Introduction

Current asthma pathophysiology evidence from biopsy samples of preschool children with wheeze suggests that remodeling of the bronchial airways is more common throughout the small conductive airways rather than the larger airways [1, 2]. Since airway remodeling begins at an early stage, improvements in the treatment of children of preschool age may result in better preserved lung function into adulthood [2].

The severity of asthma is conventionally diagnosed by clinical history of symptoms confirmed by objective measurements using spirometry or pulmonary function testing to assess the forced expiratory volume in the 1st second of exhalation (FEV1). In clinical practice, an obstructive defect is confirmed by a variation in airflow limitation and/or rapid improvements in FEV1 after bronchodilation [3]. However, FEV1 is an insensitive marker for monitoring changes in distal airways of smaller diameter [4, 5] since most asthma children have a normal or near-normal FEV1 since lung function deterioration is slow [6].

There is a need to identify other lung function tests for asthma that can identify early airway remodeling while simultaneously measuring the rate of lung function impairment. Multiple-breath washout (MBW) measures the lung clearance index (LCI), a more sensitive predictor of early airway disease that is feasible to perform in children compared to other conventional methods [7]. Measurement of LCI has been shown to be more sensitive than spirometry in cystic fibrosis (CF); however, the clinical utility in asthma has not been adequately explored. The purpose of this review is to assess the current evidence of LCI as a clinical tool in asthma patients and whether it is useful as a treatment response parameter in severe therapy‐resistant asthma (STRA) patients.

Lung Clearance Index: Background

The MBW test assesses the efficiency of gas distribution and mixing within the lungs. MBW provides a measure of lung volume (functional residual capacity) and ventilation inhomogeneity (VI) due to the heterogeneous distribution of pulmonary disease [8, 9]. To perform the MBW technique, the patient tidally breathes an inert gas (tracer gas) through a modified face mask or mouthpiece. This gas (helium, nitrogen, or sulfur hexafluoride) is first “washed in,” then “washed out” wearing a nose-clip during the washout cycle [10].

A built-in animation is used to assist the patient achieve a steady breathing pattern. Alternatively, 100% oxygen can be inhaled to wash out the residual gas from the lungs. A range of VI parameters can be calculated, including measurement of the overall VI, the LCI, and the indices Scond, which represents the VI on conductive airways, and Sacin, which represents the VI on acinar airways [9, 11].

In 1952, Becklake described for the first time measurement of LCI in patients with emphysema by estimating the liters of ventilation necessary to eliminate nitrogen from the airways while the subject inspires 100% oxygen [8]. Higher LCI values reflect a greater VI which correlates with worsening lung disease. LCI has been proven to be useful as a predictor of early airway disease in CF [9]; however, in asthma, there is still discordance regarding its clinical utility [12]. Studies suggest that LCI is elevated in school-age children and adults with asthma even when spirometry is in the normal range [13].

The Current Evidence Supporting LCI in Asthma

There are several factors that can affect LCI including age (a preschool asthma group had a significantly higher LCI z‐score than a school-age group) [13], body size (LCI decreased in a nonlinear pattern as height increases) [14], and exercise-induced bronchoconstriction [12]. Otherwise, clinical factors, past hospitalizations, use of oral glucocorticoids or emergency visits, type of controller therapy, treatment dosage, or spirometric parameters were not significantly associated with an elevated LCI [13].

There is no consensus for establishing the ideal LCI cut-off point in healthy subjects, CF patients, or children with asthma. However, some studies have determined LCI means±SD or median range values (Table 1). In the clinical setting, different factors should be considered in order to discriminate between healthy vs asthmatic patients including the closed circuit wash-in method, the different gas tracers used as sulfur hexafluoride (SF6) or nitrogen (N2) [15], and the type of flow sensor [16].

Table 1 Previous LCI variability studies in different subset of patients with asthma
Full size table

LCI showed advantages over spirometry as a way to monitor “silent” airway remodeling whereas MBW may be a useful tool to track the progression of early airway structural disease that is not currently detected by spirometry [2, 11]. Macleod et al. [11] reported that post-bronchodilator LCI was increased in presumably well-controlled asthma children with normal FEV1, indicating residual disease and abnormal gas mixing.

Bronchoconstriction in asthma results in patchy ventilation defects causing obstructive symptoms and impaired gas exchange and distribution of inhaled medications [17]. Svenningsen et al. [18] demonstrated that magnetic resonance imaging ventilation defect percent (VDP) and LCI were strongly correlated, although only VDP was an excellent predictor of asthma control. Farrow et al. [19] described that changes in lowest ventilation regions were predicted by LCI before and after a methacholine provocation test using single photon emission computed tomography.

Inflammation is linked to asthma severity and control, FeNO, or sputum eosinophil count are used to titrate inhaled glucocorticoid doses in adults with asthma [20]. LCI detects residual airways disease independently of inflammation, as a normal FeNO does not correlate with a higher LCI [11]. In contrast, Kouký et al. [21] demonstrated a high LCI in patients with eosinophilic chronic airway inflammation (allergic bronchial asthma). Lu et al. [22] reported that FeNO was significantly higher in recurrent wheezer (RW) infants with abnormal LCI, suggesting a more severe endotype of RW.

Further evidence suggests that LCI may be able to assess more severe airway obstruction and persistence of small airway disease [23, 24]. LCI is elevated in children with recurrent asthma exacerbations requiring treatment with oral glucocorticoids, in recurrent wheezers, in severe therapy‐resistant asthma (STRA), and in patients refractory to inhalant therapies [13, 22, 24, 25•, 26, 27•]. It is well known that clinical and lung function outcomes improve after a multidisciplinary intervention in children with severe asthma; however, LCI remained abnormal [24]. In contrast, some studies did not find LCI to be a reliable predictor of asthma control [7, 12, 28, 29].

LCI can predict a positive response to up-titration to a high-dose combination inhaled glucocorticoid (ICS)/long acting beta agonist (LABA) treatment in uncontrolled asthma patients [27•], leading to the hypothesis that the existence of a more refractory to inhalant therapy endotype is associated with the severity of lung ventilation inhomogeneities measured by LCI.

Subsegmental narrowing of small distal airways and poorly controlled inflammation diminishes penetration of inhalant anti-inflammatory and bronchodilator medications and accelerates the deterioration in lung function [24, 30]. Inhaled drug-based therapy for asthma is largely based on particle sizes between 3 and 5 μm and their deposition occurs three to four times higher in central lung tissue than peripheral tissue [31]. This explains why many inhalers are inefficient in minimizing airway inflammation in severe asthmatics [30]. Two ways in which to target distal airways are to use inhaled medications such as ICS alone or in combination with long-acting β-agonists extra-fine particles (smaller than 2 μm) versus systemic therapy [32].

Even though larger particles may be more efficacious and achieve greater bronchodilation, smaller aerosol particles less than 1.5 μm achieve greater total deposition and farther distal airways penetration [33]. Extra-fine particles improve long-term asthma control, quality of life in real-life studies, treatment stability, and the reduction in the daily ICS dose [32, 34,35,36].

However, studies have found no change in spirometry, indicating that these values may not reflect the effects of small-particle aerosols on peripheral airways [34]. Beclometasone dipropionate/formoterol (BDP/F) pressurized metered dose inhaler (pMDI) which delivers 1.4–1.5-μm particle sizes showed improvement in Sacin indicating that inflammation was suppressed in peripheral airways [37], especially in patients with abnormal baseline Sacin [38].

Systemic therapy is the other way to target distal airway disease. Intramuscular triamcinolone was used in STRA patients. LCI, FEV1, Sacin, and FeNO were evaluated but only LCI and FeNO significantly improved [25, 39]. LCI showed the most potential utility of the MBW indices [40]. Irving et al. [25] proposed that LCI normalization is due to a reduction in glucocorticoid‐refractory distal airway inflammation by high‐dose intramuscular glucocorticoids, leading to improvement in distal gas mixing.

Concluding Remarks

These findings suggest that spirometry is not sufficient to follow the progression of severe asthma suggesting a growing need for implementing new tests as a multidomain assessment that includes evaluation of distal airways disease. LCI may be the tool that addresses physiological changes in lung function that warrant other treatment approaches.

Current evidence suggests that LCI abnormalities may be a sensitive marker for the persistence of small distal airway disease and could relate to a more severe asthma endotype unresponsive to inhaled glucocorticoids although it is possible alternative anti-inflammatory therapies have yet to be identified. This review provides evidence about appropriate use of LCI for assessment of asthma which has previously been validated as a useful test for CF.

There remain many gaps in knowledge regarding LCI to establish its clinical utility which include no standardized cut-off point for LCI in asthma patients, the lack of real-life clinical interventions evaluating the effect of extra fine particle aerosols on LCI, and the paucity of follow-up studies that determine whether early abnormalities in LCI persist and predict a diagnosis of chronic asthma and/or a more severe form of infant asthma.