Lung clearance index in adults with non-cystic fibrosis bronchiectasis

Non-cystic fibrosis (CF) bronchiectasis is a chronic suppurative lung disease caused by a range of underlying conditions, which is increasing in prevalence [1], and which imposes a significant burden of morbidity and healthcare costs. In the United States alone, annual healthcare costs for bronchiectasis are estimated as $630 million [2]. The causes of non-CF bronchiectasis are diverse, and include autoimmune disease, primary ciliary dyskinesia, allergic bronchopulmonary aspergillosis, immune deficiency and childhood respiratory infection [3]. Regardless of the underlying cause, the pathogenesis is thought to involve a vicious cycle of bacterial colonisation, neutrophilic airway inflammation, airway damage and mucus stasis [3]. The evidence base for the treatment of non-CF bronchiectasis lags well behind that of CF, but this is expected to change in the near future as a number of non-CF bronchiectasis research registries and clinical trials are actively enrolling patients at present [4]. Such clinical trials will require robust physiological outcome measures in order to provide objective measures of improvement in lung function.

Multiple breath inert gas washout (MBW) is a technique for quantifying ventilation heterogeneity, the uneven distribution of ventilation [5]. This is an early feature of obstructive airway diseases such as asthma [6], chronic obstructive pulmonary disease [6] and cystic fibrosis (CF) [7]. A comprehensive standardisation document for the performance of inert gas washout has been recently published [8]. Lung clearance index (LCI) [9, 10] is the most commonly reported MBW parameter, and is defined as the cumulative expired volume at the point where end-tidal inert gas concentration falls below 1/40th of the original concentration, divided by the functional residual capacity (FRC). LCI has been shown to be both discriminatory and repeatable in patients with CF [7], and is increasingly being used as an outcome measure in clinical trials of CF therapies [11‐13]. A recent study has shown that LCI is repeatable in patients with non-CF bronchiectasis, and correlates with computed tomography bronchiectasis severity scores [14].

Although LCI has been shown to be a robust and repeatable measurement in patients with CF and non-CF bronchiectasis, it also represents a simplification of the washout process since it is essentially determined by data points at the start and end of the washout curve only. From a theoretical standpoint, LCI may be increased by two distinct mechanisms, namely (i) unequal convective ventilation between relatively large lung units subtended by proximal conducting airways (convection-dependent inhomogeneity), and (ii) increased respiratory dead space, which is thought to be underpinned by diffusion-dependent gas mixing inefficiencies (diffusion-convection-dependent inhomogeneity) [15]. The only published method for separating out these mechanisms is the analysis of phase III slopes, yielding the parameters S_cond (conductive ventilation heterogeneity index) and S_acin (acinar ventilation heterogeneity index) [16]. This technique was developed from elegant clinical and modelling studies in healthy adult subjects [17]. However, the use of these parameters is problematic in patients with the most severe ventilation heterogeneity, such as those with advanced CF lung disease [18], both from a practical standpoint (the requirement for controlled 1 L breaths) and because the modelling may not be directly applicable in those with severe ventilation heterogeneity. To overcome this, modified versions of these parameters (S_cond* and S_acin*) have recently been proposed for use in such patients [19]. There remains a need however for a reliable and repeatable method of extracting mechanistic information from washout curves, which has been developed for, and can be applied in, those with more severe disease.

The primary aim of this study was to determine whether or not ventilation heterogeneity is a significant feature of non-CF bronchiectasis, and whether LCI may have potential as an outcome measure in this group of patients. A further aim of the study was to extend currently available measures of ventilation heterogeneity by developing novel parameters that would distinguish between specific ventilation inequality (LCI_vent) and increased respiratory dead space (LCI_ds) as a cause of increased LCI. LCI_vent and LCI_ds would be expected to probe similar mechanisms of ventilation heterogeneity to S_cond and S_acin, respectively, but without the potential drawbacks of phase III slope analysis, and with the advantage of being directly linked to LCI.

We hypothesised that:

We have shown that LCI, and the novel parameters LCI_vent and LCI_ds, are significantly raised in patients with non-CF bronchiectasis compared to controls, and that these parameters correlate strongly with spirometric markers of airflow obstruction. LCI, LCI_vent and LCI_ds display good within-visit repeatability in patients with non-CF bronchiectasis, and superior discriminatory ability for distinguishing bronchiectasis patients from controls compared to FEV₁. Moreover, these parameters are abnormally raised in a significant proportion of non-CF bronchiectasis patients with a normal FEV₁. These findings suggest that MBW parameters may have potential as markers of disease severity in patients with non-CF bronchiectasis, and may be indicators of incipient airflow obstruction, although longitudinal studies are required to test this hypothesis. Further studies are also required to determine the between-visit variability and minimal clinically important difference of MBW parameters in patients with non-CF bronchiectasis, as well as their responsiveness to therapeutic interventions.

A major aim of this study was to develop novel markers of ventilation heterogeneity that would distinguish between the two possible mechanisms of increased LCI, namely specific ventilation inequality and increased respiratory dead space. Previous studies have used measures of the curvilinearity of the washout curve as markers of specific ventilation inequality, but these methods did not provide a formal estimate of the respiratory dead space component [15, 19]. Although in healthy subjects it is thought that specific ventilation inequality is the only mechanism of ventilation heterogeneity operative at the level of the proximal conducting airways, the situation is disease is far more complex. Depending on the extent of airway damage and obstruction, diffusion may not be neatly compartmentalised to the distal airways. An advantage of the current method is that it does not pre-suppose an anatomical location for the observed abnormalities in ventilation heterogeneity, but concentrates on the underlying mechanisms. This is particularly relevant when dealing with those with more severe airflow obstruction and ventilation heterogeneity. Furthermore, since the proximal and distal airways are not independent of each other, and form a complex interacting network [24], it is also unsurprising that we noted a correlation between LCI_vent and LCI_ds in both patient groups. LCI_vent and LCI_ds may however allow subtle distinctions to be made in terms of mechanisms of disease in airway diseases such as CF and non-CF bronchiectasis. Indeed, we observed that CF patients with chronic P. aeruginosa colonisation had increased LCI_ds compared to those who did not, whereas LCI_vent did not differ significantly between the groups. This extends the findings of Belessis et al.[25], who observed that LCI was higher in children with CF who had P. aeruginosa colonisation compared to those who did not. Our results suggest that this increase in LCI may be driven predominantly by an increased respiratory dead space. Interestingly, neither MBW parameters nor FEV₁ (% pred.) differed significantly between non-CF bronchiectasis patients with and without chronic bacterial colonisation. Chronic colonisation in our cohort was mainly with H. influenzae rather than P. aeruginosa, and our data therefore concord with previous observations that H. influenzae, unlike P. aeruginosa, is not associated with faster lung function decline in non-CF bronchiectasis [26]. The reduced FVC (% pred.) we observed in non-CF bronchiectasis patients with chronic colonisation was not associated with an abnormally low TLC (% pred.), and therefore did not represent a true restrictive deficit.

Previous attempts to apply phase III slope analysis in CF were less successful than in reports from other disease groups, because of both poor repeatability and reliance of the original method on a strict 1 L breathing protocol [18]. Although it relies on a relaxed and repeatable breathing pattern, the current method does not require strict breath volume control, something patients often find harder to maintain than well-trained volunteers. In addition, LCI_vent and LCI_ds showed superior repeatability to phase III slope parameters, in particular to S_cond and S_cond*. This is an important attribute if these measures are to be used to assess change over time, or in response to therapeutic intervention.

A potential limitation of our study was that the disease groups were not matched for age with the control group. This was to a certain extent unavoidable, since patients with non-CF bronchiectasis are in general older than those with CF, and we therefore chose our control group to be approximately intermediate in age between the two disease groups. However, recently published regression equations [27] indicate that the effects of this on our results were likely to be modest – in particular, LCI is expected to increase by 0.0223 units per year, so the 19-year difference in mean age between patients with bronchiectasis and healthy controls would be predicted to cause a relatively small 0.43 difference in LCI between the groups. Furthermore, the upper limit of normal of LCI derived from our healthy control data was slightly higher than that reported in previous studies using the same methodology [7], a difference that may be explained by the older age of our healthy cohort. Further studies are required to derive age- and sex-dependent normative ranges for LCI using the SF₆ wash-in method, as have been published for nitrogen washout [27].

In conclusion, we have shown that LCI, a marker of impaired gas mixing derived from the MBW test, is significantly raised in patients with non-CF bronchiectasis, and that this elevation correlates with spirometric airflow obstruction. LCI is repeatable and discriminatory in patients with non-CF bronchiectasis, and future studies are now required to assess the prognostic significance of a raised LCI in this patient group, as well as the potential utility of this marker as an outcome measure in interventional trials. The novel parameters LCI_vent and LCI_ds are a practical and repeatable alternative to phase III slope analysis and may allow a further level of mechanistic information to be obtained from the MBW test without any additional demand on the patient. They should be reported in conjunction with LCI in future observational and interventional studies that incorporate the MBW technique.

Alex Horsley and Salman Siddiqui are co-senior authors.