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What do you recommend for this patient with COPD?
“Janice Turner” (name changed to protect confidentiality) is a 66-year-old woman with a 40-pack per year history of smoking. She is very worried about having another COPD exacerbation and wants to know if there are additional medications she could try.
Over the past 2 weeks, her respiratory symptoms have improved and returned to her baseline. She has a daily cough with white phlegm on most days and dyspnea on exertion at one-half block on level ground. She reports using her medications as prescribed and is enrolled in a pulmonary rehabilitation program, which she attends twice per week. She uses 2 to 4 inhalations of albuterol each day.
She is on the following regimen for her COPD, which is unchanged compared with what she has been prescribed for the past 12 months: 1) combination inhaled fluticasone furoate, umeclidinium, and vilanterol via the Ellipta® device, one actuation once daily and 2) inhaled albuterol, two puffs as needed every 4 hours via metered dose inhaler. She demonstrates mastery of inhaler technique for both inhaled devices. Her vaccinations are current (pneumococcus, influenza, respiratory syncytial virus, and COVID-19).
On examination, she can complete sentences without respiratory difficulty, and her vital signs are normal. She has decreased breath sounds in all lung fields, with occasional rhonchi. Heart sounds are distant, but regular, at 92 beats per minute, and she has no peripheral edema. Arterial blood gas at rest on room air indicates a pH of 7.38, PaO2 of 63 mm Hg, and PaCO2 of 42 mm Hg. An electrocardiogram shows sinus rhythm and a QTc interval of 420 milliseconds.
Three months ago, when she was clinically stable, you obtained spirometry, a complete blood count with differential, and a chest radiograph to exclude alternate diagnoses for her ongoing respiratory symptoms. She had severe airflow limitation (post-bronchodilator FEV1 = 40% predicted, FVC = 61% predicted, FEV1/FVC = 65%). At the time, she also had peripheral eosinophilia (eosinophil count of 350 cells/μL) and hyperinflation without parenchymal infiltrates.
In summary, Ms. Turner has severe smoking-associated COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3E and chronic bronchitis with two severe exacerbations in the past 12 months.1 She is currently prescribed triple inhaled maintenance therapy with corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. She has a normal QTc interval.
So what would you recommend to reduce Ms. Turner’s risk of future exacerbations?
In 2011, the US Food and Drug Administration (FDA) approved roflumilast 500 mcg by mouth per day, a selective phosphodiesterase 4 (PDE4) inhibitor, as maintenance therapy to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis.2 The FDA approval was based on a review of the efficacy and safety of roflumilast in eight randomized, double-blind, controlled clinical trials in 9,394 adults with COPD.
Two subsequently completed randomized clinical trials in 2015 (REACT, 1,945 adults) and 2016 (RE2SPOND, 2,354 adults) also found that maintenance oral treatment escalation with roflumilast significantly reduced the risk of COPD exacerbations compared with placebo.2 The most common adverse effects reported with long-term use of roflumilast are related to the gastrointestinal tract (diarrhea, nausea, decreased appetite), weight loss, and insomnia. Four weeks of roflumilast at 250 mcg per day prior to dose escalation to 500 mcg per day reduces the risk of treatment discontinuation and improves tolerability compared with initiating treatment with the maintenance dose.
In 2022, the FDA approved a generic version of roflumilast, providing an opportunity for patients to use roflumilast at a lower cost than was previously possible. Importantly, the FDA Prescribing Information includes a warning to avoid the use of roflumilast in patients being treated with strong cytochrome P450 enzyme inducers (eg, rifampin, phenytoin). The FDA Prescribing Information also recommends weighing the risks and benefits of roflumilast in patients with a history of depression or suicidal thoughts or behavior, or patients with unexplained or clinically significant weight loss.
In 2011 (the same year as the FDA approval of roflumilast), the National Institutes of Health/National Heart, Lung, and Blood Institute-funded COPD Clinical Research Network reported that maintenance treatment with azithromycin reduced the risk of COPD exacerbations compared with placebo in a randomized clinical trial of 1,142 adults with COPD (MACRO study).3 Subgroup analyses indicated that the reduction in the risk of COPD exacerbations with azithromycin was observed in participants with or without chronic bronchitis but not in participants who currently smoked.
Subsequently, two other smaller randomized clinical trials in 2014 (COLUMBUS, 92 participants) and in 2019 (BACE, 301 participants) also demonstrated a reduction in the risk of COPD exacerbations with maintenance azithromycin treatment compared with placebo. Azithromycin can prolong the QT interval and, in rare cases, cause cardiac arrythmias, especially when used with other medications that can prolong the QT interval. There are also concerns that maintenance azithromycin therapy could lead to decrements in hearing or promote the development of macrolide-resistant bacteria. Maintenance treatment with azithromycin to prevent COPD exacerbations is not an FDA-approved indication.4 The FDA approval for azithromycin is currently limited to treatment of patients with mild to moderate infections caused by susceptible bacteria, but it is often prescribed off-label as maintenance treatment for COPD.
On the basis of this body of evidence from clinical trials in COPD, the 2015 CHEST and Canadian Thoracic Society (CTS) guidelines,5 the 2017 European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines,6 and the 2024 GOLD Strategy Report all include recommendations for treatment escalation with maintenance roflumilast or azithromycin to reduce the risk of COPD exacerbations. For example, the 2024 GOLD Strategy Report recommends roflumilast in patients with severe COPD and chronic bronchitis who continue to have exacerbations despite inhaled maintenance treatment with combination long-acting β2-agonist and long-acting muscarinic antagonist or with triple therapy with inhaled corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. An alternative, 2024 GOLD-recommended strategy in this population is maintenance therapy with azithromycin, “preferentially in former smokers.” GOLD’s preference for using azithromycin in patients with smoking history is based on post-hoc (ie, not part of the original study design) subgroup analyses “suggesting lesser benefit in active smokers” in the MACRO study. Results of such analyses have not been reported in other studies.
There are no results from clinical trials that have directly compared the harms and benefits of initiating maintenance therapy with roflumilast or azithromycin in patients with COPD. The roflumilast or azithromycin to prevent COPD exacerbations (RELIANCE; NCT04069312) multicenter clinical trial is addressing this evidence gap.7 The RELIANCE study is funded by the Patient-Centered Outcomes Research Institute and co-led by the COPD Foundation, a not-for-profit organization founded by John W. Walsh, a patient advocate with α1-related COPD. Also, results of two recently completed phase 3 clinical trials with nebulized ensifentrine (ENHANCE-1 and ENHANCE-2), a novel inhibitor of PDE3 and PDE4, were recently published. ENHANCE-1 and ENHANCE-2 studies indicate that twice daily nebulized ensifentrine reduces the risk of COPD exacerbations in patients with moderate or severe COPD.8 Ensifentrine is under review by the FDA, and a decision about its use in the US is expected in the summer of 2024.
Until the results from the RELIANCE clinical trial and the decision by the FDA about ensifentrine are available, we recommended a discussion with Ms. Turner about whether to initiate treatment with maintenance roflumilast or azithromycin. Both can reduce the risk of exacerbations, and the relative benefits and risks of these two evidence-based options are not yet known. Unless Ms. Turner has specific preferences (eg, concerns about specific adverse effects or differences in out-of-pocket cost) in favor of one over the other, she could flip a coin to decide between initiating maintenance roflumilast or azithromycin.
Dr. Krishnan is Professor of Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy, and Professor of Public Health, Division of Epidemiology and Biostatistics, University of Illinois Chicago. Dr. Adrish is Associate Professor, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston.
References:
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report. https://goldcopd.org/2024-gold-report-2/
2. US Food and Drug Administration (Daliresp®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf
3. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromucin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. PMID: 21864166. doi: 10.1056/NEJMoa1104623.
4. US Food and Drug Administration (Zithromyax®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf
5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acure exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4)894-942. PMID: 25321320. doi: 10.1378/chest.14-1676.
6. Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265. PMID: 28889106. doi:10.1183/13993003.02265-2016.
7. Krishnan JA, Albert RK, Rennard SI; RELIANCE study. Waiting for actionable evidence: roflumilast or azithromycin? Chronic Obst Pulm Dis. 2022;9(1):1-3. PMID: 34783231. doi: 10.15326/jcopdf.2021.0272.
8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phospodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. PMID: 37364283.
“Janice Turner” (name changed to protect confidentiality) is a 66-year-old woman with a 40-pack per year history of smoking. She is very worried about having another COPD exacerbation and wants to know if there are additional medications she could try.
Over the past 2 weeks, her respiratory symptoms have improved and returned to her baseline. She has a daily cough with white phlegm on most days and dyspnea on exertion at one-half block on level ground. She reports using her medications as prescribed and is enrolled in a pulmonary rehabilitation program, which she attends twice per week. She uses 2 to 4 inhalations of albuterol each day.
She is on the following regimen for her COPD, which is unchanged compared with what she has been prescribed for the past 12 months: 1) combination inhaled fluticasone furoate, umeclidinium, and vilanterol via the Ellipta® device, one actuation once daily and 2) inhaled albuterol, two puffs as needed every 4 hours via metered dose inhaler. She demonstrates mastery of inhaler technique for both inhaled devices. Her vaccinations are current (pneumococcus, influenza, respiratory syncytial virus, and COVID-19).
On examination, she can complete sentences without respiratory difficulty, and her vital signs are normal. She has decreased breath sounds in all lung fields, with occasional rhonchi. Heart sounds are distant, but regular, at 92 beats per minute, and she has no peripheral edema. Arterial blood gas at rest on room air indicates a pH of 7.38, PaO2 of 63 mm Hg, and PaCO2 of 42 mm Hg. An electrocardiogram shows sinus rhythm and a QTc interval of 420 milliseconds.
Three months ago, when she was clinically stable, you obtained spirometry, a complete blood count with differential, and a chest radiograph to exclude alternate diagnoses for her ongoing respiratory symptoms. She had severe airflow limitation (post-bronchodilator FEV1 = 40% predicted, FVC = 61% predicted, FEV1/FVC = 65%). At the time, she also had peripheral eosinophilia (eosinophil count of 350 cells/μL) and hyperinflation without parenchymal infiltrates.
In summary, Ms. Turner has severe smoking-associated COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3E and chronic bronchitis with two severe exacerbations in the past 12 months.1 She is currently prescribed triple inhaled maintenance therapy with corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. She has a normal QTc interval.
So what would you recommend to reduce Ms. Turner’s risk of future exacerbations?
In 2011, the US Food and Drug Administration (FDA) approved roflumilast 500 mcg by mouth per day, a selective phosphodiesterase 4 (PDE4) inhibitor, as maintenance therapy to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis.2 The FDA approval was based on a review of the efficacy and safety of roflumilast in eight randomized, double-blind, controlled clinical trials in 9,394 adults with COPD.
Two subsequently completed randomized clinical trials in 2015 (REACT, 1,945 adults) and 2016 (RE2SPOND, 2,354 adults) also found that maintenance oral treatment escalation with roflumilast significantly reduced the risk of COPD exacerbations compared with placebo.2 The most common adverse effects reported with long-term use of roflumilast are related to the gastrointestinal tract (diarrhea, nausea, decreased appetite), weight loss, and insomnia. Four weeks of roflumilast at 250 mcg per day prior to dose escalation to 500 mcg per day reduces the risk of treatment discontinuation and improves tolerability compared with initiating treatment with the maintenance dose.
In 2022, the FDA approved a generic version of roflumilast, providing an opportunity for patients to use roflumilast at a lower cost than was previously possible. Importantly, the FDA Prescribing Information includes a warning to avoid the use of roflumilast in patients being treated with strong cytochrome P450 enzyme inducers (eg, rifampin, phenytoin). The FDA Prescribing Information also recommends weighing the risks and benefits of roflumilast in patients with a history of depression or suicidal thoughts or behavior, or patients with unexplained or clinically significant weight loss.
In 2011 (the same year as the FDA approval of roflumilast), the National Institutes of Health/National Heart, Lung, and Blood Institute-funded COPD Clinical Research Network reported that maintenance treatment with azithromycin reduced the risk of COPD exacerbations compared with placebo in a randomized clinical trial of 1,142 adults with COPD (MACRO study).3 Subgroup analyses indicated that the reduction in the risk of COPD exacerbations with azithromycin was observed in participants with or without chronic bronchitis but not in participants who currently smoked.
Subsequently, two other smaller randomized clinical trials in 2014 (COLUMBUS, 92 participants) and in 2019 (BACE, 301 participants) also demonstrated a reduction in the risk of COPD exacerbations with maintenance azithromycin treatment compared with placebo. Azithromycin can prolong the QT interval and, in rare cases, cause cardiac arrythmias, especially when used with other medications that can prolong the QT interval. There are also concerns that maintenance azithromycin therapy could lead to decrements in hearing or promote the development of macrolide-resistant bacteria. Maintenance treatment with azithromycin to prevent COPD exacerbations is not an FDA-approved indication.4 The FDA approval for azithromycin is currently limited to treatment of patients with mild to moderate infections caused by susceptible bacteria, but it is often prescribed off-label as maintenance treatment for COPD.
On the basis of this body of evidence from clinical trials in COPD, the 2015 CHEST and Canadian Thoracic Society (CTS) guidelines,5 the 2017 European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines,6 and the 2024 GOLD Strategy Report all include recommendations for treatment escalation with maintenance roflumilast or azithromycin to reduce the risk of COPD exacerbations. For example, the 2024 GOLD Strategy Report recommends roflumilast in patients with severe COPD and chronic bronchitis who continue to have exacerbations despite inhaled maintenance treatment with combination long-acting β2-agonist and long-acting muscarinic antagonist or with triple therapy with inhaled corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. An alternative, 2024 GOLD-recommended strategy in this population is maintenance therapy with azithromycin, “preferentially in former smokers.” GOLD’s preference for using azithromycin in patients with smoking history is based on post-hoc (ie, not part of the original study design) subgroup analyses “suggesting lesser benefit in active smokers” in the MACRO study. Results of such analyses have not been reported in other studies.
There are no results from clinical trials that have directly compared the harms and benefits of initiating maintenance therapy with roflumilast or azithromycin in patients with COPD. The roflumilast or azithromycin to prevent COPD exacerbations (RELIANCE; NCT04069312) multicenter clinical trial is addressing this evidence gap.7 The RELIANCE study is funded by the Patient-Centered Outcomes Research Institute and co-led by the COPD Foundation, a not-for-profit organization founded by John W. Walsh, a patient advocate with α1-related COPD. Also, results of two recently completed phase 3 clinical trials with nebulized ensifentrine (ENHANCE-1 and ENHANCE-2), a novel inhibitor of PDE3 and PDE4, were recently published. ENHANCE-1 and ENHANCE-2 studies indicate that twice daily nebulized ensifentrine reduces the risk of COPD exacerbations in patients with moderate or severe COPD.8 Ensifentrine is under review by the FDA, and a decision about its use in the US is expected in the summer of 2024.
Until the results from the RELIANCE clinical trial and the decision by the FDA about ensifentrine are available, we recommended a discussion with Ms. Turner about whether to initiate treatment with maintenance roflumilast or azithromycin. Both can reduce the risk of exacerbations, and the relative benefits and risks of these two evidence-based options are not yet known. Unless Ms. Turner has specific preferences (eg, concerns about specific adverse effects or differences in out-of-pocket cost) in favor of one over the other, she could flip a coin to decide between initiating maintenance roflumilast or azithromycin.
Dr. Krishnan is Professor of Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy, and Professor of Public Health, Division of Epidemiology and Biostatistics, University of Illinois Chicago. Dr. Adrish is Associate Professor, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston.
References:
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report. https://goldcopd.org/2024-gold-report-2/
2. US Food and Drug Administration (Daliresp®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf
3. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromucin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. PMID: 21864166. doi: 10.1056/NEJMoa1104623.
4. US Food and Drug Administration (Zithromyax®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf
5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acure exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4)894-942. PMID: 25321320. doi: 10.1378/chest.14-1676.
6. Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265. PMID: 28889106. doi:10.1183/13993003.02265-2016.
7. Krishnan JA, Albert RK, Rennard SI; RELIANCE study. Waiting for actionable evidence: roflumilast or azithromycin? Chronic Obst Pulm Dis. 2022;9(1):1-3. PMID: 34783231. doi: 10.15326/jcopdf.2021.0272.
8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phospodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. PMID: 37364283.
“Janice Turner” (name changed to protect confidentiality) is a 66-year-old woman with a 40-pack per year history of smoking. She is very worried about having another COPD exacerbation and wants to know if there are additional medications she could try.
Over the past 2 weeks, her respiratory symptoms have improved and returned to her baseline. She has a daily cough with white phlegm on most days and dyspnea on exertion at one-half block on level ground. She reports using her medications as prescribed and is enrolled in a pulmonary rehabilitation program, which she attends twice per week. She uses 2 to 4 inhalations of albuterol each day.
She is on the following regimen for her COPD, which is unchanged compared with what she has been prescribed for the past 12 months: 1) combination inhaled fluticasone furoate, umeclidinium, and vilanterol via the Ellipta® device, one actuation once daily and 2) inhaled albuterol, two puffs as needed every 4 hours via metered dose inhaler. She demonstrates mastery of inhaler technique for both inhaled devices. Her vaccinations are current (pneumococcus, influenza, respiratory syncytial virus, and COVID-19).
On examination, she can complete sentences without respiratory difficulty, and her vital signs are normal. She has decreased breath sounds in all lung fields, with occasional rhonchi. Heart sounds are distant, but regular, at 92 beats per minute, and she has no peripheral edema. Arterial blood gas at rest on room air indicates a pH of 7.38, PaO2 of 63 mm Hg, and PaCO2 of 42 mm Hg. An electrocardiogram shows sinus rhythm and a QTc interval of 420 milliseconds.
Three months ago, when she was clinically stable, you obtained spirometry, a complete blood count with differential, and a chest radiograph to exclude alternate diagnoses for her ongoing respiratory symptoms. She had severe airflow limitation (post-bronchodilator FEV1 = 40% predicted, FVC = 61% predicted, FEV1/FVC = 65%). At the time, she also had peripheral eosinophilia (eosinophil count of 350 cells/μL) and hyperinflation without parenchymal infiltrates.
In summary, Ms. Turner has severe smoking-associated COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3E and chronic bronchitis with two severe exacerbations in the past 12 months.1 She is currently prescribed triple inhaled maintenance therapy with corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. She has a normal QTc interval.
So what would you recommend to reduce Ms. Turner’s risk of future exacerbations?
In 2011, the US Food and Drug Administration (FDA) approved roflumilast 500 mcg by mouth per day, a selective phosphodiesterase 4 (PDE4) inhibitor, as maintenance therapy to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis.2 The FDA approval was based on a review of the efficacy and safety of roflumilast in eight randomized, double-blind, controlled clinical trials in 9,394 adults with COPD.
Two subsequently completed randomized clinical trials in 2015 (REACT, 1,945 adults) and 2016 (RE2SPOND, 2,354 adults) also found that maintenance oral treatment escalation with roflumilast significantly reduced the risk of COPD exacerbations compared with placebo.2 The most common adverse effects reported with long-term use of roflumilast are related to the gastrointestinal tract (diarrhea, nausea, decreased appetite), weight loss, and insomnia. Four weeks of roflumilast at 250 mcg per day prior to dose escalation to 500 mcg per day reduces the risk of treatment discontinuation and improves tolerability compared with initiating treatment with the maintenance dose.
In 2022, the FDA approved a generic version of roflumilast, providing an opportunity for patients to use roflumilast at a lower cost than was previously possible. Importantly, the FDA Prescribing Information includes a warning to avoid the use of roflumilast in patients being treated with strong cytochrome P450 enzyme inducers (eg, rifampin, phenytoin). The FDA Prescribing Information also recommends weighing the risks and benefits of roflumilast in patients with a history of depression or suicidal thoughts or behavior, or patients with unexplained or clinically significant weight loss.
In 2011 (the same year as the FDA approval of roflumilast), the National Institutes of Health/National Heart, Lung, and Blood Institute-funded COPD Clinical Research Network reported that maintenance treatment with azithromycin reduced the risk of COPD exacerbations compared with placebo in a randomized clinical trial of 1,142 adults with COPD (MACRO study).3 Subgroup analyses indicated that the reduction in the risk of COPD exacerbations with azithromycin was observed in participants with or without chronic bronchitis but not in participants who currently smoked.
Subsequently, two other smaller randomized clinical trials in 2014 (COLUMBUS, 92 participants) and in 2019 (BACE, 301 participants) also demonstrated a reduction in the risk of COPD exacerbations with maintenance azithromycin treatment compared with placebo. Azithromycin can prolong the QT interval and, in rare cases, cause cardiac arrythmias, especially when used with other medications that can prolong the QT interval. There are also concerns that maintenance azithromycin therapy could lead to decrements in hearing or promote the development of macrolide-resistant bacteria. Maintenance treatment with azithromycin to prevent COPD exacerbations is not an FDA-approved indication.4 The FDA approval for azithromycin is currently limited to treatment of patients with mild to moderate infections caused by susceptible bacteria, but it is often prescribed off-label as maintenance treatment for COPD.
On the basis of this body of evidence from clinical trials in COPD, the 2015 CHEST and Canadian Thoracic Society (CTS) guidelines,5 the 2017 European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines,6 and the 2024 GOLD Strategy Report all include recommendations for treatment escalation with maintenance roflumilast or azithromycin to reduce the risk of COPD exacerbations. For example, the 2024 GOLD Strategy Report recommends roflumilast in patients with severe COPD and chronic bronchitis who continue to have exacerbations despite inhaled maintenance treatment with combination long-acting β2-agonist and long-acting muscarinic antagonist or with triple therapy with inhaled corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. An alternative, 2024 GOLD-recommended strategy in this population is maintenance therapy with azithromycin, “preferentially in former smokers.” GOLD’s preference for using azithromycin in patients with smoking history is based on post-hoc (ie, not part of the original study design) subgroup analyses “suggesting lesser benefit in active smokers” in the MACRO study. Results of such analyses have not been reported in other studies.
There are no results from clinical trials that have directly compared the harms and benefits of initiating maintenance therapy with roflumilast or azithromycin in patients with COPD. The roflumilast or azithromycin to prevent COPD exacerbations (RELIANCE; NCT04069312) multicenter clinical trial is addressing this evidence gap.7 The RELIANCE study is funded by the Patient-Centered Outcomes Research Institute and co-led by the COPD Foundation, a not-for-profit organization founded by John W. Walsh, a patient advocate with α1-related COPD. Also, results of two recently completed phase 3 clinical trials with nebulized ensifentrine (ENHANCE-1 and ENHANCE-2), a novel inhibitor of PDE3 and PDE4, were recently published. ENHANCE-1 and ENHANCE-2 studies indicate that twice daily nebulized ensifentrine reduces the risk of COPD exacerbations in patients with moderate or severe COPD.8 Ensifentrine is under review by the FDA, and a decision about its use in the US is expected in the summer of 2024.
Until the results from the RELIANCE clinical trial and the decision by the FDA about ensifentrine are available, we recommended a discussion with Ms. Turner about whether to initiate treatment with maintenance roflumilast or azithromycin. Both can reduce the risk of exacerbations, and the relative benefits and risks of these two evidence-based options are not yet known. Unless Ms. Turner has specific preferences (eg, concerns about specific adverse effects or differences in out-of-pocket cost) in favor of one over the other, she could flip a coin to decide between initiating maintenance roflumilast or azithromycin.
Dr. Krishnan is Professor of Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy, and Professor of Public Health, Division of Epidemiology and Biostatistics, University of Illinois Chicago. Dr. Adrish is Associate Professor, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston.
References:
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report. https://goldcopd.org/2024-gold-report-2/
2. US Food and Drug Administration (Daliresp®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf
3. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromucin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. PMID: 21864166. doi: 10.1056/NEJMoa1104623.
4. US Food and Drug Administration (Zithromyax®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf
5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acure exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4)894-942. PMID: 25321320. doi: 10.1378/chest.14-1676.
6. Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265. PMID: 28889106. doi:10.1183/13993003.02265-2016.
7. Krishnan JA, Albert RK, Rennard SI; RELIANCE study. Waiting for actionable evidence: roflumilast or azithromycin? Chronic Obst Pulm Dis. 2022;9(1):1-3. PMID: 34783231. doi: 10.15326/jcopdf.2021.0272.
8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phospodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. PMID: 37364283.
2020 Focused Updates to the Asthma Management Guidelines
National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.1
FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.2
Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.
The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.3,4
LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.5 LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.
For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.
Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.6 All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.
This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
References
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.
2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.
3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.
4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.
5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.
6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.
7. Global strategy for asthma management and prevention. 2020.
8. 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.
National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.1
FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.2
Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.
The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.3,4
LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.5 LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.
For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.
Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.6 All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.
This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
References
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.
2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.
3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.
4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.
5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.
6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.
7. Global strategy for asthma management and prevention. 2020.
8. 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.
National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.1
FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.2
Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.
The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.3,4
LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.5 LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.
For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.
Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.6 All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.
This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
References
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.
2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.
3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.
4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.
5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.
6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.
7. Global strategy for asthma management and prevention. 2020.
8. 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.