Asthma

In “Asthma: Newer Tx options mean more targeted therapy” (J Fam Pract. 2020;65:135-144), Rali et al recommend azithromycin as an add-on therapy to ICS-LABA for a select group of patients with uncontrolled persistent asthma (neutrophilic phenotype)—a Grade C recommendation. However, the best available evidence demonstrates that azithromycin is equally efficacious for uncontrolled persistent eosinophilic asthma.^1,2 Thus, family physicians need not refer patients for bronchoscopy to identify the inflammatory “phenotype.”

An important unanswered question is whether azithromycin needs to be administered continuously. Emerging evidence indicates that some patients may experience prolonged benefit after time-limited azithromycin treatment. This suggests that the mechanism of action, which has been described as anti-inflammatory, is (at least in part) antimicrobial.³

For azithromycin-treated asthma patients who experience a significant clinical response after 3 to 6 months of treatment, I recommend that the prescribing clinician try taking the patient off azithromycin to assess whether clinical improvement persists or wanes. Nothing is lost, and much is gained, by this approach; patients who relapse can resume azithromycin, and patients who remain improved are spared exposure to an unnecessary and prolonged treatment.

David L. Hahn, MD, MS
Madison, WI

In “Asthma: Newer Tx options mean more targeted therapy” (J Fam Pract. 2020;65:135-144), Rali et al recommend azithromycin as an add-on therapy to ICS-LABA for a select group of patients with uncontrolled persistent asthma (neutrophilic phenotype)—a Grade C recommendation. However, the best available evidence demonstrates that azithromycin is equally efficacious for uncontrolled persistent eosinophilic asthma.^1,2 Thus, family physicians need not refer patients for bronchoscopy to identify the inflammatory “phenotype.”

An important unanswered question is whether azithromycin needs to be administered continuously. Emerging evidence indicates that some patients may experience prolonged benefit after time-limited azithromycin treatment. This suggests that the mechanism of action, which has been described as anti-inflammatory, is (at least in part) antimicrobial.³

For azithromycin-treated asthma patients who experience a significant clinical response after 3 to 6 months of treatment, I recommend that the prescribing clinician try taking the patient off azithromycin to assess whether clinical improvement persists or wanes. Nothing is lost, and much is gained, by this approach; patients who relapse can resume azithromycin, and patients who remain improved are spared exposure to an unnecessary and prolonged treatment.

David L. Hahn, MD, MS
Madison, WI

In “Asthma: Newer Tx options mean more targeted therapy” (J Fam Pract. 2020;65:135-144), Rali et al recommend azithromycin as an add-on therapy to ICS-LABA for a select group of patients with uncontrolled persistent asthma (neutrophilic phenotype)—a Grade C recommendation. However, the best available evidence demonstrates that azithromycin is equally efficacious for uncontrolled persistent eosinophilic asthma.^1,2 Thus, family physicians need not refer patients for bronchoscopy to identify the inflammatory “phenotype.”

An important unanswered question is whether azithromycin needs to be administered continuously. Emerging evidence indicates that some patients may experience prolonged benefit after time-limited azithromycin treatment. This suggests that the mechanism of action, which has been described as anti-inflammatory, is (at least in part) antimicrobial.³

For azithromycin-treated asthma patients who experience a significant clinical response after 3 to 6 months of treatment, I recommend that the prescribing clinician try taking the patient off azithromycin to assess whether clinical improvement persists or wanes. Nothing is lost, and much is gained, by this approach; patients who relapse can resume azithromycin, and patients who remain improved are spared exposure to an unnecessary and prolonged treatment.

David L. Hahn, MD, MS
Madison, WI

Food allergies among 6- to 10-year-olds may be less common than previously reported, researchers found in a multinational study of European school-age children.

The prevalence was as low as 1.4% and as high as 3.8% using different research methods, and most likely falls somewhere in between. The findings were “considerably lower” than the 16% rate based on parental reports of symptoms such as rash, itching, or diarrhea, Linus Grabenhenrich, MD, MPH, and colleagues reported in Allergy.

In addition, peanut and hazelnut allergens were most common among the 223 children with a positive skin prick allergy assay. A total 5.6% tested sensitive to peanuts and 5.2% to hazelnuts.

Previous research reports of pediatric food allergy prevalence were largely single-center studies with heterogeneous designs, the researchers noted. These prior protocols make comparisons across countries challenging.

In search of a more definitive answer, Dr. Grabenhenrich, of the Robert Koch-Institut in Berlin, and colleagues evaluated 238 children. This group was about 10% of 2,288 children with parental face-to-face interviews and/or skin prick testing from a birth cohort in Germany, Greece, Iceland, Lithuania, the Netherlands, Poland, Spain, and United Kingdom called the EuroPrevall-iFAAM.

All participants had suspected food allergies, and the mean age at follow-up was 8 years. A total 46 children participated in a double-blind, placebo-controlled oral food allergy challenge (DBPCFC). “Most of the positively challenged children reacted only mildly or moderately, except for five children with severe signs or symptoms during DBPCFC,” Dr. Grabenhenrich and associates noted.

A food allergy to at least one allergen was confirmed in 17 children out of 2,097 who completed assessment. This yielded an average raw prevalence of 0.8% across all eight countries. The estimated 1.4%-3.8% food allergy prevalence was based on adjusted analyses that extrapolated findings to all children with questionnaire data or who completed an eligibility assessment.

“Considerable attrition” in all stages of the assessment was a potential limitation. In addition, 192 parents refused to participate in the DBPCFC food challenge component of the research. Studying a birth cohort across European countries was a study strength.

The European Commission supported this study. Dr. Grabenhenrich had no relevant disclosures. Some coauthors reported various ties to pharmaceutical and food companies.

SOURCE: Grabenhenrich L et al. Allergy. 2020 Mar 27. doi: 10.1111/all.14290.
 

Food allergies among 6- to 10-year-olds may be less common than previously reported, researchers found in a multinational study of European school-age children.

The prevalence was as low as 1.4% and as high as 3.8% using different research methods, and most likely falls somewhere in between. The findings were “considerably lower” than the 16% rate based on parental reports of symptoms such as rash, itching, or diarrhea, Linus Grabenhenrich, MD, MPH, and colleagues reported in Allergy.

In addition, peanut and hazelnut allergens were most common among the 223 children with a positive skin prick allergy assay. A total 5.6% tested sensitive to peanuts and 5.2% to hazelnuts.

Previous research reports of pediatric food allergy prevalence were largely single-center studies with heterogeneous designs, the researchers noted. These prior protocols make comparisons across countries challenging.

In search of a more definitive answer, Dr. Grabenhenrich, of the Robert Koch-Institut in Berlin, and colleagues evaluated 238 children. This group was about 10% of 2,288 children with parental face-to-face interviews and/or skin prick testing from a birth cohort in Germany, Greece, Iceland, Lithuania, the Netherlands, Poland, Spain, and United Kingdom called the EuroPrevall-iFAAM.

All participants had suspected food allergies, and the mean age at follow-up was 8 years. A total 46 children participated in a double-blind, placebo-controlled oral food allergy challenge (DBPCFC). “Most of the positively challenged children reacted only mildly or moderately, except for five children with severe signs or symptoms during DBPCFC,” Dr. Grabenhenrich and associates noted.

A food allergy to at least one allergen was confirmed in 17 children out of 2,097 who completed assessment. This yielded an average raw prevalence of 0.8% across all eight countries. The estimated 1.4%-3.8% food allergy prevalence was based on adjusted analyses that extrapolated findings to all children with questionnaire data or who completed an eligibility assessment.

“Considerable attrition” in all stages of the assessment was a potential limitation. In addition, 192 parents refused to participate in the DBPCFC food challenge component of the research. Studying a birth cohort across European countries was a study strength.

The European Commission supported this study. Dr. Grabenhenrich had no relevant disclosures. Some coauthors reported various ties to pharmaceutical and food companies.

SOURCE: Grabenhenrich L et al. Allergy. 2020 Mar 27. doi: 10.1111/all.14290.
 

Food allergies among 6- to 10-year-olds may be less common than previously reported, researchers found in a multinational study of European school-age children.

The prevalence was as low as 1.4% and as high as 3.8% using different research methods, and most likely falls somewhere in between. The findings were “considerably lower” than the 16% rate based on parental reports of symptoms such as rash, itching, or diarrhea, Linus Grabenhenrich, MD, MPH, and colleagues reported in Allergy.

In addition, peanut and hazelnut allergens were most common among the 223 children with a positive skin prick allergy assay. A total 5.6% tested sensitive to peanuts and 5.2% to hazelnuts.

Previous research reports of pediatric food allergy prevalence were largely single-center studies with heterogeneous designs, the researchers noted. These prior protocols make comparisons across countries challenging.

In search of a more definitive answer, Dr. Grabenhenrich, of the Robert Koch-Institut in Berlin, and colleagues evaluated 238 children. This group was about 10% of 2,288 children with parental face-to-face interviews and/or skin prick testing from a birth cohort in Germany, Greece, Iceland, Lithuania, the Netherlands, Poland, Spain, and United Kingdom called the EuroPrevall-iFAAM.

All participants had suspected food allergies, and the mean age at follow-up was 8 years. A total 46 children participated in a double-blind, placebo-controlled oral food allergy challenge (DBPCFC). “Most of the positively challenged children reacted only mildly or moderately, except for five children with severe signs or symptoms during DBPCFC,” Dr. Grabenhenrich and associates noted.

A food allergy to at least one allergen was confirmed in 17 children out of 2,097 who completed assessment. This yielded an average raw prevalence of 0.8% across all eight countries. The estimated 1.4%-3.8% food allergy prevalence was based on adjusted analyses that extrapolated findings to all children with questionnaire data or who completed an eligibility assessment.

“Considerable attrition” in all stages of the assessment was a potential limitation. In addition, 192 parents refused to participate in the DBPCFC food challenge component of the research. Studying a birth cohort across European countries was a study strength.

The European Commission supported this study. Dr. Grabenhenrich had no relevant disclosures. Some coauthors reported various ties to pharmaceutical and food companies.

SOURCE: Grabenhenrich L et al. Allergy. 2020 Mar 27. doi: 10.1111/all.14290.
 

EVIDENCE SUMMARY

A Cochrane systematic review of vitamin D for managing asthma performed meta-analyses on RCTs that evaluated several outcomes.¹ The review found improvement in the primary outcome of asthma exacerbations requiring systemic steroids, mainly in adult patients, and in the secondary outcomes of emergency department visits or hospitalization, in a mix of adults and children (TABLE^1-6).

Most participants had mild-to-moderate asthma; trials lasted 4 to 12 months. Vitamin D dosage regimens varied, with a median daily dose of 900 IU/d (range, 400-4000 IU/d). Six RCTs were rated high-quality, and 1 had unclear risk of bias.

Supplementation reduced exacerbations in patients with low vitamin D levels

A subsequent (2017) systematic review and meta-analysis evaluating the primary outcome of exacerbations requiring steroids⁷ included another study⁸ (in addition to the 6 RCTs in the Cochrane review).

When researchers reanalyzed individual participant data from the trials in the Cochrane review, plus the additional RCT, to include baseline vitamin D levels, they found that vitamin D supplementation reduced exacerbations overall (NNT = 7.7) and in patients with low baseline vitamin D levels (25[OH] vitamin D < 25 nmol/L; 92 participants in 3 RCTs; NNT = 4.3) but not in patients with higher baseline levels (764 participants in 6 RCTs). Vitamin D supplementation reduced the asthma exacerbation rate in patients with low baseline vitamin D levels (0.19 vs 0.42 events per participant-year; P = .046).

Smaller benefit found on ED visits and hospitalizations

The Cochrane review, with 2 RCTs with adults (n = 658)¹ and 5 RCTs with children (n = 305),^2-6 evaluated whether Vitamin D reduced the need for emergency department visits and hospitalization with asthma exacerbations; they found a smaller benefit (NNT = 26.3).

Effects on FEV₁, daily asthma symptoms, and serious adverse effects

Several RCTs included in the 2017 meta-analysis found no effect of vitamin D supplementation on FEV₁, daily asthma symptoms (evaluated with the standardized Asthma Control Test Score), or reported serious adverse events.^2-6,9,10 No deaths occurred in any trial.

Additional findings in children from lower-quality studies

A 2015 systematic review and meta-analysis of RCTs evaluating vitamin D supplementation for children with asthma found¹¹:

• moderate-quality evidence for decreased emergency department visits (1 RCT from India, 100 children ages 3 to 14 years, decrease not specified; P = .015);
• low-quality evidence for reduced exacerbations (6 RCTs [3 RCTs also in Cochrane review], 507 children ages 3 to 17 years; risk ratio = 0.41; 95% confidence interval, 0.27-0.63); and
• low-quality evidence for reduced standardized asthma symptom scores (6 RCTs [2 RCTs also in Cochrane review], 231 children ages 3 to 17 years; amount of reduction not listed; P = .01).

Continue to: RECOMMENDATIONS

No published guidelines discuss using vitamin D in managing asthma. An American Academy of Family Physicians (AAFP) summary of the Cochrane systematic review recommends that family physicians await further studies and updated guidelines before recommending vitamin D for patients with asthma.¹² The AAFP also points out that the Endocrine Society has recommended vitamin D supplementation for adults (1500-2000 IU/d) and children (at least 1000 IU/d) at risk for deficiency.

Editor's takeaway

In the meta-analyses highlighted here, researchers evaluated asthma patients with a wide range of ages, baseline vitamin D levels, and vitamin D supplementation protocols. Although vitamin D reduced asthma exacerbations requiring steroids overall, the effect was driven by 3 studies of patients with low baseline vitamin D levels. As a result, disentangling who might benefit the most remains a challenge. The conservative course for now is to manage asthma according to current guidelines and supplement vitamin D in patients at risk for, or with known, ­deficiency.

EVIDENCE SUMMARY

A Cochrane systematic review of vitamin D for managing asthma performed meta-analyses on RCTs that evaluated several outcomes.¹ The review found improvement in the primary outcome of asthma exacerbations requiring systemic steroids, mainly in adult patients, and in the secondary outcomes of emergency department visits or hospitalization, in a mix of adults and children (TABLE^1-6).

Most participants had mild-to-moderate asthma; trials lasted 4 to 12 months. Vitamin D dosage regimens varied, with a median daily dose of 900 IU/d (range, 400-4000 IU/d). Six RCTs were rated high-quality, and 1 had unclear risk of bias.

Supplementation reduced exacerbations in patients with low vitamin D levels

A subsequent (2017) systematic review and meta-analysis evaluating the primary outcome of exacerbations requiring steroids⁷ included another study⁸ (in addition to the 6 RCTs in the Cochrane review).

When researchers reanalyzed individual participant data from the trials in the Cochrane review, plus the additional RCT, to include baseline vitamin D levels, they found that vitamin D supplementation reduced exacerbations overall (NNT = 7.7) and in patients with low baseline vitamin D levels (25[OH] vitamin D < 25 nmol/L; 92 participants in 3 RCTs; NNT = 4.3) but not in patients with higher baseline levels (764 participants in 6 RCTs). Vitamin D supplementation reduced the asthma exacerbation rate in patients with low baseline vitamin D levels (0.19 vs 0.42 events per participant-year; P = .046).

Smaller benefit found on ED visits and hospitalizations

The Cochrane review, with 2 RCTs with adults (n = 658)¹ and 5 RCTs with children (n = 305),^2-6 evaluated whether Vitamin D reduced the need for emergency department visits and hospitalization with asthma exacerbations; they found a smaller benefit (NNT = 26.3).

Effects on FEV₁, daily asthma symptoms, and serious adverse effects

Several RCTs included in the 2017 meta-analysis found no effect of vitamin D supplementation on FEV₁, daily asthma symptoms (evaluated with the standardized Asthma Control Test Score), or reported serious adverse events.^2-6,9,10 No deaths occurred in any trial.

Additional findings in children from lower-quality studies

A 2015 systematic review and meta-analysis of RCTs evaluating vitamin D supplementation for children with asthma found¹¹:

• moderate-quality evidence for decreased emergency department visits (1 RCT from India, 100 children ages 3 to 14 years, decrease not specified; P = .015);
• low-quality evidence for reduced exacerbations (6 RCTs [3 RCTs also in Cochrane review], 507 children ages 3 to 17 years; risk ratio = 0.41; 95% confidence interval, 0.27-0.63); and
• low-quality evidence for reduced standardized asthma symptom scores (6 RCTs [2 RCTs also in Cochrane review], 231 children ages 3 to 17 years; amount of reduction not listed; P = .01).

Continue to: RECOMMENDATIONS

No published guidelines discuss using vitamin D in managing asthma. An American Academy of Family Physicians (AAFP) summary of the Cochrane systematic review recommends that family physicians await further studies and updated guidelines before recommending vitamin D for patients with asthma.¹² The AAFP also points out that the Endocrine Society has recommended vitamin D supplementation for adults (1500-2000 IU/d) and children (at least 1000 IU/d) at risk for deficiency.

Editor's takeaway

In the meta-analyses highlighted here, researchers evaluated asthma patients with a wide range of ages, baseline vitamin D levels, and vitamin D supplementation protocols. Although vitamin D reduced asthma exacerbations requiring steroids overall, the effect was driven by 3 studies of patients with low baseline vitamin D levels. As a result, disentangling who might benefit the most remains a challenge. The conservative course for now is to manage asthma according to current guidelines and supplement vitamin D in patients at risk for, or with known, ­deficiency.

EVIDENCE SUMMARY

A Cochrane systematic review of vitamin D for managing asthma performed meta-analyses on RCTs that evaluated several outcomes.¹ The review found improvement in the primary outcome of asthma exacerbations requiring systemic steroids, mainly in adult patients, and in the secondary outcomes of emergency department visits or hospitalization, in a mix of adults and children (TABLE^1-6).

Most participants had mild-to-moderate asthma; trials lasted 4 to 12 months. Vitamin D dosage regimens varied, with a median daily dose of 900 IU/d (range, 400-4000 IU/d). Six RCTs were rated high-quality, and 1 had unclear risk of bias.

Supplementation reduced exacerbations in patients with low vitamin D levels

A subsequent (2017) systematic review and meta-analysis evaluating the primary outcome of exacerbations requiring steroids⁷ included another study⁸ (in addition to the 6 RCTs in the Cochrane review).

When researchers reanalyzed individual participant data from the trials in the Cochrane review, plus the additional RCT, to include baseline vitamin D levels, they found that vitamin D supplementation reduced exacerbations overall (NNT = 7.7) and in patients with low baseline vitamin D levels (25[OH] vitamin D < 25 nmol/L; 92 participants in 3 RCTs; NNT = 4.3) but not in patients with higher baseline levels (764 participants in 6 RCTs). Vitamin D supplementation reduced the asthma exacerbation rate in patients with low baseline vitamin D levels (0.19 vs 0.42 events per participant-year; P = .046).

Smaller benefit found on ED visits and hospitalizations

The Cochrane review, with 2 RCTs with adults (n = 658)¹ and 5 RCTs with children (n = 305),^2-6 evaluated whether Vitamin D reduced the need for emergency department visits and hospitalization with asthma exacerbations; they found a smaller benefit (NNT = 26.3).

Effects on FEV₁, daily asthma symptoms, and serious adverse effects

Several RCTs included in the 2017 meta-analysis found no effect of vitamin D supplementation on FEV₁, daily asthma symptoms (evaluated with the standardized Asthma Control Test Score), or reported serious adverse events.^2-6,9,10 No deaths occurred in any trial.

Additional findings in children from lower-quality studies

A 2015 systematic review and meta-analysis of RCTs evaluating vitamin D supplementation for children with asthma found¹¹:

• moderate-quality evidence for decreased emergency department visits (1 RCT from India, 100 children ages 3 to 14 years, decrease not specified; P = .015);
• low-quality evidence for reduced exacerbations (6 RCTs [3 RCTs also in Cochrane review], 507 children ages 3 to 17 years; risk ratio = 0.41; 95% confidence interval, 0.27-0.63); and
• low-quality evidence for reduced standardized asthma symptom scores (6 RCTs [2 RCTs also in Cochrane review], 231 children ages 3 to 17 years; amount of reduction not listed; P = .01).

Continue to: RECOMMENDATIONS

No published guidelines discuss using vitamin D in managing asthma. An American Academy of Family Physicians (AAFP) summary of the Cochrane systematic review recommends that family physicians await further studies and updated guidelines before recommending vitamin D for patients with asthma.¹² The AAFP also points out that the Endocrine Society has recommended vitamin D supplementation for adults (1500-2000 IU/d) and children (at least 1000 IU/d) at risk for deficiency.

Editor's takeaway

In the meta-analyses highlighted here, researchers evaluated asthma patients with a wide range of ages, baseline vitamin D levels, and vitamin D supplementation protocols. Although vitamin D reduced asthma exacerbations requiring steroids overall, the effect was driven by 3 studies of patients with low baseline vitamin D levels. As a result, disentangling who might benefit the most remains a challenge. The conservative course for now is to manage asthma according to current guidelines and supplement vitamin D in patients at risk for, or with known, ­deficiency.

The monoclonal antibody omalizumab, already approved to treat allergic asthma and urticaria, has been shown to improve symptoms of patients who have chronic rhinosinusitis and nasal polyps (CRSwNP), according to recent research released as an abstract from the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

“When you give this drug to patients who have nasal polyposis and concomitant asthma, you are effectively treating both the upper and lower airway disease components,” Jonathan Corren, MD, of the University of California, Los Angeles, said in an interview. “Typically, people with nasal polyp disease have worse nasal disease than people without asthma. In addition, asthma is also generally worse in patients with nasal polyposis,” he added.

Dr. Corren reported results of a subset of patients with corticosteroid-refractory CRSwNP and comorbid asthma enrolled in phase III, placebo-controlled, 24-week, trials of omalizumab, POLYP1 (n = 74) and POLYP2 (n = 77). The analysis excluded patients who were on oral steroids or high-dose steroid inhaler therapy so the effectiveness of omalizumab could be evaluated without interfering factors, Dr. Corren explained. As a result, the study population consisted of patients with mild to moderate asthma. Dr. Corren is also principal investigator of the POLYP1 trial.

The analysis compared changes in Asthma Quality of Life Questionnaire (AQLQ) and sino-nasal outcome test (SNOT-22) measures after 24 weeks of treatment with those seen with placebo.

“With regard to asthma outcomes, we found there was a significant increase in the odds ratio that patients who received omalizumab would achieve a minimal, clinically important improvement in their asthma quality of life,” Dr. Corren said .

The study estimated the odds ratio for minimal clinically important difference in AQLQ at 24 weeks was 3.9 (95% confidence interval, 1.5-9.7; P = .0043), which Dr. Corren called “quite significant.” SNOT-22 scores showed a mean improvement of 23.3 from baseline to week 24, compared with a worsening of 8.4 in placebo (P = .0001).

Omalizumab is approved for treatment of perennial allergies and urticaria. Chronic rhinosinusitis with nasal polyps would be a third indication if the Food and Drug Administration approves it, Dr. Corren noted.

Genentech sponsored the subset analysis. Hoffmann-La Roche, Genentech’s parent company, is sponsor of the POLYP1 and POLYP2 trials. Dr. Corren disclosed financial relationships with Genentech.

SOURCE: Corren J et al. AAAAI, Session 4608, Abstract 813.

The monoclonal antibody omalizumab, already approved to treat allergic asthma and urticaria, has been shown to improve symptoms of patients who have chronic rhinosinusitis and nasal polyps (CRSwNP), according to recent research released as an abstract from the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

“When you give this drug to patients who have nasal polyposis and concomitant asthma, you are effectively treating both the upper and lower airway disease components,” Jonathan Corren, MD, of the University of California, Los Angeles, said in an interview. “Typically, people with nasal polyp disease have worse nasal disease than people without asthma. In addition, asthma is also generally worse in patients with nasal polyposis,” he added.

Dr. Corren reported results of a subset of patients with corticosteroid-refractory CRSwNP and comorbid asthma enrolled in phase III, placebo-controlled, 24-week, trials of omalizumab, POLYP1 (n = 74) and POLYP2 (n = 77). The analysis excluded patients who were on oral steroids or high-dose steroid inhaler therapy so the effectiveness of omalizumab could be evaluated without interfering factors, Dr. Corren explained. As a result, the study population consisted of patients with mild to moderate asthma. Dr. Corren is also principal investigator of the POLYP1 trial.

The analysis compared changes in Asthma Quality of Life Questionnaire (AQLQ) and sino-nasal outcome test (SNOT-22) measures after 24 weeks of treatment with those seen with placebo.

“With regard to asthma outcomes, we found there was a significant increase in the odds ratio that patients who received omalizumab would achieve a minimal, clinically important improvement in their asthma quality of life,” Dr. Corren said .

The study estimated the odds ratio for minimal clinically important difference in AQLQ at 24 weeks was 3.9 (95% confidence interval, 1.5-9.7; P = .0043), which Dr. Corren called “quite significant.” SNOT-22 scores showed a mean improvement of 23.3 from baseline to week 24, compared with a worsening of 8.4 in placebo (P = .0001).

Omalizumab is approved for treatment of perennial allergies and urticaria. Chronic rhinosinusitis with nasal polyps would be a third indication if the Food and Drug Administration approves it, Dr. Corren noted.

Genentech sponsored the subset analysis. Hoffmann-La Roche, Genentech’s parent company, is sponsor of the POLYP1 and POLYP2 trials. Dr. Corren disclosed financial relationships with Genentech.

SOURCE: Corren J et al. AAAAI, Session 4608, Abstract 813.

The monoclonal antibody omalizumab, already approved to treat allergic asthma and urticaria, has been shown to improve symptoms of patients who have chronic rhinosinusitis and nasal polyps (CRSwNP), according to recent research released as an abstract from the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

“When you give this drug to patients who have nasal polyposis and concomitant asthma, you are effectively treating both the upper and lower airway disease components,” Jonathan Corren, MD, of the University of California, Los Angeles, said in an interview. “Typically, people with nasal polyp disease have worse nasal disease than people without asthma. In addition, asthma is also generally worse in patients with nasal polyposis,” he added.

Dr. Corren reported results of a subset of patients with corticosteroid-refractory CRSwNP and comorbid asthma enrolled in phase III, placebo-controlled, 24-week, trials of omalizumab, POLYP1 (n = 74) and POLYP2 (n = 77). The analysis excluded patients who were on oral steroids or high-dose steroid inhaler therapy so the effectiveness of omalizumab could be evaluated without interfering factors, Dr. Corren explained. As a result, the study population consisted of patients with mild to moderate asthma. Dr. Corren is also principal investigator of the POLYP1 trial.

The analysis compared changes in Asthma Quality of Life Questionnaire (AQLQ) and sino-nasal outcome test (SNOT-22) measures after 24 weeks of treatment with those seen with placebo.

“With regard to asthma outcomes, we found there was a significant increase in the odds ratio that patients who received omalizumab would achieve a minimal, clinically important improvement in their asthma quality of life,” Dr. Corren said .

The study estimated the odds ratio for minimal clinically important difference in AQLQ at 24 weeks was 3.9 (95% confidence interval, 1.5-9.7; P = .0043), which Dr. Corren called “quite significant.” SNOT-22 scores showed a mean improvement of 23.3 from baseline to week 24, compared with a worsening of 8.4 in placebo (P = .0001).

Omalizumab is approved for treatment of perennial allergies and urticaria. Chronic rhinosinusitis with nasal polyps would be a third indication if the Food and Drug Administration approves it, Dr. Corren noted.

Genentech sponsored the subset analysis. Hoffmann-La Roche, Genentech’s parent company, is sponsor of the POLYP1 and POLYP2 trials. Dr. Corren disclosed financial relationships with Genentech.

SOURCE: Corren J et al. AAAAI, Session 4608, Abstract 813.

Pediatric patients with allergic rhinoconjunctivitis (AR/C) who received ragweed sublingual immunotherapy (SLIT) tablets had improvements in their comorbid asthma during ragweed pollen season, compared with placebo, according to recent research that was to be presented as an abstract for the American Academy of Allergy, Asthma & Immunology annual meeting. The AAAAI canceled its annual meeting and provided abstracts and access to presenters for press coverage.

Photo courtesy Oak Ridge National Laboratory

David I. Bernstein, MD, professor emeritus in the division of immunology, allergy and rheumatology at the University of Cincinnati and principal investigator at the Bernstein Clinical Research Center, examined exploratory endpoints of an international, double-blind, placebo-controlled trial evaluating ragweed SLIT tablets (Ragwitek; Merck) in 1,022 children with AR/C. The children enrolled were aged 5-17 years with ragweed AR/C, with 42.7% of the group having a history of asthma and the rest without asthma. Participants were included if they had a predicted first expiratory volume in 1 second (FEV₁) of ≥ 80% and if they required high-dose inhaled corticosteroids (ICS) to control their asthma or had severe, unstable, or uncontrolled asthma. The children were randomized to receive a 12 Amb a 1-unit dose of the ragweed SLIT tablet or placebo each day for 28 weeks.

The primary outcome was the total combined score (TCS), which was the sum of the daily symptom score and medication scores during ragweed season, but researchers also examined three exploratory endpoints. All patients were evaluated for their average asthma daily symptom score at the peak of ragweed pollen season and during the entire season, which was measured on a 0-3 scale based on symptoms of cough, wheeze, and chest tightness or shortness of breath. Within a subgroup of 406 participants with asthma, Dr. Bernstein and colleagues examined use of average daily short-acting beta agonists (SABA), and the number of times per week a participant would use a SABA at night at the peak of ragweed season as well as across the whole season.

Researchers found the TCS improved by 38% during ragweed pollen season in the group receiving ragweed SLIT tablets (least-square [LS] mean TCS, 7.12), compared with placebo (LS mean TCS, 4.39; P < .001). Among the asthma exploratory outcomes, asthma daily symptom scores improved by 30.7% during the peak of the season (–46.9% vs. –9.6%; LS mean difference, –0.13) and by 23.1% during the whole season (­–38.7% vs. –2.3%; LS mean difference, –0.09), compared with the placebo group. The mean number of daily puffs of rescue medication also decreased by 68.1% in the peak of ragweed season (–87.6% vs. –39.0%; LS mean difference, −0.14) and by 61.4% during the whole season (–80.9% vs. −32.9%; LS mean difference, –0.12) among participants taking ragweed SLIT tablets, compared with placebo. Participants in the group receiving ragweed SLIT tablets also had fewer nights awake using rescue medication, with a relative improvement of 75.1% during peak season (−99.3% vs. −35.2%; LS mean difference, −0.08) and 52.2% during the whole season (−80.4% vs. −3.7%; LS mean difference, −0.03), compared with the placebo group.

This magnitude of difference in the number of nocturnal awakenings in the treated group, compared with the placebo group, is similar to what researchers have seen in trials evaluating ICS or mometasone/formoterol, Dr. Bernstein said in an interview.

“Even though the magnitude in terms of difference in asthma symptoms and requirements for short-acting beta agonists was less than that of other studies of other drugs, it may reflect the fact these participants have less severe asthma,” said Dr. Bernstein. “But, there was an effect, and we did see some interesting differences between the placebo group and the treated group. This, I think, does generate at least a hypothesis that this could be an effective treatment for seasonal asthma, which would require future studies to determine that.”

Dr. Bernstein said that there were no adverse events from ragweed SLIT tablets unique to children with or without asthma, and although the data from this study cannot be compared directly to an adult population, there appeared to be a greater effect size for children than in trials evaluating adults. Compared with treatment options like subcutaneous immunotherapy, ragweed SLIT tablets may offer a relatively safer and more effective option for children and their parents, he said.

“The problem with kids is that they don’t particularly like the idea of getting injections. There’s a lot of needle-type injection phobia,” Dr. Bernstein said. “For a child who has maybe one or two major problem pollen seasons like during the ragweed and grass, they could do this.”

Ragwitek was approved by the Food and Drug Administration in 2014 for the treatment of adults with allergic rhinitis. Dr. Bernstein noted that Merck submitted this trial to the Food and Drug Administration as evidence of its effectiveness in children to secure a pediatric indication for the treatment.

This trial was funded by Merck, the developers of Ragwitek. The authors received medical writing and editing assistance from Scott Medical Communications, which was funded by ALK. Dr. Bernstein reports being on the advisory board for ALK America and GlaxoSmithKline; a consultant for Gerson-Lehman and Guidepoint Global; and received grant support from Aimmune, ALK, Amgen, AstraZeneca, Avillion, Biocryst, Boehringer Ingelheim, Cipla, Genentech, GlaxoSmithKline, Gossamer, Leo, Lupin, Menlo, Merck, Mylan, Novartis, Novum, Pearl, Regeneron, Shire, and TEVA. The other authors reported no relevant conflicts of interest.

SOURCE: Bernstein D et al. AAAAI 2020, Abstract 270.

Pediatric patients with allergic rhinoconjunctivitis (AR/C) who received ragweed sublingual immunotherapy (SLIT) tablets had improvements in their comorbid asthma during ragweed pollen season, compared with placebo, according to recent research that was to be presented as an abstract for the American Academy of Allergy, Asthma & Immunology annual meeting. The AAAAI canceled its annual meeting and provided abstracts and access to presenters for press coverage.

Photo courtesy Oak Ridge National Laboratory

David I. Bernstein, MD, professor emeritus in the division of immunology, allergy and rheumatology at the University of Cincinnati and principal investigator at the Bernstein Clinical Research Center, examined exploratory endpoints of an international, double-blind, placebo-controlled trial evaluating ragweed SLIT tablets (Ragwitek; Merck) in 1,022 children with AR/C. The children enrolled were aged 5-17 years with ragweed AR/C, with 42.7% of the group having a history of asthma and the rest without asthma. Participants were included if they had a predicted first expiratory volume in 1 second (FEV₁) of ≥ 80% and if they required high-dose inhaled corticosteroids (ICS) to control their asthma or had severe, unstable, or uncontrolled asthma. The children were randomized to receive a 12 Amb a 1-unit dose of the ragweed SLIT tablet or placebo each day for 28 weeks.

The primary outcome was the total combined score (TCS), which was the sum of the daily symptom score and medication scores during ragweed season, but researchers also examined three exploratory endpoints. All patients were evaluated for their average asthma daily symptom score at the peak of ragweed pollen season and during the entire season, which was measured on a 0-3 scale based on symptoms of cough, wheeze, and chest tightness or shortness of breath. Within a subgroup of 406 participants with asthma, Dr. Bernstein and colleagues examined use of average daily short-acting beta agonists (SABA), and the number of times per week a participant would use a SABA at night at the peak of ragweed season as well as across the whole season.

Researchers found the TCS improved by 38% during ragweed pollen season in the group receiving ragweed SLIT tablets (least-square [LS] mean TCS, 7.12), compared with placebo (LS mean TCS, 4.39; P < .001). Among the asthma exploratory outcomes, asthma daily symptom scores improved by 30.7% during the peak of the season (–46.9% vs. –9.6%; LS mean difference, –0.13) and by 23.1% during the whole season (­–38.7% vs. –2.3%; LS mean difference, –0.09), compared with the placebo group. The mean number of daily puffs of rescue medication also decreased by 68.1% in the peak of ragweed season (–87.6% vs. –39.0%; LS mean difference, −0.14) and by 61.4% during the whole season (–80.9% vs. −32.9%; LS mean difference, –0.12) among participants taking ragweed SLIT tablets, compared with placebo. Participants in the group receiving ragweed SLIT tablets also had fewer nights awake using rescue medication, with a relative improvement of 75.1% during peak season (−99.3% vs. −35.2%; LS mean difference, −0.08) and 52.2% during the whole season (−80.4% vs. −3.7%; LS mean difference, −0.03), compared with the placebo group.

This magnitude of difference in the number of nocturnal awakenings in the treated group, compared with the placebo group, is similar to what researchers have seen in trials evaluating ICS or mometasone/formoterol, Dr. Bernstein said in an interview.

“Even though the magnitude in terms of difference in asthma symptoms and requirements for short-acting beta agonists was less than that of other studies of other drugs, it may reflect the fact these participants have less severe asthma,” said Dr. Bernstein. “But, there was an effect, and we did see some interesting differences between the placebo group and the treated group. This, I think, does generate at least a hypothesis that this could be an effective treatment for seasonal asthma, which would require future studies to determine that.”

Dr. Bernstein said that there were no adverse events from ragweed SLIT tablets unique to children with or without asthma, and although the data from this study cannot be compared directly to an adult population, there appeared to be a greater effect size for children than in trials evaluating adults. Compared with treatment options like subcutaneous immunotherapy, ragweed SLIT tablets may offer a relatively safer and more effective option for children and their parents, he said.

“The problem with kids is that they don’t particularly like the idea of getting injections. There’s a lot of needle-type injection phobia,” Dr. Bernstein said. “For a child who has maybe one or two major problem pollen seasons like during the ragweed and grass, they could do this.”

Ragwitek was approved by the Food and Drug Administration in 2014 for the treatment of adults with allergic rhinitis. Dr. Bernstein noted that Merck submitted this trial to the Food and Drug Administration as evidence of its effectiveness in children to secure a pediatric indication for the treatment.

This trial was funded by Merck, the developers of Ragwitek. The authors received medical writing and editing assistance from Scott Medical Communications, which was funded by ALK. Dr. Bernstein reports being on the advisory board for ALK America and GlaxoSmithKline; a consultant for Gerson-Lehman and Guidepoint Global; and received grant support from Aimmune, ALK, Amgen, AstraZeneca, Avillion, Biocryst, Boehringer Ingelheim, Cipla, Genentech, GlaxoSmithKline, Gossamer, Leo, Lupin, Menlo, Merck, Mylan, Novartis, Novum, Pearl, Regeneron, Shire, and TEVA. The other authors reported no relevant conflicts of interest.

SOURCE: Bernstein D et al. AAAAI 2020, Abstract 270.

Pediatric patients with allergic rhinoconjunctivitis (AR/C) who received ragweed sublingual immunotherapy (SLIT) tablets had improvements in their comorbid asthma during ragweed pollen season, compared with placebo, according to recent research that was to be presented as an abstract for the American Academy of Allergy, Asthma & Immunology annual meeting. The AAAAI canceled its annual meeting and provided abstracts and access to presenters for press coverage.

Photo courtesy Oak Ridge National Laboratory

David I. Bernstein, MD, professor emeritus in the division of immunology, allergy and rheumatology at the University of Cincinnati and principal investigator at the Bernstein Clinical Research Center, examined exploratory endpoints of an international, double-blind, placebo-controlled trial evaluating ragweed SLIT tablets (Ragwitek; Merck) in 1,022 children with AR/C. The children enrolled were aged 5-17 years with ragweed AR/C, with 42.7% of the group having a history of asthma and the rest without asthma. Participants were included if they had a predicted first expiratory volume in 1 second (FEV₁) of ≥ 80% and if they required high-dose inhaled corticosteroids (ICS) to control their asthma or had severe, unstable, or uncontrolled asthma. The children were randomized to receive a 12 Amb a 1-unit dose of the ragweed SLIT tablet or placebo each day for 28 weeks.

The primary outcome was the total combined score (TCS), which was the sum of the daily symptom score and medication scores during ragweed season, but researchers also examined three exploratory endpoints. All patients were evaluated for their average asthma daily symptom score at the peak of ragweed pollen season and during the entire season, which was measured on a 0-3 scale based on symptoms of cough, wheeze, and chest tightness or shortness of breath. Within a subgroup of 406 participants with asthma, Dr. Bernstein and colleagues examined use of average daily short-acting beta agonists (SABA), and the number of times per week a participant would use a SABA at night at the peak of ragweed season as well as across the whole season.

Researchers found the TCS improved by 38% during ragweed pollen season in the group receiving ragweed SLIT tablets (least-square [LS] mean TCS, 7.12), compared with placebo (LS mean TCS, 4.39; P < .001). Among the asthma exploratory outcomes, asthma daily symptom scores improved by 30.7% during the peak of the season (–46.9% vs. –9.6%; LS mean difference, –0.13) and by 23.1% during the whole season (­–38.7% vs. –2.3%; LS mean difference, –0.09), compared with the placebo group. The mean number of daily puffs of rescue medication also decreased by 68.1% in the peak of ragweed season (–87.6% vs. –39.0%; LS mean difference, −0.14) and by 61.4% during the whole season (–80.9% vs. −32.9%; LS mean difference, –0.12) among participants taking ragweed SLIT tablets, compared with placebo. Participants in the group receiving ragweed SLIT tablets also had fewer nights awake using rescue medication, with a relative improvement of 75.1% during peak season (−99.3% vs. −35.2%; LS mean difference, −0.08) and 52.2% during the whole season (−80.4% vs. −3.7%; LS mean difference, −0.03), compared with the placebo group.

This magnitude of difference in the number of nocturnal awakenings in the treated group, compared with the placebo group, is similar to what researchers have seen in trials evaluating ICS or mometasone/formoterol, Dr. Bernstein said in an interview.

“Even though the magnitude in terms of difference in asthma symptoms and requirements for short-acting beta agonists was less than that of other studies of other drugs, it may reflect the fact these participants have less severe asthma,” said Dr. Bernstein. “But, there was an effect, and we did see some interesting differences between the placebo group and the treated group. This, I think, does generate at least a hypothesis that this could be an effective treatment for seasonal asthma, which would require future studies to determine that.”

Dr. Bernstein said that there were no adverse events from ragweed SLIT tablets unique to children with or without asthma, and although the data from this study cannot be compared directly to an adult population, there appeared to be a greater effect size for children than in trials evaluating adults. Compared with treatment options like subcutaneous immunotherapy, ragweed SLIT tablets may offer a relatively safer and more effective option for children and their parents, he said.

“The problem with kids is that they don’t particularly like the idea of getting injections. There’s a lot of needle-type injection phobia,” Dr. Bernstein said. “For a child who has maybe one or two major problem pollen seasons like during the ragweed and grass, they could do this.”

Ragwitek was approved by the Food and Drug Administration in 2014 for the treatment of adults with allergic rhinitis. Dr. Bernstein noted that Merck submitted this trial to the Food and Drug Administration as evidence of its effectiveness in children to secure a pediatric indication for the treatment.

This trial was funded by Merck, the developers of Ragwitek. The authors received medical writing and editing assistance from Scott Medical Communications, which was funded by ALK. Dr. Bernstein reports being on the advisory board for ALK America and GlaxoSmithKline; a consultant for Gerson-Lehman and Guidepoint Global; and received grant support from Aimmune, ALK, Amgen, AstraZeneca, Avillion, Biocryst, Boehringer Ingelheim, Cipla, Genentech, GlaxoSmithKline, Gossamer, Leo, Lupin, Menlo, Merck, Mylan, Novartis, Novum, Pearl, Regeneron, Shire, and TEVA. The other authors reported no relevant conflicts of interest.

SOURCE: Bernstein D et al. AAAAI 2020, Abstract 270.

The Food and Drug Administration has approved the first generic of Proventil HFA (albuterol sulfate) metered-dose inhaler, 90 mcg/inhalation, according to a release from the agency. This inhaler is indicated for prevention of bronchospasm in patients aged 4 years and older. Specifically, these are patients with reversible obstructive airway disease or exercise-induced bronchospasm.

“The FDA recognizes the increased demand for albuterol products during the novel coronavirus pandemic,” said FDA Commissioner Stephen M. Hahn, MD.

The most common side effects include upper respiratory tract infection, rhinitis, nausea, vomiting, rapid heart rate, tremor, and nervousness.

This approval comes as part of FDA’s efforts to guide industry through the development process of generic products, according to the release. Complex combination products – such as this inhaler, which comprises both medication and a delivery system – can be more challenging to develop than solid oral dosage forms, such as tablets.

The FDA released a draft guidance in March 2020 specific to proposed generic albuterol sulfate metered-dose inhalers, including drug products referencing Proventil HFA. As with other similar guidances, it details the steps companies need to take in developing generics in order to submit complete applications for those products. The full news release regarding this approval is available on the FDA website.

[email protected]

This article was updated 4/8/20.

The Food and Drug Administration has approved the first generic of Proventil HFA (albuterol sulfate) metered-dose inhaler, 90 mcg/inhalation, according to a release from the agency. This inhaler is indicated for prevention of bronchospasm in patients aged 4 years and older. Specifically, these are patients with reversible obstructive airway disease or exercise-induced bronchospasm.

“The FDA recognizes the increased demand for albuterol products during the novel coronavirus pandemic,” said FDA Commissioner Stephen M. Hahn, MD.

The most common side effects include upper respiratory tract infection, rhinitis, nausea, vomiting, rapid heart rate, tremor, and nervousness.

This approval comes as part of FDA’s efforts to guide industry through the development process of generic products, according to the release. Complex combination products – such as this inhaler, which comprises both medication and a delivery system – can be more challenging to develop than solid oral dosage forms, such as tablets.

The FDA released a draft guidance in March 2020 specific to proposed generic albuterol sulfate metered-dose inhalers, including drug products referencing Proventil HFA. As with other similar guidances, it details the steps companies need to take in developing generics in order to submit complete applications for those products. The full news release regarding this approval is available on the FDA website.

[email protected]

This article was updated 4/8/20.

The Food and Drug Administration has approved the first generic of Proventil HFA (albuterol sulfate) metered-dose inhaler, 90 mcg/inhalation, according to a release from the agency. This inhaler is indicated for prevention of bronchospasm in patients aged 4 years and older. Specifically, these are patients with reversible obstructive airway disease or exercise-induced bronchospasm.

“The FDA recognizes the increased demand for albuterol products during the novel coronavirus pandemic,” said FDA Commissioner Stephen M. Hahn, MD.

The most common side effects include upper respiratory tract infection, rhinitis, nausea, vomiting, rapid heart rate, tremor, and nervousness.

This approval comes as part of FDA’s efforts to guide industry through the development process of generic products, according to the release. Complex combination products – such as this inhaler, which comprises both medication and a delivery system – can be more challenging to develop than solid oral dosage forms, such as tablets.

The FDA released a draft guidance in March 2020 specific to proposed generic albuterol sulfate metered-dose inhalers, including drug products referencing Proventil HFA. As with other similar guidances, it details the steps companies need to take in developing generics in order to submit complete applications for those products. The full news release regarding this approval is available on the FDA website.

[email protected]

This article was updated 4/8/20.

Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.¹ As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include biological therapies, immunotherapy, bronchial thermoplasty, and anti-inflammatory agents. This review will focus on the newer therapeutic options and provide guidance on when to seek expert pulmonary consultation (TABLE 1). But before we begin, it’s important to briefly review the pathophysiology of asthma and several key diagnostic considerations.

The pathophysiology of asthma provides key targets for therapy

There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology²:

Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.^2-4

In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.^5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.^8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).

It is important to determine whether patients with asthma-COPD overlap syndrome are asthma predominant or COPD predominant, because appropriate first-line treatment will differ.

Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.¹⁰ Longstanding inflammation can lead to structural changes and reduced airflow reversibility.

Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.^11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.^12,13

What we’ve learned about asthma can inform treatment decisions

Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV₁ > 12% or FVC > 200 mL from baseline).² If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.

Continue to: Additional diagnostic considerations...

Additional diagnostic considerations may impact the treatment plan for patients with asthma:

Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.¹⁴

Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.^2,5,15

Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.^16-18

Getting a handle on an ever-expanding asthma Tx arsenal

The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.

Continue to: Over the past decade...

Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.

Inhaled medications

This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting muscarinic agonists (LAMA).

ICS is the first choice for long-term control of persistent asthma.² Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.^19-22

LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death²³—a concern that has not been demonstrated with the combination of ICS-LABA.

LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received an FDA black box warning.

LABAs cause smooth muscle relaxation in the lungs.²⁴ There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).

Continue to: Once-daily fluticasone furoate/vilanterol...

Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV₁.²⁵ In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.²⁶

Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV₁ improved with olodeaterol when compared to placebo.²⁷

Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.²⁸ However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.²⁹

The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.¹⁵

Ideal candidates for biological therapy are patients who have exhausted other forms of severe asthma treatment.

Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M₁ and M₃.³⁰ Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.¹³ The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.

Continue to: Glycopyrronium bromide...

Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.³¹

Biological therapies

In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.

Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.³²

All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 3^15,33-47 summarizes all approved biologicals for the management of severe asthma.

Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).³⁴ Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).^33,34

Continue to: Its efficacy and safety...

Mepolizumab has shown a trend of greater benefit in patients with a very high eosinophil count.

Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.^35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.¹⁵

Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.

Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).³⁷

Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.^37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.^39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.³⁸

GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.

Continue to: Reslizumab (Cinqair)...

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-­generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

Continue to: Both treatment groups...

Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV₁ for up to 5 years.⁵¹

The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.⁵²

In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.

Immunotherapy

Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).

Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.

Continue to: SCIT

SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.⁵³

SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.

The potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis.

A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.⁵⁴ A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.⁵⁵

In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.⁵⁶ Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.

Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.¹⁵

Continue to: Azithromycin

Azithromycin

Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.

The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.⁵⁷ While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.

The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.⁵⁸

Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy

The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.⁵⁹

The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.

Continue to: A new era

We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.

It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.

CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; [email protected]

Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.¹ As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include biological therapies, immunotherapy, bronchial thermoplasty, and anti-inflammatory agents. This review will focus on the newer therapeutic options and provide guidance on when to seek expert pulmonary consultation (TABLE 1). But before we begin, it’s important to briefly review the pathophysiology of asthma and several key diagnostic considerations.

The pathophysiology of asthma provides key targets for therapy

There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology²:

Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.^2-4

In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.^5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.^8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).

It is important to determine whether patients with asthma-COPD overlap syndrome are asthma predominant or COPD predominant, because appropriate first-line treatment will differ.

Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.¹⁰ Longstanding inflammation can lead to structural changes and reduced airflow reversibility.

Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.^11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.^12,13

What we’ve learned about asthma can inform treatment decisions

Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV₁ > 12% or FVC > 200 mL from baseline).² If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.

Continue to: Additional diagnostic considerations...

Additional diagnostic considerations may impact the treatment plan for patients with asthma:

Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.¹⁴

Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.^2,5,15

Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.^16-18

Getting a handle on an ever-expanding asthma Tx arsenal

The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.

Continue to: Over the past decade...

Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.

Inhaled medications

This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting muscarinic agonists (LAMA).

ICS is the first choice for long-term control of persistent asthma.² Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.^19-22

LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death²³—a concern that has not been demonstrated with the combination of ICS-LABA.

LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received an FDA black box warning.

LABAs cause smooth muscle relaxation in the lungs.²⁴ There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).

Continue to: Once-daily fluticasone furoate/vilanterol...

Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV₁.²⁵ In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.²⁶

Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV₁ improved with olodeaterol when compared to placebo.²⁷

Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.²⁸ However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.²⁹

The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.¹⁵

Ideal candidates for biological therapy are patients who have exhausted other forms of severe asthma treatment.

Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M₁ and M₃.³⁰ Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.¹³ The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.

Continue to: Glycopyrronium bromide...

Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.³¹

Biological therapies

In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.

Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.³²

All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 3^15,33-47 summarizes all approved biologicals for the management of severe asthma.

Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).³⁴ Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).^33,34

Continue to: Its efficacy and safety...

Mepolizumab has shown a trend of greater benefit in patients with a very high eosinophil count.

Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.^35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.¹⁵

Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.

Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).³⁷

Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.^37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.^39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.³⁸

GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.

Continue to: Reslizumab (Cinqair)...

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-­generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

Continue to: Both treatment groups...

Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV₁ for up to 5 years.⁵¹

The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.⁵²

In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.

Immunotherapy

Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).

Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.

Continue to: SCIT

SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.⁵³

SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.

The potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis.

A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.⁵⁴ A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.⁵⁵

In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.⁵⁶ Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.

Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.¹⁵

Continue to: Azithromycin

Azithromycin

Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.

The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.⁵⁷ While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.

The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.⁵⁸

Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy

The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.⁵⁹

The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.

Continue to: A new era

We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.

It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.

CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; [email protected]

Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.¹ As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include biological therapies, immunotherapy, bronchial thermoplasty, and anti-inflammatory agents. This review will focus on the newer therapeutic options and provide guidance on when to seek expert pulmonary consultation (TABLE 1). But before we begin, it’s important to briefly review the pathophysiology of asthma and several key diagnostic considerations.

The pathophysiology of asthma provides key targets for therapy

There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology²:

Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.^2-4

In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.^5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.^8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).

It is important to determine whether patients with asthma-COPD overlap syndrome are asthma predominant or COPD predominant, because appropriate first-line treatment will differ.

Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.¹⁰ Longstanding inflammation can lead to structural changes and reduced airflow reversibility.

Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.^11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.^12,13

What we’ve learned about asthma can inform treatment decisions

Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV₁ > 12% or FVC > 200 mL from baseline).² If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.

Continue to: Additional diagnostic considerations...

Additional diagnostic considerations may impact the treatment plan for patients with asthma:

Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.¹⁴

Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.^2,5,15

Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.^16-18

Getting a handle on an ever-expanding asthma Tx arsenal

The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.

Continue to: Over the past decade...

Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.

Inhaled medications

This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting muscarinic agonists (LAMA).

ICS is the first choice for long-term control of persistent asthma.² Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.^19-22

LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death²³—a concern that has not been demonstrated with the combination of ICS-LABA.

LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received an FDA black box warning.

LABAs cause smooth muscle relaxation in the lungs.²⁴ There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).

Continue to: Once-daily fluticasone furoate/vilanterol...

Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV₁.²⁵ In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.²⁶

Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV₁ improved with olodeaterol when compared to placebo.²⁷

Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.²⁸ However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.²⁹

The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.¹⁵

Ideal candidates for biological therapy are patients who have exhausted other forms of severe asthma treatment.

Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M₁ and M₃.³⁰ Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.¹³ The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.

Continue to: Glycopyrronium bromide...

Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.³¹

Biological therapies

In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.

Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.³²

All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 3^15,33-47 summarizes all approved biologicals for the management of severe asthma.

Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).³⁴ Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).^33,34

Continue to: Its efficacy and safety...

Mepolizumab has shown a trend of greater benefit in patients with a very high eosinophil count.

Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.^35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.¹⁵

Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.

Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).³⁷

Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.^37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.^39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.³⁸

GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.

Continue to: Reslizumab (Cinqair)...

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-­generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

Continue to: Both treatment groups...

Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV₁ for up to 5 years.⁵¹

The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.⁵²

In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.

Immunotherapy

Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).

Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.

Continue to: SCIT

SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.⁵³

SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.

The potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis.

A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.⁵⁴ A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.⁵⁵

In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.⁵⁶ Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.

Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.¹⁵

Continue to: Azithromycin

Azithromycin

Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.

The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.⁵⁷ While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.

The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.⁵⁸

Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy

The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.⁵⁹

The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.

Continue to: A new era

We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.

It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.

CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; [email protected]

Almost all patients who develop gastrointestinal side effects from oral immunotherapy for severe food allergies develop some degree of esophageal eosinophilia, but that eventually resolves in most of them after a year of treatment, according to results of a pilot study that was to be presented at the American Academy of Allergy, Asthma & Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

The findings may help identify biomarkers of persistent eosinophilia despite oral immunotherapy.

In January of this year the Food and Drug Administration approved oral immunotherapy (OIT), known as peanut allergen powder-dnfp, or peanut OIT (POIT), for severe food allergies. In an interview, lead study author Benjamin Wright, MD, of the Mayo Clinic, Phoenix, said OIT is a “promising proactive” treatment for food allergies. “But questions regarding the safety of immunotherapy remain,” he said. “About 30% of patients can develop GI side effects, including abdominal pain and vomiting; most concerning is that some patients develop eosinophilic esophagitis (EoE).”

The pilot study was a mechanistic substudy of 20 adult patients with immunoglobulin E–mediated peanut allergies enrolled in the phase 2 Peanut Oral Immunotherapy Safety, Efficacy and Discovery trial (POISED), with 15 randomized to treatment and the remainder to placebo. They had serial gastrointestinal biopsies at baseline (n = 20), 1 year (n = 7 treatment, 3 placebo) and 2 years (n = 7 treatment, 4 placebo) to evaluate eosinophils per high-power field (eos/hpf).

Baseline characteristics between the treatment and placebo groups were similar, with some having signs of preexisting disease. About 14% of them had clinically significant EoE, represented as a measure of more than 15 eos/hpf, Dr. Wright said. “One of the findings that was really fascinating to us was that all of the subjects had evidence of dilated intercellular spaces at baseline,” he said. “This indicates that all the subjects have some degree of epithelial barrier dysfunction before they start OIT.” Dilated intercellular spaces are a marker of inflammation.

Four patients in the treatment group had mild endoscopic findings at weeks 52 and 104, as did one patient on placebo, Dr. Wright said. A plot of eosinophil counts showed a peak at 52 weeks but near resolution at 104 weeks for all but one patient on OIT. “One of the most interesting trends that we noted was that, for most of patients, OIT-induced eosinophilia was transient and not fixed,” he said. “We noted a triangle pattern where tissue eosinophilia peaks and then resolves with the continuation of therapy.” EoE Histologic scoring system results followed a similar pattern in these patients, he added.

Also, results of the comprehensive GI Symptom Questionnaire, which assessed symptoms such as abdominal pain, difficulty swallowing, refusal to eat, and vomiting, showed that patient-reported GI symptoms did not correlate with tissue eosinophilia, Dr. Wright said. “To us, that suggests that perhaps eosinophils are not central to disease pathology or symptom development in these patients,” he said.

However, the findings validate that, in a small number of patients, OIT induces EoE, Dr. Wright said. He used a treadmill analogy to explain how OIT influences epithelial remodeling in some patients. “We’re constantly renewing our esophageal epithelium every 2 weeks, and when you challenge it with an antigen (i.e., OIT), the treadmill speeds up,” he said. “There may be some patients who will fall if the treadmill gets too fast, and they develop disease.”

He added, “Distinguishing someone’s fitness before they get on the treadmill is really going be a key moving forward in determining which subjects are good participants for OIT or how to dose OIT.”

Dr. Wright reported receiving grants from the Arizona Biomedical Research Consortium and Phoenix Children’s Hospital Foundation. Coauthors reported receiving grants from the National Institutes of Health and the Consortium for Food Allergy Research, as well as relationships with Aimmune Therapeutics, Regeneron Pharmaceuticals, Sanofi, Consortium for Food Allergy Research, DBV Technologies, Astellas, AnaptysBio, and Novartis.

SOURCE: Wright B et al. AAAAI, Session 2605, Abstract No. 259.

Almost all patients who develop gastrointestinal side effects from oral immunotherapy for severe food allergies develop some degree of esophageal eosinophilia, but that eventually resolves in most of them after a year of treatment, according to results of a pilot study that was to be presented at the American Academy of Allergy, Asthma & Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

The findings may help identify biomarkers of persistent eosinophilia despite oral immunotherapy.

In January of this year the Food and Drug Administration approved oral immunotherapy (OIT), known as peanut allergen powder-dnfp, or peanut OIT (POIT), for severe food allergies. In an interview, lead study author Benjamin Wright, MD, of the Mayo Clinic, Phoenix, said OIT is a “promising proactive” treatment for food allergies. “But questions regarding the safety of immunotherapy remain,” he said. “About 30% of patients can develop GI side effects, including abdominal pain and vomiting; most concerning is that some patients develop eosinophilic esophagitis (EoE).”

The pilot study was a mechanistic substudy of 20 adult patients with immunoglobulin E–mediated peanut allergies enrolled in the phase 2 Peanut Oral Immunotherapy Safety, Efficacy and Discovery trial (POISED), with 15 randomized to treatment and the remainder to placebo. They had serial gastrointestinal biopsies at baseline (n = 20), 1 year (n = 7 treatment, 3 placebo) and 2 years (n = 7 treatment, 4 placebo) to evaluate eosinophils per high-power field (eos/hpf).

Baseline characteristics between the treatment and placebo groups were similar, with some having signs of preexisting disease. About 14% of them had clinically significant EoE, represented as a measure of more than 15 eos/hpf, Dr. Wright said. “One of the findings that was really fascinating to us was that all of the subjects had evidence of dilated intercellular spaces at baseline,” he said. “This indicates that all the subjects have some degree of epithelial barrier dysfunction before they start OIT.” Dilated intercellular spaces are a marker of inflammation.

Four patients in the treatment group had mild endoscopic findings at weeks 52 and 104, as did one patient on placebo, Dr. Wright said. A plot of eosinophil counts showed a peak at 52 weeks but near resolution at 104 weeks for all but one patient on OIT. “One of the most interesting trends that we noted was that, for most of patients, OIT-induced eosinophilia was transient and not fixed,” he said. “We noted a triangle pattern where tissue eosinophilia peaks and then resolves with the continuation of therapy.” EoE Histologic scoring system results followed a similar pattern in these patients, he added.

Also, results of the comprehensive GI Symptom Questionnaire, which assessed symptoms such as abdominal pain, difficulty swallowing, refusal to eat, and vomiting, showed that patient-reported GI symptoms did not correlate with tissue eosinophilia, Dr. Wright said. “To us, that suggests that perhaps eosinophils are not central to disease pathology or symptom development in these patients,” he said.

However, the findings validate that, in a small number of patients, OIT induces EoE, Dr. Wright said. He used a treadmill analogy to explain how OIT influences epithelial remodeling in some patients. “We’re constantly renewing our esophageal epithelium every 2 weeks, and when you challenge it with an antigen (i.e., OIT), the treadmill speeds up,” he said. “There may be some patients who will fall if the treadmill gets too fast, and they develop disease.”

He added, “Distinguishing someone’s fitness before they get on the treadmill is really going be a key moving forward in determining which subjects are good participants for OIT or how to dose OIT.”

Dr. Wright reported receiving grants from the Arizona Biomedical Research Consortium and Phoenix Children’s Hospital Foundation. Coauthors reported receiving grants from the National Institutes of Health and the Consortium for Food Allergy Research, as well as relationships with Aimmune Therapeutics, Regeneron Pharmaceuticals, Sanofi, Consortium for Food Allergy Research, DBV Technologies, Astellas, AnaptysBio, and Novartis.

SOURCE: Wright B et al. AAAAI, Session 2605, Abstract No. 259.

Almost all patients who develop gastrointestinal side effects from oral immunotherapy for severe food allergies develop some degree of esophageal eosinophilia, but that eventually resolves in most of them after a year of treatment, according to results of a pilot study that was to be presented at the American Academy of Allergy, Asthma & Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

The findings may help identify biomarkers of persistent eosinophilia despite oral immunotherapy.

In January of this year the Food and Drug Administration approved oral immunotherapy (OIT), known as peanut allergen powder-dnfp, or peanut OIT (POIT), for severe food allergies. In an interview, lead study author Benjamin Wright, MD, of the Mayo Clinic, Phoenix, said OIT is a “promising proactive” treatment for food allergies. “But questions regarding the safety of immunotherapy remain,” he said. “About 30% of patients can develop GI side effects, including abdominal pain and vomiting; most concerning is that some patients develop eosinophilic esophagitis (EoE).”

The pilot study was a mechanistic substudy of 20 adult patients with immunoglobulin E–mediated peanut allergies enrolled in the phase 2 Peanut Oral Immunotherapy Safety, Efficacy and Discovery trial (POISED), with 15 randomized to treatment and the remainder to placebo. They had serial gastrointestinal biopsies at baseline (n = 20), 1 year (n = 7 treatment, 3 placebo) and 2 years (n = 7 treatment, 4 placebo) to evaluate eosinophils per high-power field (eos/hpf).

Baseline characteristics between the treatment and placebo groups were similar, with some having signs of preexisting disease. About 14% of them had clinically significant EoE, represented as a measure of more than 15 eos/hpf, Dr. Wright said. “One of the findings that was really fascinating to us was that all of the subjects had evidence of dilated intercellular spaces at baseline,” he said. “This indicates that all the subjects have some degree of epithelial barrier dysfunction before they start OIT.” Dilated intercellular spaces are a marker of inflammation.

Four patients in the treatment group had mild endoscopic findings at weeks 52 and 104, as did one patient on placebo, Dr. Wright said. A plot of eosinophil counts showed a peak at 52 weeks but near resolution at 104 weeks for all but one patient on OIT. “One of the most interesting trends that we noted was that, for most of patients, OIT-induced eosinophilia was transient and not fixed,” he said. “We noted a triangle pattern where tissue eosinophilia peaks and then resolves with the continuation of therapy.” EoE Histologic scoring system results followed a similar pattern in these patients, he added.

Also, results of the comprehensive GI Symptom Questionnaire, which assessed symptoms such as abdominal pain, difficulty swallowing, refusal to eat, and vomiting, showed that patient-reported GI symptoms did not correlate with tissue eosinophilia, Dr. Wright said. “To us, that suggests that perhaps eosinophils are not central to disease pathology or symptom development in these patients,” he said.

However, the findings validate that, in a small number of patients, OIT induces EoE, Dr. Wright said. He used a treadmill analogy to explain how OIT influences epithelial remodeling in some patients. “We’re constantly renewing our esophageal epithelium every 2 weeks, and when you challenge it with an antigen (i.e., OIT), the treadmill speeds up,” he said. “There may be some patients who will fall if the treadmill gets too fast, and they develop disease.”

He added, “Distinguishing someone’s fitness before they get on the treadmill is really going be a key moving forward in determining which subjects are good participants for OIT or how to dose OIT.”

Dr. Wright reported receiving grants from the Arizona Biomedical Research Consortium and Phoenix Children’s Hospital Foundation. Coauthors reported receiving grants from the National Institutes of Health and the Consortium for Food Allergy Research, as well as relationships with Aimmune Therapeutics, Regeneron Pharmaceuticals, Sanofi, Consortium for Food Allergy Research, DBV Technologies, Astellas, AnaptysBio, and Novartis.

SOURCE: Wright B et al. AAAAI, Session 2605, Abstract No. 259.

A small-molecule kinase inhibitor that targets a gene mutation complicit in systemic mastocytosis has been found to reduce symptoms by about 30%, according to early results of a clinical trial scheduled to be presented at the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

“This correlates with reduction from very severe to moderate or from moderate to mild category, and all the reductions in symptoms were statistically significant,” Cem Akin, MD, of the University of Michigan, Ann Arbor, said in an interview. He reported on part 1 of the phase 2 PIONEER trial of the kinase inhibitor avapritinib, described as a potent and highly selective inhibitor of the KIT D816V mutation that affects 90% of patients with systemic mastocytosis.

Currently, Dr. Akin noted, patients with indolent or smoldering systemic mastocytosis must rely on over-the-counter antihistamines used for seasonal allergies. “These patients use antihistamines in higher doses because mastocytosis patients have higher counts of mast cells that release histamines that cause a variety of symptoms,” he said. Symptoms, which can occur suddenly, include flushing and reactions that resemble allergic or anaphylactic reactions.

The purpose of the part 1 study was to evaluate three different dosing levels of avapritinib vs. placebo: 25, 50, and 100 mg. Ten patients were in each dosing group and nine were in the placebo group. The primary outcome was reduction in total symptom scores at 16 weeks as measured by the Indolent SM Symptom Assessment Form. “All three dose groups showed significant reductions in total symptom scores as well as specific symptoms that were most bothersome to the patient, whether skin symptoms or GI or neurocognitive symptoms,” Dr. Akin said. “All three doses were effective; the average reduction was about 30% compared to baseline.” Specifically, 25-mg dosing showed an average 30% reduction, 50-mg dosing showed an average 19% reduction, and 100-mg dosing showed an average 35% reduction.

The researchers determined that the 25-mg daily dose was the most effective and safest, with no patients on the dose reporting grade 3 adverse events, Dr. Akin said. In total 20% and 40% of the 50- and 100-mg dose groups, respectively, reported grade 3 AEs, according to study results.* The 25-mg daily dose will be evaluated in part 2 of the trial. The trial is estimated to enroll 112 total patients, according to the ClinicalTrials.gov filing. In part 3, patients who complete parts 1 or 2, including those initially randomized to placebo, may participate in a long-term open-label extension, receiving 25 mg avapritinib plus best supportive care.

“This is targeting a population whose symptoms are not controlled by antihistamines, based on a minimum total symptom score according to diaries they fill out, and they have to be on at least two different systemic medications – antihistamine or proton-pump inhibitor and leukotriene inhibitor – and they still have significant symptoms,” Dr. Akin said. He estimated that this describes about two-thirds of his patients with indolent or smoldering systematic mastocytosis.

“This is a disease that also takes a psychological toll,” he said. “This is a problem that starts in the bone marrow; it is similar to a hematological stem-cell disorder that affects the mast cell progenitor and it’s caused by a mutation that has not been particularly targeted until this drug,” he said. While most of these patients live with a benign mastocytosis their entire lives, the symptoms can be debilitating to the point where the disease disrupts and restricts social activities and comprises their quality of life, he said.

“This is a groundbreaking therapy that will change the way we think about mastocytosis treatment going forward,” Dr. Akin said. “It’s the first time we are actually targeting the underlying mutation that’s causing the disease, in terms of reducing directly that mutation as opposed to just treating the symptoms in indolent disease.”

Scheduled session moderator Anil Nanda, MD, of the Asthma and Allergy Center in Lewisville, Texas, said the findings are encouraging. “As a practicing allergist and immunologist in the community, it is very exciting to have a potential new treatment option for indolent or smoldering systemic mastocytosis,” he said via email. “Patients appreciate new options in therapy.”

Dr. Akin, the primary investigator, receives funding from and serves as a consultant for Blueprint Medicines, which sponsored the trial. He also disclosed a financial relationship with Novartis.

SOURCE: Akin C et al. AAAAI 2020, Presentation L5.

*Correction, 4/6/2020: An earlier version of this story misstated the percentage of grade 3 adverse events. In total 20% and 40% of the 50- and 100-mg dose groups, respectively, reported grade 3 adverse events.  

A small-molecule kinase inhibitor that targets a gene mutation complicit in systemic mastocytosis has been found to reduce symptoms by about 30%, according to early results of a clinical trial scheduled to be presented at the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

“This correlates with reduction from very severe to moderate or from moderate to mild category, and all the reductions in symptoms were statistically significant,” Cem Akin, MD, of the University of Michigan, Ann Arbor, said in an interview. He reported on part 1 of the phase 2 PIONEER trial of the kinase inhibitor avapritinib, described as a potent and highly selective inhibitor of the KIT D816V mutation that affects 90% of patients with systemic mastocytosis.

Currently, Dr. Akin noted, patients with indolent or smoldering systemic mastocytosis must rely on over-the-counter antihistamines used for seasonal allergies. “These patients use antihistamines in higher doses because mastocytosis patients have higher counts of mast cells that release histamines that cause a variety of symptoms,” he said. Symptoms, which can occur suddenly, include flushing and reactions that resemble allergic or anaphylactic reactions.

The purpose of the part 1 study was to evaluate three different dosing levels of avapritinib vs. placebo: 25, 50, and 100 mg. Ten patients were in each dosing group and nine were in the placebo group. The primary outcome was reduction in total symptom scores at 16 weeks as measured by the Indolent SM Symptom Assessment Form. “All three dose groups showed significant reductions in total symptom scores as well as specific symptoms that were most bothersome to the patient, whether skin symptoms or GI or neurocognitive symptoms,” Dr. Akin said. “All three doses were effective; the average reduction was about 30% compared to baseline.” Specifically, 25-mg dosing showed an average 30% reduction, 50-mg dosing showed an average 19% reduction, and 100-mg dosing showed an average 35% reduction.

The researchers determined that the 25-mg daily dose was the most effective and safest, with no patients on the dose reporting grade 3 adverse events, Dr. Akin said. In total 20% and 40% of the 50- and 100-mg dose groups, respectively, reported grade 3 AEs, according to study results.* The 25-mg daily dose will be evaluated in part 2 of the trial. The trial is estimated to enroll 112 total patients, according to the ClinicalTrials.gov filing. In part 3, patients who complete parts 1 or 2, including those initially randomized to placebo, may participate in a long-term open-label extension, receiving 25 mg avapritinib plus best supportive care.

“This is targeting a population whose symptoms are not controlled by antihistamines, based on a minimum total symptom score according to diaries they fill out, and they have to be on at least two different systemic medications – antihistamine or proton-pump inhibitor and leukotriene inhibitor – and they still have significant symptoms,” Dr. Akin said. He estimated that this describes about two-thirds of his patients with indolent or smoldering systematic mastocytosis.

“This is a disease that also takes a psychological toll,” he said. “This is a problem that starts in the bone marrow; it is similar to a hematological stem-cell disorder that affects the mast cell progenitor and it’s caused by a mutation that has not been particularly targeted until this drug,” he said. While most of these patients live with a benign mastocytosis their entire lives, the symptoms can be debilitating to the point where the disease disrupts and restricts social activities and comprises their quality of life, he said.

“This is a groundbreaking therapy that will change the way we think about mastocytosis treatment going forward,” Dr. Akin said. “It’s the first time we are actually targeting the underlying mutation that’s causing the disease, in terms of reducing directly that mutation as opposed to just treating the symptoms in indolent disease.”

Scheduled session moderator Anil Nanda, MD, of the Asthma and Allergy Center in Lewisville, Texas, said the findings are encouraging. “As a practicing allergist and immunologist in the community, it is very exciting to have a potential new treatment option for indolent or smoldering systemic mastocytosis,” he said via email. “Patients appreciate new options in therapy.”

Dr. Akin, the primary investigator, receives funding from and serves as a consultant for Blueprint Medicines, which sponsored the trial. He also disclosed a financial relationship with Novartis.

SOURCE: Akin C et al. AAAAI 2020, Presentation L5.

*Correction, 4/6/2020: An earlier version of this story misstated the percentage of grade 3 adverse events. In total 20% and 40% of the 50- and 100-mg dose groups, respectively, reported grade 3 adverse events.  

A small-molecule kinase inhibitor that targets a gene mutation complicit in systemic mastocytosis has been found to reduce symptoms by about 30%, according to early results of a clinical trial scheduled to be presented at the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

“This correlates with reduction from very severe to moderate or from moderate to mild category, and all the reductions in symptoms were statistically significant,” Cem Akin, MD, of the University of Michigan, Ann Arbor, said in an interview. He reported on part 1 of the phase 2 PIONEER trial of the kinase inhibitor avapritinib, described as a potent and highly selective inhibitor of the KIT D816V mutation that affects 90% of patients with systemic mastocytosis.

Currently, Dr. Akin noted, patients with indolent or smoldering systemic mastocytosis must rely on over-the-counter antihistamines used for seasonal allergies. “These patients use antihistamines in higher doses because mastocytosis patients have higher counts of mast cells that release histamines that cause a variety of symptoms,” he said. Symptoms, which can occur suddenly, include flushing and reactions that resemble allergic or anaphylactic reactions.

The purpose of the part 1 study was to evaluate three different dosing levels of avapritinib vs. placebo: 25, 50, and 100 mg. Ten patients were in each dosing group and nine were in the placebo group. The primary outcome was reduction in total symptom scores at 16 weeks as measured by the Indolent SM Symptom Assessment Form. “All three dose groups showed significant reductions in total symptom scores as well as specific symptoms that were most bothersome to the patient, whether skin symptoms or GI or neurocognitive symptoms,” Dr. Akin said. “All three doses were effective; the average reduction was about 30% compared to baseline.” Specifically, 25-mg dosing showed an average 30% reduction, 50-mg dosing showed an average 19% reduction, and 100-mg dosing showed an average 35% reduction.

The researchers determined that the 25-mg daily dose was the most effective and safest, with no patients on the dose reporting grade 3 adverse events, Dr. Akin said. In total 20% and 40% of the 50- and 100-mg dose groups, respectively, reported grade 3 AEs, according to study results.* The 25-mg daily dose will be evaluated in part 2 of the trial. The trial is estimated to enroll 112 total patients, according to the ClinicalTrials.gov filing. In part 3, patients who complete parts 1 or 2, including those initially randomized to placebo, may participate in a long-term open-label extension, receiving 25 mg avapritinib plus best supportive care.

“This is targeting a population whose symptoms are not controlled by antihistamines, based on a minimum total symptom score according to diaries they fill out, and they have to be on at least two different systemic medications – antihistamine or proton-pump inhibitor and leukotriene inhibitor – and they still have significant symptoms,” Dr. Akin said. He estimated that this describes about two-thirds of his patients with indolent or smoldering systematic mastocytosis.

“This is a disease that also takes a psychological toll,” he said. “This is a problem that starts in the bone marrow; it is similar to a hematological stem-cell disorder that affects the mast cell progenitor and it’s caused by a mutation that has not been particularly targeted until this drug,” he said. While most of these patients live with a benign mastocytosis their entire lives, the symptoms can be debilitating to the point where the disease disrupts and restricts social activities and comprises their quality of life, he said.

“This is a groundbreaking therapy that will change the way we think about mastocytosis treatment going forward,” Dr. Akin said. “It’s the first time we are actually targeting the underlying mutation that’s causing the disease, in terms of reducing directly that mutation as opposed to just treating the symptoms in indolent disease.”

Scheduled session moderator Anil Nanda, MD, of the Asthma and Allergy Center in Lewisville, Texas, said the findings are encouraging. “As a practicing allergist and immunologist in the community, it is very exciting to have a potential new treatment option for indolent or smoldering systemic mastocytosis,” he said via email. “Patients appreciate new options in therapy.”

Dr. Akin, the primary investigator, receives funding from and serves as a consultant for Blueprint Medicines, which sponsored the trial. He also disclosed a financial relationship with Novartis.

SOURCE: Akin C et al. AAAAI 2020, Presentation L5.

*Correction, 4/6/2020: An earlier version of this story misstated the percentage of grade 3 adverse events. In total 20% and 40% of the 50- and 100-mg dose groups, respectively, reported grade 3 adverse events.  

Infants who are hospitalized for severe bronchiolitis and receive acid-suppressant medications may be at risk of developing allergic disease by age 3 years, according to recent research released as an abstract for the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting.

The AAAAI canceled their annual meeting and provided abstracts and access to presenters for press coverage

“Among children with a history of severe bronchiolitis during infancy, exposure to acid-suppressant medications during infancy further increases the risk of developing recurrent wheeze by age 3 years,” Lacey B. Robinson, MD, of the division of rheumatology, allergy, and immunology in the department of medicine at Massachusetts General Hospital in Boston, said in an interview.

Bronchiolitis is a risk factor in infants for developing conditions such as recurrent wheeze and childhood asthma in early childhood. Acid-suppressant medications like proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) may further increase the risk of allergic disease. One study by Mitre et al. published in JAMA Pediatrics showed use of acid-suppressant medications in infants up to 6 months raised the risk of allergic disease (JAMA Pediatr. 2018;172[6]:e180315). Some studies suggest between 30% and 50% of infants diagnosed with bronchiolitis requiring hospitalization will develop asthma by age 5 years (J Allergy Clin Immunol Pract. 2017 Jan - Feb;5[1]:92-6).

“Children with severe bronchiolitis during infancy are at a high risk of developing recurrent wheeze and subsequent asthma. There is limited evidence to suggest that exposure to acid suppressant medications [such as proton pump inhibitors and histamine-2 receptor antagonists] prenatally and during early childhood increases the risk of childhood asthma,” Dr. Robinson said. “It is not known if exposure to acid suppressant medications during infancy further increases the risk of developing recurrent wheeze among high-risk children, such as in those with a history of severe bronchiolitis during infancy.”

Dr. Robinson and colleagues performed a multicenter, prospective cohort study of 921 infants who were hospitalized for severe bronchiolitis between 2011 and 2014. The investigators reviewed the medical records of the infants for acid suppressant medication use, as well as parent report of acid suppressant medication use, during an infant’s first 12 months. Overall, 879 children were analyzed after excluding for patients who developed recurrent wheeze prior to receiving acid suppressant medications, as well as patients with incomplete data. The investigators used the National Institutes of Health Guidelines for the Diagnosis and Management of Asthma (EPR-3) to define recurrent wheeze. A Cox-proportional hazard model was used to analyze the time to event, which was stratified by age and adjusted for confounders.

Infants with a history of severe bronchiolitis were at greater risk of developing recurrent wheeze by age 3 years after being exposed to acid-suppressant medications, compared with infants who were not exposed, Dr. Robinson said. Of the 879 infants in the final analysis, 159 (18%) received acid-suppressant medications, and 68 of 159 patients (43%) went on to develop recurrent wheeze, compared with 206 of 720 infants (29%) who were not exposed (unadjusted hazard ratio, 1.63; 95% confidence interval, 1.24-2.14).

After adjustment for confounders such as gender, race and ethnicity; gestational age; delivery type; severity of bronchiolitis; respiratory syncytial virus (RSV) infection status; maternal atopy; use of acid-suppressant medications during pregnancy; median household income; and insurance status, the association between recurrent wheeze and acid-suppressant medication use during infancy remained (adjusted HR, 1.54; 95% CI, 1.15-2.07).

“More research is needed on this important topic including studies in other populations,” such as in healthy children, Dr. Robinson said. “We encourage future research on this important and understudied topic, including further research on the potential underlying mechanisms of this association.”

Dr. Robinson reported no relevant financial disclosures.

SOURCE: Robinson L. AAAAI 2020, Abstract L1

Infants who are hospitalized for severe bronchiolitis and receive acid-suppressant medications may be at risk of developing allergic disease by age 3 years, according to recent research released as an abstract for the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting.

The AAAAI canceled their annual meeting and provided abstracts and access to presenters for press coverage

“Among children with a history of severe bronchiolitis during infancy, exposure to acid-suppressant medications during infancy further increases the risk of developing recurrent wheeze by age 3 years,” Lacey B. Robinson, MD, of the division of rheumatology, allergy, and immunology in the department of medicine at Massachusetts General Hospital in Boston, said in an interview.

Bronchiolitis is a risk factor in infants for developing conditions such as recurrent wheeze and childhood asthma in early childhood. Acid-suppressant medications like proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) may further increase the risk of allergic disease. One study by Mitre et al. published in JAMA Pediatrics showed use of acid-suppressant medications in infants up to 6 months raised the risk of allergic disease (JAMA Pediatr. 2018;172[6]:e180315). Some studies suggest between 30% and 50% of infants diagnosed with bronchiolitis requiring hospitalization will develop asthma by age 5 years (J Allergy Clin Immunol Pract. 2017 Jan - Feb;5[1]:92-6).

“Children with severe bronchiolitis during infancy are at a high risk of developing recurrent wheeze and subsequent asthma. There is limited evidence to suggest that exposure to acid suppressant medications [such as proton pump inhibitors and histamine-2 receptor antagonists] prenatally and during early childhood increases the risk of childhood asthma,” Dr. Robinson said. “It is not known if exposure to acid suppressant medications during infancy further increases the risk of developing recurrent wheeze among high-risk children, such as in those with a history of severe bronchiolitis during infancy.”

Dr. Robinson and colleagues performed a multicenter, prospective cohort study of 921 infants who were hospitalized for severe bronchiolitis between 2011 and 2014. The investigators reviewed the medical records of the infants for acid suppressant medication use, as well as parent report of acid suppressant medication use, during an infant’s first 12 months. Overall, 879 children were analyzed after excluding for patients who developed recurrent wheeze prior to receiving acid suppressant medications, as well as patients with incomplete data. The investigators used the National Institutes of Health Guidelines for the Diagnosis and Management of Asthma (EPR-3) to define recurrent wheeze. A Cox-proportional hazard model was used to analyze the time to event, which was stratified by age and adjusted for confounders.

Infants with a history of severe bronchiolitis were at greater risk of developing recurrent wheeze by age 3 years after being exposed to acid-suppressant medications, compared with infants who were not exposed, Dr. Robinson said. Of the 879 infants in the final analysis, 159 (18%) received acid-suppressant medications, and 68 of 159 patients (43%) went on to develop recurrent wheeze, compared with 206 of 720 infants (29%) who were not exposed (unadjusted hazard ratio, 1.63; 95% confidence interval, 1.24-2.14).

After adjustment for confounders such as gender, race and ethnicity; gestational age; delivery type; severity of bronchiolitis; respiratory syncytial virus (RSV) infection status; maternal atopy; use of acid-suppressant medications during pregnancy; median household income; and insurance status, the association between recurrent wheeze and acid-suppressant medication use during infancy remained (adjusted HR, 1.54; 95% CI, 1.15-2.07).

“More research is needed on this important topic including studies in other populations,” such as in healthy children, Dr. Robinson said. “We encourage future research on this important and understudied topic, including further research on the potential underlying mechanisms of this association.”

Dr. Robinson reported no relevant financial disclosures.

SOURCE: Robinson L. AAAAI 2020, Abstract L1

Infants who are hospitalized for severe bronchiolitis and receive acid-suppressant medications may be at risk of developing allergic disease by age 3 years, according to recent research released as an abstract for the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting.

The AAAAI canceled their annual meeting and provided abstracts and access to presenters for press coverage

“Among children with a history of severe bronchiolitis during infancy, exposure to acid-suppressant medications during infancy further increases the risk of developing recurrent wheeze by age 3 years,” Lacey B. Robinson, MD, of the division of rheumatology, allergy, and immunology in the department of medicine at Massachusetts General Hospital in Boston, said in an interview.

Bronchiolitis is a risk factor in infants for developing conditions such as recurrent wheeze and childhood asthma in early childhood. Acid-suppressant medications like proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) may further increase the risk of allergic disease. One study by Mitre et al. published in JAMA Pediatrics showed use of acid-suppressant medications in infants up to 6 months raised the risk of allergic disease (JAMA Pediatr. 2018;172[6]:e180315). Some studies suggest between 30% and 50% of infants diagnosed with bronchiolitis requiring hospitalization will develop asthma by age 5 years (J Allergy Clin Immunol Pract. 2017 Jan - Feb;5[1]:92-6).

“Children with severe bronchiolitis during infancy are at a high risk of developing recurrent wheeze and subsequent asthma. There is limited evidence to suggest that exposure to acid suppressant medications [such as proton pump inhibitors and histamine-2 receptor antagonists] prenatally and during early childhood increases the risk of childhood asthma,” Dr. Robinson said. “It is not known if exposure to acid suppressant medications during infancy further increases the risk of developing recurrent wheeze among high-risk children, such as in those with a history of severe bronchiolitis during infancy.”

Dr. Robinson and colleagues performed a multicenter, prospective cohort study of 921 infants who were hospitalized for severe bronchiolitis between 2011 and 2014. The investigators reviewed the medical records of the infants for acid suppressant medication use, as well as parent report of acid suppressant medication use, during an infant’s first 12 months. Overall, 879 children were analyzed after excluding for patients who developed recurrent wheeze prior to receiving acid suppressant medications, as well as patients with incomplete data. The investigators used the National Institutes of Health Guidelines for the Diagnosis and Management of Asthma (EPR-3) to define recurrent wheeze. A Cox-proportional hazard model was used to analyze the time to event, which was stratified by age and adjusted for confounders.

Infants with a history of severe bronchiolitis were at greater risk of developing recurrent wheeze by age 3 years after being exposed to acid-suppressant medications, compared with infants who were not exposed, Dr. Robinson said. Of the 879 infants in the final analysis, 159 (18%) received acid-suppressant medications, and 68 of 159 patients (43%) went on to develop recurrent wheeze, compared with 206 of 720 infants (29%) who were not exposed (unadjusted hazard ratio, 1.63; 95% confidence interval, 1.24-2.14).

After adjustment for confounders such as gender, race and ethnicity; gestational age; delivery type; severity of bronchiolitis; respiratory syncytial virus (RSV) infection status; maternal atopy; use of acid-suppressant medications during pregnancy; median household income; and insurance status, the association between recurrent wheeze and acid-suppressant medication use during infancy remained (adjusted HR, 1.54; 95% CI, 1.15-2.07).

“More research is needed on this important topic including studies in other populations,” such as in healthy children, Dr. Robinson said. “We encourage future research on this important and understudied topic, including further research on the potential underlying mechanisms of this association.”

Dr. Robinson reported no relevant financial disclosures.

SOURCE: Robinson L. AAAAI 2020, Abstract L1