Defining the Clinical Utility of the Lung Clearance Index. Are We There Yet?

The last decade has witnessed dramatic improvements in cystic fibrosis (CF) therapeutics with the introduction of a novel class of drugs known collectively as “CFTR modulators” (1). Most recently, a combination of modulators has made it possible to eventually offer “highly effective modulator therapy” (HEMT) to an estimated 90% of the U.S. population with CF (2, 3). Also, the data accumulated from multiple clinical trials has provided clear evidence for what constitutes as a disease-modifying effect in the natural history of CF. It is clearly recognized that in order for patients with CF, in particular young children, to continue to benefit from innovative therapies such as HEMT, there is a need to target therapies before irreversible lung damage has occurred. However, the ability to avert lung disease progression in CF is contingent on early detection and timely intervention. This will require the availability of tools that are both sensitive and feasible in the routine clinical setting. It is now well established that lung disease begins very early in life in children with CF (4, 5), with impaired mucociliary clearance being a hallmark and at the root of all the respiratory complications that patients experience (6, 7). Therefore, great attention has historically been paid to the accurate detection and monitoring of airway obstruction as a reflection of CF airway disease at all stages of disease progression. CF clinicians are highly familiarized with the use of spirometry, and in particular the FEV₁, as a useful tool for the detection of airway obstruction and to support clinical decision-making. However, an already large body of evidence has demonstrated that significant lung disease can be present in the face of a normal FEV₁ (8, 9). This fact, in addition to the robust and persistent changes seen in FEV₁ in response to HEMT, have identified a need to bring to the clinic assessment tools that will be more sensitive to the presence of airway disease. Perhaps of greatest importance is also the ability of such a tool to detect detrimental changes as well as support therapeutic intervention and assist in monitoring the response to such an intervention to evaluate its effects.

As a result, an array of functional and image-testing modalities have been and continue to be actively investigated on CF for their ability to provide an accurate assessment of airway disease (10–14). Thanks to technological advances, parameters obtained from the multiple-breath washout technique have emerged as providing an alternative, sensitive assessment of airway function. Among the parameters that can be estimated from the multiple-breath washout the number of FRC volume turnovers required to clear a tracer from the lungs or Lung Clearance Index (LCI) has demonstrated great sensitivity to early airway disease (15). The LCI provides a metric for the degree of heterogeneity in gas distribution present throughout the tracheobronchial tree, a key aspect of CF pathophysiology. Intensive clinical research conducted over the past few years has already demonstrated the value of the LCI in the research setting, helping to establish it as an important endpoint for clinical trials (16–18). However, there are still important gaps in the information required to understand its potential role in the clinical setting. In this issue of the Journal, Perrem and colleagues (pp. 977–986) provide evidence from a two-center prospective study on the value of the LCI as an outcome measure when applied to the routine clinical setting in the care of children with CF (19). The focus of the study was on respiratory events experienced over a 2-year period, and although clinical decisions were not formalized by the study protocol or guided by the measurements performed in the children that participated in the study, there are several valuable insights gained from the study results. Some important considerations need to be taken into account to interpret their results in their full context. First, as it has progressively become an expectation for children with CF, this cohort had, for the most part, fairly normal pulmonary function by spirometry and morbidity features typically associated with CF such as weight loss, Pseudomonas infection, hemoptysis, and radiographic changes that were of rare occurrence. Second, the investigators had to develop a categorization scheme to qualify the respiratory events experienced by these children, as many would not have fulfilled the classic definitions of CF pulmonary exacerbation but still had changes in their treatment regimens, primarily through courses of antibiotics. This basically defines this cohort as the emerging new face of CF, in which it is more challenging to apply evidence on the basis of the available guidelines for care. If anything, this makes their cohort well suited for assessing the role of the LCI to support the care decisions for children with mild evidence for active lung disease. Their study demonstrated that the LCI detected a detrimental change in association with respiratory events and without complete return to baseline values after intervention. In addition, a detrimental change in LCI (defined as a 10% increase from baseline) performed better than FEV₁ at identifying a respiratory event, but not all events were associated with either measurement worsening by this criteria. However, as has been observed with FEV₁ for this setting, the mean magnitude for change in LCI with respiratory events was not as large as what could be desired by it being larger than the variability of the test, which, in this case, was 15% (20).

For any given parameter applied to decision making, the magnitude of change that could be considered clinically significant should be larger than the difference seen between repeated measurements without intervention or change in clinical status. Besides the significance of a change, the clinical utility is certainly what is desired in practice, as it provides a better assessment of the value of a given test or intervention by identifying a meaningful benefit to the individual patient. Unfortunately, there is no clear-cut definition of what will constitute as “clinically useful” for the management of CF lung disease, as this is likely to be multidimensional and could include aspects such as biologic, economic, personal, and societal domains. The “minimal clinically important difference” has been frequently used to identify a significant change in a patient’s condition and understand the effects of an intervention that captures the net efficacy. Multiple ongoing studies are aimed at providing a clearer understanding as to the role that the application of the LCI may play in the clinical setting, but its minimal clinically important difference seems elusive. A recent example of a randomized interventional trial did not demonstrate benefits when decisions to intervene were based in the detection of an absolute change in LCI of 1 unit (21). So, are we there yet? As Perrem and colleagues conclude, their study may be interpreted as suggesting that LCI and FEV₁ are complimentary measures that capture different dimensions of CF lung disease with not too much overlap, so their use together provides a more robust assessment than using either measure alone. Taking into account that we are entering a new era in which the combination of the universal application of newborn screening and the expanding availability of HEMT are generating a cohort of children with “new CF,” we need additional studies to develop innovative management protocols based on the application of the most sensitive tools available.