Doses Of Inhaled Corticosteroids Research Articles

Associations between Inhaled Corticosteroid Use in the First 6 Years of Life and Obesity-related Traits.

Rationale: Infants and young children might be particularly likely to experience the potential clinical side effects of inhaled corticosteroids (ICSs) on body mass index (BMI), adiposity rebound (AR), and body composition, but this has rarely been studied in long-term studies in this age group. Objectives: To determine the association between ICS exposure in the first 6 years of life and the BMI, AR, body composition, and blood lipid concentrations. Methods: Children from the two mother-child cohorts of the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) were included. ICS use was registered prospectively to age 6 years, and the cumulative dose was calculated. Multiple linear regression models were used for analysis. Measurements and Main Results: A total of 932 (84%) of the 1,111 children from the COPSAC cohorts had BMI data, 786 (71%) had dual-energy X-ray absorptiometry scan data at the age of 6 years, and 815 (73%) had an AR age calculated. Two hundred ninety-one children (31%) received a cumulative ICS dose higher than that from 10 weeks of standard treatment before the age of 6. ICS treatment during 0-6 years of age was associated with an increased BMI z-score (0.05 [95% confidence interval, 0.005 to 0.09] SDs per each year of standard treatment; P = 0.03) an earlier age at AR (-0.18 [95% confidence interval, -0.28 to -0.08] yr; P = 0.0006), and a 2% increased geometric mean android fat percentage (P = 0.05). ICS exposure and dual-energy X-ray absorptiometry scan data were not associated. Conclusions: ICS use in early childhood was associated with an increased BMI z-score at age 6, an earlier AR, and a trend of association with an increased android body fat percentage.

Phenotype-Guided Asthma Therapy: An Alternative Approach to Guidelines.

Despite recent advances in therapy, a substantial proportion of asthmatics remain not well controlled. The classical stepwise approach to pharmacological therapy in adult asthma recommends that treatment is progressively stepped up by increasing the inhaled corticosteroid (ICS) dose or by adding another controller medication- to achieve symptom control and reduce the risk of exacerbations, and stepped down after a period of control. In general, asthma guideline recommendations do not reflect that there are significant differences between ICS in terms of potency. Moreover, they do not consider efficacy and safety separately, incorrectly assuming that “low” and “high” dose categories inevitably correspond with low and high risk of systemic effects. Another point of criticism is the fact that guidelines do not take into account the inflammatory profile of the patient, although substantial groups of patients with mild and moderate asthma have little evidence of “T2-high” inflammation, and by extension are likely to show a poor response to ICS treatment. On the other hand, the latest version of the Global Initiative for Asthma (GINA) equally recommends regular ICS and ICS/formoterol as needed to prevent exacerbations in step 2 patients, without taking into consideration that the therapeutic objectives (exacerbations, symptoms) may differ between individual patients and that different goals may warrant distinct treatment strategies. In this review, we bring to the table several controversial issues concerning asthma treatment and suggest an alternative proposal that takes into consideration the potential side effects of high ICS doses, the patient’s inflammatory profile and the therapeutic goals to be achieved.

Chronic infection with Chlamydia pneumoniae in asthma: a type-2 low infection related phenotype

BackgroundChlamydia pneumoniae and Mycoplasma pneumoniae have been implicated in the pathogenesis of asthma and are responsible for chronic inflammation when host immune system fails to eradicate the bacteria.MethodWe performed a prospective study on 410 patients who underwent a visit at the asthma clinic of CHU of Liege between June 2016 and June 2018 with serology testing for C. pneumoniae and M. pneumoniae.Results65% of our asthmatic population had serum IgA and/or IgG towards C. pneumoniae, while only 12.6% had IgM and/or IgG against M. pneumoniae. Compared to seronegative asthmatics, asthmatics with IgA+ and IgG+ against C. pneumoniae were more often male and older with a higher proportion of patients with smoking history. They received higher doses of inhaled corticosteroids (ICS) and displayed lower FEV1/FVC ratio, higher RV/TLC ratio and lower conductance. They had higher levels of fibrinogen, though in the normal range and had lower sputum eosinophil counts. Patients with IgA− and IgG+ against C. pneumoniae were older and had higher blood monocyte counts and alpha-1-antitrypsin levels as compared to seronegative patients. Patients with IgM and/or IgG towards M. pneumoniae were more often males than seronegative asthmatics. In a subpopulation of 14 neutrophilic asthmatics with Chlamydia pneumoniae IgA + /IgG + treated with macrolides, we found a significant decrease in blood neutrophils and normalization of sputum neutrophil count but no effect on asthma quality of life and exacerbations.ConclusionPositive Chlamydia serologic test is more common than positive Mycoplasma serology. Asthmatics with IgA and IgG against C. pneumoniae have more severe disease with increased airway obstruction, higher doses of ICS, more signs of air trapping and less type-2 inflammation.

The position of the fixed combination of indacaterol, glycopyrronium, and mometasone furoate in the management of bronchial asthma. The Report of Expert Panel of Russian Respiratory Society

Achieving the control of bronchial asthma (BA) in real clinical practice remains an unresolved problem, despite the expansion of therapeutic options in this area. Guidelines about when and for whom should a particular treatment be used continue to develop. Increasing of inhaled corticosteroid dose (ICS) in combination with a long-acting β2-agonist (LABA) does not always lead to the desired result, although a combined LABA-ICS inhaler could improve the course of asthma and increase adherence. The addition of tiotropium bromide to LABA-ICS requires the use of two inhalers. The targeted biological therapy is associated with the complexity of phenotyping and is possible only in specialized medical centers. Mometasone furoate, indacaterol acetate, and glycopyrronium bromide in fixed doses were combined in Breezhaler® inhaler for asthma maintenance therapy once per day. This way of treatment helps to realize full potential of maintenance inhalation therapy of bronchial asthma and to simplify the achievement of control over the disease in routine clinical practice.

Triple therapy in uncontrolled asthma: a network meta-analysis of phase III studies.

Conflicting evidence is currently available concerning the impact on asthma exacerbation of triple inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA)/long-acting muscarinic receptor antagonist (LAMA) fixed-dose combination (FDC).Since meta-analyses allow settling controversies of apparently inconsistent results, we performed a network meta-analysis of phase III randomised controlled trials including 9535 patients to assess the effect of ICS/LABA/LAMA combinations in uncontrolled asthma.Triple combination therapies with an ICS administered at high dose (HD) were more effective (p<0.05) than medium-dose (MD) ICS/LABA/LAMA FDC and both MD and HD ICS/LABA FDCs against moderate to severe exacerbation (relative risk 0.61-0.80) and increasing trough forced expiratory volume in 1 s (from +33 to +114 mL). Triple combination therapies including HD ICS were superior (p<0.05) to MD ICS/LABA/LAMA FDC in preventing severe exacerbation (relative risk 0.46-0.65), but not with respect to moderate exacerbation (p>0.05). Triple combination therapies were equally effective on asthma control, with no safety concerns.This quantitative synthesis suggests that ICS/LABA/LAMA FDCs are effective and safe in uncontrolled asthma, and that the dose of ICS in the combination represents the discriminating factor to treat patients with a history of moderate or severe exacerbation.

Safety of anti-inflammatory drugs in children with asthma.

Inhaled corticosteroids (ICS) are widely used as the first-line treatment of asthma. When the disease is not controlled by standard doses of ICS, other anti-inflammatory drugs should be considered. The aim of this report is to review the main adverse events induced by anti-inflammatory drugs in children with asthma and discuss possible actions to prevent or mitigate these effects. Proper interpretation of ICS safety studies requires knowledge of the pharmaceutical properties and delivery device systems of the different ICS available. Genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression were found in children and adults who use ICS to treat their asthma. There is evidence of the association between montelukast use and neuropsychiatric events. Benefits of ICS, properly prescribed and used, outweigh their potential adverse effects. There is substantial evidence that the combination of ICS with long-acting beta2 agonists is safe for asthmatic children. Awareness of the potential risks of neuropsychiatric events in children taking montelukast should inform the clinicians' prescribing practices. Omalizumab is generally well-tolerated, but the evidence on the safety of other biologic agents in children is scanty. The risk of systemic adverse events with anti-inflammatory drugs must be balanced against the risks of uncontrolled asthma and/or frequent oral steroid use.

EFFECTIVENESS OF ADD-ON SUBLINGUAL IMMUNOTHERAPY FOR THE TREATMENT OF JAPANESE CEDAR POLLINOSIS-ASSOCIATED ALLERGIC ASTHMA IS IT POSSIBLE TO REDUCE THE DOSE OF INHALED CORTICOSTEROID BY ADDING SUBLINGUAL IMMUNOTHERAPY?

This study investigated the effect of adjuvant sublingual immunotherapy (SLIT) on inhaled corticosteroid (ICS) dose in patients with pollinosis-associated asthma. We retrospectively evaluated patients with cedar pollinosis-associated asthma who initiated pharmacotherapy with or without adjuvant SLIT therapy from December 2014 to December 2016 and who continued treatment for 3 years. Changes in ICS dose (fluticasone propionate or its equivalent), antihistamine use, leukotriene antagonist use and intranasal corticosteroid (INCS) use over the 3-year period were compared. The study included 36 and 35 patients in the add-on SLIT and standard treatment groups, respectively. At 3 years, the add-on SLIT group showed a significant decline in ICS dose (p = 0.024). Although leukotriene antagonist use and INCS use did not differ between the two groups, the percentage of patients using antihistamines at 3 years was significantly lower in the add-on SLIT group than in the standard treatment group (p = 0.009); one in three patients on adjuvant SLIT therapy was able to discontinue ICS treatment. Patients who discontinued ICS treatment were younger (44.6±13.3 years vs. 55.0±14.1 years, p = 0.042), had a higher FEV1% predicted (109.9±14.4 vs. 94.8±18.6, p = 0.02), and were on a lower treatment step (2.1±0.7 vs. 3.0±0.8, p = 0.002) than those who did not. The addition of SLIT to standard pharmacotherapy resulted in a significant reduction in ICS dose at 3 years.

Long-term adherence to inhaled corticosteroids and asthma control in adult-onset asthma.

BackgroundIn short-term studies, poor adherence to inhaled corticosteroids (ICS) has been associated with worse asthma control, but the association of long-term adherence and disease control remains unclear.ObjectiveTo assess the relationship between 12-year adherence to ICS and asthma control in patients with adult-onset asthma.MethodsAs part of the Seinäjoki Adult Asthma Study, 181 patients with clinically confirmed new-onset adult asthma and regular ICS medication were followed-up for 12 years. Adherence (%) to ICS was assessed individually ((µg dispensed/µg prescribed)×100) during the follow-up. Asthma control was evaluated after 12 years of treatment according to the Global Initiative for Asthma 2010 guideline.ResultsAsthma was controlled in 31% and not controlled (partly controlled or uncontrolled) in 69% of the patients. Patients with not-controlled asthma were more often male, older, nonatopic and used higher doses of ICS than those with controlled disease. The mean±sd 12-year adherence to ICS was 63±38% in patients with controlled asthma and 76±40% in patients with not-controlled disease (p=0.042). Among patients with not-controlled asthma, those with lower 12-year adherence (<80%) had more rapid decline in forced expiratory volume in 1 s (−47 mL·year−1) compared to patients with better adherence (≥80%) (−40 mL·year−1) (p=0.024). In contrast, this relationship was not seen in patients with controlled asthma.ConclusionsIn adult-onset asthma, patients with not-controlled disease showed better 12-year adherence to ICS treatment than those with controlled asthma. In not-controlled disease, adherence <80% was associated with more rapid lung function decline, underscoring the importance of early recognition of such patients in routine clinical practice.

Effectiveness of omalizumab in children and adolescents with uncontrolled allergic asthma: a case series from Poland.

IntroductionOmalizumab has been successfully used as a supplementary therapy to improve asthma control in children aged ≥ 6 years with moderate or severe persistent allergic asthma.AimTo evaluate effectiveness ofomalizumab in children and adolescents with uncontrolled allergic asthma.Material and methodsSeventeen children and adolescents aged 8–16, treated with omalizumab from 2011 until now, were enrolled into the retrospective, open, uncontrolled, observational study. The effectiveness of therapy, asthma control, quality of life, exacerbation rate, corticosteroid use, were assessed after 16, 52 and 104 weeks of treatment and after omalizumab cessation.ResultsThe response to treatment was assessed as excellent (9 patients) and good (6 patients), according to global evaluation of treatment effectiveness (GETE). A statistically significant decrease in use of oral corticosteroids (OCS) and leukotriene receptor antagonists (LTRAs) was observed. The doses of inhaled corticosteroids (ICS) decreased significantly (the mean dose of ICS converted to a dose of budesonide before treatment was 1503.53 μg/day versus 903.53 μg after discontinuation). The mean asthma control questionnaire (ACQ) value decreased from 2.10 to 0.84 points and the mean mini asthma quality of life questionnaire (miniAQLQ) outcome increased from 4.37 to 6.1 points. The mean number of exacerbations decreased from 5.59 to 0.53 per year.ConclusionsOur results are supportive of the existing evidence that omalizumab therapy improves asthma control, reduces OCS and ICS use, decreases exacerbations in children and adolescents with severe/moderate uncontrolled allergic asthma.

Real-world evidence: Patient views on asthma in respiratory specialist clinics in America

BackgroundApproximately 30% to 50% of patients with moderate/severe asthma have inadequately controlled disease despite adherence to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) therapy. Data on prevalence and burden of uncontrolled asthma in specialty settings are lacking. ObjectiveTo evaluate the prevalence and burden of uncontrolled asthma in respiratory specialist clinics in the United States. MethodsAdults with physician-diagnosed asthma attending pulmonary and allergy clinics with self-reported ICS use in the previous 4 weeks completed an electronic questionnaire including the Asthma Control Test and St George’s Respiratory Questionnaire. Additional information was collected using an electronic case report form. ResultsOf 774 patients attending 12 pulmonary and 12 allergy clinics, 53% were not well controlled (mean [SD] Asthma Control Test, 14.3 [3.6] vs 22.4 [1.6] in well-controlled patients). Among ICS/LABA users, 56% were not well controlled, which increased with increasing ICS dose (low-dose 45.7%; high-dose 59.7%). The not well-controlled group reported more respiratory illnesses, more comorbidities, and poorer health-related quality of life (mean [SD] St George’s Respiratory Questionnaire, 46.1 [18.9] vs 19.8 [12.9] in the well-controlled group). These patients also had more asthma exacerbations (≥1 exacerbation, 68.9% vs 43.1%) and increased health care resource utilization (≥1 asthma-related hospitalization, 10.7% vs 2.7%); 27.3% were also receiving systemic corticosteroids. Approximately 40% of the population were eligible for step-up to ICS/LABA/long-acting muscarinic antagonist triple therapy, and 20% were eligible for biologic therapy. ConclusionSubstantial unmet needs exist among patients with inadequately controlled asthma managed in United States specialist settings, which may be addressed by improved patient and physician education, better guideline implementation, and improved adherence.

Risk of Rehospitalization and Death in Patients Hospitalized Due to Asthma

Asthma is a heterogeneous inflammatory airway disease that continues to cause considerable morbidity across the world, with poor asthma control leading to hospitalizations. The present study investigated the risk of rehospitalization, mortality, and the management of patients with asthma who had been hospitalized because of an asthma exacerbation. National Swedish health registries were linked for patients 6 years or older who were admitted to hospital because of asthma (index date) between January 1, 2006, and December 31, 2015. Exacerbations were defined as asthma-related hospitalization, emergency visits, or collection of oral steroids. Patients were followed for rehospitalizations 12 months after the index date, health care resource utilization and treatment for 36 months, and mortality to study end. Regression models for time-to-event analyses were applied to assess risk factors for rehospitalization and mortality. A total of 15,691 patients (mean age, 51.5 years; 63% females) were included, of whom 1,892 (12%) were rehospitalized for asthma within 12 months. Rehospitalized patients had a markedly increased risk of subsequent asthma-related mortality (adjusted hazard ratio, 2.80; 95% CI, 1.95-4.01) compared with those not rehospitalized. Two-third of the patients were not followed up by a hospital-based specialist, and 60% did not collect enough inhaled corticosteroid doses to cover daily treatment the year postindex. In this study, more than 1 in 10 patients were rehospitalized because of asthma within 12 months, and rehospitalizations were associated with asthma-related mortality. Few patients were seen by a hospital-based specialist, and few used inhaled corticosteroid continuously. Closer monitoring after hospitalization is needed.

Dupilumab Efficacy in Patients Stratified by Baseline Treatment Intensity and Lung Function.

PurposeThe Phase 3 LIBERTY ASTHMA QUEST study in patients aged ≥12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks (q2w) vs matched placebo in the overall population. This post hoc analysis assessed dupilumab efficacy by disease severity as evidenced by baseline % predicted forced expiratory volume in 1 second (FEV1) and dose of inhaled corticosteroids (ICS).Patients and MethodsSevere asthma exacerbation rates, change from baseline in FEV1, asthma control, quality of life, and fractional exhaled nitric oxide (FeNO) levels over the 52-week treatment period were assessed in patients with elevated type 2 inflammation biomarkers stratified by ICS dose and FEV1% predicted at baseline.ResultsIn patients with elevated baseline eosinophils, dupilumab 200 mg and 300 mg q2w vs placebo reduced severe exacerbation rates by 50% (P=0.06) and 67% (P=0.001), respectively, in those with medium-dose ICS/FEV1% predicted 60–90%, and by 59% (P<0.001) and 47% (P=0.006) in those with high-dose ICS/FEV1% predicted <60%, improved pre-bronchodilator FEV1 at Week 12 by 0.16L (P=0.005) and 0.08L (P=0.13), and by 0.20L (P=0.003) and 0.21L (P<0.001), respectively, in the same subgroups. Dupilumab vs placebo also improved asthma control and quality of life and suppressed FeNO levels in all patient subgroups with similar results observed irrespective of baseline biomarker status or disease severity.ConclusionDupilumab reduced severe exacerbations and improved lung function, asthma control and quality of life in patients with elevated baseline eosinophils irrespective of baseline ICS dose or FEV1% predicted.

Clinical and Economic Consequences of Inhaled Corticosteroid Doses and Particle Size in Triple Inhalation Therapy for COPD: Real-Life Study.

ObjectiveTo determine the clinical and economic consequences of inhaled corticosteroid doses and particle size in patients on triple-inhalation therapy for COPD.MethodsPatients aged ≥40 years who initiated treatment with multi-inhaler triple-inhaled therapy between 1 January 2015 and 31 March were included and followed for 1 year. Patients were grouped according to inhaled corticosteroid (ICS) dose (low/medium/high) and particle size device (extrafine/non-extrafine particles). Outcome variables were moderate and severe exacerbations, pneumonia and healthcare resource use (HCRU) costs. A multivariate analysis was performed for model correction (p<0.05).ResultsA total of 2185 patients (mean age 72.3 years, 82.9% male) were analysed. Of these, 849 (38.9%) patients received low-dose ICS, 612 medium-dose ICS (28.0%) and 724 (33.1%) high-dose ICS. Exacerbations occurred more frequently with increasing IC dose (low: 26.4%, medium: 28.7% and high: 30.4%; p=0.047), as did the proportion of pneumonia (3.4%, 4.2% and 6.9%, respectively (p=0.041)). The annual mean cost/unit was € 2383 for low dose, € 2401 for medium dose and € 2625 for high dose (p=0.024). Four hundred and sixty-two (31.6%) patients used an extrafine particle device and 999 (68.4%) a non-extrafine particle device: the proportion of exacerbations was 24.0% vs 30.4% (p=0.012), and the annual mean cost/unit was € 2090 vs € 2513, respectively (p<0.001). The number of exacerbations was directly correlated with FEV1 (β= −0.157), age (β=0.071), Charlson index (β=0.050) and device type (extrafine: β=0.049) (p<0.02).ConclusionIn patients with COPD receiving multi-inhaler triple therapy, higher ICS doses were not associated with a further reduction in exacerbations, whereas we found an increased risk of pneumonia. The use of inhaler devices delivering extrafine ICS particle was associated with a lower rate of exacerbations, resulting in lower overall HCRU costs.

Assessment of adherence to corticosteroids in asthma by drug monitoring or fractional exhaled nitric oxide: A literature review.

BackgroundAlthough the efficacy of corticosteroid treatment in controlling asthma is widely accepted, its effectiveness is undermined by poor adherence. However, the optimal method for measuring adherence to asthma therapy remains unclear.ObjectiveTo perform a review of the literature reporting biological, objective methods for assessing adherence to inhaled or oral corticosteroids in asthma; we included studies reporting direct measurement of exogenous corticosteroids in blood, or the effect of adherence on exhaled nitric oxide.DesignWe searched three databases MEDLINE (using both PubMed and Ovid), the Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Web of Science for articles published between January 1975 and July 2020. Quality of the studies was assessed using the National Institute of Health checklist.ResultsFrom 2850 screened articles, 26 fulfilled the inclusion criteria. Measurement of blood prednisolone with or without cortisol was used in eight studies as a measure of oral corticosteroid adherence, and fractional exhaled nitric oxide (FeNO) in 17 studies for inhaled corticosteroid adherence. Inhaled corticosteroids were measured directly in the blood in one study. By direct measurement of drug levels in the blood, adherence rates to oral corticosteroids ranged from 47% to 92%, although the performance and timing of the test were often not known, making interpretation of findings and serum prednisolone concentrations difficult. FeNO is generally lower in adherent than non‐adherent patients, but no absolute cut‐off can be proposed based on the available data. However, a fall in FeNO following supervised inhaled corticosteroid dosing could indicate previous poor adherence.Conclusions and Clinical RelevanceDespite prednisolone and cortisol levels commonly being used as adherence markers in clinical practice, further work is required to assess the influence of the dose and timing on blood levels. The promising findings of FeNO suppression testing should be explored in further prospective studies.

Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis

Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis

Exacerbations of asthma following step-up and step-down inhaled corticosteroid and long acting beta agonist therapy in the managing asthma in pregnancy study

Objective Guidelines for asthma management contain a consensus recommendation that inhaled corticosteroid (ICS) dose should not be stepped down in pregnancy. However, this is not consistent with consumer preferences and pharmacological principles to minimize medication exposure during pregnancy. We investigated exacerbations after changes to ICS and long acting beta agonist (LABA) therapy in pregnant women with asthma. Methods Pregnant women (n = 220) were recruited to a randomized controlled trial (RCT) where maintenance treatment was adjusted monthly based on either symptoms (control group), or fractional exhaled nitric oxide (FeNO, to alter ICS) and symptoms (to alter LABA, FeNO group). Exacerbations were monitored prospectively. Results ICS were used by 137 (62.3%) women at some time during pregnancy. ICS dose remained unchanged in 16 women (11.7%, 95% confidence interval [CI] 7–18%), increased in 37 women (27%, 95%CI 20–35%), decreased in 34 women (24.8%, 95%CI 18%–33%), or both increased and decreased in 50 women (36.5%, 95%CI 29–45%). Exacerbations occurred within 14 days of ICS step-down in 11 women (13%, 95%CI 7.5%–22%). This was not significantly different from exacerbations occurring within 14 days of step-up, in 7 women (8.1%, 95%CI 4%–16%, P = 0.294). There were no differences between management groups. Exacerbations occurred within 14 days of step-down in 14.7% (95%CI 7%–30%) of women in the control group, and in 12% (95%CI 6%–24%) of women in the FENO group. Conclusions ICS step-down could be considered when eosinophilic inflammation or symptoms are low, and may be a useful management approach for women, doctors, and midwives wishing to minimize ICS exposure during pregnancy.

A Randomized, Noninferiority Trial Comparing ICS + LABA with ICS + LABA + LAMA in Asthma-COPD Overlap (ACO) Treatment: The ACO Treatment with Optimal Medications (ATOMIC) Study

Current guidelines for the treatment of asthma and chronic obstructive pulmonary disease overlap (ACO) recommend initial treatment using inhaled corticosteroids (ICSs) plus 1 or more bronchodilators. To clarify which therapeutic effect is better between the ICS+ long-acting β2 agonist (LABA) and ICS+ LABA+ long-acting muscarinic antagonist (LAMA) treatment in patients with ACO. We conducted a multicenter, 48-week, randomized, noninferiority trial. Patients with ACO were enrolled if they were treated with a moderate to high dose of ICS+ LABA. In total, 303 patients were involved in the present trial, with 149 receiving ICS+ LABA+ LAMA. The primary end point was the time to first exacerbation. Secondary outcomes included changes in FEV1, forced vital capacity, FEV1/forced vital capacity ratio, asthma control, blood eosinophil count, and fractional exhaled nitric oxide. In the ICS+ LABA treatment group, 29 of 154 patients (18.83%) experienced exacerbation, whereas 28 of 149 patients (18.79%) experienced exacerbation in the ICS+ LABA+ LAMA treatment group. The results of this noninferiority study were ultimately inconclusive (hazard ratio, 1.1; 95% CI, 0.66-1.84). However, the patients treated with the addition of LAMA showed significant improvements in FEV1 and forced vital capacity (P < .001). Asthma control did not improve in either group. Although this study was unable to conclude that ICS+ LABA treatment is not inferior to ICS+ LABA+ LAMA in terms of exacerbation, it is obvious that the ICS+ LABA+ LAMA treatment group had improved lung function in ACO.

Inhaled corticosteroids in COPD and the risk for coronary heart disease: a nationwide cohort study

Inhaled corticosteroids (ICS) might lower the risk of coronary heart disease (CHD) in patients with chronic obstructive pulmonary disease (COPD). This study aimed to assess the association of ICS with the development of CHD in COPD patients by using data from the Korean Nationwide study. Patients who were newly diagnosed with COPD between 2004 and 2013 and who were not diagnosed with coronary heart disease before their diagnosis of COPD were included. Exposure of ICS was incorporated into multivariable Cox regression models using time-dependent methods. To accurately estimate ICS-exposure accumulation, a washout period of 2 years from 2002 to 2003 was applied. Among a total of 4,400 newly diagnosed COPD patients, 771 patients were diagnosed as CHD incident cases during a median follow-up of one year (interquartile range 0.1–2.9). The cumulative dose of ICS was associated with a reduced risk of CHD (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], 0.52–0.89). When the cumulative exposure dose of ICS was divided into quartiles, the aHR for CHD incidence was 0.70 (95% CI, 0.55–0.88) in the highest quartile ICS dose use. The effect of ICS on reducing CHD incidence was pronounced in adults over 55 years, men under 55 years, and former smokers. Our findings demonstrate the role of ICS for the prevention of CHD in COPD patients without a history of CHD. Further research is needed to determine whether a certain amount of ICS exposure in COPD patients is protective against CHD.

Onset of action of inhaled glucocorticoids on bronchial and alveolar nitric oxide output

Fractional exhaled nitric oxide (FENO) is a marker of airway inflammation. Measuring FENO at multiple flow rates enables calculation of NO parameters: bronchial NO output (J awNO), bronchial wall (C awNO) and alveolar (C ANO) NO concentrations, and bronchial diffusion factor of NO (D awNO). FENO is known to rapidly reduce after the commencement of inhaled corticosteroid (ICS) treatment. However, little is known on the effect of ICS on the other NO parameters. We assessed (1) the onset of action of ICS treatment on the NO parameters and (2) whether the changes in bronchial NO output are due to changes in bronchial wall NO concentration or diffusion factor. FENO and other NO parameters were measured at baseline and after 1, 3 and 7 d of treatment with inhaled fluticasone propionate 250 μg b.i.d. in 23 allergic children with a history of asthma-like symptoms. There was a decrease in J awNO (from 680 (244/1791) (median (1st/3rd quartile)) to 357 (165/753) pl s−1, p < 0.001) and FENO50( from 13.8 (7.5/35) to 8.3 (5.36/17.0) ppb, p < 0.001) in 3 d from the first dose of ICS. Also, C awNO seemed to reduce after 3 d (from 171 (89/328) to 79 (54/157) ppb, p = 0.041), while D awNO remained unchanged. Furthermore, C ANO reduced during the 7 d treatment (from 3.0 (2.0/5.0) to 2.3 (1.9/2.6) ppb, p = 0.004). ICS treatment reduced FENO50 and J awNO rapidly and the decline was caused by decreased bronchial wall NO concentration while bronchial NO diffusion factor remained unchanged. These findings suggest that C awNO could be a more specific marker of airway inflammation and treatment response than J awNO or FENO50, which are both determined also by D awNO that seems to be resistant to the treatment with ICS.

ICS-formoterol reliever versus ICS and short-acting β2-agonist reliever in asthma: a systematic review and meta-analysis.

BackgroundThe Global Initiative for Asthma recommends as-needed inhaled corticosteroid (ICS)-formoterol as an alternative to maintenance ICS plus short-acting β2-agonist (SABA) reliever at step 2 of its stepwise treatment algorithm. Our aim was to assess the efficacy and safety of these two treatment regimens, with a focus on prevention of severe exacerbation.MethodsWe performed a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing as-needed ICS-formoterol with maintenance ICS plus SABA. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov were searched from database inception to 12 December 2019. The primary outcome was time to first severe exacerbation. RCTs were excluded if they used as-needed budesonide-formoterol as part of a maintenance and reliever regimen, or did not report on severe exacerbations. The review is registered with PROSPERO (identifier number CRD42020154680).ResultsFour RCTs (n=8065 participants) were included in the analysis. As-needed ICS-formoterol was associated with a prolonged time to first severe exacerbation (hazard ratio 0.85, 95% CI 0.73–1.00; p=0.048) and reduced daily ICS dose (mean difference −177.3 μg, 95% CI −182.2–−172.4 μg). Asthma symptom control was worse in the as-needed group (Asthma Control Questionnaire-5 mean difference 0.12, 95% CI 0.09–0.14), although this did not meet the minimal clinically important difference of 0.50 units. There was no significant difference in serious adverse events (OR 1.07, 95% CI 0.84–1.36).ConclusionAs-needed ICS-formoterol offers a therapeutic alternative to maintenance low-dose ICS plus SABA in asthma and may be the preferred option when prevention of severe exacerbation is the primary aim of treatment.