Low-dose Inhaled Corticosteroids Research Articles

Global Initiative for Asthma 2016–derived asthma control with fluticasone propionate and salmeterol: A Gaining Optimal Asthma Control (GOAL) study reanalysis

BackgroundIn 2004, the landmark Gaining Optimal Asthma Control (GOAL) study demonstrated that most patients can achieve asthma control through sustained treatment and that adding a long-acting β2-adrenoreceptor agonist to an inhaled corticosteroid (ICS) is more effective than ICS alone in this regard. Definitions of asthma control have since evolved, and the consequent implications for the GOAL study findings are unclear. ObjectiveTo evaluate the efficacy of fluticasone propionate and salmeterol and fluticasone propionate alone in achieving and maintaining asthma control, as derived from the Global Initiative for Asthma (GINA) 2016 report. MethodsIn total, 3416 patients were stratified by prior medication (ICS-naive [stratum 1], low-dose ICS [stratum 2], or medium-dose ICS [stratum 3]) and randomized to receive fluticasone propionate and salmeterol or fluticasone propionate. The primary end point was the proportion of patients achieving well-controlled or partly controlled asthma; secondary end points included the proportion of patients achieving well-controlled asthma. Control was evaluated during the last 4 weeks of each dose titration. ResultsIn all strata, more patients achieved well-controlled or partly controlled asthma with fluticasone propionate and salmeterol vs fluticasone propionate alone (stratum 1: 91% vs 85%; P = .003; stratum 2: 86% vs 82%; P = .07; and stratum 3: 76% vs 66%; P < .001), as well as patients with well-controlled asthma (stratum 1: 64% vs 56%; P = .005; stratum 2: 59% vs 41%; P < .001; and stratum 3: 40% vs 22%; P < .001). ConclusionA markedly higher proportion of patients with uncontrolled asthma in each stratum achieved control according to GINA 2016 criteria compared with the original study criteria. The proportion of patients achieving control remained greater with fluticasone propionate and salmeterol than with fluticasone propionate alone.

Influence of weight status in the response to Step-2 maintenance therapies in children with asthma

IntroductionOverweight children with asthma may display impaired response to inhaled corticosteroids (ICS), possibly due to non-eosinophilic inflammation or weight-related lung compression; these mechanisms may differentially affect response to ICS and...

Weight status and nonadherence to asthma maintenance therapy among children enrolled in a public drug insurance plan

Objective: The pediatric obese-asthma phenotype is associated with poor control, perhaps because of medication nonadherence. This study aimed to assess whether weight status is associated with nonadherence in children prescribed new asthma maintenance therapies.Methods: A historical cohort was constructed from a clinical database linking individual patient and prescription data to Quebec’s prescription claims registry. Children aged 2–18 years with specialist-diagnosed asthma who were newly prescribed one of the following maintenance controllers: leukotriene receptor antagonists (LTRA); low-dose inhaled corticosteroids (ICS); medium/high-dose ICS; or combination therapy (ICS with long-acting beta-2 agonists and/or LTRA), at the Asthma Center of the Montreal Children’s Hospital from 2000–2007 were included. Primary nonadherence was defined as not claiming any prescriptions, whereas secondary nonadherence was measured with the proportion of prescribed days covered (PPDC ≤ 50%) among primary adherers over a 6-month follow-up period. A modified Poisson regression model served to estimate the effect of excess weight (BMI > 85th percentile) on primary and secondary nonadherence.Results: Approximately one third of patients were primary nonadherers and 60% took less than 50% of prescribed therapy. Excess weight was associated with a trend toward increased risk of primary nonadherence in children newly prescribed low-dose ICS (RR 1.53, 95%CI 0.94–2.49), and of secondary nonadherence in children initiating medium/high-dose ICS (RR 1.24; 95%CI 0.98–1.59).Conclusions: Excess weight status is a possible determinant of primary nonadherence in children initiating low-dose ICS and secondary nonadherence to higher-dose ICS regimens. This hypothesis-generating study suggests that nonadherence may be a potential contributor to higher morbidity in children with obese-asthma.

Changing prevalence of current asthma and inhaled corticosteroid treatment inthe UK: population-based cohort 2006-2016.

Asthma is the most common respiratory disorder in the UK, yet we have incomplete knowledge on the prevalence of current disease, treatment and exacerbations.We used UK electronic healthcare records, 2006-2016, to estimate the prevalence of current asthma by year, sex and age (<5, 5-11, 12-17, 18-24, 25-54 and ≥55 years), and the proportion prescribed inhaled corticosteroids (ICS) and additional asthma therapy, treated for exacerbations and other asthma care markers.Overall current asthma prevalence was 6.5% in 2016 (7.2% in 2006). Prevalence fell in those aged <45 years. The lowest prevalence and largest absolute decrease was in children aged <5 years. In 2016, 80% of current asthma patients were managed on ICS (65% in 2006); this increase occurred in all age groups, primarily due to an increase in low-dose ICS. During this time there was an increase in all age groups in the proportion prescribed additional asthma therapy, treated for an exacerbation within primary care and given an annual asthma review or management plan. Hospitalised exacerbations showed minimal change over time.Asthma remains highly prevalent and a significant healthcare burden. In those with a diagnosis, there was an increase in ICS prescriptions and treatment of exacerbations across all age groups. This may reflect a trend towards more aggressive asthma management within primary care. An apparent decline in prevalence was observed in those aged <45 years, particularly in children aged <5 years.

A systematic review of second-line controller combination therapy options for the management of asthma

First-line controller combination therapy for the management of asthma is a low-dose inhaled corticosteroid (LD-ICS) + a long-acting β-agonist (LABA), and second-line options are a LD-ICS + a leukotriene receptor antagonist (LTRA), LD-ICS + sustained-release theophylline (SR-T), and a medium-/high-dose ICS (HD-ICS). The purpose of this review is to assess the various second-line combination therapy options for the management of asthma. We systematically reviewed randomized controlled trials (RCTs) in adult patients with asthma, extracting and synthesizing data from eligible articles on study design, duration, randomization, blinding, withdrawal, run-in period, type of analysis, and names and doses of drugs. The primary outcome measure was change in percentage predicted forced expiratory volume in 1 second (% FEV1), and the secondary outcome was frequency of asthma exacerbations. Nine RCTs (three blinded and six open-label trials) were selected for the review. One study investigated LD-ICS + LTRA compared with HD-ICS, two studies investigated LD-ICS + SR-T compared with HD-ICS, and five studies investigated LD-ICS + LTRA compared with LD-ICS + SR-T. Only one of the nine RCTs compared all treatment options as mentioned in Global Initiative for Asthma (GINA) guidelines. Seven RCTs examined the primary outcome (change in % FEV1). No significant difference was observed (four RCTs; % FEV1) between LD-ICS + LTRA and LD-ICS + SR-T, but one RCT reported better clinical improvement with LD-ICS + LTRA than with LD-ICS + SR-T (% FEV1). Likewise, similar clinical effects (two RCTs) were observed between LD-ICS + SR-T and HD-ICS, one based on % FEV1 and the other based on exacerbation improvement. One RCT concluded that LD-ICS + LTRA was an effective and well-tolerated alternative to HD-ICS (exacerbation improvement). LD-ICS + LTRA resulted in greater clinical improvement when comparing all second-line treatment options in one RCT (% FEV1 and exacerbation improvement). All nine studies had a high risk of bias according to a modified Cochrane risk-of-bias tool for quality assessment of RCTs. Existing RCTs provide low-quality evidence of the superiority of second-line controller options for asthma management. This systematic review recommends that clinically relevant, stringently designed RCTs with appropriate sample sizes and durations are conducted to identify the best second-line controller option.

Inhaled corticosteroids and risk of upper respiratory tract infection in patients with asthma: a meta-analysis.

Recent studies have suggested a possible association between respiratory infection and the use of inhaled corticosteroids (ICS). We aimed to ascertain the risk of upper respiratory tract infection (URTI) with long-term inhaled corticosteroid use among patients with asthma. Through a comprehensive literature search of PubMed, Cochrane Library, EMBASE, and Google Scholar from inception to May 2018, we included randomized controlled trials of any ICS vs. a control treatment for asthma, with reporting of URTI as an adverse event. We conducted meta-analyses by the Peto approaches to generate summary estimates comparing ICS with non-ICS treatment on the risk of URTI. Seventeen trials (15,336 subjects) were included. Compared with non-ICS treatment, ICSs were associated with a significantly increased risk of URTI (Peto OR, 1.24; 95% CI 1.08-1.42; I2 = 5%, p = 0.002). Subgroup analyses were performed for different dose, both high- and low-dose ICSs were associated with a significantly increased risk of URTI (high dose: Peto OR, 1.46; 95% CI 1.05-2.03; I2 = 0%; p = 0.03) (low dose: Peto OR, 1.20; 95% CI 1.04-1.39; I2 = 25%; p = 0.01). Moreover, fluticasone was observed with an increased risk of URTI (Peto OR, 1.18; 95% CI 1.02-1.38; p = 0.03; heterogeneity: I2 = 21%) but not budesonide, low-dose fluticasone treatment was associated with a significantly higher risk of URTI but not high dose. This study raises safety concerns about the risk of URTI associated with ICS use in patients with asthma, but it should be further investigated.

Focus on Innuvair® Inhaler for Asthma

No abstract available.

General practitioners' views on the influence of cost on the prescribing of asthma preventer medicines: a qualitative study.

Objective Out-of-pocket costs strongly affect patient adherence with medicines. For asthma, guidelines recommend that most patients should be prescribed regular low-dose inhaled corticosteroids (ICS) alone, but in Australia most are prescribed combination ICS-long-acting β2-agonists (LABA), which cost more to patients and government. The present qualitative study among general practitioners (GPs) explored the acceptability, and likely effect on prescribing, of lower patient copayments for ICS alone. Methods Semistructured telephone interviews were conducted with 15 GPs from the greater Sydney area; the interviews were transcribed and thematically analysed. Results GPs reported that their main criteria for selecting medicines were appropriateness and effectiveness. They did not usually discuss costs with patients, had low awareness of out-of-pocket costs and considered that these were seldom prohibitive for asthma patients. GPs strongly believed that patient care should not be compromised to reduce cost to government. They favoured ICS-LABA combinations over ICS alone because they perceived that ICS-LABA combinations enhanced adherence and reduced costs for patients. GPs did not consider that lower patient copayments for ICS alone would affect their prescribing. Conclusion The results suggest that financial incentives, such as lower patient copayments, would be unlikely to encourage GPs to preferentially prescribe ICS alone, unless accompanied by other strategies, including evidence for clinical effectiveness. GPs should be encouraged to discuss cost barriers to treatment with patients when considering treatment choices. What is known about the topic? Australian guidelines recommend that most patients with asthma should be treated with low-dose ICS alone to minimise symptom burden and risk of flare ups. However, most patients in Australian general practice are instead prescribed combination ICS-LABA preventers, which are indicated if asthma remains uncontrolled despite treatment with ICS alone. It is not known whether GPs are aware that the combination preventers have a higher patient copayment and a higher cost to government. What does this paper add? This qualitative study found that GPs favoured combination ICS-LABA inhalers over ICS alone because they perceived ICS-LABA combinations to have greater effectiveness and promote patient adherence. This aligned with GPs' views that their primary responsibility was patient care rather than generating cost savings for government. However, it emerged that GPs rarely discussed medicine costs with patients, had low knowledge of medicine costs to patients and the health system and reported that patients rarely volunteered cost concerns. GPs believed that lower patient copayments for asthma preventer medicines would have little effect on their prescribing practices. What are the implications for practitioners? This study suggests that, when considering asthma treatment choices, GPs should empathically explore with the patient whether cost-related medication underuse is an issue, and should be aware of the option of lower out-of-pocket costs with guideline-recommended ICS alone treatment. Policy makers must be aware that differential patient copayments for ICS preventer medicines are unlikely to act as an incentive for GPs to preferentially prescribe ICS alone preventers, unless the position of these preventers in guidelines and evidence for their clinical effectiveness are also reiterated.

Individualized Therapy for Persistent Asthma in Young Children

AM Fitzpatrick, DJ Jackson, DT Mauger. J Allergy Clin Immunol. 2016;138(6):1608–1618.e12 To determine if a differential response to asthma controller medications exists among young children with a history of wheezing requiring step 2 therapy and if this response can be predicted by phenotype and clinically available biomarkers. Enrolled subjects were 300 children aged 12 to 59 months who required step 2 asthma therapy, including those who were naive to inhaled corticosteroids (ICSs) and leukotriene receptor antagonist (LTRA) medications and those who had been treated with low-dose ICSs or LTRAs at any point in the 6 months before enrollment but still experiencing symptoms warranting daily controller medication. This …

Physicians' preference for controller medication in mild persistent asthma.

Although the asthma guidelines recommend inhaled corticosteroids(ICS) or leukotriene receptor antagonists-(LTRAs) for the treatment of mild persistent asthma, factors governing the physicians' preference are unknown. We aimed to investigate the preference of physicians for the controller medication and the factors governing their choice. A self-administered questionnaire composed of 16 questions that aimed to determine the preference of the physicians for the first choice controller medication in mild persistent asthma and physician and patient related factors that may be associated with this selection was e-mailed to the members of the Turkish National Society of Allergy and Clinical Immunology and distributed to participants in the 21st congress. Of the 670 questionnaires, there were 51% participants and 336 of them were complete enough to be included in the analysis. Low dose ICS was preferred as the first choice controller medication for mild persistent asthma by 84.5% of the physicians. The reasons for physicians' preference were different for ICS and LTRA. In the logistic regression analysis, use of asthma guidelines (OR:3.5, 95%CI:1.3-9.3, p=0.01), alignment in guidelines (OR:2.9, 95%CI:1.4-5.8, p=0.002) and the opinion that it is a more effective (OR:2.3, 95%CI:1.1-4.8, p=0.02) were independently associated with ICS preference. Being a pediatrician (OR:5.4, 95%CI: 2.7-10.5, p<0.001) and the opinion that it has better patient compliance (OR:4.4, 95%CI: 1.6-12.0, p=0.004) were independently associated with LTRA preference. Surveyed Turkish physicians, the majority of whom were specialists, preferred ICS over LTRA as controller medication in mild persistent asthma. Asthma guidelines, training background (pediatrician versus not) and perceived efficacy and patient compliance appeared to influence their preferences.

A “real-life” study on height in prepubertal asthmatic children receiving inhaled steroids

ABSTRACTIntroduction: Asthma is the most common chronic respiratory disease in children and inhaled corticosteroids (ICS) constitute the first line of treatment for these patients. However, the potential growth-inhibiting effect of ICS has often been a cause of concern for both caregivers as well as physicians, and there still remains conflict regarding their safety profile. Objective: To assess whether the administration of ICS in low or medium doses is associated with height reduction in prepubertal children. Methods: We performed a retrospective study to examine the association between ICS treatment and growth deceleration in children with mild persistent asthma. The comparison of height measurements every 6 months from 3 to 8 years of age was conducted among three groups of patients: patients not receiving ICS, patients being treated with low dose of ICS and patients being treated with medium dose of ICS (GINA Guidelines 2015). Results: This study included 284 patients (198 male, 86 female) aged 3–8 years; 75 patients were not receiving ICS, 63 patients were on low-dose ICS and 146 patients were on medium-dose ICS. The measured height every 6 months did not differ significantly (p > 0.05) among the three groups while the difference remained stable (p > 0.05), even when we evaluated males and females separately. Conclusions: In this “real-life” study we found that long-term treatment with ICS in low or medium doses is not associated with height reduction in prepubertal children with asthma.

Long-term use of inhaled corticosteroids and risk of upper respiratory tract infection in chronic obstructive pulmonary disease: a meta-analysis

Recent studies have suggested that inhaled corticosteroids (ICS) may be associated with higher risks of tuberculosis and pneumonia in patients with COPD. However, it is not known whether ICS increases the risk of upper respiratory tract infection (URTI). Aim of this study was to explore the relationship between ICS and URTI. Through a comprehensive literature search of PubMed, EMBASE, Cochrane Library, and Google Scholar from inception to March 2016, we identified randomized controlled trials of ICS therapy lasting at least 6 months. A meta-analysis by the Peto approach was also conducted to generate summary estimates comparing ICS with non-ICS treatment on the risk of URTI. A total of 14 studies involving 19,777 subjects were considered in the meta-analysis. Compared with non-ICS treatment, ICS were associated with a significantly increased risk of URTI (Peto OR: 1.16; 95% CI: 1.05–1.29; I2 = 9%; p = .004). Subgroup analyzes were performed for different dose, high-dose ICS was associated with a significantly increased risk of URTI (Peto OR: 1.19; 95% CI: 1.05–1.34; I2 = 0%; p = .005), whereas low-dose ICS showed a non-significant increased risk of URTI (Peto OR: 1.10; 95% CI: 0.91–1.33; I2 = 0%; p = .32). Moreover, fluticasone was observed with an increased risk of URTI but not mometasone; high-dose fluticasone treatment was associated with a significantly higher risk of URTI but not low-dose. These results suggested to us that ICS use may increase the risk of URTI in patients with COPD, but it should be further investigated.

Efficacy and safety of budesonide/formoterol pMDI vs budesonide pMDI in asthmatic children (6–

BackgroundThe efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI) have been demonstrated in patients with asthma at least 12 years old. ObjectiveTo evaluate the efficacy of 2 formoterol doses added to budesonide as fixed combinations vs budesonide alone in children 6 to younger than 12 years with asthma. MethodsThis randomized, double-blinded, parallel-group, multicenter study (NCT02091986; CHASE 3) included children 6 to younger than 12 years with asthma previously receiving a medium-dose inhaled corticosteroid (ICS) or an ICS plus a long-acting β2-agonist. Children symptomatic during a 7–28-day run-in on low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 μg twice daily (BID), were randomized to receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 μg (160/9 μg) BID (n = 92), budesonide/formoterol pMDI 80/2.25 μg (160/4.5 μg) BID (n = 95), or budesonide pMDI 80 μg (160 μg) BID (n = 92) for 12 weeks. ResultsChange in forced expiratory volume in 1 second from baseline to 1 hour after dosing (primary end point), change in forced expiratory volume in 1 second 15 minutes after dosing, and peak expiratory flow 1 hour after dosing at week 12 were statistically significantly greater for budesonide/formoterol 160/9 μg vs budesonide (P ≤ .015 for all comparisons), but not for budesonide/formoterol 160/4.5 μg vs budesonide. Bronchodilator effects, evident 15 minutes after the dose on day 1, were maintained at week 12. Incidence of protocol-defined asthma exacerbations and improvements in asthma symptom-related and quality-of-life outcomes were similar across treatments. There were no notable safety differences among treatments. ConclusionBudesonide/formoterol pMDI 160/9 μg showed statistically significant and clinically meaningful lung function improvements vs budesonide pMDI 160 μg, demonstrating appropriateness as a therapeutic option for children 6 to younger than 12 years with asthma symptomatic on ICS alone. Trial RegistrationClinicalTrials.gov Identifier: NCT02091986.

AB039. Pragmatic trial stepping down Flutiform® in patients maintained on high dose ICS

Background Global Initiative for Asthma (GINA) guidelines recommend a gradual step-down of asthma therapy if asthma has been well-controlled for at least 3 months. In real life, however, many well-controlled patients are prescribed high doses of inhaled corticosteroids (ICS), and are therefore unnecessarily at risk of systemic side effects associated with long-term ICS use. To encourage and facilitate step-down in a clinical setting, further pragmatic studies are required to demonstrate that good control of asthma can be maintained with a lower dose of ICS in stable and controlled patients, and to explore potential predictors for response to step-down.To test if good control of asthma can be maintained in adult patients previously stable on Flutiform® 250 (250 mcg fluticasone/10 mcg formoterol) for 12 weeks, after step-down to Flutiform® 125 (250 mcg fluticasone/5 mcg formoterol).

Fluticasone furoate and vilanterol trifenatate combination therapy for the treatment of asthma

ABSTRACTIntroduction: Combination inhaled corticosteroids (ICS) and long acting β2-adrenergic agonists (LABA) are used in a stepwise fashion for patients whose asthma is not controlled by low dose ICS alone. Adherence is one of the main issues facing clinicians in the control of asthma symptoms with currently available combination inhalers requiring twice-daily (BD) inhalation. Fluticasone furoate (FF) and vilanterol trifenatate (VI) both have prolonged retention in the lung with effects on lung function over 24-hours and as such the combination has been proposed for once-daily (OD) dosing.Areas covered: The stepwise pharmacologic approach to asthma management is addressed, followed by a detailed assessment of the literature pertaining to the efficacy, tolerability and safety of FF/VI combination therapy for the treatment of asthma.Expert commentary: Doses of 100/25µg and 200/25µg inhaled OD, have similar improvements in lung function, asthma control as well as rates of side effects to one of the currently available BD ICS/LABA combinations, fluticasone propionate and salmeterol (FP/SAL) but have not been compared with other commonly used combinations. It is hoped that OD dosage of FF/VI can improve adherence and hence asthma control in these patients, however evidence to support this has yet to become available.

Inflammatory markers as exacerbation risk factors after asthma therapy switch from inhaled steroids to montelukast

BackgroundAsthma guidelines allow anti-leukotriene medications to be used as an alternative to inhaled corticosteroids (ICS) in second-step intensity therapy. The aim of the study was to analyze the risk factors of exacerbations, particularly inflammatory markers, during the 12-month period following therapy reduction from an ICS to montelukast in young patients with mild asthma. MethodsA total of 84 patients (aged 7–18 years old) with mild asthma controlled by low-dose ICS, had their treatment switched to montelukast. Exhaled nitric oxide (eNO), sputum eosinophils (sEos), and bronchial hyperreactivity (BHR) were assessed at the beginning and then every three months throughout the one-year period. The patients with asthma exacerbations (first severe or third mild) were discontinued from the study. ResultsOver the study period, 22 patients (26%) discontinued montelukast due to asthma exacerbations. An increased risk of exacerbations was noted among patients with initial sEos above 2.5% (relative risk, RR 36.6; 95% CI: 7.1–189.3; p < 0.001), as well as those with augmented BHR (RR 9.5; 2.8–31.6; p < 0.001), or eNO greater than 20 ppb (RR 3.7; 95% CI: 1.3–10.7; p = 0.013). An increase in BHR and eNO was observed during the last visit before exclusion. ConclusionsAfter switching treatment from a low-dose ICS, montelukast maintained control of asthma symptoms in 75% of patients. High sEos before the treatment change was the strongest exacerbation risk factor. In patients with asthma controlled by low-dose ICS and low inflammatory markers, treatment could be safely switched to montelukast.

Evaluation of switching low-dose inhaled corticosteroid to pranlukast for step-down therapy in well-controlled patients with mild persistent asthma

Objective: Treatment guidelines for asthma recommend step-down therapy for well-controlled asthma patients. However, the precise strategy for step-down therapy has not been well defined. We investigated whether well-controlled patients with mild persistent asthma can tolerate a step-down therapy of either a reduced dose of inhaled corticosteroid (ICS) or a switch to a leukotriene receptor antagonist (LTRA), pranlukast hydrate. Methods: We recruited 40 adult patients with mild persistent asthma who were well-controlled for at least 3 months with a low-dose ICS therapy. The patients were randomly assigned to either an ICS dose reduction or a switch to pranlukast for 6 months. Results: FeNO levels in the pranlukast group were significantly increased over that in the ICS group. There were no significant differences between the two groups for lung function, FOT, at the endpoint. The percentage of patients with controlled asthma was 72.2% in the pranlukast group and 90% in the ICS group. No statistically significant difference between the two groups in the percentages of patients with treatment failure was observed. Conclusions: Patients with mild persistent asthma that is well-controlled by a low dose of ICS can be switched to pranlukast safely for at least 6 months. However, 27.8% of the pranlukast group failed to maintain well-control, and FeNO levels increased with the switch to pranlukast at 6 months. This study was been limited by the small sample size and should therefore be considered preliminary. Further studies are needed to investigate the therapeutic efficacy of LTRA monotherapy as a step-down therapy.

Predictive risk factors for relapse after cessation of inhaled corticosteroids in well-controlled childhood asthma.

There is limited data for predicting the risk of exacerbations following the cessation of inhaled corticosteroids (ICS) in well controlled childhood asthma. In current study, clinical, functional and inflammatory parameters at the time of ICS withdrawal were investigated in that respect. Forty children asymptomatic for at least 3 months on low dose ICS's were enrolled and ICS were discontinued in summer. At enrolment symptom/medication diary, pulmonary function parameters, methacholine provocation testing, peripheral blood eosinophilia, serum total and allergen-specific IgE levels and skin prick testing were performed. In a subgroup of patients, phytohemaglutinin induced secretion of IL-5, IL-13, IFN-γ and IL-10 from blood mononuclear cells were measured. Patients were assessed with symptom/medication diary and pulmonary function test every 2 months for 6 months. Eighteen of 37 patients experienced recurrence of acute asthma symptoms. In patients with acute attack (group I), changes in rhinitis symptom scores at 2nd month vs. baseline were statistically higher. In addition, group I had significantly higher rhinitis symptom scores compared to group II at fourth-month visit. Patients with acute exacerbation revealed a significant decrease in FEV1% at 2nd month compared to baseline. Moreover, group I showed significantly lower FEF 25-75% compared to group II at 2nd month. Baseline bronchial hyper-responsiveness with methacholine was found to be an independent risk factor for asthma exacerbation. The findings of this study identified baseline bronchial hyperreactivity, higher rhinitis symptom scores and gradual decrease in pulmonary function parameters during follow-up as risk factors for subsequent exacerbation of asthma.

Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth.

Background Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. Objectives To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. Search methods We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. Selection criteria Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. Data collection and analysis Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. Main results Among 22 eligible trials, 17 pairs of groups comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 μg) versus low to medium (200 μg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X2 = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, body mass index and skeletal maturation reported with low quality of evidence due to imprecision. Authors' conclusions In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents’ and physicians’ concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma.

S92 Efficacy Of Once-daily Tiotropium Respimat(R) 5 g From Five Phase Iii Trials In Adults With Symptomatic Asthma

Background Recent clinical trials have indicated that the long-acting antimuscarinic agent tiotropium, a once-daily long-acting bronchodilator, may provide benefit to patients with symptomatic asthma. We investigated primary efficacy data (lung function, risk of severe exacerbation and seven-question Asthma Control Questionnaire [ACQ-7] response) from five Phase III, randomised, double-blind, parallel-group trials that evaluated the efficacy and safety of once-daily tiotropium add-on versus placebo add-on (all tiotropium doses delivered via the Respimat ® SoftMist™ inhaler) in adults with symptomatic asthma on inhaled corticosteroid (ICS) ± long-acting β 2 -agonist (LABA) maintenance therapy. Methods Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients on high-dose ICS (≥800 µg budesonide or equivalent) + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients on moderate-dose ICS (400–800 µg budesonide or equivalent); one 12-week trial of tiotropium Respimat ® 5 µg and 2.5 µg (GraziaTinA-asthma ® : NCT01316380) in patients on low-dose ICS (200–400 µg budesonide or equivalent). Results 3476 patients were treated, of whom 1128 received tiotropium Respimat ® 5 µg. Once-daily tiotropium Respimat ® 5 µg significantly improved lung function (Table) in patients with not fully controlled asthma receiving low- to high-dose ICS. In addition, tiotropium Respimat ® 5 µg reduced the risk of severe exacerbations versus placebo (co-primary end point) in patients on high-dose ICS + LABA (hazard ratio 0.79; p = 0.0343), and there was an increase in ACQ-7 responder rate (co-primary end point) with the5 µg dose (odds ratio 1.32; p = 0.0308) compared with placebo in patients on moderate-dose ICS. Conclusion Once-daily tiotropium Respimat ® significantly improves lung function in adult patients with symptomatic asthma receiving a range of doses of ICS, including even high-dose ICS + LABA, suggesting a potential role for this treatment as add-on to ICS in adults with symptomatic asthma.