Comparisons Between Multiple Breath Washout and Standard-of-Care Spirometry in Children Undergoing Allogenic Hematopoietic Stem Cell Transplant: A Transpire Study

Abstract

Rationale: Multiple breath N2 washout (MBW) is a passive pulmonary function test (PFT) that measures ventilation inhomogeneity in patients as young as 2-3 years of age. Lung clearance index (LCI2.5) is the primary outcome variable of interest and widely recognized as a sensitive biomarker for peripheral airways disease. There is evidence that MBW is more sensitive than standard-of-care spirometry, but this relationship has not been fully explored in children undergoing allogenic hematopoietic stem cell transplant. In this study, we aim to compare LCI2.5 with common spirometric indices including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) in children undergoing HSCT. Methods: We performed MBW (ECO MEDICS EXHALYZER® D, SPIROWARE® 3.3.1) and standard-of-care spirometry in a prospective cohort of children undergoing HSCT at three participating TRANSPIRE centers: Seattle Children's Hospital, Texas Children's Hospital, and University of Minnesota Children's Hospital. Children ≥6 years and older were eligible for the study. Subjects were identified as having normal vs abnormal baseline pulmonary status by the site PI at the time of enrollment. MBW and spirometry were performed prior to transplant and set time intervals thereafter, all in accordance with American Thoracic Society (ATS) / European Respiratory Society (ERS) standards. LCI2.5, FVC, and FEV1 were converted to Z-scores using Global Lung Function Initiative reference equations. Variables were compared using a linear mixed effects model to account for multiple measurements per patient. Results: Of 48 patients with simultaneous MBW and spirometry results, 85 unique data points were included in the analysis. There was a significant inverse relationship when comparing LCI2.5 to FVC (coef -0.4594; p=.0006) and FEV1 (coef -0.4035; p=0.0023). In 13/85 instances, LCI2.5 was abnormal while corresponding spirometry was not. Of these 13 patients, 7 (53.8%) were identified as having abnormal baseline pulmonary status. Conclusions: In this large multicenter prospective cohort of children undergoing HSCT, we found a strong inverse relationship between LCI2.5 and standard spirometric indices including FVC and FEV1. A substantial number of patients with significantly elevated LCI2.5 had normal lung function, suggesting that in some cases, LCI2.5 may be a more sensitive biomarker for disease when compared to standard-of-care spirometry. Although this discrepancy did not differentiate those with and without abnormal baseline pulmonary status, further sub-analysis is needed.