Multiple breath-washout for pulmonary function assessment in young childhood cancer survivors: a multicenter study

Childhood cancer survivors (CCS) are at risk for long-term pulmonary complications from treatment-related toxicity. Nitrogen multiple-breath washout (N2MBW) may detect small airway dysfunction earlier than standard pulmonary function tests (PFTs), but its value in CCS remains uncertain.

To determine the prevalence of ventilation inhomogeneity measured by N2MBW in CCS, evaluate whether it detects abnormalities beyond spirometry and diffusion capacity for carbon monoxide (DLCO), and explore associations with treatment exposures.

In this prospective multicenter study (Bern, Basel, Geneva), we measured lung function in all CCS aged 6-21 years who were undergoing routine follow-up. We stratified participants into high-risk (pulmotoxic chemotherapy [busulfan, bleomycin, nitrosoureas], thoracic surgery, radiotherapy, or hematopoietic stem cell transplantation [HSCT]) and standard-risk (other systemic anticancer treatments). PFTs included N2MBW (lung clearance index [LCI], acinar [SACIN] and conductive [SCOND] inhomogeneity), spirometry (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC]), and DLCO. Abnormal values were defined as z-score < -1.645 or > 1.645, calculated using the Global Lung Initiative references. We quantified the proportion of participants with isolated elevated LCI and analyzed associations with treatment exposures using multivariable linear regression.

We included 191 CCS (median 7 years post-diagnosis). Mean LCI was 6.27 (95%CI 6.17-6.37), with 7% of participants showing abnormal values. N2MBW results did not differ between high- and standard-risk groups, but allogeneic HSCT survivors had the highest mean LCI (7.18, 95%CI 5.88-8.37), with 33% abnormal. Survivors had mildly impaired mean FEV1, FVC, and DLCO z-scores (-0.21, -0.34, 0.23), more pronounced in high-risk CCS (-0.67, -0.85, -0.05). Isolated LCI impairment, without abnormalities in spirometry or DLCO, occurred in only 3%. Among treatment exposures, only allogeneic HSCT was associated with higher LCI (1.40, 95%CI 0.57-2.33) and SACIN (1.24, 95%CI 0.20-2.28).

Most pediatric CCS had normal lung function. N2MBW abnormalities were rare, occurring mainly in allogeneic HSCT survivors. Overall, N2MBW added little beyond standard PFTs, suggesting it may not be needed for routine follow-up at this stage, except after allogeneic HSCT. Larger, longitudinal studies should clarify the onset, progression, and prognostic significance of N2MBW abnormalities and their potential role in risk-adapted follow-up care.