Physiological phenotyping of pediatric chronic obstructive airway diseases

Abstract

Inert tracer gas washout (IGW) measurements detect increased ventilation inhomogeneity (VI) in chronic lung diseases. Their suitability for different diseases, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), has already been shown. However, it is still unclear if physiological phenotypes based on different IGW variables can be defined independently of underlying disease. Eighty school-age children, 20 with CF, 20 with PCD, 20 former preterm children, and 20 healthy children, performed nitrogen multiple-breath washout, double-tracer gas (DTG) single-breath washout, and spirometry. Our primary outcome was the definition of physiological phenotypes based on IGW variables. We applied principal component analysis, hierarchical Ward's clustering, and enrichment analysis to compare clinical characteristics between the clusters. IGW variables used for clustering were lung clearance index (LCI) and convection-dependent [conductive ventilation heterogeneity index (Scond)] and diffusion-convection-dependent variables [acinar ventilation heterogeneity index (Sacin) and carbon dioxide and DTG phase III slopes]. Three main phenotypes were identified. Phenotype I (n = 38) showed normal values in all IGW outcome variables. Phenotype II (n = 21) was characterized by pronounced global and convection-dependent VI while diffusion-dependent VI was normal. Phenotype III (n = 21) was characterized by increased global and diffusion- and convection-dependent VI. Enrichment analysis revealed an overrepresentation of healthy children and former preterm children in phenotype I and of CF and PCD in phenotypes II and III. Patients in phenotype III showed the highest proportion and frequency of exacerbations and hospitalization in the year prior to the measurement. IGW techniques allow identification of clinically meaningful, disease-independent physiological clusters. Their predictive value of future disease outcomes remains to be determined.

Agreement between multiple-breath nitrogen washout systems in children and adults

“…Compared to forced expiratory volume of the first second (FEV 1 ) from spirometry, LCI is more specific and sensitive for structural and functional pathology detected in computed tomography scans and treatment response in mild CF lung disease [6][7][8]. Accordingly, LCI from different setups is reported from studies targeting early origins of mild CF [4,7,[9][10][11]. Though, agreement between systems is largely unknown.…”

Single‐breath washout and association with structural lung disease in children with cystic fibrosis

“…Generally, SIII showed quite heterogeneous results within different disease groups . Through collective interpretation of different lung function tests it is possible to assign heterogeneous SIII results to different physiological and disease phenotypes.…”

“…However, lung MRI as a monitoring tool in CF, especially in children, is still relatively new and requires further validation before it can be used routinely in the clinic. We learned from cross‐sectional studies that elevated Scond appears to be an early event in CF, followed by elevated LCI, and only later in more severe disease course by elevated Sacin . This may reflect a disease pathology of well‐preserved alveolar structure until late in CF due to the predominant airway involvement, minimal loss of alveolar‐capillary units, and improved ventilation‐perfusion relationship due to the process of “claustration.” While certain lung areas supplied by the same mucus‐impacted bronchus become simultaneously hypoventilated and underperfused, the remaining well‐preserved lung areas show enhanced ventilation—perfusion relationship.…”

Multiple breath washout: A new and promising lung function test for patients with idiopathic pulmonary fibrosis

“…Both global (LCI) and S acin are sensitive to evaluate disease extent and progression in small airway diseases . Although chronic obstructive and productive lung diseases have been primary applications for N 2 ‐MBW previously, LCI and S acin were highly abnormal in IPF.…”