Between August 2013 and August 2020, 34 children with asthma were prescribed tiotropium; all were eligible to participate and had confirmation of drug dispensation by pharmacy records. Physicians completed the questionnaire for all 34 children. With 3 parents (9%) declining participation and 4 (12%) consenting without completing the questionnaire, 27 parental questionnaires were completed, 7 of which with the child’s input. The questionnaire was completed less than a year after tiotropium initiation in 6 (22%), between 1 to 2 years in 14 (52%) and more than 2 years in 7 (26%) patients; most parents 18 (67%) reported that the delay did not affect their ability to answer the questions. Similarly, with access to medical records, physicians reported no interference of the delay on the perceived accuracy of their responses for all children.
The 34 (11 females; 23 males) children had a median (range) age of 9.1 (1.4–17.8) years; 7 (21%) were less than 6 years, 18 (53%) between 6 and 11 years, and 9 (26%) were 12 years and older at tiotropium initiation. Spiriva Respimat® Softmist 2.5 ug 1 puff or 2 puffs once daily via a holding chamber or Spiriva Handihaler 18 ug 1 puff once daily were used in 1 (3%), 21 (62%), and 12 (35%) children, respectively. Using the GINA’s 2020 age-specific defined treatment steps (23) prior to tiotropium initiation, 3 (9%) children (which were all aged ≥ 12 years) were on GINA Step 3 therapy (low dose ICS with LABA, or leukotriene receptor antagonists (LTRA)), 29 (85%) on Step 4 with a medium ICS dose with LABA or LTRA or a high ICS dose and 2 (6%) on Step 5 with high dose ICS with LABA and/or LTRA (Figs. 1A and 1B). The initiation of tiotropium resulted in only 4 (13%) patients moving to a higher treatment GINA Step; 26 (84%) children maintained their initial treatment step either by replacing another adjunct therapy (LABA or LTRA) or by decreasing the ICS dose, and the remaining 1 (3%) child decreased his treatment step, primarily by the daily ICS dose (Fig. 1B). In three patients, namely one aged < 6 years old at step 4 (high ICS dose) therapy, one aged 6–11 years at step 4 (medium ICS dose + 1 adjunct therapy), and one aged > 12 years old at step 3 (low ICS dose + 1 adjunct therapy) before tiotropium initiation, the treatment step after tiotropium initiation could not be determined because missing information. Of note, although there is no GINA Step 5 for preschoolers, we assumed that all those on Step 4 in whom tiotropium was an added adjunct therapy moved to Step 5.
Treatment goals for the addition of tiotropium according to the parents/children and the physicians are depicted in Fig. 2. Physicians prescribed tiotropium, primarily to improve lung function in 23 (68%), improve control of interim (between-exacerbation) symptoms in 22 (65%) and/or reduce adverse effects on current therapy in 16 (47%), children. In addition to these, parents also primarily perceived tiotropium as a means to decrease the severity and frequency of exacerbations in 19 (70%) and 18 (67%) children, respectively. More than one indication was reported for 26/27 (96%) children by parents and 25/34 (74%) children by physicians. Of note, improving lung function or reducing adverse effects was the only physician-reported indication in 7 (21%) and 2 (6%) children, respectively. In fact, the only indication for initiating tiotropium in the 3 patients aged ≥ 12 years on GINA Step 3 prior to initiation, was to reverse an otherwise asymptomatic fixed airway obstruction.
The main adverse effects on prior therapy motivating the initiation of tiotropium were; (i) growth retardation (9/16), attributed to fluticasone, fluticasone/salmeterol or mometasone furoate, (ii) adrenal insufficiency (1/16), attributed to fluticasone/salmeterol, or (iii) neuropsychiatric symptoms such as aggressivity (6/16) and sleep disorder (3/16), attributed to montelukast, fluticasone/salmeterol and/or budesonide/formoterol, and tachyphylaxis of long-acting beta-agonists (mentioned in the lessons learned by 2 physicians). In 91% (31/34) of children, tiotropium was prescribed as a means to replace or reduce the dose of the perceived offending molecule, most frequently the ICS (alone or in a fixed ICS/LABA combination), LABA (in a fixed combination) or LTRA. Other indications to add tiotropium included decreasing ICS/LABA dose to prevent adverse effects (4/34), preventing ICS dose escalation (1/34), and difficulty administering another drug (1/34). Physicians were comfortable prescribing tiotropium in 71% of patients, and most parents (89%; 24/27) were comfortable with initiating it.
Overall, 93% of parents and 71% of physicians reported asthma improvement (+ 1 to + 3 on the 7-point Likert scale) after tiotropium initiation; no parent described deterioration (-3 to -1). Reported changes following initiation of tiotropium bromide were decreased interim symptoms in 76% and 89% children, according to physicians and parents, respectively, followed by decreased severity and frequency of exacerbations, and improved lung function (Fig. 3A). According to parents and physicians, the most improved symptoms were cough, breathing difficulty, whistling breath, and bronchial secretions/mucus. (Fig. 3B) Other perceived improvements included better control during exercise and reduction in thoracic pain.
Only 8/34 (24%) patients had stopped the medication prior to completing the survey. According to physicians, the main reasons for cessation were significant asthma improvement (3 [38%]), lack of improvement (2 [25%]), slight asthma deterioration (2 [25%]) and poor medication adherence (1 [13%]). After a trial of cessation, 5 (63%) children restarted tiotropium, following which improvement was reported in 3/5, no significant change in 1/5, and unsure in the remainder child.
No patient stopped using tiotropium because of adverse effects. Adverse effects were reported by parents in 2 (7%) children, one with xerostomia and one with insomnia. Physicians reported adverse effects in 2 (6%) children, one with constipation and one with insomnia; headaches were reported as an uncertain side effect in a third one. The overwhelming majority (93%) of parents and all physicians indicated that they would try tiotropium again based on their experience.
While most (93%) parents and physicians (82%) reported that the initiation of tiotropium to the treatment plan did not affect the parents’ ability to give other prescribed medications, some physicians raised caution about initiating another inhaler in patients with doubtful medication adherence and those taking numerous (anti-asthmatic or other) drugs.
Physicians were asked the main lessons learned from initiating tiotropium. A majority mentioned the good improvement in chronic symptoms, particularly in children with prominent moist cough and bronchial secretions, followed by the ability to decrease the dose of ICS and/or LABA combination to lessen associated adverse effects (e.g., growth retardation, adrenal insufficiency, neuropsychiatric symptoms, tachyphylaxis etc.). Several physicians noted a significant improvement in lung function, indicating that they would try tiotropium again in the future, in children with apparent fixed airflow obstruction despite optimized standard therapy. After gaining experience with several individual patient trials, most physicians mentioned increasing comfort with prescribing this drug. even if still off labeled for specific age groups or indications in Canada.