The aim of this review was to systematically assess the clinimetric properties of outcome measures when used to measure the effect of ACTs following the guidance described by the COSMIN group[17, 28]. No RCTs met the inclusion criteria for our primary or secondary objectives. This was not unexpected, as historical practice has been the adoption of outcome measures used in other aspects of CF care. Furthermore, several Cochrane reviews into ACTs have highlighted the need for more robust outcome measures in this area[6, 9].
The COSMIN group advocate that for effective outcome measurement it is essential that the construct being measured is clearly defined. Based upon measurement theory[10, 29] airway clearance could be considered as a complex construct combining many different items which influence it (formative model) and which it influences (reflective model), for example, sputum production, breathlessness and ventilation inhomogeneity. In considering this, it could be concluded that assessing ACT by use of a single measure which may only reflect one item of the airway clearance construct could over simplify conclusions as to ACT effect. Ideally an outcome measure would be able to assess the construct of ACT as a whole.
From our literature search we note that many different outcome measures are being used in CF airway clearance research in addition to the traditional measures of FEV1 and sputum weight. These include LCI derived from MBW tests, electrical impedance tomography and a variety of radiological techniques including 3-helium MRI. We acknowledge that within our excluded studies there was a pilot study investigating hyperpolarized 3-Helium MRI, and two studies investigating the effect of ACT upon LCI, suggesting preliminary work has been carried out in this area. While there were no accepted studies evaluating any measures, these outcomes may have been assessed for their clinimetric properties in regard to other aspects of CF, although identifying those validation studies was outside the scope of this review.
This review identified two ongoing studies[22, 23], which could suggest that the CF research community is trying to address the lack of robust ACT outcome measures. The results of these trials, which appear to be assessing the clinimetric properties of some of the emerging measures against historical outcomes (spirometry, LCI, plus two forms of MRI and LCI, impulse oscillometry and electrical impedance compared to spirometry and sputum weight) are urgently needed. Randomised controlled trials such as these are essential to enable clinicians and researchers to identify which outcome measures are appropriate to use for airway clearance assessment.
The demographics of the CF population is changing; there are now more adults than children with CF as people with CF live longer. The development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator medications, particularly the compound, elexacaftor/ tezacaftor/ ivacaftor (KaftrioTM/ Trikafta™) potentially suitable for 80–90% of the CF population, is likely to dramatically change the outlook for people with CF for the future. These medications target the CF defect at the protein level, correcting abnormal ion transportation across cell membranes, thus preventing airway dehydration within the lungs. This limits the thick sticky mucus which traditionally has been a breeding ground for infection and a major cause of CF lung damage, leading to respiratory failure. It is thought that while early introduction of CFTR modulators will limit the development of CF lung disease, it will not be possible to correct established lung damage, and sputum will still be produced. While post-CFTR modulator sputum appears to be more fluid and easier to clear, ACTs to promote clearance and prevent lung infections may well remain part of daily management for many people with CF for the foreseeable future.
This positive advancement in CF management does provide a welcome problem when considering outcome measures for airway clearance assessment. Outcomes that have been used traditionally may not be relevant in this new post-CTFR modulator population, for example, sputum measures will not be helpful in people with minimal secretions, and spirometry may not be sensitive enough to pick up changes in a population with “normal” values. A recent review into monitoring early stage lung disease in CF highlighted that the lack of measurable defects in spirometric values does not “indicate the absence of inflammation, infection and remodelling”. Outcome measures used to assess people with CF, and other respiratory diseases, whether post-exacerbation, for monitoring or for the effects of ACT, need to be sensitive enough to pick up these early lung changes.
Furthermore, and essential for all CF healthcare professionals to consider, as the CF population continues to change, the recommendation of ‘daily ACT for all’ may change and the ability to thoroughly assess when ACT is required e.g. in times of exacerbation or declining respiratory status and equally, when it could be withdrawn, will be essential. LCI may be one measure which could be used for these assessments, having been shown to be sensitive enough to detect small changes in CF lungs. However, although LCI has good clinimetric evidence as a long term outcome for use in the CF population[31, 34], validation is still needed for the use of LCI to measure short-term treatment effects, especially in relation to ACTs[25–27]. The use of LCI as an outcome may also be dependent upon disease stage, with emerging evidence that it may be impractical for those with severe lung disease due to prolonged test duration. People with advanced disease may also exhibit paradoxical LCI results due to changes in occluded lung units causing differences in the amount of communicating lung contributing to the MBW signal.
Similarly to this review, a recent systematic review investigating outcomes and endpoints used in CF pulmonary exacerbation studies also reported a wide range of outcomes used, with FEV1 being the most common. The authors suggested the choice of outcomes may have historically been influenced by cost, available expertise and equipment. This may also be the case for previous ACT trials, with spirometry and sputum weight being cheap and relatively easy. The authors highlighted a need for a core outcome set for use in research into pulmonary exacerbations as described by the Core Outcome Measures in Effectiveness Trials (COMET) initiative and emphasised that these endpoints should fulfil the desired characteristics of being both clinimetrically validated and clinically meaningful to people with CF, something which ACT research also requires.