Can a better patient phenotyping predict the efficacy of tiotropium in asthmatic adolescents?

KEYWORDS:

• Adolescent asthma
• anticholinergics
• asthma phenotype
• bronchial asthma
• increased cholinergic tone
• long-acting muscarinic antagonists
• stress
• tiotropium

To the Editor

We read with interest the excellent article of Hamelmann et al. [1] concerning the use of tiotropium for the treatment of moderate to severe asthma in adolescents. The authors reported the clinical efficacy of the compound in adolescents by describing the results of three recent published articles [2–4].

The authors stated as follows:

Each of these studies enrolled patients with at least a 3-month history of symptomatic asthma, defined as a 7 question Asthma Control Questionnaire (ACQ-7) mean score of ≥ 1.5 at screening and before randomization, and who had never smoked or who had stopped smoking within the year before enrollment. … In each study, the primary endpoint was peak forced expiratory volume in 1 s (FEV1) response (change from baseline) within 3 h post-dose (0–3 h). Secondary endpoints included trough FEV₁ response (change from baseline pre-dose FEV₁) and ACQ-7 score.

Describing the results of these studies, the authors also stated as follows:

Trials in adolescent patients (aged 12–17 years) with moderate or severe symptomatic asthma have shown that tiotropium Respimat as add-on to inhaled corticosteroids (ICSs) with or without other maintenance therapies, is a well-tolerated and efficacious bronchodilator showing trends towards improved asthma control, similar to data in adult patients.

From a general point of view, considering the role of cholinergic tone in determining bronchial obstruction in asthmatics, it should be expected that a long-acting anti-muscarinic agent such as tiotropium may determine a bronchodilator effect.

Although the results of these studies have been considered positive in terms of numerical improvements versus placebo, limited statistical significance was detected, suggesting that the clinical relevance was weak. Hamelmann et al. have provided some interpretations of these data as well as some limitations of the trials, and further possible explanations may be those proposed by J Grigg on the unclear role of tiotropium in pediatric asthma as a comment to Ref. 4 [5].

We are not surprised with these not relevant results because we believe that two crucial points have been neglected during adolescents’ selection, in addition to the other limitations already recognized by Hamelmann et al.

A fundamental premise, not adequately considered by the authors (Hamelmann et al.), is that asthmatic adolescents may experience a period of physical and psychosocial changes that affect their health and well-being. Overall, adolescents with asthma are at increased risk for asthma morbidity and death. Increased rates of depression and anxiety, for the adolescent and their caregivers, can lead to nonadherence to their medical regimens, poor symptom control, and poor treatment outcomes [6]. Asthma during adolescence impairs health-related quality of life, especially if the asthma is uncontrolled [7]. So, in our opinion, a selection based essentially on pathophysiological parameters does not reflect all variables linked to this phase of life.

The first point to consider is the lack of relevant information on the occurrence of atopic status in the adolescent population. It is widely recognized that allergic sensitization to inhalant allergens (particularly those perennial) represents the main risk factor of asthma development, and the degree of sensitization is usually correlated with asthma severity. Moreover, massive inhalation of some allergens, such as those from dust mites and molds, might be responsible of severe and life-threatening asthma exacerbations requiring hospital attendance [8]. In the case of adolescent atopic asthma, the use of long-acting muscarinic antagonists (LAMAs), in addition to usual anti-asthma therapy, should be not considered a priority step compared with other options such as allergen avoidance, educational procedures, and anti-IgE treatment (omalizumab), unless an adequate phenotype characterization of asthmatic adolescents is performed.

We have recently shown that about 63% of asthmatics reported at least one non-respiratory symptom (n-RS) before an asthma attack [9]. Some n-RSs observed in our study are the consequence of an imbalance between sympathetic/parasympathetic systems, with a prevalence of cholinergic tone. As a consequence, it is likely that some symptoms induced by cholinergic hyperactivity/hyperactivation (e.g. dry mouth, sweating, heartburn, and abdominal pain) or associated with this condition (e.g. psychological stress) could be present together with parasympathetic-associated RSs such as those elicited by airway narrowing [9].

On the basis of these considerations, we suggest that attention should be focused on considering the role of the parasympathetic system as a trigger of bronchial obstruction in asthmatics who report the usual onset of cholinergic-related n-RSs before an asthma attack. Indirectly, the results of our study [9] confirmed the assumption that cholinergic pathway is a determinant broncho-constrictor at least in a group of asthmatic patients. In fact, some n-RSs that precede the appearance of an asthma attack are clearly the expression of an increased cholinergic tone.

We have hypothesized that, in some individuals, this condition might play a predominant role in determining airway obstruction, compared with other well-known factors such as allergens/air pollutants, infections, exercise, etc. (a definite ‘asthma phenotype’?) [10]. Consequently, we could postulate that blocking muscarinic impulse transmission at the airway smooth muscle might be more beneficial to control airway obstruction and mucus secretions in these asthmatics.

Therefore, the use of anticholinergic agents (especially LAMAs) in patients suffering from asthma may be more useful in those patients characterized by increased cholinergic activity [11]. Furthermore, it is well known that psychosocial stress is very common in adolescents[12] and that this condition is strictly linked to an increased cholinergic tone [13].

Considering this background, we suggest the necessity of a better phenotyping of adolescent patients with moderate/severe asthma, who could benefit from the use of tiotropium or ipratropium through the evaluation of basal cholinergic tone. Nevertheless, it is not easy to measure this parameter via noninvasive technology. However, stimuli such as O₂ inhalation, neck suction, slow deep breathing, metacholine inhalation, and multiple frequency forced oscillation technique have been suggested to study the effect of cholinergic tone on cardiovascular and respiratory systems [14]; measurement of resting heart rate [15] and pupillometry have also been suggested [16].

Several studies have investigated the tolerability and efficacy of tiotropium as add-on to maintenance treatment of adults, adolescents, and children with asthma. Although the majority of these studies, excluded that of Peters et al. in which the authors explored the predictors of positive response to tiopropium [15], reported the necessity of finding a predictor of positive response to tiotropium, none have planned the evaluation of these predictors in tiotropium-responder individuals among subgroups of patients.

According to our previous study [9], a simple question exploring the presence of vagal-related n-RSs during the collection of anamnestic data could help to identify asthmatics with imbalance between sympathetic and parasympathetic systems who could benefit from further diagnostic evaluation of vagal tone. Since the degree of cholinergic tone is likely to be different among asthmatics, we think it is not possible to rule out that the effectiveness of anticholinergic agents such as tiotropium could be greater in patients with an increased degree of cholinergic tone. This possible increased responsiveness to tiotropium may be usefully exploited also in the event of poor efficacy or occurrence of adverse events with the use of long-acting β₂ agonists.

As mentioned earlier, psychological stress is an aspect of adolescent asthmatics, and it has been established that the main mechanism of asthma exacerbation during psychological stress is increased cholinergic activity [17].

In conclusion, the effectiveness of tiotropium in adolescent moderate/severe asthmatics has not been established in the article of Hamelmann et al. probably because asthma has been not adequately phenotyped in patients with particular characteristics. We believe that a basal increase of cholinergic tone might be considered as the possible predictor of response to LAMA. If our hypothesis is confirmed by further studies using the aforementioned methods to measure cholinergic tone, the use of anticholinergic agents could be indicated either as ‘reliever’ or as ‘maintenance’ therapy in asthma as a consequence of a more appropriate prediction of positive response.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.