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FDA reverses warning on LABA-containing asthma medications
The combination a by 17%, without increasing the risk of asthma-related intubation or death.
An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.
“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.
The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.
In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.
“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.
The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.
Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.
Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.
However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.
The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.
“… Our data provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report 3 of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus,” the committee wrote. “Finally, our combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for asthma treatment.”
Dr. Busse disclosed financial relationships with a number of pharmaceutical companies, including Novartis, but noted that none of them were relevant to this work.
SOURCE: Busse WW et al. N Engl J Med. 2018;78:2497-505.
It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory committee meeting.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory committee meeting.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory committee meeting.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
The combination a by 17%, without increasing the risk of asthma-related intubation or death.
An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.
“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.
The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.
In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.
“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.
The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.
Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.
Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.
However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.
The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.
“… Our data provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report 3 of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus,” the committee wrote. “Finally, our combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for asthma treatment.”
Dr. Busse disclosed financial relationships with a number of pharmaceutical companies, including Novartis, but noted that none of them were relevant to this work.
SOURCE: Busse WW et al. N Engl J Med. 2018;78:2497-505.
The combination a by 17%, without increasing the risk of asthma-related intubation or death.
An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.
“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.
The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.
In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.
“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.
The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.
Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.
Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.
However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.
The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.
“… Our data provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report 3 of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus,” the committee wrote. “Finally, our combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for asthma treatment.”
Dr. Busse disclosed financial relationships with a number of pharmaceutical companies, including Novartis, but noted that none of them were relevant to this work.
SOURCE: Busse WW et al. N Engl J Med. 2018;78:2497-505.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Combination LABA/inhaled glucocorticoid products appear safe for patients with asthma.
Major finding: The products reduced the risk of an asthma exacerbation by 17%, without increasing the risk of a serious adverse outcome.
Study details: The four randomized studies comprised more than 13,000 patients.
Disclosures: The studies were sponsored by AstraZeneca, GlaxoSmithKline, Merck, and Novartis. Dr. Busse disclosed a financial relationship with Novartis, but said it was not relevant to this work.
Source: Busse WW. N Engl J Med. 2018;78:2497-505.
Dupilumab reduces exacerbations, cuts glucocorticoid use in moderate to severe asthma
Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.
The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.
By week 12, FEV1 it had already increased by 0.32 L, they said.
“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”
Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
Liberty Asthma Quest
This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.
Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.
Both doses outperformed placebo in all endpoints.
Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.
The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.
By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.
Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.
The benefit was already noticeable by the 2-week evaluation, the investigators noted.
Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).
Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
Liberty Asthma Venture
In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.
These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.
Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.
By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.
Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”
In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.
Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.
Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.
The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.
Antidrug antibodies developed in five patients in each group, without clinical effect.
Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.
Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.
The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.
By week 12, FEV1 it had already increased by 0.32 L, they said.
“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”
Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
Liberty Asthma Quest
This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.
Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.
Both doses outperformed placebo in all endpoints.
Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.
The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.
By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.
Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.
The benefit was already noticeable by the 2-week evaluation, the investigators noted.
Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).
Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
Liberty Asthma Venture
In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.
These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.
Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.
By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.
Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”
In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.
Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.
Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.
The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.
Antidrug antibodies developed in five patients in each group, without clinical effect.
Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.
Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.
The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.
By week 12, FEV1 it had already increased by 0.32 L, they said.
“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”
Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
Liberty Asthma Quest
This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.
Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.
Both doses outperformed placebo in all endpoints.
Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.
The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.
By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.
Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.
The benefit was already noticeable by the 2-week evaluation, the investigators noted.
Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).
Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
Liberty Asthma Venture
In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.
These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.
Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.
By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.
Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”
In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.
Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.
Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.
The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.
Antidrug antibodies developed in five patients in each group, without clinical effect.
Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Dupilumab allowed asthma patients to decrease glucocorticoids with no risk of asthma exacerbation.
Major finding: Dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%.
Study details: Liberty Asthma Quest comprised 1,902 patients and Liberty Asthma Venture comprised 210. Both were randomized, placebo-controlled trials.
Disclosures: Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
Sources: Castro M et al. N Engl J Med. 2018;378:2486-96; Rabe KF et al. N Engl J Med. 2018;378:2475-85.
Pediatric asthma patients should be considered priority for flu vaccine
Children with asthma who present to emergency departments for treatment are significantly more likely to test positive for one or more respiratory pathogens, reported Dr. Joanna Merckx of the Montreal Children’s Hospital at the McGill University Health Centre, and her associates.
Nearly two-thirds of patients tested positive for one or more respiratory viruses in a study conducted by Dr. Merckx and her associates. “Given the documented safety of influenza immunization in children with asthma and its expected protective effect,” such cases should be among those prioritized to receive influenza immunization.
In reviewing the findings of the study, Dr. Merckx and her colleagues sought to determine whether closely evaluating the effects of specific respiratory pathogens could be useful in further developing appropriate preventive treatments for children with asthma; improving efforts to diagnose pathogens at the time of ED treatment; and identifying patients at higher risk of treatment failure who could be candidates for more intensive treatment protocols.
Children aged 1-17 years presenting to one of five EDs in the Pediatric Emergency Research Canada network during 2011-2013 with moderate or severe asthma flares were considered for the study. All eligible DOORWAY study participants with a valid respiratory specimen were included in the study and received a standardized dose of oral and bronchodilator treatment with salbutamol; those with severe exacerbations also received ipratropium bromide (Atrovent).
Within 1 hour of study inclusion, patients were tested by way of nasopharyngeal aspirate or swab. Patients identified with coinfection presented with two or more pathogens. Failure of ED management was defined as patients admitted to the hospital for asthma; ED treatment lasting 8 or more hours after corticosteroid treatment; or returns to the ED within 72 hours after discharge that led to hospital admission or prolonged ED stay.
Of 1,012 children enrolled in the study, 958 were assessed for worsening of asthma symptoms. Of the 958 respiratory specimens tested, 62% tested positive for one or more pathogens, 8.5% were found to have coinfection, of which respiratory syncytial virus (RSV) and coronavirus were the most frequent copathogens. Rhinovirus was the most prevalent pathogen, occurring in 29%, and of these, rhinovirus C was the most frequent species (18.2%), followed by RSV (17.9%); only two patients tested positive for Mycoplasma pneumoniae.
Children with a laboratory-confirmed pathogen were younger, had higher tobacco exposure, and were slightly more likely to present with fever (29% vs. 24%), compared with children without a laboratory-confirmed pathogen. Children with rhinovirus were less often febrile (16% vs 41%) and less frequently diagnosed with pneumonia (5% vs. 16%.) than those without a rhinovirus infection The proportion of children presenting with a severe exacerbation of asthma was 33%.
Overall, 17% of patients experienced treatment failure. Those with current respiratory infection were at increased risk of treatment failure, for a risk difference of 8% (95% confidence interval, 3.3%-13.1%). RSV, influenza, and parainfluenza virus (PIV) were associated with 21%, 38%, and 47% higher risks of treatment failure, respectively, noted Dr. Merckx and her associates. These resulted in absolute risks of 9%, 25%, and 34%, respectively, the authors reported in Pediatrics.
Coronavirus, adenovirus, enterovirus D68, and the presence of a coinfection, however, were not found to increase the risk of treatment failure, they noted.
Although rhinovirus may play a role in triggering reactions that require medical attention, such cases still appear to respond favorably to treatment, they said.
A separate study cited by Dr. Merckx and her associates observed the same outcome for rhinovirus patients but more patients diagnosed with nonrhinovirus pathogens, especially human metapneumovirus (hMPV) and PIV, had moderate, rather than severe, symptoms and were much more likely to experience higher treatment failure, particularly those infected with RSV, influenza, and PIV.
“It appears reasonable to pursue strategies to improve immunization coverage for influenza and invest in efforts for the development of vaccines for RSV and rhinovirus,” they said.
In cases in which respiratory pathogens were present (especially nonrhinovirus pathogens), greater treatment failure occurred, despite use of inhaler and corticosteroids. The researchers noted that severity of condition at time of treatment and patient response to treatment should be considered as two separate, distinct dimensions of viral infection impact in children with acute asthma. “The high prevalence of rhinovirus C in children presenting with asthma exacerbation, its presumed association with asthma-related hospitalization, and its peak in the fall,” also should be considered as a leading cause for more potential severe disease.
Dr. Merckx and her associates did point to several possibly significant implications with their findings. Intensifying treatment using inhaled anticholinergics or magnesium sulfate could block the vagally mediated reflex bronchoconstriction typically seen in cases of asthma exacerbation worsened by viral infection. Although these therapies currently only are used only in severe reactions, it may be useful to examine their efficacy in any cases triggered by RSV, influenza, and PIV because these have been associated with a poor treatment response.
While it still is necessary to clarify its mechanism of action, azithromycin’s demonstrated benefit in preschoolers with severe reactions suggests it could be a possible alternative pathogen–nonspecific therapy to address antineutrophilic inflammation, they said.
Any treatment intensification would first require clear identification of responsible pathogens using on-site diagnostic measures in the ED. Until such testing is possible, preventive measures need to be prioritized, they advised.
Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.
SOURCE: Merckx J et al. Pediatrics. 2018 Jun;142(1):e20174105.
Children with asthma who present to emergency departments for treatment are significantly more likely to test positive for one or more respiratory pathogens, reported Dr. Joanna Merckx of the Montreal Children’s Hospital at the McGill University Health Centre, and her associates.
Nearly two-thirds of patients tested positive for one or more respiratory viruses in a study conducted by Dr. Merckx and her associates. “Given the documented safety of influenza immunization in children with asthma and its expected protective effect,” such cases should be among those prioritized to receive influenza immunization.
In reviewing the findings of the study, Dr. Merckx and her colleagues sought to determine whether closely evaluating the effects of specific respiratory pathogens could be useful in further developing appropriate preventive treatments for children with asthma; improving efforts to diagnose pathogens at the time of ED treatment; and identifying patients at higher risk of treatment failure who could be candidates for more intensive treatment protocols.
Children aged 1-17 years presenting to one of five EDs in the Pediatric Emergency Research Canada network during 2011-2013 with moderate or severe asthma flares were considered for the study. All eligible DOORWAY study participants with a valid respiratory specimen were included in the study and received a standardized dose of oral and bronchodilator treatment with salbutamol; those with severe exacerbations also received ipratropium bromide (Atrovent).
Within 1 hour of study inclusion, patients were tested by way of nasopharyngeal aspirate or swab. Patients identified with coinfection presented with two or more pathogens. Failure of ED management was defined as patients admitted to the hospital for asthma; ED treatment lasting 8 or more hours after corticosteroid treatment; or returns to the ED within 72 hours after discharge that led to hospital admission or prolonged ED stay.
Of 1,012 children enrolled in the study, 958 were assessed for worsening of asthma symptoms. Of the 958 respiratory specimens tested, 62% tested positive for one or more pathogens, 8.5% were found to have coinfection, of which respiratory syncytial virus (RSV) and coronavirus were the most frequent copathogens. Rhinovirus was the most prevalent pathogen, occurring in 29%, and of these, rhinovirus C was the most frequent species (18.2%), followed by RSV (17.9%); only two patients tested positive for Mycoplasma pneumoniae.
Children with a laboratory-confirmed pathogen were younger, had higher tobacco exposure, and were slightly more likely to present with fever (29% vs. 24%), compared with children without a laboratory-confirmed pathogen. Children with rhinovirus were less often febrile (16% vs 41%) and less frequently diagnosed with pneumonia (5% vs. 16%.) than those without a rhinovirus infection The proportion of children presenting with a severe exacerbation of asthma was 33%.
Overall, 17% of patients experienced treatment failure. Those with current respiratory infection were at increased risk of treatment failure, for a risk difference of 8% (95% confidence interval, 3.3%-13.1%). RSV, influenza, and parainfluenza virus (PIV) were associated with 21%, 38%, and 47% higher risks of treatment failure, respectively, noted Dr. Merckx and her associates. These resulted in absolute risks of 9%, 25%, and 34%, respectively, the authors reported in Pediatrics.
Coronavirus, adenovirus, enterovirus D68, and the presence of a coinfection, however, were not found to increase the risk of treatment failure, they noted.
Although rhinovirus may play a role in triggering reactions that require medical attention, such cases still appear to respond favorably to treatment, they said.
A separate study cited by Dr. Merckx and her associates observed the same outcome for rhinovirus patients but more patients diagnosed with nonrhinovirus pathogens, especially human metapneumovirus (hMPV) and PIV, had moderate, rather than severe, symptoms and were much more likely to experience higher treatment failure, particularly those infected with RSV, influenza, and PIV.
“It appears reasonable to pursue strategies to improve immunization coverage for influenza and invest in efforts for the development of vaccines for RSV and rhinovirus,” they said.
In cases in which respiratory pathogens were present (especially nonrhinovirus pathogens), greater treatment failure occurred, despite use of inhaler and corticosteroids. The researchers noted that severity of condition at time of treatment and patient response to treatment should be considered as two separate, distinct dimensions of viral infection impact in children with acute asthma. “The high prevalence of rhinovirus C in children presenting with asthma exacerbation, its presumed association with asthma-related hospitalization, and its peak in the fall,” also should be considered as a leading cause for more potential severe disease.
Dr. Merckx and her associates did point to several possibly significant implications with their findings. Intensifying treatment using inhaled anticholinergics or magnesium sulfate could block the vagally mediated reflex bronchoconstriction typically seen in cases of asthma exacerbation worsened by viral infection. Although these therapies currently only are used only in severe reactions, it may be useful to examine their efficacy in any cases triggered by RSV, influenza, and PIV because these have been associated with a poor treatment response.
While it still is necessary to clarify its mechanism of action, azithromycin’s demonstrated benefit in preschoolers with severe reactions suggests it could be a possible alternative pathogen–nonspecific therapy to address antineutrophilic inflammation, they said.
Any treatment intensification would first require clear identification of responsible pathogens using on-site diagnostic measures in the ED. Until such testing is possible, preventive measures need to be prioritized, they advised.
Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.
SOURCE: Merckx J et al. Pediatrics. 2018 Jun;142(1):e20174105.
Children with asthma who present to emergency departments for treatment are significantly more likely to test positive for one or more respiratory pathogens, reported Dr. Joanna Merckx of the Montreal Children’s Hospital at the McGill University Health Centre, and her associates.
Nearly two-thirds of patients tested positive for one or more respiratory viruses in a study conducted by Dr. Merckx and her associates. “Given the documented safety of influenza immunization in children with asthma and its expected protective effect,” such cases should be among those prioritized to receive influenza immunization.
In reviewing the findings of the study, Dr. Merckx and her colleagues sought to determine whether closely evaluating the effects of specific respiratory pathogens could be useful in further developing appropriate preventive treatments for children with asthma; improving efforts to diagnose pathogens at the time of ED treatment; and identifying patients at higher risk of treatment failure who could be candidates for more intensive treatment protocols.
Children aged 1-17 years presenting to one of five EDs in the Pediatric Emergency Research Canada network during 2011-2013 with moderate or severe asthma flares were considered for the study. All eligible DOORWAY study participants with a valid respiratory specimen were included in the study and received a standardized dose of oral and bronchodilator treatment with salbutamol; those with severe exacerbations also received ipratropium bromide (Atrovent).
Within 1 hour of study inclusion, patients were tested by way of nasopharyngeal aspirate or swab. Patients identified with coinfection presented with two or more pathogens. Failure of ED management was defined as patients admitted to the hospital for asthma; ED treatment lasting 8 or more hours after corticosteroid treatment; or returns to the ED within 72 hours after discharge that led to hospital admission or prolonged ED stay.
Of 1,012 children enrolled in the study, 958 were assessed for worsening of asthma symptoms. Of the 958 respiratory specimens tested, 62% tested positive for one or more pathogens, 8.5% were found to have coinfection, of which respiratory syncytial virus (RSV) and coronavirus were the most frequent copathogens. Rhinovirus was the most prevalent pathogen, occurring in 29%, and of these, rhinovirus C was the most frequent species (18.2%), followed by RSV (17.9%); only two patients tested positive for Mycoplasma pneumoniae.
Children with a laboratory-confirmed pathogen were younger, had higher tobacco exposure, and were slightly more likely to present with fever (29% vs. 24%), compared with children without a laboratory-confirmed pathogen. Children with rhinovirus were less often febrile (16% vs 41%) and less frequently diagnosed with pneumonia (5% vs. 16%.) than those without a rhinovirus infection The proportion of children presenting with a severe exacerbation of asthma was 33%.
Overall, 17% of patients experienced treatment failure. Those with current respiratory infection were at increased risk of treatment failure, for a risk difference of 8% (95% confidence interval, 3.3%-13.1%). RSV, influenza, and parainfluenza virus (PIV) were associated with 21%, 38%, and 47% higher risks of treatment failure, respectively, noted Dr. Merckx and her associates. These resulted in absolute risks of 9%, 25%, and 34%, respectively, the authors reported in Pediatrics.
Coronavirus, adenovirus, enterovirus D68, and the presence of a coinfection, however, were not found to increase the risk of treatment failure, they noted.
Although rhinovirus may play a role in triggering reactions that require medical attention, such cases still appear to respond favorably to treatment, they said.
A separate study cited by Dr. Merckx and her associates observed the same outcome for rhinovirus patients but more patients diagnosed with nonrhinovirus pathogens, especially human metapneumovirus (hMPV) and PIV, had moderate, rather than severe, symptoms and were much more likely to experience higher treatment failure, particularly those infected with RSV, influenza, and PIV.
“It appears reasonable to pursue strategies to improve immunization coverage for influenza and invest in efforts for the development of vaccines for RSV and rhinovirus,” they said.
In cases in which respiratory pathogens were present (especially nonrhinovirus pathogens), greater treatment failure occurred, despite use of inhaler and corticosteroids. The researchers noted that severity of condition at time of treatment and patient response to treatment should be considered as two separate, distinct dimensions of viral infection impact in children with acute asthma. “The high prevalence of rhinovirus C in children presenting with asthma exacerbation, its presumed association with asthma-related hospitalization, and its peak in the fall,” also should be considered as a leading cause for more potential severe disease.
Dr. Merckx and her associates did point to several possibly significant implications with their findings. Intensifying treatment using inhaled anticholinergics or magnesium sulfate could block the vagally mediated reflex bronchoconstriction typically seen in cases of asthma exacerbation worsened by viral infection. Although these therapies currently only are used only in severe reactions, it may be useful to examine their efficacy in any cases triggered by RSV, influenza, and PIV because these have been associated with a poor treatment response.
While it still is necessary to clarify its mechanism of action, azithromycin’s demonstrated benefit in preschoolers with severe reactions suggests it could be a possible alternative pathogen–nonspecific therapy to address antineutrophilic inflammation, they said.
Any treatment intensification would first require clear identification of responsible pathogens using on-site diagnostic measures in the ED. Until such testing is possible, preventive measures need to be prioritized, they advised.
Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.
SOURCE: Merckx J et al. Pediatrics. 2018 Jun;142(1):e20174105.
FROM PEDIATRICS
Key clinical point: Nearly two-thirds of emergency asthma cases test positive for multiple pathogens.
Major finding: Risk of treatment failure is higher with respiratory syncytial virus, influenza, and parainfluenza virus.
Study details: Ancillary multicenter, prospective, ethics-approved cohort study of 958 children with asthma.
Disclosures: Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.
Source: Merckx J et al. Pediatrics. 2018;142(1):e20174105.
As-needed budesonide-formoterol prevented exacerbations in mild asthma
according to the results of two large, double-blind, 52-week, randomized phase 3 trials.
In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.
Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.
In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).
Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.
In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.
Results from both trials suggested that as-needed budesonide-formoterol provided better symptom control than did terbutaline but worse symptom control than did twice-daily budesonide. In SYGMA1, the change from baseline on the Asthma Control Questionnaire-5 (ACQ-5) favored budesonide-formoterol over terbutaline by an average of 0.15 units and similarly favored twice-daily budesonide over budesonide-formoterol. In SYGMA2, the budesonide maintenance group averaged 0.11 units greater improvement on the ACQ-5 and 0.10 better improvement on the standardized Asthma Quality of Life Questionnaire, compared with as-needed budesonide-formoterol recipients.
Finally, lung function assessments favored as-needed budesonide-formoterol over terbutaline but not over maintenance budesonide. SYGMA1, mean changes (from baseline) in FEV1 before bronchodilator use were 11.2 mL with terbutaline, 65.0 mL with budesonide-formoterol, and 119.3 mL with maintenance budesonide. In SYGMA2, these values were 104 mL with budesonide-formoterol and 136.6 mL with maintenance budesonide.
AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
SOURCES: O’Byrne PM et al. N Engl J Med. 2018;378(20):1865-76.Bateman ED et al. N Engl J Med. 2018;378(20):1877-87.
In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.
“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.
Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.
Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”
Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).
In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.
“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.
Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.
Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”
Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).
In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.
“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.
Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.
Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”
Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).
according to the results of two large, double-blind, 52-week, randomized phase 3 trials.
In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.
Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.
In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).
Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.
In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.
Results from both trials suggested that as-needed budesonide-formoterol provided better symptom control than did terbutaline but worse symptom control than did twice-daily budesonide. In SYGMA1, the change from baseline on the Asthma Control Questionnaire-5 (ACQ-5) favored budesonide-formoterol over terbutaline by an average of 0.15 units and similarly favored twice-daily budesonide over budesonide-formoterol. In SYGMA2, the budesonide maintenance group averaged 0.11 units greater improvement on the ACQ-5 and 0.10 better improvement on the standardized Asthma Quality of Life Questionnaire, compared with as-needed budesonide-formoterol recipients.
Finally, lung function assessments favored as-needed budesonide-formoterol over terbutaline but not over maintenance budesonide. SYGMA1, mean changes (from baseline) in FEV1 before bronchodilator use were 11.2 mL with terbutaline, 65.0 mL with budesonide-formoterol, and 119.3 mL with maintenance budesonide. In SYGMA2, these values were 104 mL with budesonide-formoterol and 136.6 mL with maintenance budesonide.
AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
SOURCES: O’Byrne PM et al. N Engl J Med. 2018;378(20):1865-76.Bateman ED et al. N Engl J Med. 2018;378(20):1877-87.
according to the results of two large, double-blind, 52-week, randomized phase 3 trials.
In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.
Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.
In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).
Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.
In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.
Results from both trials suggested that as-needed budesonide-formoterol provided better symptom control than did terbutaline but worse symptom control than did twice-daily budesonide. In SYGMA1, the change from baseline on the Asthma Control Questionnaire-5 (ACQ-5) favored budesonide-formoterol over terbutaline by an average of 0.15 units and similarly favored twice-daily budesonide over budesonide-formoterol. In SYGMA2, the budesonide maintenance group averaged 0.11 units greater improvement on the ACQ-5 and 0.10 better improvement on the standardized Asthma Quality of Life Questionnaire, compared with as-needed budesonide-formoterol recipients.
Finally, lung function assessments favored as-needed budesonide-formoterol over terbutaline but not over maintenance budesonide. SYGMA1, mean changes (from baseline) in FEV1 before bronchodilator use were 11.2 mL with terbutaline, 65.0 mL with budesonide-formoterol, and 119.3 mL with maintenance budesonide. In SYGMA2, these values were 104 mL with budesonide-formoterol and 136.6 mL with maintenance budesonide.
AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
SOURCES: O’Byrne PM et al. N Engl J Med. 2018;378(20):1865-76.Bateman ED et al. N Engl J Med. 2018;378(20):1877-87.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: As-needed budesonide-formoterol (Symbicort) prevented exacerbations in patients with mild persistent asthma.
Major finding: In the SYGMA1 trial, the regimen outperformed as-needed terbutaline for asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (RR, 0.36; 95% CI, 0.27-0.49). In SYGMA2, the regimen was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% confidence limit, 1.16).
Study details: SYGMA1 and SYGMA2, randomized phase 3 trials of 8,012 patients aged 12 years and older with mild persistent asthma.
Disclosures: AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
Sources: O’Byrne PM et al. N Engl J Med. 2018 May 17;378(20);1865-76. Bateman ED et al. N Engl J Med. 2018 May 17;378(20):1877-87.
ADHD, asthma Rxs up
Use of prescription medication overall decreased in children and adolescents over the past 15 years, but certain medication classes saw increases over that time period, according to a comprehensive analysis of cross-sectional, nationally representative survey data.
Reported use of any prescription medication in the past 30 days decreased from 25% during 1999-2002 to 22% during 2011-2014 (P = .04), according to the analysis based on data from 38,277 children and adolescents aged 0-19 years in the National Health and Nutrition Examination Survey (NHANES).
However, the study showed increases over time in prescribing of medications for asthma, ADHD, and contraception, according to Craig M. Hales, MD, of the National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Md., and his coinvestigators.
“Monitoring trends in use of prescription medications among children and adolescents provides insights on several important public health concerns, such as shifting disease burden, changes in access to health care and medicines, increases in the adoption of appropriate therapies, and decreases in use of inappropriate or ineffective treatments,” Dr. Hales and his coauthors said.
They found significant linear trends in 14 therapeutic classes or subclasses, including six decreases and eight increases, when looking at combined survey data for reported use of any prescription medication and reported use of two or more prescription medications in the prior 30 days.
Of note, antibiotic usage decreased significantly from 8% during 1999-2002 to 5% during 2011-2014, including decreases in amoxicillin, amoxicillin/clavulanate, and cephalosporins. Likewise, antihistamine use was down over time, from 4% to 2%, as was use of upper respiratory combination medications, which decreased from 2% to 0.5%.
Conversely, they found prevalence of ADHD medication usage increased significantly from 3% during 1999-2002 to 4% during 2011-2014, including significant increases for both amphetamines and centrally acting adrenergic agents.
Asthma medication also increased, from 4% to 6%, including significant increases in inhaled corticosteroids and montelukast. Likewise, a significant increase in proton pump inhibitors was reported from 0.2% to 0.7%, while contraceptive use in girls increased significantly in prevalence, from 1% to 2%.
Taken together, these findings suggest an overall decrease in medication prescribing among children and adolescents, despite significantly increased prevalence of prescribing for certain drug classes, the investigators said.
They noted that the study had limitations. For example, NHANES does not include data on most over-the-counter medications, and for the drugs it does include, there are no data on dosages, frequency of use, or specific formulations, they said.
Dr. Hales and his coauthors had no conflicts of interest.
SOURCE: Hales CM et al. JAMA. 2018;319(19):2009-20.
These thorough analyses of medication prescribing for children and adolescents are much needed, but are “frustrating” because definitive conclusions cannot be drawn because of inherent limitations of the serial, cross-sectional study design, Gary L. Freed, MD, MPH, said in an editorial.
The study by Hales et al. shows an overall decrease in prescription medication use in children and adolescents based on data from the 1999-2014 National Health and Examination Survey (NHANES). The study shows increased use of medications for asthma, ADHD, and contraception, and decreased use of antibiotics, antihistamines, and upper respiratory combination medications.
“Some of these trends likely signal potential improvements in the care of children, others may suggest little progress has been made, and yet others are difficult to interpret with certainty,” Dr. Freed wrote.
One finding that seems clear in the data, according to Dr. Freed, is a decrease in antibiotic use among children and adolescents, from 8% to 5% from the 1999-2002 to 2011-2014 time period. That likely reflects the success of efforts to decrease overuse of these agents in community settings.
On the other hand, the decreased use of antihistamines documented in this study may reflect the success of efforts to reduce overuse, or the fact that several prescription medications became approved for OTC use over the course of the study. NHANES does not include OTC drug data in its survey.
“It is unclear whether there was simply a substitution effect and the actual overall rate of utilization of these medications was unchanged,” Dr. Freed wrote.
Increased amphetamine use for the treatment of children aged 6-11 years with ADHD is “vexing” to see, but again, caution must be exercised in interpreting the results, he said, because they do not clearly demonstrate whether these agents are being overused or underused.
“The findings reported by Hales et al. will require additional studies, using different data sources, to provide clarity in the clinical and policy implications of recent trends in medication use among children,” Dr. Freed wrote.
Dr. Freed is a pediatrician with the Child Health Evaluation and Research Center, University of Michigan, Ann Arbor. These comments are derived from his editorial accompanying the study by Hales et al. (JAMA. 2018;319[19]:1988-9). Dr. Freed had no conflicts of interest.
These thorough analyses of medication prescribing for children and adolescents are much needed, but are “frustrating” because definitive conclusions cannot be drawn because of inherent limitations of the serial, cross-sectional study design, Gary L. Freed, MD, MPH, said in an editorial.
The study by Hales et al. shows an overall decrease in prescription medication use in children and adolescents based on data from the 1999-2014 National Health and Examination Survey (NHANES). The study shows increased use of medications for asthma, ADHD, and contraception, and decreased use of antibiotics, antihistamines, and upper respiratory combination medications.
“Some of these trends likely signal potential improvements in the care of children, others may suggest little progress has been made, and yet others are difficult to interpret with certainty,” Dr. Freed wrote.
One finding that seems clear in the data, according to Dr. Freed, is a decrease in antibiotic use among children and adolescents, from 8% to 5% from the 1999-2002 to 2011-2014 time period. That likely reflects the success of efforts to decrease overuse of these agents in community settings.
On the other hand, the decreased use of antihistamines documented in this study may reflect the success of efforts to reduce overuse, or the fact that several prescription medications became approved for OTC use over the course of the study. NHANES does not include OTC drug data in its survey.
“It is unclear whether there was simply a substitution effect and the actual overall rate of utilization of these medications was unchanged,” Dr. Freed wrote.
Increased amphetamine use for the treatment of children aged 6-11 years with ADHD is “vexing” to see, but again, caution must be exercised in interpreting the results, he said, because they do not clearly demonstrate whether these agents are being overused or underused.
“The findings reported by Hales et al. will require additional studies, using different data sources, to provide clarity in the clinical and policy implications of recent trends in medication use among children,” Dr. Freed wrote.
Dr. Freed is a pediatrician with the Child Health Evaluation and Research Center, University of Michigan, Ann Arbor. These comments are derived from his editorial accompanying the study by Hales et al. (JAMA. 2018;319[19]:1988-9). Dr. Freed had no conflicts of interest.
These thorough analyses of medication prescribing for children and adolescents are much needed, but are “frustrating” because definitive conclusions cannot be drawn because of inherent limitations of the serial, cross-sectional study design, Gary L. Freed, MD, MPH, said in an editorial.
The study by Hales et al. shows an overall decrease in prescription medication use in children and adolescents based on data from the 1999-2014 National Health and Examination Survey (NHANES). The study shows increased use of medications for asthma, ADHD, and contraception, and decreased use of antibiotics, antihistamines, and upper respiratory combination medications.
“Some of these trends likely signal potential improvements in the care of children, others may suggest little progress has been made, and yet others are difficult to interpret with certainty,” Dr. Freed wrote.
One finding that seems clear in the data, according to Dr. Freed, is a decrease in antibiotic use among children and adolescents, from 8% to 5% from the 1999-2002 to 2011-2014 time period. That likely reflects the success of efforts to decrease overuse of these agents in community settings.
On the other hand, the decreased use of antihistamines documented in this study may reflect the success of efforts to reduce overuse, or the fact that several prescription medications became approved for OTC use over the course of the study. NHANES does not include OTC drug data in its survey.
“It is unclear whether there was simply a substitution effect and the actual overall rate of utilization of these medications was unchanged,” Dr. Freed wrote.
Increased amphetamine use for the treatment of children aged 6-11 years with ADHD is “vexing” to see, but again, caution must be exercised in interpreting the results, he said, because they do not clearly demonstrate whether these agents are being overused or underused.
“The findings reported by Hales et al. will require additional studies, using different data sources, to provide clarity in the clinical and policy implications of recent trends in medication use among children,” Dr. Freed wrote.
Dr. Freed is a pediatrician with the Child Health Evaluation and Research Center, University of Michigan, Ann Arbor. These comments are derived from his editorial accompanying the study by Hales et al. (JAMA. 2018;319[19]:1988-9). Dr. Freed had no conflicts of interest.
Use of prescription medication overall decreased in children and adolescents over the past 15 years, but certain medication classes saw increases over that time period, according to a comprehensive analysis of cross-sectional, nationally representative survey data.
Reported use of any prescription medication in the past 30 days decreased from 25% during 1999-2002 to 22% during 2011-2014 (P = .04), according to the analysis based on data from 38,277 children and adolescents aged 0-19 years in the National Health and Nutrition Examination Survey (NHANES).
However, the study showed increases over time in prescribing of medications for asthma, ADHD, and contraception, according to Craig M. Hales, MD, of the National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Md., and his coinvestigators.
“Monitoring trends in use of prescription medications among children and adolescents provides insights on several important public health concerns, such as shifting disease burden, changes in access to health care and medicines, increases in the adoption of appropriate therapies, and decreases in use of inappropriate or ineffective treatments,” Dr. Hales and his coauthors said.
They found significant linear trends in 14 therapeutic classes or subclasses, including six decreases and eight increases, when looking at combined survey data for reported use of any prescription medication and reported use of two or more prescription medications in the prior 30 days.
Of note, antibiotic usage decreased significantly from 8% during 1999-2002 to 5% during 2011-2014, including decreases in amoxicillin, amoxicillin/clavulanate, and cephalosporins. Likewise, antihistamine use was down over time, from 4% to 2%, as was use of upper respiratory combination medications, which decreased from 2% to 0.5%.
Conversely, they found prevalence of ADHD medication usage increased significantly from 3% during 1999-2002 to 4% during 2011-2014, including significant increases for both amphetamines and centrally acting adrenergic agents.
Asthma medication also increased, from 4% to 6%, including significant increases in inhaled corticosteroids and montelukast. Likewise, a significant increase in proton pump inhibitors was reported from 0.2% to 0.7%, while contraceptive use in girls increased significantly in prevalence, from 1% to 2%.
Taken together, these findings suggest an overall decrease in medication prescribing among children and adolescents, despite significantly increased prevalence of prescribing for certain drug classes, the investigators said.
They noted that the study had limitations. For example, NHANES does not include data on most over-the-counter medications, and for the drugs it does include, there are no data on dosages, frequency of use, or specific formulations, they said.
Dr. Hales and his coauthors had no conflicts of interest.
SOURCE: Hales CM et al. JAMA. 2018;319(19):2009-20.
Use of prescription medication overall decreased in children and adolescents over the past 15 years, but certain medication classes saw increases over that time period, according to a comprehensive analysis of cross-sectional, nationally representative survey data.
Reported use of any prescription medication in the past 30 days decreased from 25% during 1999-2002 to 22% during 2011-2014 (P = .04), according to the analysis based on data from 38,277 children and adolescents aged 0-19 years in the National Health and Nutrition Examination Survey (NHANES).
However, the study showed increases over time in prescribing of medications for asthma, ADHD, and contraception, according to Craig M. Hales, MD, of the National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Md., and his coinvestigators.
“Monitoring trends in use of prescription medications among children and adolescents provides insights on several important public health concerns, such as shifting disease burden, changes in access to health care and medicines, increases in the adoption of appropriate therapies, and decreases in use of inappropriate or ineffective treatments,” Dr. Hales and his coauthors said.
They found significant linear trends in 14 therapeutic classes or subclasses, including six decreases and eight increases, when looking at combined survey data for reported use of any prescription medication and reported use of two or more prescription medications in the prior 30 days.
Of note, antibiotic usage decreased significantly from 8% during 1999-2002 to 5% during 2011-2014, including decreases in amoxicillin, amoxicillin/clavulanate, and cephalosporins. Likewise, antihistamine use was down over time, from 4% to 2%, as was use of upper respiratory combination medications, which decreased from 2% to 0.5%.
Conversely, they found prevalence of ADHD medication usage increased significantly from 3% during 1999-2002 to 4% during 2011-2014, including significant increases for both amphetamines and centrally acting adrenergic agents.
Asthma medication also increased, from 4% to 6%, including significant increases in inhaled corticosteroids and montelukast. Likewise, a significant increase in proton pump inhibitors was reported from 0.2% to 0.7%, while contraceptive use in girls increased significantly in prevalence, from 1% to 2%.
Taken together, these findings suggest an overall decrease in medication prescribing among children and adolescents, despite significantly increased prevalence of prescribing for certain drug classes, the investigators said.
They noted that the study had limitations. For example, NHANES does not include data on most over-the-counter medications, and for the drugs it does include, there are no data on dosages, frequency of use, or specific formulations, they said.
Dr. Hales and his coauthors had no conflicts of interest.
SOURCE: Hales CM et al. JAMA. 2018;319(19):2009-20.
FROM JAMA
Key clinical point: Nationally representative survey data demonstrate an overall decrease in use of any medication among children and adolescents, although use of certain medications increased.
Major finding: (P = 0.04).
Study details: Analysis of survey data for U.S. children and adolescents aged 0-19 years in the 1999-2014 NHANES.
Disclosures: Dr. Hales and his coauthors had no conflicts of interest.
Source: Hales CM et al. JAMA. 2018;319(19):2009-20.
When and how to suspect asthma misdiagnosis
NEW ORLEANS – Kyle I. Happel, MD, said at the annual meeting of the American College of Physicians.
“Asthma is a disease whose symptoms are caused by variable airflow obstruction. It varies throughout the day, usually, and certainly by the week or by the month. I want you to think about the variability of a patient’s disease symptoms in forming your index of suspicion for this disease,” urged Dr. Happel, of the section of pulmonary, critical care, and allergy/immunology at Louisiana State University Medical Center in New Orleans.
These phenomena occur often. In a Canadian multicenter study of more than 700 patients with a history of physician-diagnosed asthma within the past 5 years, current asthma was ruled out in fully 33% of them on the basis of no deterioration of asthma symptoms, no evidence of reversible airway obstruction, and no bronchial hyperresponsiveness after all asthma drugs were tapered off (JAMA. 2017 Jan 17;317[3]:269-79).
Wheezing is the most specific symptom of asthma, although it is not, in fact, terribly specific. In descending order, the next most specific symptoms are breathlessness, chest tightness, and cough.
The top seven diseases that mimic asthma symptoms are chronic obstructive pulmonary disease, rhinosinusitis, heart failure with preserved or reduced ejection fraction, gastroesophageal reflux disease, angina, anxiety, and vocal cord dysfunction syndrome.
Strike two for an asthma diagnosis is a patient’s report that albuterol doesn’t improve the symptoms. That definitely raises questions about the diagnosis.
“Most asthmatics get symptomatic relief from their disease,” Dr. Happel observed.
And, if there is no indication in the patient’s chart that the asthma diagnosis was based upon demonstration of airflow obstruction on spirometry, the diagnosis is thrown further into doubt. In the recent Canadian study, patients who didn’t undergo pulmonary function testing (PFT) to establish airflow limitation at their time of diagnosis were significantly less likely to have current asthma.
“I would strongly suggest everyone with the diagnosis of asthma get spirometry with bronchodilator testing,” Dr. Happel said. “Good-quality PFTs are critical in forming a solid diagnosis of asthma.”
In a patient who has symptoms consistent with asthma, a 200-cc and 12% or more improvement in forced expiratory volume in 1 second (FEV1) in response to bronchodilator challenge is supportive of the diagnosis. However, absence of reversible airway obstruction doesn’t exclude the possibility of asthma.
In the setting of low to-moderate clinical suspicion of asthma plus no demonstrable obstruction on spirometry, Dr. Happel recommends moving on to bronchial hyperreactivity testing via a methacholine challenge.
“The beauty of a methacholine challenge is that is has a high negative predictive value to help exclude the diagnosis of asthma, particularly in people who are having symptoms suggestive of asthma,” Dr. Happel explained. “If it takes more than 8 mg/mL of methacholine to elicit a 20% or greater decrease in FEV1, it’s probably something else. It’s not a particularly specific test, though; you can get false positives from a methacholine challenge.”
NEW ORLEANS – Kyle I. Happel, MD, said at the annual meeting of the American College of Physicians.
“Asthma is a disease whose symptoms are caused by variable airflow obstruction. It varies throughout the day, usually, and certainly by the week or by the month. I want you to think about the variability of a patient’s disease symptoms in forming your index of suspicion for this disease,” urged Dr. Happel, of the section of pulmonary, critical care, and allergy/immunology at Louisiana State University Medical Center in New Orleans.
These phenomena occur often. In a Canadian multicenter study of more than 700 patients with a history of physician-diagnosed asthma within the past 5 years, current asthma was ruled out in fully 33% of them on the basis of no deterioration of asthma symptoms, no evidence of reversible airway obstruction, and no bronchial hyperresponsiveness after all asthma drugs were tapered off (JAMA. 2017 Jan 17;317[3]:269-79).
Wheezing is the most specific symptom of asthma, although it is not, in fact, terribly specific. In descending order, the next most specific symptoms are breathlessness, chest tightness, and cough.
The top seven diseases that mimic asthma symptoms are chronic obstructive pulmonary disease, rhinosinusitis, heart failure with preserved or reduced ejection fraction, gastroesophageal reflux disease, angina, anxiety, and vocal cord dysfunction syndrome.
Strike two for an asthma diagnosis is a patient’s report that albuterol doesn’t improve the symptoms. That definitely raises questions about the diagnosis.
“Most asthmatics get symptomatic relief from their disease,” Dr. Happel observed.
And, if there is no indication in the patient’s chart that the asthma diagnosis was based upon demonstration of airflow obstruction on spirometry, the diagnosis is thrown further into doubt. In the recent Canadian study, patients who didn’t undergo pulmonary function testing (PFT) to establish airflow limitation at their time of diagnosis were significantly less likely to have current asthma.
“I would strongly suggest everyone with the diagnosis of asthma get spirometry with bronchodilator testing,” Dr. Happel said. “Good-quality PFTs are critical in forming a solid diagnosis of asthma.”
In a patient who has symptoms consistent with asthma, a 200-cc and 12% or more improvement in forced expiratory volume in 1 second (FEV1) in response to bronchodilator challenge is supportive of the diagnosis. However, absence of reversible airway obstruction doesn’t exclude the possibility of asthma.
In the setting of low to-moderate clinical suspicion of asthma plus no demonstrable obstruction on spirometry, Dr. Happel recommends moving on to bronchial hyperreactivity testing via a methacholine challenge.
“The beauty of a methacholine challenge is that is has a high negative predictive value to help exclude the diagnosis of asthma, particularly in people who are having symptoms suggestive of asthma,” Dr. Happel explained. “If it takes more than 8 mg/mL of methacholine to elicit a 20% or greater decrease in FEV1, it’s probably something else. It’s not a particularly specific test, though; you can get false positives from a methacholine challenge.”
NEW ORLEANS – Kyle I. Happel, MD, said at the annual meeting of the American College of Physicians.
“Asthma is a disease whose symptoms are caused by variable airflow obstruction. It varies throughout the day, usually, and certainly by the week or by the month. I want you to think about the variability of a patient’s disease symptoms in forming your index of suspicion for this disease,” urged Dr. Happel, of the section of pulmonary, critical care, and allergy/immunology at Louisiana State University Medical Center in New Orleans.
These phenomena occur often. In a Canadian multicenter study of more than 700 patients with a history of physician-diagnosed asthma within the past 5 years, current asthma was ruled out in fully 33% of them on the basis of no deterioration of asthma symptoms, no evidence of reversible airway obstruction, and no bronchial hyperresponsiveness after all asthma drugs were tapered off (JAMA. 2017 Jan 17;317[3]:269-79).
Wheezing is the most specific symptom of asthma, although it is not, in fact, terribly specific. In descending order, the next most specific symptoms are breathlessness, chest tightness, and cough.
The top seven diseases that mimic asthma symptoms are chronic obstructive pulmonary disease, rhinosinusitis, heart failure with preserved or reduced ejection fraction, gastroesophageal reflux disease, angina, anxiety, and vocal cord dysfunction syndrome.
Strike two for an asthma diagnosis is a patient’s report that albuterol doesn’t improve the symptoms. That definitely raises questions about the diagnosis.
“Most asthmatics get symptomatic relief from their disease,” Dr. Happel observed.
And, if there is no indication in the patient’s chart that the asthma diagnosis was based upon demonstration of airflow obstruction on spirometry, the diagnosis is thrown further into doubt. In the recent Canadian study, patients who didn’t undergo pulmonary function testing (PFT) to establish airflow limitation at their time of diagnosis were significantly less likely to have current asthma.
“I would strongly suggest everyone with the diagnosis of asthma get spirometry with bronchodilator testing,” Dr. Happel said. “Good-quality PFTs are critical in forming a solid diagnosis of asthma.”
In a patient who has symptoms consistent with asthma, a 200-cc and 12% or more improvement in forced expiratory volume in 1 second (FEV1) in response to bronchodilator challenge is supportive of the diagnosis. However, absence of reversible airway obstruction doesn’t exclude the possibility of asthma.
In the setting of low to-moderate clinical suspicion of asthma plus no demonstrable obstruction on spirometry, Dr. Happel recommends moving on to bronchial hyperreactivity testing via a methacholine challenge.
“The beauty of a methacholine challenge is that is has a high negative predictive value to help exclude the diagnosis of asthma, particularly in people who are having symptoms suggestive of asthma,” Dr. Happel explained. “If it takes more than 8 mg/mL of methacholine to elicit a 20% or greater decrease in FEV1, it’s probably something else. It’s not a particularly specific test, though; you can get false positives from a methacholine challenge.”
REPORTING FROM ACP INTERNAL MEDICINE
ED visits higher among pediatric asthma patients with comorbid depression, anxiety
TORONTO – Children with asthma who have a comorbid diagnosis of anxiety or depression are significantly more likely to make asthma-related visits to the emergency department, compared with their peers who do not have a mental health condition, results from a large administrative data analysis showed.
“There has been a fair bit of research on how comorbid mental health conditions can affect health care utilization for asthma in adults, but few studies have examined how comorbid mental health conditions like anxiety or depression can affect children with asthma,” one of the study authors, Caroline Neel, said in an interview in advance of the Pediatric Academic Societies meeting.
In all, the researchers identified 71,326 patients with asthma, with an overall rate of 16.3 ED visits per 100 child-years. Among these, children with a diagnosis of depression had significantly higher rates of ED visits (21.5 visits per 100 child-years; P less than .01), as did those with a diagnosis of anxiety (19.5 ED visits per 100 child-years; P less than .01). Being enrolled in a Medicaid managed care plan or Medicaid fee-for-service plan also increased the rates of asthma-related ED visits (20.3 and 21.5 ED visits per 100 child-years, respectively; P less than .01 for both associations.)
“We were surprised to see that anxiety and depression seemed to increase asthma emergency department visits as much as other medical chronic illnesses like cystic fibrosis or sickle cell disease, and that kids on Medicaid, who tend to be our poorer kids, also had an independent risk of going to the emergency department,” Ms. Neel said. “Having Medicaid as well as anxiety or depression were independently related to going to the emergency room for asthma, so the study suggests that some of our highest-risk kids for asthma have multiple different contributors to getting sick and needing to go to the emergency room for an asthma attack.”
She acknowledged certain limitations of the analysis, including its reliance on administrative claims data to identify whether or not children had a diagnosis of anxiety or depression. “This doesn’t necessarily identify all the kids who may have these mental health conditions, since sometimes providers are less likely to document a diagnosis of a mental health conditions for children,” she said. “However, we still saw a significant association between a comorbid mental health condition and emergency department use for asthma, despite the potential that mental health conditions may have been under reported.”
The study’s senior author was Naomi Bardach, MD. The researchers reported having no financial disclosures.
TORONTO – Children with asthma who have a comorbid diagnosis of anxiety or depression are significantly more likely to make asthma-related visits to the emergency department, compared with their peers who do not have a mental health condition, results from a large administrative data analysis showed.
“There has been a fair bit of research on how comorbid mental health conditions can affect health care utilization for asthma in adults, but few studies have examined how comorbid mental health conditions like anxiety or depression can affect children with asthma,” one of the study authors, Caroline Neel, said in an interview in advance of the Pediatric Academic Societies meeting.
In all, the researchers identified 71,326 patients with asthma, with an overall rate of 16.3 ED visits per 100 child-years. Among these, children with a diagnosis of depression had significantly higher rates of ED visits (21.5 visits per 100 child-years; P less than .01), as did those with a diagnosis of anxiety (19.5 ED visits per 100 child-years; P less than .01). Being enrolled in a Medicaid managed care plan or Medicaid fee-for-service plan also increased the rates of asthma-related ED visits (20.3 and 21.5 ED visits per 100 child-years, respectively; P less than .01 for both associations.)
“We were surprised to see that anxiety and depression seemed to increase asthma emergency department visits as much as other medical chronic illnesses like cystic fibrosis or sickle cell disease, and that kids on Medicaid, who tend to be our poorer kids, also had an independent risk of going to the emergency department,” Ms. Neel said. “Having Medicaid as well as anxiety or depression were independently related to going to the emergency room for asthma, so the study suggests that some of our highest-risk kids for asthma have multiple different contributors to getting sick and needing to go to the emergency room for an asthma attack.”
She acknowledged certain limitations of the analysis, including its reliance on administrative claims data to identify whether or not children had a diagnosis of anxiety or depression. “This doesn’t necessarily identify all the kids who may have these mental health conditions, since sometimes providers are less likely to document a diagnosis of a mental health conditions for children,” she said. “However, we still saw a significant association between a comorbid mental health condition and emergency department use for asthma, despite the potential that mental health conditions may have been under reported.”
The study’s senior author was Naomi Bardach, MD. The researchers reported having no financial disclosures.
TORONTO – Children with asthma who have a comorbid diagnosis of anxiety or depression are significantly more likely to make asthma-related visits to the emergency department, compared with their peers who do not have a mental health condition, results from a large administrative data analysis showed.
“There has been a fair bit of research on how comorbid mental health conditions can affect health care utilization for asthma in adults, but few studies have examined how comorbid mental health conditions like anxiety or depression can affect children with asthma,” one of the study authors, Caroline Neel, said in an interview in advance of the Pediatric Academic Societies meeting.
In all, the researchers identified 71,326 patients with asthma, with an overall rate of 16.3 ED visits per 100 child-years. Among these, children with a diagnosis of depression had significantly higher rates of ED visits (21.5 visits per 100 child-years; P less than .01), as did those with a diagnosis of anxiety (19.5 ED visits per 100 child-years; P less than .01). Being enrolled in a Medicaid managed care plan or Medicaid fee-for-service plan also increased the rates of asthma-related ED visits (20.3 and 21.5 ED visits per 100 child-years, respectively; P less than .01 for both associations.)
“We were surprised to see that anxiety and depression seemed to increase asthma emergency department visits as much as other medical chronic illnesses like cystic fibrosis or sickle cell disease, and that kids on Medicaid, who tend to be our poorer kids, also had an independent risk of going to the emergency department,” Ms. Neel said. “Having Medicaid as well as anxiety or depression were independently related to going to the emergency room for asthma, so the study suggests that some of our highest-risk kids for asthma have multiple different contributors to getting sick and needing to go to the emergency room for an asthma attack.”
She acknowledged certain limitations of the analysis, including its reliance on administrative claims data to identify whether or not children had a diagnosis of anxiety or depression. “This doesn’t necessarily identify all the kids who may have these mental health conditions, since sometimes providers are less likely to document a diagnosis of a mental health conditions for children,” she said. “However, we still saw a significant association between a comorbid mental health condition and emergency department use for asthma, despite the potential that mental health conditions may have been under reported.”
The study’s senior author was Naomi Bardach, MD. The researchers reported having no financial disclosures.
Key clinical point: Anxiety and depression are associated with higher rates of ED use in children with asthma.
Major finding: (21.5 visits per 100 child-years; P less than .01), as did those with a diagnosis of anxiety (19.5 ED visits per 100 child-years; P less than .01).
Study details: An analysis of 71,326 patients with asthma from the Massachusetts All Payer Claims Database for 2014-2015.
Disclosures: The researchers reported having no financial disclosures.
Allergy, eczema common after pediatric solid organ transplantation
A total of 34% of children who underwent solid organ transplantation subsequently developed eczema, food allergy, rhinitis, eosinophilic gastrointestinal disease, or asthma, according to the results of a single-center retrospective cohort study.
Another 6.6% of patients developed autoimmunity, usually autoimmune cytopenia, inflammatory bowel disease, or vasculitis, wrote Nufar Marcus, MD, of the University of Toronto, and her associates.
Posttransplant allergy, autoimmunity, and immune-mediated disorders (PTAA) likely share a common pathogenesis “and may represent a unique state of post-transplant immune-dysregulation,” they wrote. The report was published in the Journal of Pediatrics.
The study included 273 children who underwent solid organ transplantation and were followed for a median 3.6 years (range, 1.7-6.3 years). None had immune-mediated conditions or allergies diagnosed at baseline. Posttransplantation allergies most commonly included eczema (51%), asthma (32%), food allergy (25%, including 5% with associated anaphylaxis), rhinitis (17%), and eosinophilic esophagitis, gastritis, or enteritis (13%).
Although only 31% of patients had information available on family history of allergy, those with a positive family history of allergy had a fivefold greater odds of posttransplantation PTAA, compared with other patients. Other risk factors for PTAA included female sex, young age at transplantation, eosinophilia, and a positive test for Epstein-Barr virus after transplantation, Dr. Marcus and associates said.
“The association of blood eosinophilia and PTAA reached statistical significance only when the transplant recipient was at least 6 months of age, demonstrating the nonspecific nature of abnormally high eosinophil counts during the first months of life,” they noted. The longer patients had eosinophilia after transplantation, the more likely they were to develop PTAA, “suggest[ing] a potential detrimental effect of prolonged activation of the eosinophilic-associated immune arms.”
Factors that appeared unlinked with PTAA included acute organ rejection, duration of posttransplantation steroidal treatment, organ type (living versus cadaveric), donor/recipient blood type and compatibility, infections besides Epstein-Barr virus, and posttransplant lymphoproliferative disease. “The specific type of post-transplantation immunosuppression regimen was neither associated nor protective of PTAA,” the investigators wrote. “However, a significant limitation was our inability to assess the effect of tacrolimus, as nearly all the cohort (97.8%) was treated with this medication.”
Ashley’s Angels fund provided support. The researchers reported having no conflicts of interest.
SOURCE: Marcus N et al. J Pediatr. 2018;196:154-60.
The study is one of several to highlight the occurrence of atopy and allergy following solid organ transplantation in children, Helen M. Evans, MBChB, wrote in an editorial accompanying the report by Marcus et al.
This report differed because it studied the differences in rates of atopy and allergy between transplanted solid organ groups. These occurred in 41% and 40% of liver and heart recipients, respectively, but in only 4% of kidney recipients. Atopy or allergy developed in 57% of multivisceral transplant patients, but the number of patients was very small (n = 7). The majority of the conditions developed within 1 year of transplantation.
The recent spike in these reports could signify better recognition of the problem or “the widespread switch of primary immunosuppression from cyclosporine to tacrolimus over the last few decades,” wrote Dr. Evans.
Most of these reports have been single-center retrospective studies, which are subject to inconsistent case definitions and recall bias, she noted. “The time is right for well-conducted multicenter prospective studies to better inform the true extent of these conditions after solid organ transplantation.”
In the meantime, transplantation centers should routinely track de novo eczema, allergy, and eosinophilic gastrointestinal disease in children being assessed for solid organ transplantation, and should take “rigorous” personal and family histories, said Dr. Evans. Ultimately, this work will help “minimize the risk of children developing these conditions” and “effectively treat them in the setting of immunosuppression after transplantation.”
Dr. Evans is a pediatric gastroenterologist at Starship Child Health in Aukland, New Zealand. She reported having no conflicts of interest. These comments summarize her editorial ( J Pediatr. 2018;196:10-11 ).
The study is one of several to highlight the occurrence of atopy and allergy following solid organ transplantation in children, Helen M. Evans, MBChB, wrote in an editorial accompanying the report by Marcus et al.
This report differed because it studied the differences in rates of atopy and allergy between transplanted solid organ groups. These occurred in 41% and 40% of liver and heart recipients, respectively, but in only 4% of kidney recipients. Atopy or allergy developed in 57% of multivisceral transplant patients, but the number of patients was very small (n = 7). The majority of the conditions developed within 1 year of transplantation.
The recent spike in these reports could signify better recognition of the problem or “the widespread switch of primary immunosuppression from cyclosporine to tacrolimus over the last few decades,” wrote Dr. Evans.
Most of these reports have been single-center retrospective studies, which are subject to inconsistent case definitions and recall bias, she noted. “The time is right for well-conducted multicenter prospective studies to better inform the true extent of these conditions after solid organ transplantation.”
In the meantime, transplantation centers should routinely track de novo eczema, allergy, and eosinophilic gastrointestinal disease in children being assessed for solid organ transplantation, and should take “rigorous” personal and family histories, said Dr. Evans. Ultimately, this work will help “minimize the risk of children developing these conditions” and “effectively treat them in the setting of immunosuppression after transplantation.”
Dr. Evans is a pediatric gastroenterologist at Starship Child Health in Aukland, New Zealand. She reported having no conflicts of interest. These comments summarize her editorial ( J Pediatr. 2018;196:10-11 ).
The study is one of several to highlight the occurrence of atopy and allergy following solid organ transplantation in children, Helen M. Evans, MBChB, wrote in an editorial accompanying the report by Marcus et al.
This report differed because it studied the differences in rates of atopy and allergy between transplanted solid organ groups. These occurred in 41% and 40% of liver and heart recipients, respectively, but in only 4% of kidney recipients. Atopy or allergy developed in 57% of multivisceral transplant patients, but the number of patients was very small (n = 7). The majority of the conditions developed within 1 year of transplantation.
The recent spike in these reports could signify better recognition of the problem or “the widespread switch of primary immunosuppression from cyclosporine to tacrolimus over the last few decades,” wrote Dr. Evans.
Most of these reports have been single-center retrospective studies, which are subject to inconsistent case definitions and recall bias, she noted. “The time is right for well-conducted multicenter prospective studies to better inform the true extent of these conditions after solid organ transplantation.”
In the meantime, transplantation centers should routinely track de novo eczema, allergy, and eosinophilic gastrointestinal disease in children being assessed for solid organ transplantation, and should take “rigorous” personal and family histories, said Dr. Evans. Ultimately, this work will help “minimize the risk of children developing these conditions” and “effectively treat them in the setting of immunosuppression after transplantation.”
Dr. Evans is a pediatric gastroenterologist at Starship Child Health in Aukland, New Zealand. She reported having no conflicts of interest. These comments summarize her editorial ( J Pediatr. 2018;196:10-11 ).
A total of 34% of children who underwent solid organ transplantation subsequently developed eczema, food allergy, rhinitis, eosinophilic gastrointestinal disease, or asthma, according to the results of a single-center retrospective cohort study.
Another 6.6% of patients developed autoimmunity, usually autoimmune cytopenia, inflammatory bowel disease, or vasculitis, wrote Nufar Marcus, MD, of the University of Toronto, and her associates.
Posttransplant allergy, autoimmunity, and immune-mediated disorders (PTAA) likely share a common pathogenesis “and may represent a unique state of post-transplant immune-dysregulation,” they wrote. The report was published in the Journal of Pediatrics.
The study included 273 children who underwent solid organ transplantation and were followed for a median 3.6 years (range, 1.7-6.3 years). None had immune-mediated conditions or allergies diagnosed at baseline. Posttransplantation allergies most commonly included eczema (51%), asthma (32%), food allergy (25%, including 5% with associated anaphylaxis), rhinitis (17%), and eosinophilic esophagitis, gastritis, or enteritis (13%).
Although only 31% of patients had information available on family history of allergy, those with a positive family history of allergy had a fivefold greater odds of posttransplantation PTAA, compared with other patients. Other risk factors for PTAA included female sex, young age at transplantation, eosinophilia, and a positive test for Epstein-Barr virus after transplantation, Dr. Marcus and associates said.
“The association of blood eosinophilia and PTAA reached statistical significance only when the transplant recipient was at least 6 months of age, demonstrating the nonspecific nature of abnormally high eosinophil counts during the first months of life,” they noted. The longer patients had eosinophilia after transplantation, the more likely they were to develop PTAA, “suggest[ing] a potential detrimental effect of prolonged activation of the eosinophilic-associated immune arms.”
Factors that appeared unlinked with PTAA included acute organ rejection, duration of posttransplantation steroidal treatment, organ type (living versus cadaveric), donor/recipient blood type and compatibility, infections besides Epstein-Barr virus, and posttransplant lymphoproliferative disease. “The specific type of post-transplantation immunosuppression regimen was neither associated nor protective of PTAA,” the investigators wrote. “However, a significant limitation was our inability to assess the effect of tacrolimus, as nearly all the cohort (97.8%) was treated with this medication.”
Ashley’s Angels fund provided support. The researchers reported having no conflicts of interest.
SOURCE: Marcus N et al. J Pediatr. 2018;196:154-60.
A total of 34% of children who underwent solid organ transplantation subsequently developed eczema, food allergy, rhinitis, eosinophilic gastrointestinal disease, or asthma, according to the results of a single-center retrospective cohort study.
Another 6.6% of patients developed autoimmunity, usually autoimmune cytopenia, inflammatory bowel disease, or vasculitis, wrote Nufar Marcus, MD, of the University of Toronto, and her associates.
Posttransplant allergy, autoimmunity, and immune-mediated disorders (PTAA) likely share a common pathogenesis “and may represent a unique state of post-transplant immune-dysregulation,” they wrote. The report was published in the Journal of Pediatrics.
The study included 273 children who underwent solid organ transplantation and were followed for a median 3.6 years (range, 1.7-6.3 years). None had immune-mediated conditions or allergies diagnosed at baseline. Posttransplantation allergies most commonly included eczema (51%), asthma (32%), food allergy (25%, including 5% with associated anaphylaxis), rhinitis (17%), and eosinophilic esophagitis, gastritis, or enteritis (13%).
Although only 31% of patients had information available on family history of allergy, those with a positive family history of allergy had a fivefold greater odds of posttransplantation PTAA, compared with other patients. Other risk factors for PTAA included female sex, young age at transplantation, eosinophilia, and a positive test for Epstein-Barr virus after transplantation, Dr. Marcus and associates said.
“The association of blood eosinophilia and PTAA reached statistical significance only when the transplant recipient was at least 6 months of age, demonstrating the nonspecific nature of abnormally high eosinophil counts during the first months of life,” they noted. The longer patients had eosinophilia after transplantation, the more likely they were to develop PTAA, “suggest[ing] a potential detrimental effect of prolonged activation of the eosinophilic-associated immune arms.”
Factors that appeared unlinked with PTAA included acute organ rejection, duration of posttransplantation steroidal treatment, organ type (living versus cadaveric), donor/recipient blood type and compatibility, infections besides Epstein-Barr virus, and posttransplant lymphoproliferative disease. “The specific type of post-transplantation immunosuppression regimen was neither associated nor protective of PTAA,” the investigators wrote. “However, a significant limitation was our inability to assess the effect of tacrolimus, as nearly all the cohort (97.8%) was treated with this medication.”
Ashley’s Angels fund provided support. The researchers reported having no conflicts of interest.
SOURCE: Marcus N et al. J Pediatr. 2018;196:154-60.
FROM JOURNAL OF PEDIATRICS
Key clinical point: Children undergoing solid organ transplantation often developed allergy or autoimmunity.
Major finding: Study details: Single-center retrospective cross-sectional study of 273 patients aged 18 and under who underwent solid organ transplantation followed for a median 3.6 years.
Disclosures: Ashley’s Angels fund provided support. The researchers reported having no conflicts of interest.
Source: Marcus N et al. J Pediatr. 2018;196:154-60.
When the correct Dx is elusive
In this issue of JFP, Dr. Mendoza reminds us that “Parkinson’s disease can be a tough diagnosis to navigate.”1 Classically, Parkinson’s disease (PD) is associated with a resting tremor, but bradykinesia is actually the hallmark of the disease. PD can also present with subtle movement disorders, as well as depression and early dementia. It is, indeed, a difficult clinical diagnosis, and consultation with an expert to confirm or deny its presence can be quite helpful.
Other conundrums. PD, however, is not the only illness whose signs and symptoms can present a challenge. Chronic and intermittent shortness of breath, for example, can be very difficult to sort out. Is the shortness of breath due to congestive heart failure, chronic obstructive pulmonary disease, asthma, or a neurologic condition such as myasthenia gravis? Or is it the result of several causes?
When asthma isn’t asthma. Because it is a common illness, physicians often diagnose asthma in patients with shortness of breath or wheezing. But a recent study suggests that as many as 30% of primary care patients with a current diagnosis of asthma do not have asthma at all.2
In the study, Canadian researchers recruited 701 adults with physician-diagnosed asthma, all of whom were taking asthma medications regularly. The researchers did baseline pulmonary function testing (including methacholine challenge testing, if needed) and monitored symptoms frequently. Then they gradually withdrew asthma medications from those who did not appear to have a definitive diagnosis of asthma. They followed these patients for one year. One-third (203 of 613) of the patients with complete follow-up data were no longer taking asthma medications one year later and had no symptoms of asthma. Twelve patients had serious alternative diagnoses such as coronary artery disease and bronchiectasis.
Closer to home. In my practice, I found 2 patients with long-standing diagnoses of asthma who didn’t, in fact, have the condition at all. In both cases, my suspicion was raised by lung examination. In one case, fine bibasilar rales suggested pulmonary fibrosis, which was the correct diagnosis, and the patient is now on the lung transplant list. In the other case, a loud venous hum suggested an arteriovenous malformation. Surgery corrected the patient’s “asthma.”
I urge you to reevaluate your asthma patients to be sure they have the correct diagnosis and to keep PD in your differential for patients who present with atypical symptoms. Primary care clinicians must be expert diagnosticians, willing to question prior diagnoses.
1. Young J, Mendoza M. Parkinson’s disease: a treatment guide. J Fam Pract. 2018;67:276-286.
2. Aaron SD, Vandemheen KL, FitzGerald JM, et al for the Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017:317:269-279.
Editor-in-Chief
Editor-in-Chief
Editor-in-Chief
In this issue of JFP, Dr. Mendoza reminds us that “Parkinson’s disease can be a tough diagnosis to navigate.”1 Classically, Parkinson’s disease (PD) is associated with a resting tremor, but bradykinesia is actually the hallmark of the disease. PD can also present with subtle movement disorders, as well as depression and early dementia. It is, indeed, a difficult clinical diagnosis, and consultation with an expert to confirm or deny its presence can be quite helpful.
Other conundrums. PD, however, is not the only illness whose signs and symptoms can present a challenge. Chronic and intermittent shortness of breath, for example, can be very difficult to sort out. Is the shortness of breath due to congestive heart failure, chronic obstructive pulmonary disease, asthma, or a neurologic condition such as myasthenia gravis? Or is it the result of several causes?
When asthma isn’t asthma. Because it is a common illness, physicians often diagnose asthma in patients with shortness of breath or wheezing. But a recent study suggests that as many as 30% of primary care patients with a current diagnosis of asthma do not have asthma at all.2
In the study, Canadian researchers recruited 701 adults with physician-diagnosed asthma, all of whom were taking asthma medications regularly. The researchers did baseline pulmonary function testing (including methacholine challenge testing, if needed) and monitored symptoms frequently. Then they gradually withdrew asthma medications from those who did not appear to have a definitive diagnosis of asthma. They followed these patients for one year. One-third (203 of 613) of the patients with complete follow-up data were no longer taking asthma medications one year later and had no symptoms of asthma. Twelve patients had serious alternative diagnoses such as coronary artery disease and bronchiectasis.
Closer to home. In my practice, I found 2 patients with long-standing diagnoses of asthma who didn’t, in fact, have the condition at all. In both cases, my suspicion was raised by lung examination. In one case, fine bibasilar rales suggested pulmonary fibrosis, which was the correct diagnosis, and the patient is now on the lung transplant list. In the other case, a loud venous hum suggested an arteriovenous malformation. Surgery corrected the patient’s “asthma.”
I urge you to reevaluate your asthma patients to be sure they have the correct diagnosis and to keep PD in your differential for patients who present with atypical symptoms. Primary care clinicians must be expert diagnosticians, willing to question prior diagnoses.
In this issue of JFP, Dr. Mendoza reminds us that “Parkinson’s disease can be a tough diagnosis to navigate.”1 Classically, Parkinson’s disease (PD) is associated with a resting tremor, but bradykinesia is actually the hallmark of the disease. PD can also present with subtle movement disorders, as well as depression and early dementia. It is, indeed, a difficult clinical diagnosis, and consultation with an expert to confirm or deny its presence can be quite helpful.
Other conundrums. PD, however, is not the only illness whose signs and symptoms can present a challenge. Chronic and intermittent shortness of breath, for example, can be very difficult to sort out. Is the shortness of breath due to congestive heart failure, chronic obstructive pulmonary disease, asthma, or a neurologic condition such as myasthenia gravis? Or is it the result of several causes?
When asthma isn’t asthma. Because it is a common illness, physicians often diagnose asthma in patients with shortness of breath or wheezing. But a recent study suggests that as many as 30% of primary care patients with a current diagnosis of asthma do not have asthma at all.2
In the study, Canadian researchers recruited 701 adults with physician-diagnosed asthma, all of whom were taking asthma medications regularly. The researchers did baseline pulmonary function testing (including methacholine challenge testing, if needed) and monitored symptoms frequently. Then they gradually withdrew asthma medications from those who did not appear to have a definitive diagnosis of asthma. They followed these patients for one year. One-third (203 of 613) of the patients with complete follow-up data were no longer taking asthma medications one year later and had no symptoms of asthma. Twelve patients had serious alternative diagnoses such as coronary artery disease and bronchiectasis.
Closer to home. In my practice, I found 2 patients with long-standing diagnoses of asthma who didn’t, in fact, have the condition at all. In both cases, my suspicion was raised by lung examination. In one case, fine bibasilar rales suggested pulmonary fibrosis, which was the correct diagnosis, and the patient is now on the lung transplant list. In the other case, a loud venous hum suggested an arteriovenous malformation. Surgery corrected the patient’s “asthma.”
I urge you to reevaluate your asthma patients to be sure they have the correct diagnosis and to keep PD in your differential for patients who present with atypical symptoms. Primary care clinicians must be expert diagnosticians, willing to question prior diagnoses.
1. Young J, Mendoza M. Parkinson’s disease: a treatment guide. J Fam Pract. 2018;67:276-286.
2. Aaron SD, Vandemheen KL, FitzGerald JM, et al for the Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017:317:269-279.
1. Young J, Mendoza M. Parkinson’s disease: a treatment guide. J Fam Pract. 2018;67:276-286.
2. Aaron SD, Vandemheen KL, FitzGerald JM, et al for the Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017:317:269-279.
Abstract: Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection: A Randomized Clinical Trial
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Hay, A.D., et al, JAMA 318(8):721, August 22, 2017
BACKGROUND: Although symptoms and underlying bronchial hyperresponsiveness are similar in asthma and acute lower respiratory tract infection, guidelines do not include recommendations, and evidence is scarce, regarding the use of corticosteroids for acute lower respiratory infections.
METHODS: In this multinational trial, 401 patients (mean age, 47.4 years) without a history of asthma who presented to primary care with suspected acute lower respiratory tract infection were randomized to a five-day course of oral prednisolone (40mg daily) or placebo. Study participants were followed for 28 days for the primary outcomes of the duration of moderately bad or worse cough, and mean symptom severity score on days two to four (score range 0 to 6, for the main symptoms of cough, phlegm production, shortness of breath, sleep disturbance, feeling unwell and activity disturbance).
RESULTS: In both groups, the median duration of moderately bad or worse cough was five days (hazard ratio 1.11, p=NS). On days two to four, the mean symptom severity score was 1.99 points in the prednisolone group vs. 2.16 points in placebo-treated controls (adjusted difference 0.20 point, p=0.05). Absence of a statistically significant difference between the groups persisted in sensitivity and subgroup analyses. Both groups were similar in terms of symptom duration, antibiotic use, patient satisfaction and the nature of adverse events (no serious adverse events occurred).
CONCLUSIONS: This study does not support the use of oral corticosteroids in primary care patients without asthma who present with acute lower respiratory tract infection. 35 references (alastair.hay@bristol.ac.uk – no reprints)
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Hay, A.D., et al, JAMA 318(8):721, August 22, 2017
BACKGROUND: Although symptoms and underlying bronchial hyperresponsiveness are similar in asthma and acute lower respiratory tract infection, guidelines do not include recommendations, and evidence is scarce, regarding the use of corticosteroids for acute lower respiratory infections.
METHODS: In this multinational trial, 401 patients (mean age, 47.4 years) without a history of asthma who presented to primary care with suspected acute lower respiratory tract infection were randomized to a five-day course of oral prednisolone (40mg daily) or placebo. Study participants were followed for 28 days for the primary outcomes of the duration of moderately bad or worse cough, and mean symptom severity score on days two to four (score range 0 to 6, for the main symptoms of cough, phlegm production, shortness of breath, sleep disturbance, feeling unwell and activity disturbance).
RESULTS: In both groups, the median duration of moderately bad or worse cough was five days (hazard ratio 1.11, p=NS). On days two to four, the mean symptom severity score was 1.99 points in the prednisolone group vs. 2.16 points in placebo-treated controls (adjusted difference 0.20 point, p=0.05). Absence of a statistically significant difference between the groups persisted in sensitivity and subgroup analyses. Both groups were similar in terms of symptom duration, antibiotic use, patient satisfaction and the nature of adverse events (no serious adverse events occurred).
CONCLUSIONS: This study does not support the use of oral corticosteroids in primary care patients without asthma who present with acute lower respiratory tract infection. 35 references (alastair.hay@bristol.ac.uk – no reprints)
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Hay, A.D., et al, JAMA 318(8):721, August 22, 2017
BACKGROUND: Although symptoms and underlying bronchial hyperresponsiveness are similar in asthma and acute lower respiratory tract infection, guidelines do not include recommendations, and evidence is scarce, regarding the use of corticosteroids for acute lower respiratory infections.
METHODS: In this multinational trial, 401 patients (mean age, 47.4 years) without a history of asthma who presented to primary care with suspected acute lower respiratory tract infection were randomized to a five-day course of oral prednisolone (40mg daily) or placebo. Study participants were followed for 28 days for the primary outcomes of the duration of moderately bad or worse cough, and mean symptom severity score on days two to four (score range 0 to 6, for the main symptoms of cough, phlegm production, shortness of breath, sleep disturbance, feeling unwell and activity disturbance).
RESULTS: In both groups, the median duration of moderately bad or worse cough was five days (hazard ratio 1.11, p=NS). On days two to four, the mean symptom severity score was 1.99 points in the prednisolone group vs. 2.16 points in placebo-treated controls (adjusted difference 0.20 point, p=0.05). Absence of a statistically significant difference between the groups persisted in sensitivity and subgroup analyses. Both groups were similar in terms of symptom duration, antibiotic use, patient satisfaction and the nature of adverse events (no serious adverse events occurred).
CONCLUSIONS: This study does not support the use of oral corticosteroids in primary care patients without asthma who present with acute lower respiratory tract infection. 35 references (alastair.hay@bristol.ac.uk – no reprints)
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