Longitudinal Analysis of Lung Clearance Index in Children Undergoing Hematopoietic Stem Cell Transplant: A Transpire Study

Abstract

Rationale: Multiple breath N2 washout (MBW) is a passive pulmonary function test that measures ventilation inhomogeneity in patients as young as 2-3 years of age. Lung clearance index (LCI2.5) is the primary outcome variable and widely recognized as a sensitive biomarker for peripheral airways disease. In the setting of pediatric allogenic hematopoietic stem cell transplant (HSCT), LCI2.5 may be used as a tool to detect early manifestations of chronic lung graft-vs-host disease (GVHD). We previously reported on the feasibility and success of MBW in this patient population (TRANSPIRE, Abts et al), but little is known about the longitudinal trajectory of LCI2.5 in patients with and without pre-existing lung dysfunction.Methods: We performed MBW (ECO MEDICS EXHALYZER® D, SPIROWARE® 3.3.1) 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 were eligible to perform MBW. Subjects were identified as having normal vs abnormal baseline pulmonary status by the site PI at the time of enrollment. MBW was performed at baseline and at set time intervals thereafter, all in accordance with the American Thoracic Society (ATS)/European Respiratory Society (ERS) standards. Operators and site PIs were trained and certified in performing MBW and interpreting results. LCI2.5 was converted to Z-scores using recently published Global Lung Function Initiative reference equations. Results: Of 148 subjects enrolled, 61 performed at least one MBW test for a total of 110 unique results. Mean baseline LCI2.5 ZS was 0.4, SD 1.2 in those with preexisting lung pulmonary disease and 0.4, SD 1.4 in those without (p = 0.871). In total, 4 (14%) patients had abnormal LCI2.5 prior to transplant. From 0-6 months, mean LCI2.5 increased in both groups, but change over time was not statistically significant (p-value for time effect = 0.1812). At one year, mean LCI2.5 remained elevated in abnormals (1.2, SD 1.5) compared to normals (0.2, SD 1.0).Conclusions: In this large multicenter prospective cohort of children undergoing HSCT, mean LCI2.5 ZS was above 0 at all time points. From 0-6 months, there were no significant differences in LCI2.5 ZS when comparing subjects with and without pre-existing lung disease. At one year, however, there is a trend towards sustained LCI2.5 elevation in the abnormal group.