Effects of inhaled beclomethasone dipropionate/formoterol fumarate/glycopyrronium on diaphragmatic workload and lung function in uncontrolled asthma: a case report

Beclomethasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) single inhaler extrafine triple therapy is effective for the treatment of uncontrolled asthma. Nevertheless, there is a lack of data about the use of diaphragmatic ultrasonography to monitor adult asthmatics while they are receiving inhaled treatment. We took into consideration a 78-year-old woman complaining of asthma, treated with inhaled corticosteroid/long-acting β2-adrenergic agonist (ICS/LABA), characterized by an asthma control questionnaire-5 (ACQ-5) score and a lung function test suggestive of uncontrolled asthma. Moreover, a diaphragmatic ultrasound showed signs of high diaphragm workload. Because of these findings, we proposed to our patient a shift toward triple inhaled therapy with BDP/FF/G, and she underwent a second evaluation after 7 days of treatment. Improvements in the diaphragmatic ultrasound parameters, lung function test, and ACQ-5 score were found. In particular, we detected a reduction of thickening fraction (TF), and a normalization of the other diaphragmatic measures, indicative of a decrease in diaphragmatic workload. To our knowledge, this is the first literature report showing concomitant improvements of both lung function tests and diaphragmatic ultrasonography parameters, observed in an adult patient with uncontrolled asthma after short-term treatment with the single inhaler triple therapy BDP/FF/G.


Background
Single inhaler extrafine triple therapy with beclomethasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) is efficacious in the treatment of uncontrolled asthma (1).However, current evidence is quite scarce about the application of ultrasound to follow-up adult asthmatic patients during inhaled therapy.Scioscia et al. evaluated 72 patients complaining of severe uncontrolled asthma using a transthoracic ultrasound (TUS) examination, thus finding thickened and/or irregular pleural lines, associated with either a lack or reduction of the gliding sign (2).Del Colle et al. carried out TUS in three patients using the M-mode pattern, and they did not detect gliding and barcode signs (3).Nevertheless, these observations were based only on TUS, not associated with diaphragmatic ultrasound.Therefore, we herein describe the first reported case of a patient with uncontrolled asthma, treated with the single inhaler extrafine triple therapy BDP/FF/G, who experienced relevant improvements of diaphragmatic function detected by an ultrasound, paralleled by marked amelioration of symptom control and lung function.
Moreover, baseline diaphragmatic ultrasound evaluation was carried out by a pulmonologist with many years of certified experience.All measurements were made under conditions of spontaneous and resting tidal breathing, during seated and lying down positions, in an abdominal setting, using a 3.5-5-MHz convex ultrasound probe in brightness mode (B-mode) for thickness, and a 7-15-MHz linear probe in B-mode and motion mode (M-mode) for right diaphragmatic shift, respectively (Esaote MyLab XPro30, Esaote S.p.A., Genoa, Italy).The liver was considered as a marker to find an echographic window for the right hemidiaphragm.During the lying down position, the probe was placed between the midclavicular and anterior axillary lines, using the B-mode pattern to select the right hemidiaphragm exploration line.The normal diaphragm contracts and moves to the transducer during inspiration.This is recorded as an upward motion during M-mode, regarded as the diaphragmatic excursion during inspiration, measured on the vertical axis from baseline to the point of maximum height of inspiration.Diaphragmatic excursion was recorded in a frozen image made up of at least three consecutive respiratory cycles, to reduce the measurement error.In the seated position, the diaphragmatic thickness was assessed by B-mode ultrasonography, fixing the linear probe below the phrenicocostal sinus, near the mid-axillary line at the eighth intercostal space, thus identifying the diaphragm as a structure with two parallel echogenic lines, among which there was the hypoechoic diaphragmatic muscle.Its thickness was considered as the distance between the pleural and peritoneal membranes.The measurements were performed at the end of inspiration and expiration during quiet breathing at tidal volume and the end of inspiration after deep breathing.We took into consideration three different breathing cycles.Normal ranges were considered according to those previously described by Boussuges et al. (4,5) and Zambon et al. (6).We detected the following ultrasound baseline parameters (Figures 2A, 3A): tidal volume excursion, 3.1 cm (normal range: 0.9-2.5 cm); tidal volume inspiratory time, 0.98 s (normal range: 0.5-1.7 s); tidal volume inspiratory velocity, 3.5 cm/s (normal range: 0.7-2.6 cm/s); tidal volume expiratory time, 2.7 s (normal range: 0.4-1.6 s); tidal volume expiratory velocity, 1.2 cm/s (normal range: 0.2-2.8cm/s); tidal volume duration of motion, 3.8 s (normal range: 1.1-3.4s); deep breathing excursion, 8.26 mm (normal range: 3.3-7.5 mm); deep breathing inspiratory time, 1.7 s (normal range: 0.4-2.4s); deep breathing inspiratory velocity, 4.2 cm/s (normal range: 1.5-7.3cm/s); thickness at end-expiration (FRC), 1.1 mm (normal range: 1.1-2.7 mm); thickness at end-inspiration, 2.0 mm (normal range: 1.3-3.7 mm); tidal volume thickening fraction (TF), 81% (normal range: 30-36%); and thickness at deep breathing, 3.6 mm (normal range: 2.4-5.4 mm).

Discussion
This case report highlights the improvements in diaphragmatic thickness and motion, detected by ultrasound after 7 days of single inhaler triple therapy with BDP/FF/G (Table 1).Asthma is a chronic obstructive respiratory disease, characterized by bronchial hyperresponsiveness and reversible airflow limitation, caused by airway inflammation and remodeling.In asthma, airway structural changes include subepithelial fibrosis, neo-angiogenesis, smooth muscle thickening, and goblet cell metaplasia/hyperplasia (7).Asthma heterogeneity is expressed by many phenotypes sustained by different endotypes (8).The most common endotypes are included under the umbrella term "type 2 asthma, " referring to either allergic or non-allergic traits, very often associated with airway eosinophilic inflammation (9).
Over time, small airway inflammation can promote expiratory airflow limitation and dynamic hyperinflation, causing daily exercise  intolerance, especially in obese asthmatic patients because of reduced chest wall compliance (10).This finding is well-known in chronic obstructive pulmonary disease (COPD), resulting from expiratory airflow limitation and ventilatory demand, thus contributing to dyspnea and activity impairment (11).These functional limitations can be improved in COPD patients by BDP/FF/G treatment, which decreases air trapping and lung hyperinflation, and also improves lung diffusing capacity (12).Moreover, COPD patients may develop both respiratory and locomotor muscle dysfunctions (13).In hyperinflated patients, the diaphragm works against increased mechanical loads, caused by airflow limitation and geometrical chest changes driven by RV increase (14).Hence, ultrasound may be helpful to evaluate diaphragmatic function in COPD patients, with regard to thickening (15) and motion parameters (16).Moreover, in COPD patients, BDP/ FF/G could positively impact the structural changes of the diaphragm (e.g., fiber type transformation, sarcomere injury, and diaphragm atrophy), which contributes to its dysfunction.Thus far, no report has been published about the potential utility of diaphragmatic ultrasound in adult patients with uncontrolled asthma.However, considering the increasing application of ultrasounds in clinical practice, e.g., to evaluate right heart dysfunction (17), presence or absence of pleural effusion (18), COPD abnormalities (19), and liver diseases (20), we decided to study diaphragmatic function using ultrasound in a patient with uncontrolled asthma, before and after therapy with BDP/ FF/G.Diaphragmatic ultrasound is not routinely used to follow-up adult patients with severe asthma, before and after inhaled treatments.However, we hypothesized that the occurrence in asthmatic patients of small airway impairment, eventually associated with dynamic hyperinflation (10), could cause diaphragmatic dysfunction (14).The patient evaluated in the present case report was characterized by severe reversible airway obstruction and small airway impairment.This dysfunctional condition was associated with an increased work of the diaphragm, documented by ultrasound and reasonably explained by increased tidal volume motion, expiratory time, motion time, and thickening fraction.The single inhaler double therapy BDP/ FF was shifted to single inhaler triple therapy BDP/FF/G, and after a week, the tidal volume TF value was 45%.Other parameters changed and were found to be included within normal ranges.Such data were also reflected by functional respiratory improvements.Therefore, it is reasonable to speculate that the relevant improvement of the diaphragmatic function, which we detected in our patients after BDP/ FF/G treatment, was mainly due to a marked decrease in airway resistance, consequently associated with a reduced work of the diaphragm muscle fibers.Furthermore, the patient reported a marked reduction in cough and dyspnea, associated with good control of asthma symptoms, as shown by a decrease in the ACQ-5 score.To the best of our knowledge, this case report represents the first evidence of concomitant improvements involving lung function tests and diaphragmatic ultrasound evaluation, experienced after treatment with single inhaler triple therapy BDP/FF/G by an adult asthmatic patient with uncontrolled asthma.

Conclusion
This case report highlights for the first time the utility of diaphragmatic ultrasound as a follow-up examination of severe asthmatic patients.In particular, after short-term treatment with the single inhaler triple therapy BDP/FF/G, we detected relevant improvements in functional diaphragmatic performance, paralleled by an important amelioration of lung function.Such a preliminary  observation suggests that it could be useful to carry out further studies with the aim of better elucidating the role of diaphragmatic ultrasound evaluation in the management and monitoring of patients with severe uncontrolled asthma.Indeed, although our present considerations are restricted to only one patient, we think that the innovative methodological approach proposed in this case report deserves extensive application in asthmatic patients treated with triple inhaled therapy.The well-known beneficial effect exerted by BDP/FF/G might also depend on the positive role played by this inhaled treatment on the diaphragmatic function of patients with uncontrolled asthma.

FIGURE 1 (
FIGURE 1 (A) Flow-volume curves before BDP/FF/G (blue line for baseline curve and red line for post-bronchodilator test curve), showing the reversibility of airflow limitation.(B) Flow-volume curve after BDP/FF/G.

TABLE 1
Diaphragmatic parameters before and after BDP/FF/G treatment.