (age <50y), >900 (age 50-75y), and >1800 (age >75y). Summary statistics are reported. Relationships to provisional reaction diagnosis and clinical features were also explored using appropriate tests (Student's t-test, Mann-Whitney U, Pearson's correlation, and/or Fisher's exact test). Discrimination between possible-to-definite TACO and doubtful or ruled-out TACO was assessed using receiver operating characteristic (ROC) curve analysis with logistic regression. RESULTS: At the study mid-point, 1180 TR (604 TADPOL-eligible) occurred, with NT-proBNP tested in 77/100 enrolled patients. NT-proBNP was significantly higher in patients enrolled in the CRTR arms compared to HRFTR (p=0.0009), with no difference between CRTR+F and CRTR-F (p=0.4). NT-proBNP was also significantly higher in patients with dyspnea in the TR (p=0.005). There was no correlation between NT-proBNP and systolic blood pressure change (p=0.1) or at baseline (p=0.1). Provisional reaction diagnoses were available for 55 patients including 32/39 in the CRTR arms: for possible-to-definite TACO (n=14) and TAD (n=19), vs. standalone FNHTR (n=38), the median NT-proBNP (IQR) was 3,439 (1,587-10,668) and 1,893 (674-5,361), vs. 710 (124-10,542), respectively. Transfusion-related acute lung injury was considered possible in 3 cases, all with TACO. Among CRTR, there was a trend towards higher NT-proBNP values in patients with TACO (p=0.05), with no difference in ages (p=0.8). Using the age-adjusted reference cut-off, the sensitivity of high NT-proBNP for TACO was 86%; specificity was 54% when differentiating TACO from all enrolled TR and 38% between TACO and non-TACO CRTR. In ROC curve analysis (Fig. 1), the area under the curve was 72% (95% CI 55-88%) and the threshold value for discriminating TACO from other TR was 1606 with 60% sensitivity and 65% specificity (Fig. 2). CONCLUSIONS: NT-proBNP is strongly correlated with dyspneic TRs compared to isolated febrile TRs. Elevations appeared more marked in TACO, with a sensitivity of 86% using existing laboratory reference values. However, specificity and discrimination within CRTR were poor. These results affirm that NT-proBNP is helpful in ruling out TACO, whereas ruling in TACO continues to demand a more integrated approach. Whether cardiac strain in unclassified CRTR and TAD is evidence of missed TACO or other insults remains to be determined. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal