Can the response to a single dose of beclomethasone dipropionate predict the outcome of long-term treatment in childhood exercise-induced bronchoconstriction?

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is a frequent and highly specific symptom of childhood asthma. Inhaled corticosteroids (ICS) are the mainstay of controller therapy for EIB and asthma; however, a proportion of asthmatic children and adolescents is less responsive to ICS. We hypothesized that a single dose response to ICS could function as a predictor for individual long-term efficacy of ICS. OBJECTIVE: To assess the predictive value of the bronchoprotective effect of a single-dose beclomethasone dipropionate (BDP) against EIB for the bronchoprotective effect of 4 weeks of treatment, using an exercise challenge test (ECT). METHODS: Thirty-two steroid-naïve children and adolescents aged 6 to 18 years with EIB were included in this prospective cohort study. They performed an ECT at baseline, after a single-dose BDP (200µg) and after 4 weeks of BDP treatment (100 µg twice daily) to assess EIB severity. RESULTS: The response to a single-dose BDP on exercise-induced fall in FEV1 showed a significant correlation with the response on exercise-induced fall in FEV1 after 4 weeks of BDP treatment (r = .38, p = .004). A reduction in post-exercise fall in FEV1 of more than 8% after a single-dose BDP could predict BDP efficacy against EIB after 4 weeks of treatment with a positive predictive value of 100% (CI: 86.1-100%) and a negative predictive value of 29.4% (CI: 11.7%-53.7%). CONCLUSION: We found that the individual response to a single-dose BDP against EIB has a predictive value for the efficacy of long-term treatment with BDP. This could support clinicians in providing personalized management of EIB in childhood asthma.

Concerns with beta2-agonists in pediatric asthma - a clinical perspective.

Beta2-adrenoreceptor agonists (ß2-agonists) are extensively used in the treatment of childhood asthma. However, there have been concerns regarding their adverse effects and safety. In 2005, the FDA commissioned a "Black Box Warning" communicating the potential for an increased risk for serious asthma exacerbations or asthma related deaths, with the regular use of LABAs. In a meta-analysis of controlled clinical trials, the incidence of severe adverse events appeared to be highest in the 4-11 year age group. Several mechanisms have been proposed regarding the risk of regular use of ß2-agonists, such as masking patients' perception of worsening asthma, desensitization and downregulation of the ß2-adrenoreceptor, pro-inflammatory effects of ß2-agonists, pharmacogenetic effects of ß2-adrenoreceptor polymorphisms and age related differences in pathophysiology of asthma. In this paper, we review ß2-receptor pharmacology, discuss the concerns regarding treatment with ß2-agonists in childhood asthma, and provide suggestions for clinical pediatric practice in the light of current literature.

Comparison of inhalation technique with the Diskus and Autohaler in asthmatic children at home.

OBJECTIVE: Asthma is the most common chronic disease in childhood and anti-inflammatory medication is the cornerstone of treatment. Inhalers are frequently used incorrectly when demonstrated in the hospital, suggesting poor technique at home. We aimed to 1) compare daily inhalation technique with the Diskus and Autohaler in asthmatic children by filming inhalations at home and 2) compare daily inhalation technique with technique demonstrated in the hospital. METHODS: We performed a randomised study in asthmatic children (aged 6-18 years) from the outpatient clinic of Medisch Spectrum Twente hospital (Enschede, The Netherlands) from July 2014 to April 2016. Children received inhalation instructions for the Diskus and Autohaler and were randomised to use one device in the morning and the other in the evening. During the 28-day study period, inhalations were filmed at home and subsequently demonstrated in the hospital. All inhalations were checked for seven critical errors per device. RESULTS: 636 videos with the Diskus and 663 with the Autohaler were provided by 27 children. The most common critical error in daily life was an incorrect device position during preparation of the Diskus (n=271) and an insufficiently deep inhalation (n=39) using the Autohaler. Percentage of correct days using the Diskus was 44%, compared to 96% with the Autohaler (p<0.001). The two most common errors with the Diskus were made at least twice as often at home than in the hospital. CONCLUSION: Inhalation technique at home was markedly better with the Autohaler than with the Diskus. Paediatricians should be aware that hospital-based demonstrations can overestimate daily inhalation technique with the Diskus.

BMI predicts exercise induced bronchoconstriction in asthmatic boys.

BACKGROUND: Exercise induced bronchoconstriction (EIB) is a frustrating morbidity of asthma in children. Obesity has been associated with asthma and with more severe EIB in asthmatic children. OBJECTIVES: To quantify the effect of BMI on the risk of the occurrence of EIB in children with asthma. METHODS: Data were collected from six studies in which exercise challenge tests were performed according to international guidelines. We included 212 Children aged 7-18 years, with a pediatrician-diagnosed mild-to-moderate asthma. RESULTS: A total of 103 of 212 children (49%) had a positive exercise challenge (fall of FEV1 ≥ 13%). The severity of EIB, as measured by the maximum fall in FEV1 , was significantly greater in overweight and obese children compared to normal weight children (respectively 23.9% vs 17.9%; P = 0.045). Asthmatic children with a BMI z-score around +1 had a 2.9-fold higher risk of the prevalence of EIB compared to children with a BMI z-score around the mean (OR 2.9; 95%CI: 1.3-6.1; P < 0.01). An increase in BMI z-score of 0.1 in boys led to a 1.4-fold increased risk of EIB (OR 1.4; 95%CI: 1.0-1.9; P = 0.03). A reduction in pre-exercise FEV1 was associated with a higher risk of EIB (last quartile six times higher risk compared to highest quartile (OR 6.1 [95%CI 2.5-14.5]). CONCLUSIONS: The severity of EIB is significantly greater in children with overweight and obesity compared to non-overweight asthmatic children. Furthermore, this study shows that the BMI-z-score, even with a normal weight, is strongly associated with the incidence of EIB in asthmatic boys.

Can a single dose response predict the effect of montelukast on exercise-induced bronchoconstriction?

RATIONALE: Exercise-induced bronchoconstriction (EIB) can be prevented by a single dose of montelukast (MLK). The effect is variable, similar to the variable responsiveness observed after daily treatment with MLK. We hypothesized that the effect of a single MLK-dose (5 or 10 mg) on EIB could predict the clinical effectiveness of longer term once daily treatment. METHODS: This was a prospective, open-label study. Twenty-four asthmatic adolescents (12-17 years) suboptimally controlled by low-dose inhaled corticosteroids, with ≥10% post-exercise fall in FEV1 , were included. They performed an exercise test at baseline, 20 hr after a single MLK-dose and 40-44 hr after the last dose of 4 weeks once daily treatment. The correlations between the effect of a single dose and 4 weeks treatment on area under the curve (AUC) and maximum % fall in FEV1 were calculated. RESULTS: AUC0-20 min decreased significantly after a single MLK-dose (P = 0.001, CI: 64.9-218.2), but not after 4 weeks of treatment (P = 0.080, CI: -12.2 to 200.4). There was a moderate correlation between the effect of a single MLK-dose and 4 weeks treatment on AUC0-20 min , r = 0.49 (P = 0.011), and maximum % fall in FEV1 , r = 0.40 (P = 0.035). CONCLUSION: The protection provided by a single MLK-dose against EIB only modestly predicts the effect of regular treatment against EIB in adolescent asthmatics on low-dose inhaled corticosteroids. If used on a daily base, MLK offered clinically significant protection against EIB in two thirds of adolescents suboptimally controlled by low-dose ICS.

The effect of body posture during medication inhalation on exercise induced bronchoconstriction in asthmatic children.

RATIONALE: Inhaling medication in a standard body posture leads to impaction of particles in the sharp angle of the upper airway. Stretching the upper airway by extending the neck in a forward leaning body posture may improve pulmonary deposition. A single dose of inhaled corticosteroids (ICS) offers acute, but moderate protection against exercise induced bronchoconstriction (EIB). This study investigated whether inhaling a single dose of ICS in a forward leaning posture improves this protection against EIB. METHODS: 32 Asthmatic children, 5-16 years, with EIB (Median fall in FEV1 or FEV0.5 30.9%) performed two exercise challenge tests (ECT's) with spirometry in a single blinded cross-over trial design. Children inhaled a single dose of 200 µg beclomethasone dipropionate (BDP) 4 h before the ECT, once in the standard posture and once with the neck extended in a forward leaning posture. Spirometry was also performed before the inhalation of the single dose of BDP. RESULTS: Inhalation of BDP in both body postures provided similar protection against EIB (fall in FEV1 or FEV0.1 in standard posture 16.7%; in forward leaning posture 15.1%, p = 0.83). Inhaling ICS in a forward leaning posture significantly delayed EIB compared to inhaling in the standard posture (respectively 2.5 min ± 1.0 min vs. 1.6 min ± 0.8 min; difference 0.9 min (95CI 0.25; 1.44 min); p = 0.01). CONCLUSION: Inhalation of a single dose BDP in both the forward leaning posture and the standard posture provided effective and similar protection against EIB in asthmatic children, but the forward leaning posture resulted in a delay of EIB. REGISTER: NTR3432 (www.trialregister.nl).

Assessment of exercise-induced bronchoconstriction in adolescents and young children.

Recent research shows important differences in exercise-induced bronchoconstriction (EIB) between children and adults, suggesting a different pathophysiology of EIB in children. Although exercise can trigger classic symptoms of asthma, in children symptoms can be subtle and nonspecific; parents, children, and clinicians often do not recognize EIB. With an age-adjusted protocol, an exercise challenge test can be performed in children as young as 3 years of age. However, an alternative challenge test is sometimes necessary to assess potential for EIB in children. This review summarizes age-related features of EIB and recommendations for assessing EIB in young children and adolescents.

Effect of an intranasal corticosteroid on exercise induced bronchoconstriction in asthmatic children.

RATIONALE: Allergic rhinitis and exercise induced bronchoconstriction (EIB) are common in asthmatic children. The aim of this study was to investigate whether treatment of allergic rhinitis with an intranasal corticosteroid protects against EIB in asthmatic children. METHODS: This was a double-blind, randomized, placebo-controlled, parallel group study. Subjects aged 12-17 years, with mild-to-moderate asthma, intermittent allergic rhinitis and ≥ 10% fall in FEV(1) at a screening exercise challenge were randomized to 22 ± 3 days treatment with intranasal fluticasone furoate or placebo. The primary outcome was change in exercise induced fall in FEV(1) . Secondary outcomes were changes in the area under the curve (AUC), asthma control questionnaire (ACQ), pediatric asthma quality of life questionnaire (PAQLQ), and exhaled nitric oxide (FeNO). RESULTS: Twenty-five children completed the study. Mean exercise induced fall in FEV(1) (± SD) decreased significantly (95% CI: 0.7-18.2%, P = 0.04) in the fluticasone furoate group from 28.4 ± 15.8% to 19.0 ± 13.8%, compared to the placebo group (27.4 ± 16.0% to 27.4 ± 19.2%). The change in AUC was not significantly different between treatment groups. However, within the fluticasone furoate group the AUC decreased significantly (P = 0.01). Although total PAQLQ score did not improve, the activity limitation domain score improved significantly within the fluticasone furoate group (P = 0.03). No significant changes were observed in FeNO and ACQ. CONCLUSION: Treatment of allergic rhinitis in asthmatic children with an intranasal corticosteroid reduces EIB and tends to improve quality of life.

The effect of stepping down combination therapy on airway hyperresponsiveness to mannitol.

RATIONALE: Controversy exists about the safety of long acting beta2-agonist (LABA) treatment, in particular in children. Combination therapy with a LABA and an inhaled corticosteroid (ICS) is prescribed to children with moderate asthma and can be stepped down by withdrawal of the LABA when asthma is well controlled. OBJECTIVE: To analyze the effect of stepping down from LABA/ICS combination therapy to monotherapy with the same dose of ICS on the airway response to mannitol in asthmatic children. METHODS: 17 children, aged 12-17 years, with clinically stable asthma, receiving combination therapy, were analyzed in this observational prospective open-label study. Children performed a mannitol challenge at baseline and 30±4 days after their medication was stepped down to ICS monotherapy. The changes in the provoking dose of mannitol to cause a 15% fall in FEV(1) (PD(15)), response-dose ratio and recovery time following a short acting beta2-agonist to ≥95% of baseline FEV(1) were assessed. RESULTS: Mannitol PD(15) and response-dose ratio did not significantly change after stepping down. The recovery time following a short acting beta2-agonist to ≥95% of baseline FEV(1) was significantly shorter (p=0.01) after the withdrawal of the LABA. CONCLUSIONS: In short-term follow-up, stepping down clinically stable asthmatic children from combination therapy to monotherapy with an ICS does not change airway hyperresponsiveness (AHR) to mannitol but does shorten recovery time to baseline lung function following a rescue short acting beta2-agonist.

Mannitol and exercise challenge tests in asthmatic children.

BACKGROUND: Bronchial hyperresponsiveness (BHR), a characteristic feature of asthma, can be assessed through standardized bronchial provocation tests (BPT). Exercise as a BPT is used in diagnosing and monitoring exercise induced bronchoconstriction (EIB). Recently a novel osmotic BPT has been developed, using dry powder mannitol. The aim of this study was to investigate the clinical utility of the mannitol challenge to identify asthmatic children with EIB. MATERIALS AND METHODS: Thirty-three clinically stable children, aged 9-18 years, with a history of EIB, performed both mannitol and exercise provocation challenges. Data were composed of a cross tabulation comparing the reaction on exercise provocation challenge to mannitol challenge. Correlations between post-exercise fall in FEV1 and response-dose ratio (RDR) and PD1) of mannitol were calculated. RESULTS: Twenty-five children completed both tests. Pearson's correlation between log-transformed RDR for mannitol and post-exercise fall in FEV1 was r(p) = 0.666 (P < 0.001). There was no significant relationship between the log PD1) of mannitol and post-exercise fall in FEV1. Children on long acting bronchodilator agents (LABA) were significantly (P < 0.05) more likely to have a positive response on the mannitol challenge. Positive and negative predictive values of the mannitol challenge for EIB were 69% and 91%. CONCLUSION: Mannitol challenge appears to be a suitable alternative for an exercise provocation test to assess EIB in asthmatic children. Given the negative predictive value of 91%, it is especially useful to exclude EIB.