Advances in the Management of Patients with Asthma: Clinical Year in Review

As part of the Clinical Year in Review symposia at the American Thoracic Society 2020 Virtual Conference, Sunita Sharma, MD, MPH, Associate Professor, Medicine-Pulmonary Sciences and Critical Care, University of Colorado Denver, Aurora, offered a literature review highlighting some of the exciting developments in the management of patients with asthma. The topics covered in her review included updates on the prevention and treatment of asthma, the economic burden associated with the disease, and a brief overview of the new European Respiratory Society’s and American Thoracic Society (ERS-ATS) Severe Asthma Guidelines.

Vitamin D Supplementation for Asthma Prevention

Dr Sharma began her review by discussing the results of a study by Litonjua and colleagues,1 which sought to determine whether prenatal vitamin D supplementation can reduce the risk for asthma and recurrent wheeze in children. She noted that previous observational studies have suggested that higher maternal vitamin D levels are associated with a lower risk for asthma-related outcomes in their children.

The vitamin D Antenatal Asthma Reduction Trial was a randomized, double-blind, placebo-controlled study of prenatal vitamin D supplementation. Pregnant women aged 18 to 39 years with an estimated duration of pregnancy of 10 to 18 weeks were recruited from 3 sites across the United States.

Participants were randomized to receive either a daily vitamin dose of 4000 international units plus a multivitamin with 400 international units of vitamin D (the vitamin D group) or a daily placebo plus a multivitamin with 400 international units of vitamin D (the control group). Children were initially followed up to 3 years of age, and these results were previously reported.2

The investigators reported the results of a follow-up study that examined whether prenatal supplementation with vitamin D would lead to decreased incidence of asthma and recurrent wheeze at 6 years of age. The primary outcome for this follow-up study was an extension of the original analyses. This included asthma, recurrent wheeze (or both), as well as time to onset of these diagnoses. The prespecified secondary analyses included measures of atopy, including physician-diagnosed eczema and/or allergic rhinitis.

The investigators used an intent-to-treat analysis using nonparametric, interval-censored, lifetime regression models for the assessment of first onset of asthma or recurrent wheeze. They also performed a stratified analysis according to the mean maternal vitamin D concentration in pregnancy, which included appropriate covariate adjustments.

The primary outcomes of the study showed that there was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intent-to-treat analysis or in an analysis with stratification according to the maternal vitamin D level. Notably, the effect of vitamin D supplementation had no impact on secondary outcomes as well, which included eczema, allergic rhinitis, or lower respiratory tract infections at 6 years of age.

The results suggested that supplementation with vitamin D during the prenatal period alone did not prevent the development of asthma or recurrent wheeze in offspring through 6 years of age. Although a between-group difference was suggested at early time points, including 3 years of age, this effect was not sustained through 6 years of age. Furthermore, prenatal vitamin D supplementation did not reduce the risk for atopic conditions, including eczema and allergic rhinitis, at 6 years of age.

“Importantly, because this trial did not supplement the children, the question remains whether combined prenatal and postnatal supplementation would influence allergy and asthma incidence later in life,” Dr Sharma noted. “Therefore, additional investigation may be warranted in this context,” she added.

Budesonide–Formoterol Reliever Therapy for Mild Asthma

Dr Sharma went on to discuss the results from the randomized START trial by Beasley and colleagues,3 which was designed to determine whether budesonide-formoterol therapy could be used on an as-needed basis in adults with mild asthma who had been treated with as-needed short-acting beta agonist therapy.

“A better understanding of how to treat patients with mild disease has been the focus of several large clinical trials over the past several years,” she said.

The START trial was a 52-week randomized, open-label, parallel-group control study conducted at 16 trial centers based in New Zealand, the United Kingdom, Italy, and Australia. Patients aged 18 to 75 years with physician-diagnosed asthma and mild disease were randomly assigned to 1 of 3 treatment groups: albuterol as needed for asthma symptoms (the albuterol group); budesonide plus as-needed albuterol (the budesonide maintenance group); or budesonide–formoterol, as needed (the budesonide–formoterol group). Electronic monitoring of inhalers was implemented to measure medication use. The primary outcome of the study was the annualized rate of asthma exacerbations. Secondary outcome measures included the number of exacerbations, the time to first exacerbation, and the number of severe exacerbations.

The primary statistical analysis was a comparison of the annualized rate of asthma exacerbations, which was the rate of exacerbations per patient per year between treatment groups using a Poisson regression model.

The annualized asthma exacerbation rate in the budesonide–formoterol group was lower than that in the albuterol group, but this did not differ significantly from the budesonide maintenance group. However, the number of severe exacerbations in the budesonide–formoterol group was lower than the number in both the albuterol and the budesonide maintenance group. Notably, maintenance treatment with budesonide was superior for asthma control symptoms than the other 2 treatment groups.

The results suggested that, among patients with mild asthma who had previously been taking only a short-acting beta agonist on an as-needed basis, the risk for asthma exacerbations was lower with budesonide–formoterol used as needed than with albuterol used as needed but had a similar impact to budesonide maintenance therapy.

Treatment with as-needed budesonide–formoterol was superior to both as-needed albuterol and budesonide maintenance therapy plus as-needed albuterol in reducing the risk for severe exacerbations. However, maintenance treatment with budesonide was superior for control of asthma symptoms, which suggests that, for the patient for whom asthma symptoms rather than exacerbations are the most bothersome, maintenance therapy with budesonide has value.

“It is important to recognize that, based on the results of this and other studies, there have been several changes to recent guidelines. The Global Initiative for Asthma (GINA) guidelines now state that as-needed budesonide–formoterol therapy is recommended as step 1 and step 2 therapy and is to be used on an as-needed basis with concurrent asthma maintenance therapy on steps 3 to 5,” Dr Sharma said. “However, the National Asthma Education and Prevention Program [NAEPP] Coordinating Committee Expert Panel 4 guideline only recommends as-needed for steps 3 to 5, in addition to appropriate asthma maintenance regimens,” she added.

Step-Up Therapy for Black Patients with Poorly Controlled Asthma

Dr Sharma also discussed results from 2 important parallel Best African American Response to Asthma Drugs (BARD) trials by Wechsler and colleagues,4 which sought to determine the preferred step-up therapy in black children and adults with poorly controlled asthma.

She noted that epidemiologic studies involving patients with asthma in the United States show a disproportionately greater burden of asthma in persons identified as black. Inhaled glucocorticoids are very effective first-line therapies for asthma control, but when asthma remains poorly controlled on this maintenance therapy, the recommended treatment of add-on long-acting beta agonist therapy is based on studies that included very few black patients. Therefore, the appropriate step-up therapy for this population of patients on inhaled corticosteroid therapy is still not known.

BARD included 2 prospective, randomized, double-blind, 4-treatment crossover trials that lasted a total of 56 weeks in duration. In the first study, 280 children aged 5 to 11 years who had at least 1 grandparent who identified as black were included in the study. In the second trial, 294 adolescents and adults who were aged ≥12 years, and who had at least 1 grandparent who identified as black, were included in the study. A total of 280 children and 294 adolescents and adults underwent randomization at 9 clinical sites.

Patients who met the randomization criteria were randomized to a step-up treatment sequence in a 4-way crossover design with add-on long-acting beta agonist therapy, different strengths of increased doses of inhaled corticosteroids, or an increased dose of inhaled corticosteroids with an additional long-acting beta agonist therapy. Each treatment period lasted a total of 14 weeks. The initial 2 weeks of each period were considered to be a washout period for the previous treatment and a wash-in period for the new treatment regimen.

In children, doubling the dose of an inhaled corticosteroid resulted in the double fluticasone treatment arm. Doubling the dose of fluticasone and adding a long-acting beta agonist was the salmeterol double fluticasone treatment arm. Quintupling the dose of fluticasone to 250 mcg was the quintuple fluticasone treatment arm. Finally, quintupling the dose of fluticasone and adding salmeterol was considered the salmeterol quintuple fluticasone treatment arm.

In adults, twice-daily salmeterol was added to inhaled corticosteroid administration twice daily. This was the salmeterol fluticasone treatment arm. Increasing the dose of fluticasone by a factor of 2.5 mcg to 250 mcg was the 2.5 fluticasone treatment arm. Quintupling the dose of fluticasone to 500 mcg was the quintuple fluticasone treatment arm. Increasing the dose of fluticasone by a factor of 2.5 and adding salmeterol was considered the salmeterol 2.5 fluticasone treatment arm.

The primary goals of these trials were to evaluate the superiority of different treatments and the effect of the proportion of African Ancestry using genetics on the composite clinical outcome. The primary outcome of each trial was a hierarchical composite measure that sequentially evaluated asthma exacerbations, asthma control days, and the percentage of predicted forced expiratory volume in 1 second at the end of the 14-week treatment regimen to determine differential responses to therapy.

Results showed that children who were reported to have at least one black grandparent had similar improvement in asthma outcomes when the dose of inhaled corticosteroid was increased, or a long-acting beta agonist was added to the regimen. Black adolescents and adults had a superior response to the addition of a long-acting beta agonist than to an increase in the dose of inhaled corticosteroids.

Dr Sharma said that these were the first trials to evaluate the appropriate step-up therapy for black patients with uncontrolled asthma. “The results of these studies are essential to understanding the appropriate step-up regimens for black patients who are disproportionately affected by this disease,” she said.

She also noted that in a pharmacogenetic analysis investigating the impact of genetic ancestry on treatment response in the same patient population, genetic ancestry informative markers were not associated with differences in treatment response in black children, adolescents, and adults. Therefore, further investigation in this patient population is warranted in the future.

Projected Economic and Health Burden of Uncontrolled Asthma

Dr Sharma also discussed results from a study by Yaghoubi and colleagues,5 which explored the current and future economic and health burdens associated with suboptimal asthma control in adolescents and adults in the United States.

The investigators created a model that linked state-specific estimates of population growth, aging, asthma prevalence, and asthma control levels, and then conducted several meta-analyses to estimate the adjusted differences in healthcare resource use, quality-adjusted life-years (QALYs), and productivity loss across control levels. They also projected—nationally and at the state level—total direct and indirect costs and reduction in QALYs that could be attributed to uncontrolled asthma for a 20-year period (2019-2038).

The results showed that the total estimated excess direct and indirect costs associated with uncontrolled versus controlled asthma were $1349 and $3350 per patient year, respectively. The pooled estimate of the mean reduction in QALYs resulting from uncontrolled versus controlled asthma was 0.07. The investigators also found that on average, an individual with uncontrolled asthma lost an extra 12.7% of his or her work time compared with an individual who had controlled disease, which translated to a loss of an extra 6.6 weeks of productivity per year.

They concluded that a substantial fraction of the burden of uncontrolled asthma is preventable, and better adherence to evidence-based management strategies has the potential to reduce costs and improve patient quality of life.

“The results of this study highlight the fact that around 20% of the direct costs of asthma can potentially be prevented by achieving asthma control in this population,” Dr Sharma said. 

“While the authors recognize that strategies and interventions targeted toward better asthma control are likely to be associated with additional costs and are unlikely to result in complete asthma control in all patients, they suggest that their results can be used as estimates of the maximum potential return on investment from strategies that are aimed at improving asthma control overall,” she added.

Updates to the ERS-ATS Severe Asthma Guideline

Dr Sharma concluded her presentation with a brief overview of the new Severe Asthma Treatment Guideline. She explained the focus of the original ERS-ATS Guideline on Severe Asthma, published in 2014,6 was on the need to confirm the diagnosis of asthma, to exclude other conditions that may mimic the disease, and to address associated comorbidities that contribute to disease severity.

She explained that when a diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined by the original guideline as asthma that requires treatment with high-dose inhaled corticosteroids, plus a second controller, plus or minus systemic corticosteroids to prevent it from becoming uncontrolled. With the advent of new biologics for the treatment of severe disease, the guideline was updated by Holguin and colleagues and published in January 2020.7 The joint ERS-ATS Severe Asthma Guideline provides updated recommendations for the clinical management of severe asthma, and a comprehensive synthesis of the current evidence, including meta-analyses to summarize all available evidence that is relevant to the task force questions.

“The current guideline represents an ERS-ATS collaboration and was initiated because of the rapid introduction of new treatments for severe asthma, particularly the new biologic agents approved for the management of patients with severe eosinophilic disease,” she said. “The evidence was appraised using the GRADE system, Grading of Recommendations, Assessment, Development, and Evaluation,” she added.

The guideline now recommends anti–interleukin-5 (IL-5) therapy for patients with severe eosinophilic disease, establishes biomarker cutoffs to guide both anti–IL-5 and anti–immunoglobulin E therapies, and recommends the additions of tiotropium for patients with uncontrolled disease on GINA steps 4 and 5 therapy and NAEPP step 5 therapy.

Furthermore, a trial of macrolide therapy should be considered in adults who are poorly controlled on GINA and NAEPP step 5 therapy. More importantly, the guideline recommends against the use of chronic macrolide treatment in children and adolescents with severe uncontrolled asthma.

Finally, the guideline recommends the addition of dupilumab for adults with severe eosinophilic disease and those with steroid-dependent disease, independent of eosinophil level.

The ERS-ATS Severe Asthma Guideline represents the updated clinical recommendations for the treatment of patients with severe disease. It now focuses on the use of biologic agents for the treatment of severe disease and establishes biomarker cut points to help guide these treatments.

The guideline sets forth a strong recommendation for use of tiotropium in those with severe, uncontrolled disease. Furthermore, it supports the user of macrolides in adults with uncontrolled disease with frequent exacerbations.

“Although this document is the first to set forth guidance on the use of the new biologic agents in the treatment of severe eosinophilic disease, additional head-to-head trials of these agents are still needed to further define treatment recommendations,” she concluded.


  1. Litonjua AA, Carey VJ, Laranjo N, et al. Six-year follow-up of a trial of antenatal vitamin D for asthma reduction. N Engl J Med. 2020;382:525-533.
  2. Litonjua AA, Carey VJ, Laranjo N, et al. Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years: the VDAART randomized clinical trial. JAMA. 2016;315:362-370.
  3. Beasley R, Holliday M, Reddel HK, et al; for the Novel START Study Team. Controlled trial of budesonide–formoterol as needed for mild asthma. N Engl J Med. 2019;380:2020-2030.
  4. Wechsler ME, Szefler SJ, Ortega VE, et al; for the NHLBI AsthmaNet. Step-up therapy in Black children and adults with poorly controlled asthma. N Engl J Med. 2019;381:1227-1239.
  5. Yaghoubi M, Adibi A, Safari A, et al. The projected economic and health burden of uncontrolled asthma in the United States. Am J Respir Crit Care Med. 2019; 200:1102-1112. Published online 2019 Nov 1. doi: 10.1164/rccm.201901-0016OC.
  6. Chung, KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343-373. Erratum in: Eur Respir J. 2014;43:1216.
  7. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.

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