Corresponding author:
Prof. Dr. med. Philipp Latzin, PhD
Inselspital, University Children’s Hospital of Bern
Freiburgstrasse 15, 3010 Bern, Switzerland
E-mail: philipp.latzin@insel.ch
Phone: +41 31 632 9353
Keywords: Multiple-breath washout; Cystic fibrosis, pulmonary
function testing
Running title: LCI properties hold after correction of sensor
error
Word count: 2942/3500
Figures and tables: 5/6 (1 Table, 4 Figures)
References: 24/40
Online Supplement: This manuscript has supplemental material.
Abstract (221/250)
Background: The recently described sensor-crosstalk error in
the multiple-breath washout (MBW) device (Exhalyzer D, Eco Medics AG,
Duernten, Switzerland) could highly influence clinimetric properties and
the current interpretation of MBW results. This study reanalyzes MBW
data from clinical routine in the corrected software version Spiroware®
3.3.1 and evaluates the effect on outcomes.
Methods: We included nitrogen-MBW data from healthy children
and children with CF from previously published trials and ongoing cohort
studies. We specifically compared LCI analyzed in Spiroware 3.2.1 and
3.3.1 with regards to i) feasibility, ii) repeatability and iii)
validity as outcome parameters in children with CF.
Results: (i) All previously collected measurements could be
reanalyzed and resulted in unchanged feasibility in Spiroware 3.3.1.
(ii) Short- and midterm repeatability of LCI was similar in both
software versions. (iii) Clinical validity of LCI remained similar in
Spiroware 3.3.1, however, resulted in lower values. Discrimination
between health and disease was comparable between both software
versions. The increase in LCI over time was less pronounced with 0.16
LCI units/year (95% CI 0.08; 0.24) vs. 0.30 LCI units/year (95% CI
0.21; 0.38) in 3.2.1. Response to intervention in children receiving
CFTR-modulator therapy resulted in a comparable improvement in LCI in
both Spiroware versions.
Conclusion: Our study confirms that clinimetric properties of
LCI remain unaffected after correction for the cross-sensitivity error
in Spiroware software.
Introduction
We recently described and characterized a substantial sensor-crosstalk
error in a commercially available and widely used multiple-breath
washout (MBW) device (Exhalyzer D, Eco Medics AG, Duernten, Switzerland)
and suggested a possible correction which is now available in an updated
version of Spiroware analysis software (Spiroware 3.3.1, Eco Medics AG,
Duernten, Switzerland) 1. There is an obvious sense of
concern in the MBW community as the potential impact of these findings
on existing and ongoing studies could highly influence clinimetric
properties of MBW results and their current clinical interpretation2.
MBW has become an important diagnostic tool in cystic fibrosis (CF) for
both, clinical follow-up of the patients and as an endpoint for clinical
trials of new therapies 3-8. The lung clearance index
(LCI) is a feasible, repeatable, and sensitive marker of ventilation
inhomogeneity that correlates well with structural lung disease and
tracks disease progression in children with CF5,6,9,10. LCI is calculated as the ratio of the
cumulative expired volume divided by the functional residual capacity
(FRC), based on indirect calculation of nitrogen (N2)
from oxygen (O2) and carbon dioxide
(CO2) signals. This results in inherent sensitivity to
measurement errors in these signals, and the error described above
previously resulted in a prolongation of the washout with falsely
elevated LCI values 1.
To evaluate the potential clinical impact of these findings, this study
aims to reanalyze published and collected MBW data from clinical routine
by applying the corrected signal processing algorithm and evaluating the
effect on outcomes. We assessed if previously described clinimetric
properties of LCI hold for corrected results. We specifically examined
corrected LCI with regards to i) feasibility, ii) repeatability, and
iii) validity as outcome parameters in children with CF.
Methods