Looking beyond LCI: Multiple breath washout phase III slope derived indices and their application in chronic respiratory disease in children

Abstract

The multiple breath washout (MBW) test is widely reported in the context of Lung Clearance Index (LCI). LCI reflects global ventilation inhomogeneity but does not provide information regarding the localization of disease along the respiratory tree. The MBW-derived normalized phase III slope (S_nIII) indices (S_cond and S_acin), instead, can distinguish between convective-dependent and diffusion-convection-dependent ventilation inhomogeneity considered to occur within the conductive and acinar airways, respectively. In cystic fibrosis, S_cond tends to become abnormal even earlier than LCI and spirometry. The value of S_cond and S_acin in clinical practice has been recently explored in other respiratory conditions, including asthma, primary ciliary dyskinesia, bronchopulmonary dysplasia, bronchiolitis obliterans, and sickle cell disease. In this narrative review we offer an overview on the theoretical background, potentialities, and limitations of S_nIII analysis in children, including challenges and feasibility aspects. Moreover, we summarize current evidence on the use of S_nIII-derived indices across different groups of pediatric chronic respiratory disease and we highlight the gaps in knowledge that need to be addressed in future studies.

Keywords: children; cystic fibrosis; multiple breath washout; phase III slope analysis; ventilation inhomogeneity.

Figure 1

A schematic model of the branching airway tree with the conducting and acinar airways labeled (created with BioRender.com).

Figure 2

Graphic representation of S_cond from one multiple breath washout (MBW) trial. Three breaths at different stages of an SF₆ MBW are displayed. Figure 2A displays the expirogram of each breath (SF₆ concentration against volume [L]). As the SF₆ concentration decreases and expiratory volume changes over the course of the washout, the scaling of the x and y‐axes are not uniform. The phase III slope is numerically the coefficient of the linear regression (red line) of the tracer gas concentration (y‐axis) versus expired volume (x‐axis) in the alveolar phase III (50%–95% of the expired volume, delimited by vertical blue lines). The alveolar slope is divided by mean expired SF₆ concentration over the phase III interval and multiplied by the expiratory tidal volume of the breath in liters, to give a final number which represents the normalized alveolar slope (S_nIII).

Figure 3

Two expirograms (SF₆ concentration against volume [L]) representing two individual breaths of a washout from adolescents with CF. Breath (A) has an adequate expired vT with a sufficient phase III portion of the breath regressed. Breath (B) has a small expired vT with no clear phase III portion of the breath and is not suitable for S_nIII analysis.