Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.769477
Title: Lung Clearance Index as a definitive surrogate endpoint for therapeutic interventions in cystic fibrosis
Author: Bayfield, Katie Jill
ISNI:       0000 0004 7657 8589
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Abstract:
Lung Clearance Index (LCI), a measure of ventilation inhomogeneity, reflects disease in distal airways predominantly affected in cystic fibrosis (CF). I hypothesised that improved understanding of LCI's clinimetric properties could support its progression to an accepted outcome measure. I aimed to define and explain differences between techniques and assess responsiveness to interventions. LCI is derived from multibreath washout of inert gas, usually sulphur hexafluoride (SF6) or Nitrogen (N2). I tested 47 CF patients and 42 healthy controls on both the Exhalyzer D (N2) and a modified Innocor device (SF6) demonstrating that although both correlated with forced expiratory volume in the 1st second (FEV1), LCI from N2 was consistently higher i.e. more abnormal. I designed a novel simultaneous washout system, which indicated that tissue N2 was likely a major contributor. I produced normal range data and confirmed the absence of diurnal effects. I was the senior site physiologist for the UK CF Gene Therapy Consortium's phase 2b multi-dose trial. 116 CF patients completed 12 months of nebulised liposome-mediated gene therapy or placebo; the primary outcome, relative improvement in FEV1, was met. Similar improvements were not detected by LCI. My detailed exploratory analysis failed to fully explain this although it seems likely related to failure of sufficient inhaled drug reaching the distal airways. In parallel, I performed serial LCIs on CF patients prescribed treatment changes. Although FEV1 improved LCI did not, even in subgroups based on disease severity/ stability and intervention. Sample sizes were small, and patient convenience precluded standardisation of time points; further prospective data are needed. This thesis contributes to our understanding of differences between LCI techniques, emphasising the fact that results are not interchangeable. Unlike in early CF, when used in a population with wider disease severity, LCI does not appear to offer an advantage for monitoring over FEV1.
Supervisor: Davies, Jane C. ; Alton, Eric Sponsor: Novartis Pharma
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.769477  DOI:
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