Annals of the American Thoracic Society

Rationale: Childhood cancer survivors are at risk of long-term pulmonary dysfunction, but we lack sensitive outcome measures to detect early pulmonary damage.

Objectives: To assess the ability of nitrogen multiple-breath washout (N2MBW) for detecting pulmonary dysfunction compared with spirometry in long-term survivors of childhood cancer.

Methods: We analyzed cross-sectional data from long-term (≥5-yr) survivors of childhood cancer, aged ≤16 years at cancer diagnosis, ≥16 years at study (assessment period 2015–2019). We categorized survivors by risk: high risk for those having had pulmotoxic chemotherapy, chest radiation, thoracic surgery, and/or hematopoietic stem cell transplantation, and standard risk for other cancer therapies. Primary outcomes were the global lung clearance index (LCI) and acinar ventilation inhomogeneity index (SACIN) from N2MBW, and forced expiratory volume in 1 second (FEV1) and functional vital capacity (FVC) from spirometry. We calculated z-scores for N2MBW and spirometry parameters and compared pulmonary dysfunction between risk groups. Pulmonary dysfunction was defined as z-score +1.64 for N2MBW and −1.64 for spirometry.

Results: We studied 46 survivors, median age at diagnosis 10 years (interquartile range, 4–14), median age at study 30 years (interquartile range, 25–40). Thirty-seven percent were at high risk and 63% at standard risk for pulmonary dysfunction. LCI and SACIN were higher in the high-risk group compared with the standard-risk group (mean LCI z-scores 2.09, standard deviation [SD] 2.39 vs. 0.95, SD 2.81; mean SACIN z-scores 2.45, SD 3.29 vs. 0.65, SD 2.79). FEV1 and FVC were lower in the high-risk compared with the standard-risk group (mean FEV1 z-scores −0.94, SD 1.39 vs. −0.10, SD 1.07; mean FVC z-scores −1.14, SD 1.23 vs. 0.15, SD 1.61). Overall, LCI, SACIN, FEV1, and FVC were abnormal in 60%, 53%, 33%, and 33% of high-risk patients compared with 23%, 21%, 0%, and 4% of standard-risk patients.

Conclusions: N2MBW identified more cases of pulmonary dysfunction in long-term survivors of childhood cancer than spirometry, even in patients who had cancer therapy not specifically known as being pulmotoxic. N2MBW could be a complementary screening tool for early pulmonary damage after treatment for childhood cancer.

Clinical trial registered with (NCT 02730767).

Correspondence and requests for reprints should be addressed to Claudia Elisabeth Kuehni, M.D., Institute of Social and Preventive Medicine, University of Bern, Mittelstrasse 43, 3012 Bern, Switzerland. E-mail: .

*Co–first authors.

Co–senior authors.

Supported by the Swiss Cancer League (KLS-3175-02-2013, KLS-3886-02-2016), Swiss Cancer Research (KFS-4157-02-2017), Stiftung für krebskranke Kinder, Regio Basiliensis, FORCE–Fondation Recherche sur le Cancer de l’Enfant, Gedächtnis-Stiftung Susy Rückert zur Krebsbekämpfung, Fond’Action, Taecker Stiftung, Stiftung Krebshilfe Zürich Schweiz, and Stiftung Henriette and Hans-Rudolf Dubach-Bucher.

Author Contributions: Conception and design of the study: C.S.R., P.L., and N.X.v.d.W. Acquisition of data: C.S., J.U., S.J.Z., R.J., R.K., B.F., and G.N. Statistical analysis: C.S., J.U., and C.E.K. Interpretation: C.S., J.U., P.L., C.E.K., and N.X.v.d.W. Drafting the work: C.S., J.U., and C.E.K. All authors edited, reviewed, and approved the final version of the manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are investigated and resolved.

This article has an online supplement, which is accessible from this issue’s table of contents at

Author disclosures are available with the text of this article at


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Annals of the American Thoracic Society

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