Background
There are two distinct classes of inhaled bronchodilators (IB): anticholinergic (AC) IB and Beta-2 agonist (BA) IB. Even if with different mechanisms of action, both cause relaxation of bronchial wall muscles. Both classes include short– and long–acting drugs and can be administered by different methods (dry powder, metered dose inhaler, aerosol). Besides their activity as bronchodilators, AC may reduce mucus secretion, whereas BA can increase it. BA can improve mucociliary clearance and avoid bacterial damage in the bronchial mucosa.
It must be stressed that, in severe lung diseases, IB may worsen airway function, causing a ‘paradoxical bronchoconstriction’ as a result of the abnormal airway compliance associated with bronchiectasis.
IB are widely used in obstructive lung diseases other than CF, such as COPD, asthma, and bronchiectasis. Regarding these conditions, the opportunity to use long-acting AC and BA combinations has been hypothesized (Tashking DP, 2013).
Short–term IB administration are recommended in CF to relieve symptoms associated with bronchospasm and to prevent adverse events during nebulised therapies (Mogayzel PJ, 2013). However, without a documented reversible obstruction, there are conflicting recommendations (Levine H, 2016) about the use of bronchodilators in CF because of a lack of evidence to be effective in improving lung condition (Barry PJ, 2017).
Recently (Kieninger E, 2022) has been speculated, on the basis of new diagnostic measures (Multiple- breath washout and MRI), that there is a IB positive short-term effect on FEV1, which is indipendent of ventilation inhomogeneity. However, heterogenous response between patients suggest that IB should be tested in every patient individually.
Issues
IB efficacy in CF lung disease (lung function, respiratory symptoms, quality of life, pulmonary exacerbation rates, mortality rates)
IB adverse effects (tremor, increased heart rate, dry mouth, increased wheeze, and shortness of breath)
What is known
One Cochrane Review (Halfhide C, 2011) collected eighteen RCTs with a total of 369 patients, both children and adults. Beneficial effects were observed, above all, in patients with evidence of bronchodilator responsiveness or bronchial hyperreactivity. No relevant adverse event was reported also in case of long-term treatment. The use of BA seemed more supported by evidence than the use of AC.
In 2016 this review has been split into the following Cohrane reviews:’Long-acting inhaled bronchodilators for cystic fibrosis’ and ’Short-acting inhaled bronchodilators for cystic fibrosis’.
About the first one, a Cochrane Review updated December 2017 (Smith S, 2017) has been published. On the basis of three trials looked at the effects in both the short term (up to 28 days) and the longer term (up to three months) on 1066 CF patients, the Authors concluded that no significant differences have appeared between intervention and placebo groups, in terms of quality of life, adverse events and spirometric changes. Up to now there is limited evidence of IB long-term effect, also considering the concomitant action on mucus production and mucociliary clearance. It would be important to better study the effect of BA and AC combinations and of IB therapy associated with inhaled corticosteroids and/or other mucoactive agents.
In 2022 (Smith S, 2022) a short-acting inhaled bronchodilators for Cistic Fibrosis Cochrane review has been published. 11 trials with 191 partecipants have been included. All the included trials are small, of a cross-over design and did not measure longer term outcomes. On this basis Authors have concluded that the evidence across all outcomes has been very low.
In november 2017 a study (Furlan LL,2017) highlighted the importance of the rs4073 variant of the interleukin 8 gene, regarding response to inhaled bronchodilators,
Unresolved questions
IB efficacy in CF lung disease (lung function, respiratory symptoms, quality of life, pulmonary exacerbation rates, mortality rates)
IB adverse effects (tremor, increased heart rate, dry mouth, increased wheeze, and shortness of breath)
No RCT are ongoing about this issue.