THE ASSOCIATION OF CLINICAL PROGNOSTIC FACTORS WITH VENTILATION INHOMOGENEITY: SINGLE CENTRE ANALYSIS OF PATIENTS WITH CYSTIC FIBROSIS FROM 2014 TO 2019

BACKGROUND. Especially in children, spirometry may not capture the underlying lung disease, which has been described in small airways since young ages in cystic fibrosis (CF). Lung Clearance Index (LCI2.5) is one of the derivatives obtained by the multiple breath washout (MBWN2) test, recognized as a sensitive alternative for the assessment of lung function. The potential of this outcome in clinical setting has not been fully explored yet. METHODS. Data were collected for each patient’s visit from 2014 up to September 2019 from the CF Centre of Milano and analyzed according to different perspective. The association between lung function measures and selected prognostic variables was investigated by means of ordinary least-square regression models; disease phenotypes were obtained according to children’s clinical characteristics by means of agglomerative nesting hierarchical clustering; longitudinal association between lung function and selected variables, and phenotypes, was assayed fitting linear-mixed effect models; recurrence of pulmonary exacerbations (PE) was evaluated by extensions of the Cox proportional hazard models. RESULTS. A total of 433 MBWN2 measurements from 245 children with CF were analyzed. Cross-sectionally, both LCI2.5 and FEV1 %predicted showed significant association with CF clinical prognostic variables, i.e., Pseudomonas aeruginosa infection, pancreatic function, BMI Z-score and age, whereas only LCI2.5 was associated with genotype. Two different phenotypes of children around 11 years old emerged, differentiating one from another also by a mean LCI2.5 difference of 3.37 (95%CI: 2.57 to 4.16) and by a mean FEV1 difference of 1.2 (95%CI:0.7 to 1.6) Z-score. Children with the best phenotype were mainly characterized by absence of F508del mutation and by a normal pancreatic function. Longitudinally, LCI2.5 and FEV1 % predicted remained stable over time and showed meaningful differences between phenotypes at each follow-up visit. However, infection by Pseudomonas aeruginosa was associated with longitudinal variation of LCI2.5 only, showing that being free from Pseudomonas aeruginosa lowers LCI2.5 by 0.82 (95%CI: -1.36 to -0.27). Eventually, mean number of PE in the present cohort was 1.8, varying from 0 to 4. Children with higher LCI2.5 are expected to experience a 6% higher risk of PE recurrence during their follow-up (HR 1.06, 95%CI 1.01 to 1.10), whereas FEV1 % predicted did not show any evidence of association. An association with PE recurrence was also detected between phenotypes in favour of children with better clinical status (HR 0.46, 95%CI 0.34 to 0.60). CONCLUSIONS. LCI2.5 shows interesting associations with clinical characteristics not shared with FEV1, %predicted, both in cross-sectional and longitudinal analyses. Clustering has shown a disease profile of children who share negative clinical prognostic factors, also in terms of ventilation inhomogeneity, and are at higher risk of recurrent pulmonary exacerbations. Altogether these findings add to the available literature in confirming the clinical utility of MBWN2.