The effects of the addition of a new airway clearance device to chest physiotherapy in children with cystic fibrosis pulmonary exacerbations

Cystic fibrosis (CF) is a multisystem disease. However, in most cases, quality of life and longevity are determined by the progression of lung disease. Alternating periods of stability and pulmonary exacerbation (PEx) contribute to gradual clinical deterioration and the worsening of lung function. Respiratory failure is still the most frequent cause of death in CF patients, which is why slowing the progression of lung disease is central to CF management strategies [1]. Furthermore, chronic inflammation and infection with pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa and Aspergillus fumigatus require daily treatment. PEx are serious events for CF patients. They are associated with major clinical consequences such as the irreversible and progressive loss of lung function [2, 3, 4], increased risk for future exacerbations [5], reduced health-related quality of life and increased risk of death [6]. To prevent lung function decline, PEx must be treated properly. Management should include an intensification of chronic daily therapies [7] (chronic medications, airway clearance techniques [ACTs]) and antibiotics [8].

Effective mucus clearance is essential to reduce symptoms and optimise treatment in CF, particularly during PEx. There

are a number of ACTs that have been utilised in patients with CF, including an active cycle of breathing techniques, autogenic drainage, positive expiratory pressure (PEP), high pressure PEP, oscillating PEP, postural drainage and percussion and physical exercise. Guidelines state that chest physiotherapy (CP) and ACTs should be individually tailored to the need and preference of every patient and that no approach has shown superiority over another [9]. New and modified approaches to physiotherapy are always being investigated in order to increase the effectiveness, tolerability and safety of treatment. Assessment of the benefits of these new approaches is based on improvements in clinical parameters and lung function.

A new airway clearance device (ACD) that uses a pneumatic vibratory stimulus has been developed (Simeox; PhysioAssist, France). The action of this device is based on the rheological and thixotropic properties of mucus. It spreads a vibratory pneumatic signal in the bronchial tree during relaxed exhalation by disseminating a succession of very short negative air pressure pulses of adjustable constant volume at a frequency of 6 or 12 Hz. The device is designed to modify mucus viscosity and elasticity, mobilising mucus in the distal airways and transporting it to more proximal airways for productive expectoration.

This study evaluated the effects of this new ACD on lung function in subjects with CF who were hospitalised due to PEx. Secondary objectives were to examine safety, tolerability, quality of life and patient satisfaction with the device.

The results of this study showed significant improvement in spirometry parameters in CF patients treated for PEx with IV antibiotic therapy and intensive CP, with or without a new ACD. Small airway function appeared to improve to a greater extent when the device was added to CP. Treatment was safe and well tolerated, and patients were satisfied with device therapy. Based on our findings, the mechanism benefit of the airway clearance device in CF is presumed to be the more efficient mobilization of mucus in the distal airways as well as the proximal bronchi.

We used pulmonary function tests (spirometry and N₂MBW) to evaluate the effects of the interventions in this study. FEV₁ is considered to be the cornerstone of pulmonary function testing. It is the most widely used method for clinical monitoring of lung function in children, adolescents and adults with CF. FEV₁ shows strong correlation with airway wall thickness and mucus plugging, both features of larger airway obstruction [17]. However, this parameter has some limitations. Spirometry is very difficult to perform for young children, and FEV₁ is not sensitive to the small airway damage that occurs during early disease progression [17, 18]. Therefore, in early CF, there can be considerable disturbance of a large numbers of small airways, with relatively little effect on FEV₁ [17].

In our study, spirometry parameters reflecting larger airways (i.e. FEV₁, FVC, MEF₇₅ and MEF₅₀) increased significantly after IV antibiotic therapy in both groups of patients who were hospitalised due to PEx of CF. These improvements were seen in both treatment groups. Interestingly, MEF₂₅ (a surrogate endpoint for assessing obstruction of peripheral bronchi and bronchioles) only improved from the baseline in the CP + device group (p < 0.01). This suggests that use of the ACD may reduce peripheral bronchial obstruction, thus improving function in small as well as large airways. MEF₂₅ has also been shown to improve significantly during drug treatment of CF [19], despite the high intra- and inter-individual variability of this parameter.

MEF₂₅, indicating the maximum exhalatory flow after 75% of the air has been exhaled from the lung, is a parameter that reflects changes in the peripheral airways [20]. Deterioration in MEF₂₅ over time has been shown to occur as symptoms increase, and this parameter has been shown to correlate well with trapped air on computed tomographic scanning [21]. Van der Giessen and colleagues showed that improvement in MEF₂₅ with dornase alfa was significantly greater when treatment was given before versus after ACT, while there were no changes in other spirometric parameters [22]. In another study, deterioration in MEF_25-75 in children and adolescents with CF was detected before any changes were seen in FEV₁ and FVC [23]. In a study using data from 15,700 spirometric test cycles in CF patients and healthy children, MEF₂₅ was shown to be a more sensitive indicator of disease progression than FEV₁ or FVC, and there was no increase in MEF₂₅ with age [24]. However, a significant amount of variability in MEF₂₅ has been reported [22]. Therefore, this variability could impact the interpretation of test results and influence conclusions about changes during therapy.

In contrast to FEV₁, LCI derived from MBW is a measurement of lung function that is capable of detecting early airway disease in CF [13]. This test measures the tidal breaths needed to remove an inert tracer gas present in the lungs. LCI is sensitive to damage in both large and small airways before a noticeable drop in spirometry measurements [13], enabling detection of early airway disease in CF [25]. The LCI provides an indication of ventilation heterogeneity based on how many breaths it takes to wash a tracer gas out of the lungs during tidal breathing [13]. LCI values increase in parallel with increasing lung disease severity [13], and LCI correlates with the risk of PEx in patients with CF [26]. In addition, LCI has been shown to decrease significantly based on pulmonary symptoms and improve with antibiotic treatment [27]. LCI also appears to worsen during cough episodes and pulmonary exacerbations in children with CF, but not in healthy children [28].In our study, the LCI showed a downward trend over time and reductions from baseline were clinically relevant, but LCI z-score decreases did not reach statistical significance in either group. This may have been a result of the small sample size especially in the device group, with 6/24 patients (mean FEV₁ 53% of predicted; range 23%-59%) unable to perform the test required to determine LCI. Indeed, LCI is not practical for patients with advanced lung disease (FEV₁ < 60% of predicted) due to profound ventilation heterogeneity and extended wash-in and wash-out periods [17], which was the issue with patients unable to complete the test in our study. It is also possible that some patients have “peeled off” areas that have remained “stuck” and that this increased the ventilation heterogeneity. In CF chronic lung disease, treatment of PEx with IV antibiotics and intensive CP can lead to the recruitment of additional lung units not involved in LCI measurement previously, causing ventilation inhomogeneity [29]. The heterogeneous response of LCI to antibiotic therapy during PEx has been reported previously, with reductions of 2.2–5.5%, similar in magnitude to the changes seen in our study [27, 29, 30, 31, 32, 33]. It was emphasised that LCI alone shouldn’t be used to assess the short-term response to IV antibiotic therapy. While some patients in our study experienced a large reduction in LCI, this parameter remained unchanged or worsened in many others. In summary, LCI response to therapy for PEx is heterogeneous in CF patients. The overall improvement is small, and results are often discordant with FEV₁.

As noted above, LCI and FEV₁ measure different aspect of lung physiology. FEV₁ mainly reflects large airways function and will be affected by changes in airway tone, mucus accumulation in the airways and air trapping. Previous studies with computed tomography demonstrated improvement of all these factors after treatment of PEx, but the main factor contributing to that improvement may vary between patients [30, 34]. Other studies suggested that mucus plugging – and especially large-airway mucus plugging – changes more than other aspects of CF lung disease during antibiotic therapy [35]. In contrast, LCI is a more sensitive marker for peripheral airway abnormalities and their heterogeneities. However, LCI results do not correlate to changes in bronchomotor tone, which is the case for FEV₁, as demonstrated by studies investigating LCI before and after administration of bronchodilators [36, 37]. LCI response could also have been affected by previously closed compartments contributing to the measurement.

The influence of physiotherapy in CF on LCI measurements remains unclear. In one small study, the authors concluded that there was no relationship between the timing of physiotherapy sessions and LCI values [38], and another suggested that LCI can change markedly when assessed after physiotherapy [39]. Although there are a number of factors in our study that make it dificult to interpret the LCI results, we feel that it was important to include this measure of small airway function in our analyses.

Questionnaire responses in our study suggest that patients considered the new ACD to be efective in removing pulmonary tract secretions, well tolerated, safe and convenient to use. Patients reported that the efort associated with respiratory drainage was slighter when using the ACD compared with conventional physiotherapy techniques; most of the children did not feel any pain or fatigue. The device was judged useful in the hospital and was able to be used autonomously during daily respiratory rehabilitation. All patients gave a positive response to the question whether they thought they could use the device at home. Manual CP is often time-consuming and burdensome for patients and can be quite tiring. Therefore, the right level of patient acceptability is an important feature of the new device that would facilitate its incorporation into clinical practice as part of routine patient care.

This study provides useful initial data on the use of a new ACD in hospitalised CF patients with PEx. However, the study has a number of limitations. The study had a non-randomised design where treatment allocation was done on a consecutive, alternate 1:1 basis. This lack of randomisation to treatment likely contributed to the imbalance in baseline characteristics between groups. The open-label nature of the study means that sources of bias cannot be excluded. In addition, the sample size was small, and the duration of follow-up was short. The two weeks of the follow-up period provided good information about the efects of the ACD in hospitalised patients, but longer-term efects in the ambulatory setting need to be studied. In addition, a variety of factors can afect the outcome of PEx in CF, and these may have confounded our results. The value and reliability of spirometry to assess treatment efects in CF has been questioned [40], but this remains a commonly used tool, and its inclusion facilitates comparison of our results with other studies. Finally, use of antibiotic therapy during the PEx likely influenced the efects of the study interventions on LCI, again indicating that evaluation of the device in stable CF patients is required.

There were some diferences between the control and device groups at baseline that may have confounded our findings. The proportion of females was higher in the device group, which may explain the lower lung volumes in this group. Moreover, the degree of bronchial obstruction seemed to be more severe in the device group.

Despite these limitations, our study provides some of the first data on use of the new ACD in clinical practice. The device represents an interesting potential alternative therapy that appears to have activity in smaller airways and some benefits for patients with CF in terms of comfort and eficacy of the drainage session. These factors could be helpful in driving long-term adherence in this chronic disease population. Randomised trials of the device in larger patient populations followed over a longer period are planned.

In conclusion, the novel ACD is a promising new therapeutic option for patients with CF. It is safe, well tolerated, has good patient acceptability, and appears to improve drainage of the central and peripheral airways.