Asthma

Benralizumab is safe and effective for the treatment of uncontrolled asthma out to 2 years, according findings of the BORA trial, an extension study of the phase 3 SIROCCO and CALIMA trials. The study follows up and reinforces previously reported 1-year data and was reported by William W. Busse, MD, of University of Wisconsin, Madison, and his colleagues in the Lancet Respiratory Medicine.

Courtesy University of Wisconsin Health System

Benralizumab is a monoclonal antibody that targets interleukin-5 receptor alpha. It causes rapid deletion of eosinophils through cell-mediated cytotoxicity. A 30-mg dose of benralizumab every 8 weeks is approved for severe asthma treatment in Canada, Europe, Japan, the United States, and other countries.

In the second year of treatment, there were no new adverse events associated with depleted eosinophils, and the frequency of opportunistic infections was similar to that observed in the first year.

Eosinophilic inflammation occurs in about half of asthma cases and is associated with greater severity.

The 48-week SIROCCO trial, the 56-week CALIMA trial, and the 28-week ZONDA trial tested the effect of benralizumab 30 mg given every 4 weeks or 8 weeks, combined with high-dosage inhaled steroids and long-acting beta₂-agonists. The 8-week dose of the drug reduced annual exacerbations by 51%, compared with placebo in the SIROCCO trial and by 28% in the CALIMA trial. In the ZONDA trial, benralizumab reduced oral glucocorticoid use by 75%, compared with placebo, and by 25% from baseline.

The BORA extension trial included participants in the previous three trials. In the current report, researchers presented results from the analysis from BORA participants recruited from the SIROCCO and CALIMA trials. Data from participants from all three trials will be reported in the future.

The analysis included 1,576 patients who continued to receive benralizumab after being assigned to the treatment arm in SIROCCO or CALIMA, or who had received placebo were randomized to benralizumab on the 4-week (n = 783; 265 from placebo) or 8-week dose (n = 793; 281 from placebo) schedule.

A total of 166 patients, or about 10% in each group, discontinued treatment. The frequency of any serious adverse event (SAE) ranged between 10% and 11% in all groups. SAEs associated with infections ranged from 1% to 3%, indicating that there were no significant differences in SAE frequencies between those who were originally assigned to placebo and those who originally received benralizumab. That suggests no safety differences between receiving the drug for 1 year or 2 years.

A total of 1,046 subjects had blood eosinophil counts of 300 cells per mcL or greater at baseline; 72% of these patients had no asthma exacerbations during the BORA study. This was true for 74% of patients in the 8-week treatment arm.

The crude asthma exacerbation rate for patients who received benralizumab in SIROCCO or CALIMA was 0.48 in the 4-week arm, compared with placebo (95% confidence interval, 0.42-0.56) and 0.46 in the 8-week arm (95% CI, 0.39-0.53). For patients who started out on placebo, the crude exacerbation rate during BORA was 0.53 in the 4-week group (95% CI, 0.43-0.65) and 0.57 in the 8-week group (95% CI, 0.47-0.68).

Patients who started on benralizumab had similar exacerbation frequencies during year 1 and year 2.

AstraZeneca and Kyowa Hakko Kirin funded the studies. The authors have received fees from AstraZeneca and other pharmaceutical companies, and some are employees of AstraZeneca.

SOURCE: Busse WW et al. Lancet Respir Med. 2019 Jan 1;7(1):46-59.

Benralizumab is safe and effective for the treatment of uncontrolled asthma out to 2 years, according findings of the BORA trial, an extension study of the phase 3 SIROCCO and CALIMA trials. The study follows up and reinforces previously reported 1-year data and was reported by William W. Busse, MD, of University of Wisconsin, Madison, and his colleagues in the Lancet Respiratory Medicine.

Courtesy University of Wisconsin Health System

Benralizumab is a monoclonal antibody that targets interleukin-5 receptor alpha. It causes rapid deletion of eosinophils through cell-mediated cytotoxicity. A 30-mg dose of benralizumab every 8 weeks is approved for severe asthma treatment in Canada, Europe, Japan, the United States, and other countries.

In the second year of treatment, there were no new adverse events associated with depleted eosinophils, and the frequency of opportunistic infections was similar to that observed in the first year.

Eosinophilic inflammation occurs in about half of asthma cases and is associated with greater severity.

The 48-week SIROCCO trial, the 56-week CALIMA trial, and the 28-week ZONDA trial tested the effect of benralizumab 30 mg given every 4 weeks or 8 weeks, combined with high-dosage inhaled steroids and long-acting beta₂-agonists. The 8-week dose of the drug reduced annual exacerbations by 51%, compared with placebo in the SIROCCO trial and by 28% in the CALIMA trial. In the ZONDA trial, benralizumab reduced oral glucocorticoid use by 75%, compared with placebo, and by 25% from baseline.

The BORA extension trial included participants in the previous three trials. In the current report, researchers presented results from the analysis from BORA participants recruited from the SIROCCO and CALIMA trials. Data from participants from all three trials will be reported in the future.

The analysis included 1,576 patients who continued to receive benralizumab after being assigned to the treatment arm in SIROCCO or CALIMA, or who had received placebo were randomized to benralizumab on the 4-week (n = 783; 265 from placebo) or 8-week dose (n = 793; 281 from placebo) schedule.

A total of 166 patients, or about 10% in each group, discontinued treatment. The frequency of any serious adverse event (SAE) ranged between 10% and 11% in all groups. SAEs associated with infections ranged from 1% to 3%, indicating that there were no significant differences in SAE frequencies between those who were originally assigned to placebo and those who originally received benralizumab. That suggests no safety differences between receiving the drug for 1 year or 2 years.

A total of 1,046 subjects had blood eosinophil counts of 300 cells per mcL or greater at baseline; 72% of these patients had no asthma exacerbations during the BORA study. This was true for 74% of patients in the 8-week treatment arm.

The crude asthma exacerbation rate for patients who received benralizumab in SIROCCO or CALIMA was 0.48 in the 4-week arm, compared with placebo (95% confidence interval, 0.42-0.56) and 0.46 in the 8-week arm (95% CI, 0.39-0.53). For patients who started out on placebo, the crude exacerbation rate during BORA was 0.53 in the 4-week group (95% CI, 0.43-0.65) and 0.57 in the 8-week group (95% CI, 0.47-0.68).

Patients who started on benralizumab had similar exacerbation frequencies during year 1 and year 2.

AstraZeneca and Kyowa Hakko Kirin funded the studies. The authors have received fees from AstraZeneca and other pharmaceutical companies, and some are employees of AstraZeneca.

SOURCE: Busse WW et al. Lancet Respir Med. 2019 Jan 1;7(1):46-59.

Benralizumab is safe and effective for the treatment of uncontrolled asthma out to 2 years, according findings of the BORA trial, an extension study of the phase 3 SIROCCO and CALIMA trials. The study follows up and reinforces previously reported 1-year data and was reported by William W. Busse, MD, of University of Wisconsin, Madison, and his colleagues in the Lancet Respiratory Medicine.

Courtesy University of Wisconsin Health System

Benralizumab is a monoclonal antibody that targets interleukin-5 receptor alpha. It causes rapid deletion of eosinophils through cell-mediated cytotoxicity. A 30-mg dose of benralizumab every 8 weeks is approved for severe asthma treatment in Canada, Europe, Japan, the United States, and other countries.

In the second year of treatment, there were no new adverse events associated with depleted eosinophils, and the frequency of opportunistic infections was similar to that observed in the first year.

Eosinophilic inflammation occurs in about half of asthma cases and is associated with greater severity.

The 48-week SIROCCO trial, the 56-week CALIMA trial, and the 28-week ZONDA trial tested the effect of benralizumab 30 mg given every 4 weeks or 8 weeks, combined with high-dosage inhaled steroids and long-acting beta₂-agonists. The 8-week dose of the drug reduced annual exacerbations by 51%, compared with placebo in the SIROCCO trial and by 28% in the CALIMA trial. In the ZONDA trial, benralizumab reduced oral glucocorticoid use by 75%, compared with placebo, and by 25% from baseline.

The BORA extension trial included participants in the previous three trials. In the current report, researchers presented results from the analysis from BORA participants recruited from the SIROCCO and CALIMA trials. Data from participants from all three trials will be reported in the future.

The analysis included 1,576 patients who continued to receive benralizumab after being assigned to the treatment arm in SIROCCO or CALIMA, or who had received placebo were randomized to benralizumab on the 4-week (n = 783; 265 from placebo) or 8-week dose (n = 793; 281 from placebo) schedule.

A total of 166 patients, or about 10% in each group, discontinued treatment. The frequency of any serious adverse event (SAE) ranged between 10% and 11% in all groups. SAEs associated with infections ranged from 1% to 3%, indicating that there were no significant differences in SAE frequencies between those who were originally assigned to placebo and those who originally received benralizumab. That suggests no safety differences between receiving the drug for 1 year or 2 years.

A total of 1,046 subjects had blood eosinophil counts of 300 cells per mcL or greater at baseline; 72% of these patients had no asthma exacerbations during the BORA study. This was true for 74% of patients in the 8-week treatment arm.

The crude asthma exacerbation rate for patients who received benralizumab in SIROCCO or CALIMA was 0.48 in the 4-week arm, compared with placebo (95% confidence interval, 0.42-0.56) and 0.46 in the 8-week arm (95% CI, 0.39-0.53). For patients who started out on placebo, the crude exacerbation rate during BORA was 0.53 in the 4-week group (95% CI, 0.43-0.65) and 0.57 in the 8-week group (95% CI, 0.47-0.68).

Patients who started on benralizumab had similar exacerbation frequencies during year 1 and year 2.

AstraZeneca and Kyowa Hakko Kirin funded the studies. The authors have received fees from AstraZeneca and other pharmaceutical companies, and some are employees of AstraZeneca.

SOURCE: Busse WW et al. Lancet Respir Med. 2019 Jan 1;7(1):46-59.

Just like exposure to secondhand smoke, exposure to secondhand aerosols from e-cigarettes is associated with an increased risk of asthma exacerbations in children, according to a review of the 11,830 kids with asthma in the 2016 Florida Youth Tobacco survey.

diego_cervo/Thinkstock

Every year, the Florida Department of Health surveys public school children aged 11-17 years about various tobacco issues. In 2016, almost 12% of the asthmatic children in the survey said they vaped. Almost half were exposed to secondhand smoke, and a third reported exposure to secondhand vaping aerosols within the past 30 days. Overall, 21% reported an asthma attack in the past 12 months.

Using data from the Florida survey, the investigators crunched the numbers and found that secondhand aerosol exposure increased the odds of an asthma attack by 27%, independent of exposure to secondhand smoke and whether children smoked or vaped themselves (adjusted odds ratio, 1.27; 95% confidence interval, 1.11-1.47).

“Health professionals may wish to counsel asthmatic youth and their families regarding the potential risks of ENDS [electronic nicotine delivery system] use and exposure to ENDS aerosols.” Providers “may also consider including ENDS aerosol exposure as a possible trigger in asthma self-management/action plans and updating asthma home environment assessments to include exposure to ENDS aerosols,” said investigators led by medical student Jennifer Bayly, a research fellow at the National Institute on Minority Health and Health Disparities in Bethesda, Md.

About 4% of adults in the United States and 11% of high school students vape, and almost 10% of U.S. adolescents reported living with an ENDS user in 2014. Given the data, “it is likely that a substantial number of asthmatic youth are exposed,” the investigators said.

The study adds to a growing body of evidence linking e-cigarettes to asthma. There’s moderate evidence for increased cough and wheezing in adolescents who use e-cigarettes, plus an association with e-cigarette use and increased asthma exacerbations. The new study, however, is likely the first to look specifically at secondhand exposure among asthmatic children. Ingredients in vaping aerosols, including flavorings, propylene glycol, and vegetable glycerin, are physiologically active in the lungs, and may be lung irritants.

Overall, about half of the respondents were female, and two-thirds were 11-13 years old. About a third identified as Hispanic, a third as white, and just over a fifth as black. Three-quarters of the sample lived in large or midsized metropolitan areas, and close to two-thirds in stand-alone homes. Participants were considered exposed to secondhand aerosols if they reported that in the past month they were in a room or car with someone who was vaping.

The work was funded by the National Institutes of Health. The investigators had no disclosures.

[email protected]

SOURCE: Bayly JE et al. CHEST®. 2018 Oct 22. doi: 10.1016/j.chest.2018.10.005.

Just like exposure to secondhand smoke, exposure to secondhand aerosols from e-cigarettes is associated with an increased risk of asthma exacerbations in children, according to a review of the 11,830 kids with asthma in the 2016 Florida Youth Tobacco survey.

diego_cervo/Thinkstock

Every year, the Florida Department of Health surveys public school children aged 11-17 years about various tobacco issues. In 2016, almost 12% of the asthmatic children in the survey said they vaped. Almost half were exposed to secondhand smoke, and a third reported exposure to secondhand vaping aerosols within the past 30 days. Overall, 21% reported an asthma attack in the past 12 months.

Using data from the Florida survey, the investigators crunched the numbers and found that secondhand aerosol exposure increased the odds of an asthma attack by 27%, independent of exposure to secondhand smoke and whether children smoked or vaped themselves (adjusted odds ratio, 1.27; 95% confidence interval, 1.11-1.47).

“Health professionals may wish to counsel asthmatic youth and their families regarding the potential risks of ENDS [electronic nicotine delivery system] use and exposure to ENDS aerosols.” Providers “may also consider including ENDS aerosol exposure as a possible trigger in asthma self-management/action plans and updating asthma home environment assessments to include exposure to ENDS aerosols,” said investigators led by medical student Jennifer Bayly, a research fellow at the National Institute on Minority Health and Health Disparities in Bethesda, Md.

About 4% of adults in the United States and 11% of high school students vape, and almost 10% of U.S. adolescents reported living with an ENDS user in 2014. Given the data, “it is likely that a substantial number of asthmatic youth are exposed,” the investigators said.

The study adds to a growing body of evidence linking e-cigarettes to asthma. There’s moderate evidence for increased cough and wheezing in adolescents who use e-cigarettes, plus an association with e-cigarette use and increased asthma exacerbations. The new study, however, is likely the first to look specifically at secondhand exposure among asthmatic children. Ingredients in vaping aerosols, including flavorings, propylene glycol, and vegetable glycerin, are physiologically active in the lungs, and may be lung irritants.

Overall, about half of the respondents were female, and two-thirds were 11-13 years old. About a third identified as Hispanic, a third as white, and just over a fifth as black. Three-quarters of the sample lived in large or midsized metropolitan areas, and close to two-thirds in stand-alone homes. Participants were considered exposed to secondhand aerosols if they reported that in the past month they were in a room or car with someone who was vaping.

The work was funded by the National Institutes of Health. The investigators had no disclosures.

[email protected]

SOURCE: Bayly JE et al. CHEST®. 2018 Oct 22. doi: 10.1016/j.chest.2018.10.005.

Just like exposure to secondhand smoke, exposure to secondhand aerosols from e-cigarettes is associated with an increased risk of asthma exacerbations in children, according to a review of the 11,830 kids with asthma in the 2016 Florida Youth Tobacco survey.

diego_cervo/Thinkstock

Every year, the Florida Department of Health surveys public school children aged 11-17 years about various tobacco issues. In 2016, almost 12% of the asthmatic children in the survey said they vaped. Almost half were exposed to secondhand smoke, and a third reported exposure to secondhand vaping aerosols within the past 30 days. Overall, 21% reported an asthma attack in the past 12 months.

Using data from the Florida survey, the investigators crunched the numbers and found that secondhand aerosol exposure increased the odds of an asthma attack by 27%, independent of exposure to secondhand smoke and whether children smoked or vaped themselves (adjusted odds ratio, 1.27; 95% confidence interval, 1.11-1.47).

“Health professionals may wish to counsel asthmatic youth and their families regarding the potential risks of ENDS [electronic nicotine delivery system] use and exposure to ENDS aerosols.” Providers “may also consider including ENDS aerosol exposure as a possible trigger in asthma self-management/action plans and updating asthma home environment assessments to include exposure to ENDS aerosols,” said investigators led by medical student Jennifer Bayly, a research fellow at the National Institute on Minority Health and Health Disparities in Bethesda, Md.

About 4% of adults in the United States and 11% of high school students vape, and almost 10% of U.S. adolescents reported living with an ENDS user in 2014. Given the data, “it is likely that a substantial number of asthmatic youth are exposed,” the investigators said.

The study adds to a growing body of evidence linking e-cigarettes to asthma. There’s moderate evidence for increased cough and wheezing in adolescents who use e-cigarettes, plus an association with e-cigarette use and increased asthma exacerbations. The new study, however, is likely the first to look specifically at secondhand exposure among asthmatic children. Ingredients in vaping aerosols, including flavorings, propylene glycol, and vegetable glycerin, are physiologically active in the lungs, and may be lung irritants.

Overall, about half of the respondents were female, and two-thirds were 11-13 years old. About a third identified as Hispanic, a third as white, and just over a fifth as black. Three-quarters of the sample lived in large or midsized metropolitan areas, and close to two-thirds in stand-alone homes. Participants were considered exposed to secondhand aerosols if they reported that in the past month they were in a room or car with someone who was vaping.

The work was funded by the National Institutes of Health. The investigators had no disclosures.

[email protected]

SOURCE: Bayly JE et al. CHEST®. 2018 Oct 22. doi: 10.1016/j.chest.2018.10.005.

ORLANDO – The goal of treatment is the same for all asthma cases, regardless of severity: “to enable a patient to achieve and maintain control over their asthma,” according to Stanley J. Szefler, MD, a professor of pediatrics at the University of Colorado at Denver, Aurora.

That goal includes “reducing the risk of exacerbations, emergency department visits, hospitalizations, and progression as well as reducing impairments, including symptoms, functional limitations, poor quality of life, and other manifestations of asthma,” Dr. Szefler, also director of the Children’s Hospital of Colorado pediatric asthma research program, told colleagues at the annual meeting of the American Academy of Pediatrics.

Severe asthma challenges

These aims are more difficult with severe asthma, defined by the World Health Organization as “the current level of clinical control and risks which can result in frequent severe exacerbations and/or adverse reactions to medications and/or chronic morbidity,” Dr. Szefler explained. Severe asthma includes untreated severe asthma, difficult-to-treat asthma, and treatment-resistant severe asthma, whether controlled on high-dose medication or not.

Allergen sensitization, viral respiratory infections, and respiratory irritants (such as air pollution and smoking) are common features of severe asthma in children. Also common are challenges specific to management: poor medication adherence, poor technique for inhaled medications, and undertreatment. Poor management can lead to repeated exacerbations, adverse effects from drugs, disease progression, possible development of chronic obstructive pulmonary disease (COPD), and early mortality.

xavier gallego morel/fotolia.com

The National Heart, Lung, and Blood Institute EPR-3 guidelines for treatment of pediatric asthma recommend a stepwise approach to therapy, starting with short-acting beta₂-agonists as needed (SABA p.r.n.). The clinician then assesses the patient’s symptoms, exacerbations, side effects, quality of life, and lung function to determine whether the asthma is well managed or requires inhaled corticosteroids, or another therapy in moving through the steps. Each step also involves patient education, environmental control, and management of the child’s comorbidities.

It is not until steps 5 and 6 that the guidelines advise considering the biologic omalizumab for patients who have allergies. But other biologic options exist as well. Four biologics currently approved for treating asthma include omalizumab, mepolizumab, benralizumab, and reslizumab, but reslizumab is approved only for patients at least 18 years old.
 

Biologics for pediatric asthma

Omalizumab, which targets IgE, is appropriate for patients at least 6 years old in whom inhaled corticosteroids could not adequately control the symptoms of moderate to-severe persistent asthma. Dosing of omalizumab is a subcutaneous injection every 2-4 weeks based on pretreatment serum IgE and body weight using a dosing table that starts at 0.016 mg/kg/IgE (IU/mL). Maximum dose is 375 mg every 2 weeks in the United States and 600 mg every 2 weeks in the European Union.

The advantages of an anti-IgE drug are its use only once a month and its substantial effect on reducing exacerbations in a clearly identified population. However, these drugs are costly and require supervised administration, Dr. Szefler noted. They also carry a risk of anaphylaxis in less than 0.2% of patients, requiring the patient to be monitored after first administration and to carry an injectable epinephrine after omalizumab administration as a precaution for late-occurring anaphylaxis.

Mepolizumab is an anti–interleukin (IL)–5 drug used in patients at least 12 years old with severe persistent asthma that’s inadequately controlled with inhaled corticosteroids. Peripheral blood counts of eosinophilia determine if a patient has an eosinophilic phenotype, which has the best response to mepolizumab. People with at least 150 cells per microliter at baseline or at least 300 cells per microliter within the past year have shown a good response to mepolizumab. Dosing is 100 mg subcutaneously every 4 weeks.

For patients with atopic asthma, mepolizumab is effective in reducing the daily oral corticosteroid dose and the number of both annual exacerbations and exacerbations requiring hospitalization or an emergency visit. Other benefits of mepolizumab include increasing the time to a first exacerbation, the pre- and postbronchodilator forced expiratory volume in one second (FEV₁) and overall quality of life.

Patient reductions in exacerbations while taking mepolizumab were associated with eosinophil count but not IgE, atopic status, FEV₁ or bronchodilator response in the DREAM study (Lancet. 2012 Aug 18;380[9842]:651-9.).

Two safety considerations with mepolizumab include an increased risk of shingles and the risk of a preexisting helminth infection getting worse. Providers should screen for helminth infection and might consider a herpes zoster vaccination prior to starting therapy, Dr. Szefler said.

Benralizumab is an anti-IL5Ra for use in people at least 12 years old with severe persistent asthma and an eosinophilic phenotype (at least 300 cells per microliter). Dosing begins with three subcutaneous injections of 30 mg every 4 weeks, followed by administration every 8 weeks thereafter.

Benralizumab’s clinical effects include reduced exacerbations and oral corticosteroid use, and improved asthma symptom scores and prebronchodilator FEV₁. Higher serum eosinophils and a history of more frequent exacerbations are both biomarkers for reduced exacerbations with benralizumab treatment.

Dupilumab: New kid on the block

The newest biologic for asthma is dupilumab, approved Oct. 19, 2018, by the Food and Drug Administration as the only asthma biologic that patients can administer at home. Dupilumab is an anti–IL-4 and anti–IL-13 biologic whose most recent study results showed a severe exacerbations rate 50% lower than placebo (N Engl J Med. 2018 Jun 28;378[26]:2486-96.). Patients with higher baseline levels of eosinophils had the best response, although some patients showed hypereosinophilia following dupilumab therapy.

The study had a low number of adolescents enrolled, however, and more data on predictive biomarkers are needed. Dupilumab also requires a twice-monthly administration.

“It could be potentially better than those currently available due to additional effect on FEV₁,” Dr. Szefler said, but cost and safety may determine how dupilumab is recommended and used, including possible use for early intervention.

As development in biologics for pediatric asthma continues to grow, questions about best practices for management remain, such as what age is best for starting biologics, what strategies are most safe and effective, and what risks and benefits exist for each strategy. Questions also remain regarding the risk factors for asthma and what early intervention strategies might change the disease’s natural history.

“Look at asthma in children as a chronic disease that can result in potentially preventable adverse respiratory outcomes in adulthood,” Dr. Szefler said. He recommended monitoring children’s lung function over time and using “measures of clinical outcomes, lung function, and biomarkers to assess potential benefits of biologic therapy.”

Dr. Szefler has served on the advisory board for Regeneron and Sanofi, and he has consulted for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Novartis, and Propeller Health.

ORLANDO – The goal of treatment is the same for all asthma cases, regardless of severity: “to enable a patient to achieve and maintain control over their asthma,” according to Stanley J. Szefler, MD, a professor of pediatrics at the University of Colorado at Denver, Aurora.

That goal includes “reducing the risk of exacerbations, emergency department visits, hospitalizations, and progression as well as reducing impairments, including symptoms, functional limitations, poor quality of life, and other manifestations of asthma,” Dr. Szefler, also director of the Children’s Hospital of Colorado pediatric asthma research program, told colleagues at the annual meeting of the American Academy of Pediatrics.

Severe asthma challenges

These aims are more difficult with severe asthma, defined by the World Health Organization as “the current level of clinical control and risks which can result in frequent severe exacerbations and/or adverse reactions to medications and/or chronic morbidity,” Dr. Szefler explained. Severe asthma includes untreated severe asthma, difficult-to-treat asthma, and treatment-resistant severe asthma, whether controlled on high-dose medication or not.

Allergen sensitization, viral respiratory infections, and respiratory irritants (such as air pollution and smoking) are common features of severe asthma in children. Also common are challenges specific to management: poor medication adherence, poor technique for inhaled medications, and undertreatment. Poor management can lead to repeated exacerbations, adverse effects from drugs, disease progression, possible development of chronic obstructive pulmonary disease (COPD), and early mortality.

xavier gallego morel/fotolia.com

The National Heart, Lung, and Blood Institute EPR-3 guidelines for treatment of pediatric asthma recommend a stepwise approach to therapy, starting with short-acting beta₂-agonists as needed (SABA p.r.n.). The clinician then assesses the patient’s symptoms, exacerbations, side effects, quality of life, and lung function to determine whether the asthma is well managed or requires inhaled corticosteroids, or another therapy in moving through the steps. Each step also involves patient education, environmental control, and management of the child’s comorbidities.

It is not until steps 5 and 6 that the guidelines advise considering the biologic omalizumab for patients who have allergies. But other biologic options exist as well. Four biologics currently approved for treating asthma include omalizumab, mepolizumab, benralizumab, and reslizumab, but reslizumab is approved only for patients at least 18 years old.
 

Biologics for pediatric asthma

Omalizumab, which targets IgE, is appropriate for patients at least 6 years old in whom inhaled corticosteroids could not adequately control the symptoms of moderate to-severe persistent asthma. Dosing of omalizumab is a subcutaneous injection every 2-4 weeks based on pretreatment serum IgE and body weight using a dosing table that starts at 0.016 mg/kg/IgE (IU/mL). Maximum dose is 375 mg every 2 weeks in the United States and 600 mg every 2 weeks in the European Union.

The advantages of an anti-IgE drug are its use only once a month and its substantial effect on reducing exacerbations in a clearly identified population. However, these drugs are costly and require supervised administration, Dr. Szefler noted. They also carry a risk of anaphylaxis in less than 0.2% of patients, requiring the patient to be monitored after first administration and to carry an injectable epinephrine after omalizumab administration as a precaution for late-occurring anaphylaxis.

Mepolizumab is an anti–interleukin (IL)–5 drug used in patients at least 12 years old with severe persistent asthma that’s inadequately controlled with inhaled corticosteroids. Peripheral blood counts of eosinophilia determine if a patient has an eosinophilic phenotype, which has the best response to mepolizumab. People with at least 150 cells per microliter at baseline or at least 300 cells per microliter within the past year have shown a good response to mepolizumab. Dosing is 100 mg subcutaneously every 4 weeks.

For patients with atopic asthma, mepolizumab is effective in reducing the daily oral corticosteroid dose and the number of both annual exacerbations and exacerbations requiring hospitalization or an emergency visit. Other benefits of mepolizumab include increasing the time to a first exacerbation, the pre- and postbronchodilator forced expiratory volume in one second (FEV₁) and overall quality of life.

Patient reductions in exacerbations while taking mepolizumab were associated with eosinophil count but not IgE, atopic status, FEV₁ or bronchodilator response in the DREAM study (Lancet. 2012 Aug 18;380[9842]:651-9.).

Two safety considerations with mepolizumab include an increased risk of shingles and the risk of a preexisting helminth infection getting worse. Providers should screen for helminth infection and might consider a herpes zoster vaccination prior to starting therapy, Dr. Szefler said.

Benralizumab is an anti-IL5Ra for use in people at least 12 years old with severe persistent asthma and an eosinophilic phenotype (at least 300 cells per microliter). Dosing begins with three subcutaneous injections of 30 mg every 4 weeks, followed by administration every 8 weeks thereafter.

Benralizumab’s clinical effects include reduced exacerbations and oral corticosteroid use, and improved asthma symptom scores and prebronchodilator FEV₁. Higher serum eosinophils and a history of more frequent exacerbations are both biomarkers for reduced exacerbations with benralizumab treatment.

Dupilumab: New kid on the block

The newest biologic for asthma is dupilumab, approved Oct. 19, 2018, by the Food and Drug Administration as the only asthma biologic that patients can administer at home. Dupilumab is an anti–IL-4 and anti–IL-13 biologic whose most recent study results showed a severe exacerbations rate 50% lower than placebo (N Engl J Med. 2018 Jun 28;378[26]:2486-96.). Patients with higher baseline levels of eosinophils had the best response, although some patients showed hypereosinophilia following dupilumab therapy.

The study had a low number of adolescents enrolled, however, and more data on predictive biomarkers are needed. Dupilumab also requires a twice-monthly administration.

“It could be potentially better than those currently available due to additional effect on FEV₁,” Dr. Szefler said, but cost and safety may determine how dupilumab is recommended and used, including possible use for early intervention.

As development in biologics for pediatric asthma continues to grow, questions about best practices for management remain, such as what age is best for starting biologics, what strategies are most safe and effective, and what risks and benefits exist for each strategy. Questions also remain regarding the risk factors for asthma and what early intervention strategies might change the disease’s natural history.

“Look at asthma in children as a chronic disease that can result in potentially preventable adverse respiratory outcomes in adulthood,” Dr. Szefler said. He recommended monitoring children’s lung function over time and using “measures of clinical outcomes, lung function, and biomarkers to assess potential benefits of biologic therapy.”

Dr. Szefler has served on the advisory board for Regeneron and Sanofi, and he has consulted for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Novartis, and Propeller Health.

ORLANDO – The goal of treatment is the same for all asthma cases, regardless of severity: “to enable a patient to achieve and maintain control over their asthma,” according to Stanley J. Szefler, MD, a professor of pediatrics at the University of Colorado at Denver, Aurora.

That goal includes “reducing the risk of exacerbations, emergency department visits, hospitalizations, and progression as well as reducing impairments, including symptoms, functional limitations, poor quality of life, and other manifestations of asthma,” Dr. Szefler, also director of the Children’s Hospital of Colorado pediatric asthma research program, told colleagues at the annual meeting of the American Academy of Pediatrics.

Severe asthma challenges

These aims are more difficult with severe asthma, defined by the World Health Organization as “the current level of clinical control and risks which can result in frequent severe exacerbations and/or adverse reactions to medications and/or chronic morbidity,” Dr. Szefler explained. Severe asthma includes untreated severe asthma, difficult-to-treat asthma, and treatment-resistant severe asthma, whether controlled on high-dose medication or not.

Allergen sensitization, viral respiratory infections, and respiratory irritants (such as air pollution and smoking) are common features of severe asthma in children. Also common are challenges specific to management: poor medication adherence, poor technique for inhaled medications, and undertreatment. Poor management can lead to repeated exacerbations, adverse effects from drugs, disease progression, possible development of chronic obstructive pulmonary disease (COPD), and early mortality.

xavier gallego morel/fotolia.com

The National Heart, Lung, and Blood Institute EPR-3 guidelines for treatment of pediatric asthma recommend a stepwise approach to therapy, starting with short-acting beta₂-agonists as needed (SABA p.r.n.). The clinician then assesses the patient’s symptoms, exacerbations, side effects, quality of life, and lung function to determine whether the asthma is well managed or requires inhaled corticosteroids, or another therapy in moving through the steps. Each step also involves patient education, environmental control, and management of the child’s comorbidities.

It is not until steps 5 and 6 that the guidelines advise considering the biologic omalizumab for patients who have allergies. But other biologic options exist as well. Four biologics currently approved for treating asthma include omalizumab, mepolizumab, benralizumab, and reslizumab, but reslizumab is approved only for patients at least 18 years old.
 

Biologics for pediatric asthma

Omalizumab, which targets IgE, is appropriate for patients at least 6 years old in whom inhaled corticosteroids could not adequately control the symptoms of moderate to-severe persistent asthma. Dosing of omalizumab is a subcutaneous injection every 2-4 weeks based on pretreatment serum IgE and body weight using a dosing table that starts at 0.016 mg/kg/IgE (IU/mL). Maximum dose is 375 mg every 2 weeks in the United States and 600 mg every 2 weeks in the European Union.

The advantages of an anti-IgE drug are its use only once a month and its substantial effect on reducing exacerbations in a clearly identified population. However, these drugs are costly and require supervised administration, Dr. Szefler noted. They also carry a risk of anaphylaxis in less than 0.2% of patients, requiring the patient to be monitored after first administration and to carry an injectable epinephrine after omalizumab administration as a precaution for late-occurring anaphylaxis.

Mepolizumab is an anti–interleukin (IL)–5 drug used in patients at least 12 years old with severe persistent asthma that’s inadequately controlled with inhaled corticosteroids. Peripheral blood counts of eosinophilia determine if a patient has an eosinophilic phenotype, which has the best response to mepolizumab. People with at least 150 cells per microliter at baseline or at least 300 cells per microliter within the past year have shown a good response to mepolizumab. Dosing is 100 mg subcutaneously every 4 weeks.

For patients with atopic asthma, mepolizumab is effective in reducing the daily oral corticosteroid dose and the number of both annual exacerbations and exacerbations requiring hospitalization or an emergency visit. Other benefits of mepolizumab include increasing the time to a first exacerbation, the pre- and postbronchodilator forced expiratory volume in one second (FEV₁) and overall quality of life.

Patient reductions in exacerbations while taking mepolizumab were associated with eosinophil count but not IgE, atopic status, FEV₁ or bronchodilator response in the DREAM study (Lancet. 2012 Aug 18;380[9842]:651-9.).

Two safety considerations with mepolizumab include an increased risk of shingles and the risk of a preexisting helminth infection getting worse. Providers should screen for helminth infection and might consider a herpes zoster vaccination prior to starting therapy, Dr. Szefler said.

Benralizumab is an anti-IL5Ra for use in people at least 12 years old with severe persistent asthma and an eosinophilic phenotype (at least 300 cells per microliter). Dosing begins with three subcutaneous injections of 30 mg every 4 weeks, followed by administration every 8 weeks thereafter.

Benralizumab’s clinical effects include reduced exacerbations and oral corticosteroid use, and improved asthma symptom scores and prebronchodilator FEV₁. Higher serum eosinophils and a history of more frequent exacerbations are both biomarkers for reduced exacerbations with benralizumab treatment.

Dupilumab: New kid on the block

The newest biologic for asthma is dupilumab, approved Oct. 19, 2018, by the Food and Drug Administration as the only asthma biologic that patients can administer at home. Dupilumab is an anti–IL-4 and anti–IL-13 biologic whose most recent study results showed a severe exacerbations rate 50% lower than placebo (N Engl J Med. 2018 Jun 28;378[26]:2486-96.). Patients with higher baseline levels of eosinophils had the best response, although some patients showed hypereosinophilia following dupilumab therapy.

The study had a low number of adolescents enrolled, however, and more data on predictive biomarkers are needed. Dupilumab also requires a twice-monthly administration.

“It could be potentially better than those currently available due to additional effect on FEV₁,” Dr. Szefler said, but cost and safety may determine how dupilumab is recommended and used, including possible use for early intervention.

As development in biologics for pediatric asthma continues to grow, questions about best practices for management remain, such as what age is best for starting biologics, what strategies are most safe and effective, and what risks and benefits exist for each strategy. Questions also remain regarding the risk factors for asthma and what early intervention strategies might change the disease’s natural history.

“Look at asthma in children as a chronic disease that can result in potentially preventable adverse respiratory outcomes in adulthood,” Dr. Szefler said. He recommended monitoring children’s lung function over time and using “measures of clinical outcomes, lung function, and biomarkers to assess potential benefits of biologic therapy.”

Dr. Szefler has served on the advisory board for Regeneron and Sanofi, and he has consulted for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Novartis, and Propeller Health.

Around one-quarter of new asthma cases in children with obesity may be attributable to their obesity, according to research published in Pediatrics.

moodboard/thinkstockphotos

Jason E. Lang, MD, MPH, of Duke University, Durham, N.C., and his coauthors used the PEDSnet clinical data research network to conduct a retrospective cohort study of 507,496 children aged 2-17 years from 2009-2015, comparing the incidence of asthma in overweight and obese children to the incidence in healthy weight children.

The overall rate of new diagnoses of asthma was 2.4 per 1,000 patient years among normal-weight children and 3.2 per 1,000 patient years among obese children.

After adjustment for factors such as age, ethnicity, insurance status, sex, allergic rhinitis, food allergy, and proton pump inhibitor use, overweight children had a 17% higher risk of incident asthma, and obese children had a 26% higher risk of asthma, compared with children of normal weight. The relative risk of spirometry-confirmed asthma was 29% higher in obese children compared with normal-weight children, and the association between obesity and asthma persisted even when a second asthma encounter was required for the diagnosis.

Overall, the authors estimated that 23%-25% of clinically diagnosed asthma in children with obesity could be specifically attributed to obesity, and that in the overall population of children 10% of asthma was attributable to obesity.

“Currently, there are few known preventable risk factors that can be used to reduce childhood asthma,” wrote Dr. Lang and his coauthors. “With these data, it is suggested that reducing the onset of obesity in childhood would significantly reduce the public health burden of asthma in children.”

They noted that with current estimates of U.S. pediatric asthma prevalence being around 6-8 million cases, obesity could therefore account for up to 1 million of these cases.

The study was funded by the Patient-Centered Outcomes Research Institute, the Nemours Children’s Hospital and Nemours Children’s Health System. One author declared advisory board positions and consultancies with the pharmaceutical industry. The remaining researchers said they had no conflicts of interest.

SOURCE: Lang J et al. Pediatrics. 2018 Dec;142(6):e20182119.

Around one-quarter of new asthma cases in children with obesity may be attributable to their obesity, according to research published in Pediatrics.

moodboard/thinkstockphotos

Jason E. Lang, MD, MPH, of Duke University, Durham, N.C., and his coauthors used the PEDSnet clinical data research network to conduct a retrospective cohort study of 507,496 children aged 2-17 years from 2009-2015, comparing the incidence of asthma in overweight and obese children to the incidence in healthy weight children.

The overall rate of new diagnoses of asthma was 2.4 per 1,000 patient years among normal-weight children and 3.2 per 1,000 patient years among obese children.

After adjustment for factors such as age, ethnicity, insurance status, sex, allergic rhinitis, food allergy, and proton pump inhibitor use, overweight children had a 17% higher risk of incident asthma, and obese children had a 26% higher risk of asthma, compared with children of normal weight. The relative risk of spirometry-confirmed asthma was 29% higher in obese children compared with normal-weight children, and the association between obesity and asthma persisted even when a second asthma encounter was required for the diagnosis.

Overall, the authors estimated that 23%-25% of clinically diagnosed asthma in children with obesity could be specifically attributed to obesity, and that in the overall population of children 10% of asthma was attributable to obesity.

“Currently, there are few known preventable risk factors that can be used to reduce childhood asthma,” wrote Dr. Lang and his coauthors. “With these data, it is suggested that reducing the onset of obesity in childhood would significantly reduce the public health burden of asthma in children.”

They noted that with current estimates of U.S. pediatric asthma prevalence being around 6-8 million cases, obesity could therefore account for up to 1 million of these cases.

The study was funded by the Patient-Centered Outcomes Research Institute, the Nemours Children’s Hospital and Nemours Children’s Health System. One author declared advisory board positions and consultancies with the pharmaceutical industry. The remaining researchers said they had no conflicts of interest.

SOURCE: Lang J et al. Pediatrics. 2018 Dec;142(6):e20182119.

Around one-quarter of new asthma cases in children with obesity may be attributable to their obesity, according to research published in Pediatrics.

moodboard/thinkstockphotos

Jason E. Lang, MD, MPH, of Duke University, Durham, N.C., and his coauthors used the PEDSnet clinical data research network to conduct a retrospective cohort study of 507,496 children aged 2-17 years from 2009-2015, comparing the incidence of asthma in overweight and obese children to the incidence in healthy weight children.

The overall rate of new diagnoses of asthma was 2.4 per 1,000 patient years among normal-weight children and 3.2 per 1,000 patient years among obese children.

After adjustment for factors such as age, ethnicity, insurance status, sex, allergic rhinitis, food allergy, and proton pump inhibitor use, overweight children had a 17% higher risk of incident asthma, and obese children had a 26% higher risk of asthma, compared with children of normal weight. The relative risk of spirometry-confirmed asthma was 29% higher in obese children compared with normal-weight children, and the association between obesity and asthma persisted even when a second asthma encounter was required for the diagnosis.

Overall, the authors estimated that 23%-25% of clinically diagnosed asthma in children with obesity could be specifically attributed to obesity, and that in the overall population of children 10% of asthma was attributable to obesity.

“Currently, there are few known preventable risk factors that can be used to reduce childhood asthma,” wrote Dr. Lang and his coauthors. “With these data, it is suggested that reducing the onset of obesity in childhood would significantly reduce the public health burden of asthma in children.”

They noted that with current estimates of U.S. pediatric asthma prevalence being around 6-8 million cases, obesity could therefore account for up to 1 million of these cases.

The study was funded by the Patient-Centered Outcomes Research Institute, the Nemours Children’s Hospital and Nemours Children’s Health System. One author declared advisory board positions and consultancies with the pharmaceutical industry. The remaining researchers said they had no conflicts of interest.

SOURCE: Lang J et al. Pediatrics. 2018 Dec;142(6):e20182119.

Vitamin D levels measured in maternal sera during gestation and in umbilical cord blood were not predictive of the prevalence of eczema, food allergy, asthma and allergic rhinitis in children at ages 2 years and 5 years, according to study results published in the journal Allergy.

copyright istock/Thinkstock

Áine Hennessy, PhD, from the School of Food and Nutritional Sciences at the University College Cork (Ireland), and her colleagues performed a prospective cohort study of 1,537 women in the Cork BASELINE Birth Cohort Study who underwent measurement of serum 25-hydroxyvitamin D (25[OH]D) from maternal sera followed by measurement of 25(OH)D in umbilical cord blood (1,050 cases). They then measured the prevalence of eczema, food allergy, allergic rhinitis, and asthma in infants at aged 2 and 5 years.

The researchers found at 2 years old, 5% of infants had persistent eczema, 4% of infants had a food allergy and 8% of infants had aeroallergen sensitization. At age 5 years, 15% of infants had asthma, while 5% had allergic rhinitis. Mothers whose children went on to have atopy did not differ in their 25(OH)D levels at 15 weeks’ gestation (mean 58.4 nmol/L vs. 58.5 nmol/L) or in the levels in umbilical cord blood (mean 35.2 nmol/L and 35.4 nmol/L).

Of the women in the cohort, 74% ranged in age from 25 to 34 years; 49% reported a personal history of allergy and 37% reported a paternal allergy. The mean birth weight of the infants was 3,458 g; infants were breastfed for mean 11.9 weeks, 73% of infants were breastfeeding by the time they left the hospital and 45% of infants were breastfeeding by age 2 months.

Limitations of the study included that parental atopy status was self-reported and that the researchers noted they did not examine genetic variants of immunoglobulin E synthesis or vitamin D receptor polymorphisms.

“To fully characterize relationships between intrauterine vitamin D exposure and allergic disease, analysis of well‐constructed, large‐scale prospective cohorts of maternal‐infant dyads, which take due consideration of an individual’s inherited risk, early‐life exposures and environmental confounders, is still needed,” Dr. Hennessy and her colleagues wrote.

The study was funded by grants from the European Commission, Ireland Health Research Board, National Children’s Research Centre, Food Standards Agency and Science Foundation Ireland. The authors report no relevant conflicts of interest.

SOURCE: Hennessy A et al. Allergy. 2018 Aug 7. doi: 10.1111/all.13590.

Vitamin D levels measured in maternal sera during gestation and in umbilical cord blood were not predictive of the prevalence of eczema, food allergy, asthma and allergic rhinitis in children at ages 2 years and 5 years, according to study results published in the journal Allergy.

copyright istock/Thinkstock

Áine Hennessy, PhD, from the School of Food and Nutritional Sciences at the University College Cork (Ireland), and her colleagues performed a prospective cohort study of 1,537 women in the Cork BASELINE Birth Cohort Study who underwent measurement of serum 25-hydroxyvitamin D (25[OH]D) from maternal sera followed by measurement of 25(OH)D in umbilical cord blood (1,050 cases). They then measured the prevalence of eczema, food allergy, allergic rhinitis, and asthma in infants at aged 2 and 5 years.

The researchers found at 2 years old, 5% of infants had persistent eczema, 4% of infants had a food allergy and 8% of infants had aeroallergen sensitization. At age 5 years, 15% of infants had asthma, while 5% had allergic rhinitis. Mothers whose children went on to have atopy did not differ in their 25(OH)D levels at 15 weeks’ gestation (mean 58.4 nmol/L vs. 58.5 nmol/L) or in the levels in umbilical cord blood (mean 35.2 nmol/L and 35.4 nmol/L).

Of the women in the cohort, 74% ranged in age from 25 to 34 years; 49% reported a personal history of allergy and 37% reported a paternal allergy. The mean birth weight of the infants was 3,458 g; infants were breastfed for mean 11.9 weeks, 73% of infants were breastfeeding by the time they left the hospital and 45% of infants were breastfeeding by age 2 months.

Limitations of the study included that parental atopy status was self-reported and that the researchers noted they did not examine genetic variants of immunoglobulin E synthesis or vitamin D receptor polymorphisms.

“To fully characterize relationships between intrauterine vitamin D exposure and allergic disease, analysis of well‐constructed, large‐scale prospective cohorts of maternal‐infant dyads, which take due consideration of an individual’s inherited risk, early‐life exposures and environmental confounders, is still needed,” Dr. Hennessy and her colleagues wrote.

The study was funded by grants from the European Commission, Ireland Health Research Board, National Children’s Research Centre, Food Standards Agency and Science Foundation Ireland. The authors report no relevant conflicts of interest.

SOURCE: Hennessy A et al. Allergy. 2018 Aug 7. doi: 10.1111/all.13590.

Vitamin D levels measured in maternal sera during gestation and in umbilical cord blood were not predictive of the prevalence of eczema, food allergy, asthma and allergic rhinitis in children at ages 2 years and 5 years, according to study results published in the journal Allergy.

copyright istock/Thinkstock

Áine Hennessy, PhD, from the School of Food and Nutritional Sciences at the University College Cork (Ireland), and her colleagues performed a prospective cohort study of 1,537 women in the Cork BASELINE Birth Cohort Study who underwent measurement of serum 25-hydroxyvitamin D (25[OH]D) from maternal sera followed by measurement of 25(OH)D in umbilical cord blood (1,050 cases). They then measured the prevalence of eczema, food allergy, allergic rhinitis, and asthma in infants at aged 2 and 5 years.

The researchers found at 2 years old, 5% of infants had persistent eczema, 4% of infants had a food allergy and 8% of infants had aeroallergen sensitization. At age 5 years, 15% of infants had asthma, while 5% had allergic rhinitis. Mothers whose children went on to have atopy did not differ in their 25(OH)D levels at 15 weeks’ gestation (mean 58.4 nmol/L vs. 58.5 nmol/L) or in the levels in umbilical cord blood (mean 35.2 nmol/L and 35.4 nmol/L).

Of the women in the cohort, 74% ranged in age from 25 to 34 years; 49% reported a personal history of allergy and 37% reported a paternal allergy. The mean birth weight of the infants was 3,458 g; infants were breastfed for mean 11.9 weeks, 73% of infants were breastfeeding by the time they left the hospital and 45% of infants were breastfeeding by age 2 months.

Limitations of the study included that parental atopy status was self-reported and that the researchers noted they did not examine genetic variants of immunoglobulin E synthesis or vitamin D receptor polymorphisms.

“To fully characterize relationships between intrauterine vitamin D exposure and allergic disease, analysis of well‐constructed, large‐scale prospective cohorts of maternal‐infant dyads, which take due consideration of an individual’s inherited risk, early‐life exposures and environmental confounders, is still needed,” Dr. Hennessy and her colleagues wrote.

The study was funded by grants from the European Commission, Ireland Health Research Board, National Children’s Research Centre, Food Standards Agency and Science Foundation Ireland. The authors report no relevant conflicts of interest.

SOURCE: Hennessy A et al. Allergy. 2018 Aug 7. doi: 10.1111/all.13590.

Inflammation is a double-edged sword. Controlled and modest proinflammatory responses can enhance host immunity against viruses and decrease bacterial colonization and infection, whereas excessive uncontrolled proinflammatory responses may increase the susceptibility to bacterial colonization and secondary infection to facilitate disease pathogenesis. The immune system produces both proinflammatory and anti-inflammatory cytokines and chemokines. It is a balanced response that is key to maintaining good health.

Cynthia Goldsmith/CDC photo #10073

Viral upper respiratory tract infections (URIs) are caused by rhinoviruses, coronaviruses, enteroviruses, respiratory syncytial viruses, influenza A and B viruses, parainfluenza viruses, adenoviruses, and human metapneumoviruses. Viruses are powerful. In the nose, they induce hypersecretion of mucus, slow cilia beating, up-regulate nasal epithelial cell receptors to facilitate bacterial attachment, suppress neutrophil function, and cause increased release of proinflammatory cytokines and chemokines. All these actions by respiratory viruses promote bacterial overgrowth in the nasopharynx and thereby facilitate bacterial superinfections. In fact, progression in pathogenesis of the common bacterial respiratory infections – acute otitis media, acute sinusitis, acute conjunctivitis, and pneumonia – almost always is preceded by a viral URI. Viruses activate multiple target cells in the upper respiratory tract to produce an array of proinflammatory cytokines and chemokines. The symptoms of a viral URI resolve coinciding with an anti-inflammatory response and adaptive immunity.

In recent work, we found a higher frequency of viral URIs in children who experienced more frequent acute otitis media (AOM). We sought to understand why this might occur by comparing levels of inflammatory cytokines/chemokines in the nose during viral URI that did not precipitate AOM versus when a viral URI precipitated an AOM episode. When a child had a viral URI but did not go on to experience an AOM, the child had higher proinflammatory responses than when the viral URI precipitated an AOM. When differences of levels of proinflammatory cytokines/chemokines were compared in otitis-prone and non–otitis-prone children, lower nasal responses were associated with higher otitis-prone classification frequency (Clin Infect Dis. 2018. doi: 10.1093/cid/ciy750).

The powerful virus and the inflammatory response it can induce also play a major role in allergy and asthma. Viral URIs enhance allergic sensitization to respiratory viruses, such as influenza and respiratory syncytial virus, cause cytopathic damage to airway epithelium, promote excessive proinflammatory cytokine/chemokine production, and increase the exposure of allergens and irritants to antigen-presenting cells. Viral infections also may induce the release of epithelial mediators and cytokines that may propagate eosinophilia. Viral URIs, particularly with respiratory syncytial virus and rhinovirus, are the most common causes of wheezing in children, and they have important influences on the development of asthma. Studies have shown that viral infections trigger up to 85% of asthma exacerbations in school-aged children.

Because this column is being published during the winter, a brief discussion of influenza as a powerful virus is appropriate. Influenza occurs in winter outbreaks of varying extent every year. The severity of the influenza season reflects the changing nature of the antigenic properties of influenza viruses, and their spread depends on susceptibility of the population. Influenza outbreaks typically peak over a 2-3 week period and last for 2-3 months. Most outbreaks have attack rates of 10%-20% in children. There may be variations in disease severity caused by different influenza virus types. The symptoms are caused by excessive proinflammatory cytokine/chemokine production in the nose and lung.

Influenza and other viruses can precipitate the systemic inflammatory response syndrome (SIRS), a manifestation of extreme immune dysregulation resulting in organ dysfunction that clinically resembles bacterial sepsis. In this syndrome, tissues remote from the original insult display the cardinal signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation. SIRS is another example of the double-edged sword of inflammation.

The onset and progression of SIRS occurs because of dysregulation of the normal inflammatory response, usually with an increase in both proinflammatory and anti-inflammatory cytokines and chemokines, initiating a chain of events that leads to organ failure.

Dr. Pichichero is a specialist in pediatric infectious diseases and director of the Research Institute at Rochester (N.Y.) General Hospital. He reported having no conflicts of interest. Email him at [email protected].

Inflammation is a double-edged sword. Controlled and modest proinflammatory responses can enhance host immunity against viruses and decrease bacterial colonization and infection, whereas excessive uncontrolled proinflammatory responses may increase the susceptibility to bacterial colonization and secondary infection to facilitate disease pathogenesis. The immune system produces both proinflammatory and anti-inflammatory cytokines and chemokines. It is a balanced response that is key to maintaining good health.

Cynthia Goldsmith/CDC photo #10073

Viral upper respiratory tract infections (URIs) are caused by rhinoviruses, coronaviruses, enteroviruses, respiratory syncytial viruses, influenza A and B viruses, parainfluenza viruses, adenoviruses, and human metapneumoviruses. Viruses are powerful. In the nose, they induce hypersecretion of mucus, slow cilia beating, up-regulate nasal epithelial cell receptors to facilitate bacterial attachment, suppress neutrophil function, and cause increased release of proinflammatory cytokines and chemokines. All these actions by respiratory viruses promote bacterial overgrowth in the nasopharynx and thereby facilitate bacterial superinfections. In fact, progression in pathogenesis of the common bacterial respiratory infections – acute otitis media, acute sinusitis, acute conjunctivitis, and pneumonia – almost always is preceded by a viral URI. Viruses activate multiple target cells in the upper respiratory tract to produce an array of proinflammatory cytokines and chemokines. The symptoms of a viral URI resolve coinciding with an anti-inflammatory response and adaptive immunity.

In recent work, we found a higher frequency of viral URIs in children who experienced more frequent acute otitis media (AOM). We sought to understand why this might occur by comparing levels of inflammatory cytokines/chemokines in the nose during viral URI that did not precipitate AOM versus when a viral URI precipitated an AOM episode. When a child had a viral URI but did not go on to experience an AOM, the child had higher proinflammatory responses than when the viral URI precipitated an AOM. When differences of levels of proinflammatory cytokines/chemokines were compared in otitis-prone and non–otitis-prone children, lower nasal responses were associated with higher otitis-prone classification frequency (Clin Infect Dis. 2018. doi: 10.1093/cid/ciy750).

The powerful virus and the inflammatory response it can induce also play a major role in allergy and asthma. Viral URIs enhance allergic sensitization to respiratory viruses, such as influenza and respiratory syncytial virus, cause cytopathic damage to airway epithelium, promote excessive proinflammatory cytokine/chemokine production, and increase the exposure of allergens and irritants to antigen-presenting cells. Viral infections also may induce the release of epithelial mediators and cytokines that may propagate eosinophilia. Viral URIs, particularly with respiratory syncytial virus and rhinovirus, are the most common causes of wheezing in children, and they have important influences on the development of asthma. Studies have shown that viral infections trigger up to 85% of asthma exacerbations in school-aged children.

Because this column is being published during the winter, a brief discussion of influenza as a powerful virus is appropriate. Influenza occurs in winter outbreaks of varying extent every year. The severity of the influenza season reflects the changing nature of the antigenic properties of influenza viruses, and their spread depends on susceptibility of the population. Influenza outbreaks typically peak over a 2-3 week period and last for 2-3 months. Most outbreaks have attack rates of 10%-20% in children. There may be variations in disease severity caused by different influenza virus types. The symptoms are caused by excessive proinflammatory cytokine/chemokine production in the nose and lung.

Influenza and other viruses can precipitate the systemic inflammatory response syndrome (SIRS), a manifestation of extreme immune dysregulation resulting in organ dysfunction that clinically resembles bacterial sepsis. In this syndrome, tissues remote from the original insult display the cardinal signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation. SIRS is another example of the double-edged sword of inflammation.

The onset and progression of SIRS occurs because of dysregulation of the normal inflammatory response, usually with an increase in both proinflammatory and anti-inflammatory cytokines and chemokines, initiating a chain of events that leads to organ failure.

Dr. Pichichero is a specialist in pediatric infectious diseases and director of the Research Institute at Rochester (N.Y.) General Hospital. He reported having no conflicts of interest. Email him at [email protected].

Inflammation is a double-edged sword. Controlled and modest proinflammatory responses can enhance host immunity against viruses and decrease bacterial colonization and infection, whereas excessive uncontrolled proinflammatory responses may increase the susceptibility to bacterial colonization and secondary infection to facilitate disease pathogenesis. The immune system produces both proinflammatory and anti-inflammatory cytokines and chemokines. It is a balanced response that is key to maintaining good health.

Cynthia Goldsmith/CDC photo #10073

Viral upper respiratory tract infections (URIs) are caused by rhinoviruses, coronaviruses, enteroviruses, respiratory syncytial viruses, influenza A and B viruses, parainfluenza viruses, adenoviruses, and human metapneumoviruses. Viruses are powerful. In the nose, they induce hypersecretion of mucus, slow cilia beating, up-regulate nasal epithelial cell receptors to facilitate bacterial attachment, suppress neutrophil function, and cause increased release of proinflammatory cytokines and chemokines. All these actions by respiratory viruses promote bacterial overgrowth in the nasopharynx and thereby facilitate bacterial superinfections. In fact, progression in pathogenesis of the common bacterial respiratory infections – acute otitis media, acute sinusitis, acute conjunctivitis, and pneumonia – almost always is preceded by a viral URI. Viruses activate multiple target cells in the upper respiratory tract to produce an array of proinflammatory cytokines and chemokines. The symptoms of a viral URI resolve coinciding with an anti-inflammatory response and adaptive immunity.

In recent work, we found a higher frequency of viral URIs in children who experienced more frequent acute otitis media (AOM). We sought to understand why this might occur by comparing levels of inflammatory cytokines/chemokines in the nose during viral URI that did not precipitate AOM versus when a viral URI precipitated an AOM episode. When a child had a viral URI but did not go on to experience an AOM, the child had higher proinflammatory responses than when the viral URI precipitated an AOM. When differences of levels of proinflammatory cytokines/chemokines were compared in otitis-prone and non–otitis-prone children, lower nasal responses were associated with higher otitis-prone classification frequency (Clin Infect Dis. 2018. doi: 10.1093/cid/ciy750).

The powerful virus and the inflammatory response it can induce also play a major role in allergy and asthma. Viral URIs enhance allergic sensitization to respiratory viruses, such as influenza and respiratory syncytial virus, cause cytopathic damage to airway epithelium, promote excessive proinflammatory cytokine/chemokine production, and increase the exposure of allergens and irritants to antigen-presenting cells. Viral infections also may induce the release of epithelial mediators and cytokines that may propagate eosinophilia. Viral URIs, particularly with respiratory syncytial virus and rhinovirus, are the most common causes of wheezing in children, and they have important influences on the development of asthma. Studies have shown that viral infections trigger up to 85% of asthma exacerbations in school-aged children.

Because this column is being published during the winter, a brief discussion of influenza as a powerful virus is appropriate. Influenza occurs in winter outbreaks of varying extent every year. The severity of the influenza season reflects the changing nature of the antigenic properties of influenza viruses, and their spread depends on susceptibility of the population. Influenza outbreaks typically peak over a 2-3 week period and last for 2-3 months. Most outbreaks have attack rates of 10%-20% in children. There may be variations in disease severity caused by different influenza virus types. The symptoms are caused by excessive proinflammatory cytokine/chemokine production in the nose and lung.

Influenza and other viruses can precipitate the systemic inflammatory response syndrome (SIRS), a manifestation of extreme immune dysregulation resulting in organ dysfunction that clinically resembles bacterial sepsis. In this syndrome, tissues remote from the original insult display the cardinal signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation. SIRS is another example of the double-edged sword of inflammation.

The onset and progression of SIRS occurs because of dysregulation of the normal inflammatory response, usually with an increase in both proinflammatory and anti-inflammatory cytokines and chemokines, initiating a chain of events that leads to organ failure.

Dr. Pichichero is a specialist in pediatric infectious diseases and director of the Research Institute at Rochester (N.Y.) General Hospital. He reported having no conflicts of interest. Email him at [email protected].

After a long absence, Primatene Mist, an over-the-counter asthma inhaler removed from the market in 2011, is being reintroduced in a metered-dose inhaler with a new, environmentally friendly propellant.

Wikimedia Commons/FitzColinGerald/Creative Commons License

But the inhaler’s comeback may prove as controversial as its removal. Respiratory medicine associations have taken issue with the Food and Drug Administration’s decision, warning patients that asthma is not a “do-it-yourself” disease that can be managed with over-the-counter medications.

The American College of Allergy, Asthma, and Immunology, American College of Chest Physicians, American Lung Association, American Thoracic Society, and the American Association of Asthma Educators have each individually protested the decision, and together sent a joint resolution to FDA decrying it. At the core of their protest are the facts that epinephrine is a symptomatic, not therapeutic, asthma treatment and that racemic epinephrine is not a not a recommended asthma treatment under the National Institutes of Health’s “Guidelines for the Diagnosis and Management of Asthma.”

CHEST has published the following statement: “The American College of Chest Physicians (CHEST) is disappointed with the FDA’s decision to approve over-the counter epinephrine (Primatene® Mist HFA) for the treatment of asthma. CHEST is a nonprofit organization dedicated to advancing best patient outcomes. Our membership of more than 19,000 members from around the world provides patient care in pulmonary, critical care, and sleep medicine.

Asthma is a serious and chronic condition with associated high health-care burden. Care for ALL patients with asthma should be under the guidance of a health-care provider. The majority of asthma patients requires treatment with a controller medication, which is only available by prescription. Frequent rescue inhaler use has been associated with increased morbidity and mortality. Over the counter availability of a reliever medication like Primatene Mist can endanger a patient’s wellbeing by providing temporary relief in symptoms, resulting in delay in seeking medical care.”

The inhaler was pulled from sales as part of an international pact to reduce ozone-depleting substances. The 1989 Montreal Protocol of Substances that Deplete the Ozone Layer and the Clean Air Act of 1990 targeted chlorofluorocarbons among those substances, and epinephrine inhalers that contained CFCs were phased out.

The new Primatene Mist HFA (Amphastar Pharmaceuticals) contains hydrofluoroalkane (HFA) propellants, which are permitted under current international and U.S. law. This puts Primatene in the same category with other inhalers, including albuterol and levalbuterol, which also use HFAs as propellants. Each dose delivers 125 mcg of epinephrine.

The inhaler itself has also been redesigned, according to Theresa Michele, MD, director of the FDA’s Division of Nonprescription Drug Products in the Center for Drug Evaluation and Research. The active ingredient is still epinephrine, albeit a smaller dose than found in the original 200-mcg mist. However, the inhaler needs to be activated before first use and cleaned every day after use to prevent a medication buildup. Like other metered-dose inhalers, it requires a priming spray before the inhalation dose, Dr. Michele noted in her online column.

“The inhaler also needs to be shaken and then sprayed once into the air before each use. It may seem strange to shake and spray the inhaler into the air each time before using it. But these two steps are critical to ensure that the medicine is properly mixed before each dose,” Dr. Michele wrote.

A public statement by FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, asserted that the inhaler fills a clinical gap for patients with mild to moderate intermittent asthma.

“The scientific information we reviewed to approve the new version of OTC Primatene Mist shows there is a narrow population of those diagnosed with asthma that may benefit from having access to this type of OTC asthma inhaler. But the product has certain cautions. Making sure that patients can understand and apply the instructions for use was a critical consideration for the FDA. The new product is only appropriate for those with a diagnosis of mild, intermittent asthma. Patients with more severe asthma should not rely on it. Instead, they should be working with their health care provider to ensure an appropriate treatment plan for their condition.”

Before this approval, Amphastar had unsuccessfully brought the reformulated Primatene before FDA several times. The move to finally reinstate it comes after a long, and sometimes contentious, debate among patients and FDA’s Nonprescription Drugs and Pulmonary-Allergy Drugs advisory committee. A quick Internet or Facebook search brings up dozens of stories from patients who say they effectively managed their mild to moderate asthma for years with Primatene. Typically, the stories describe changing to prescription asthma medications that, for some, run into the hundreds of dollars per month. Supporters often negatively compare decades of using the inexpensive Primatene with no ill effects to their recent experiences using prescription corticosteroid inhalers.

It was 4 years ago when Amphastar first appeared before the advisory committee with the reformulated inhaler and positive safety and efficacy data. Although agreeing with the efficacy data, the advisory committee voted against approval, because some felt that asthma should always be managed by a physician; an OTC bronchodilator encouraged self-medicating and discouraged patients from seeking medical care, they said.

“On the one hand, it has been stated that a quick-relief medication available OTC is needed for use in low-income, elderly, and uninsured individuals who might otherwise not have access to treatment or be able to see a health care practitioner,” FDA documents noted. “In contrast, there is also a concern that because asthma is a potentially life-threatening condition that should be diagnosed and treated by a health care professional, availability of an OTC bronchodilator product may discourage consumers from seeking appropriate care, resulting in worse asthma outcomes.”

Two years later, the company received another blow to Primatene program. FDA’s Complete Response Letter required Amphastar to make additional changes to the packaging and run a consumer product safety study, intended to show that people could learn to use the metered-dose inhaler correctly.

In Amphastar’s 2018 first-quarter report, however, company CEO Jack Zhang, PhD, finally shared some good news. “We are pleased to announce that we have resubmitted our NDA for Primatene Mist after receiving good results from our recent human factors study. While we don’t have a Prescription Free User Drug Act [PDUFA] date yet, we plan to begin producing inventory in preparation for a launch.”

That day arrived on Nov. 8, when the PDUFA was granted. In their public letter, Dr. Gottlieb and Dr. Woodcock acknowledged the long and difficult approval path and offered reassurance that Primatene is safe and effective.

“For the right patient, our analysis of the data, including new information that was developed since this product was previously on the market, shows that there are no serious safety concerns when Primatene Mist is used as directed. The product is appropriate for mild symptoms of intermittent asthma, however, even patients with mild asthma can have severe exacerbations – so it’s still important to consult a health care provider about appropriate care and have their condition reassessed. And, of course, all patients who experience severe exacerbations should go to the emergency room right away.”

Primatene Mist HFA is intended for the temporary relief of mild symptoms of intermittent asthma (wheezing, tightness of chest, shortness of breath) in patients aged 12 years and older. It should not be considered a replacement for prescription asthma medications. It should be available in stores early next year.
 

[email protected]

After a long absence, Primatene Mist, an over-the-counter asthma inhaler removed from the market in 2011, is being reintroduced in a metered-dose inhaler with a new, environmentally friendly propellant.

Wikimedia Commons/FitzColinGerald/Creative Commons License

But the inhaler’s comeback may prove as controversial as its removal. Respiratory medicine associations have taken issue with the Food and Drug Administration’s decision, warning patients that asthma is not a “do-it-yourself” disease that can be managed with over-the-counter medications.

The American College of Allergy, Asthma, and Immunology, American College of Chest Physicians, American Lung Association, American Thoracic Society, and the American Association of Asthma Educators have each individually protested the decision, and together sent a joint resolution to FDA decrying it. At the core of their protest are the facts that epinephrine is a symptomatic, not therapeutic, asthma treatment and that racemic epinephrine is not a not a recommended asthma treatment under the National Institutes of Health’s “Guidelines for the Diagnosis and Management of Asthma.”

CHEST has published the following statement: “The American College of Chest Physicians (CHEST) is disappointed with the FDA’s decision to approve over-the counter epinephrine (Primatene® Mist HFA) for the treatment of asthma. CHEST is a nonprofit organization dedicated to advancing best patient outcomes. Our membership of more than 19,000 members from around the world provides patient care in pulmonary, critical care, and sleep medicine.

Asthma is a serious and chronic condition with associated high health-care burden. Care for ALL patients with asthma should be under the guidance of a health-care provider. The majority of asthma patients requires treatment with a controller medication, which is only available by prescription. Frequent rescue inhaler use has been associated with increased morbidity and mortality. Over the counter availability of a reliever medication like Primatene Mist can endanger a patient’s wellbeing by providing temporary relief in symptoms, resulting in delay in seeking medical care.”

The inhaler was pulled from sales as part of an international pact to reduce ozone-depleting substances. The 1989 Montreal Protocol of Substances that Deplete the Ozone Layer and the Clean Air Act of 1990 targeted chlorofluorocarbons among those substances, and epinephrine inhalers that contained CFCs were phased out.

The new Primatene Mist HFA (Amphastar Pharmaceuticals) contains hydrofluoroalkane (HFA) propellants, which are permitted under current international and U.S. law. This puts Primatene in the same category with other inhalers, including albuterol and levalbuterol, which also use HFAs as propellants. Each dose delivers 125 mcg of epinephrine.

The inhaler itself has also been redesigned, according to Theresa Michele, MD, director of the FDA’s Division of Nonprescription Drug Products in the Center for Drug Evaluation and Research. The active ingredient is still epinephrine, albeit a smaller dose than found in the original 200-mcg mist. However, the inhaler needs to be activated before first use and cleaned every day after use to prevent a medication buildup. Like other metered-dose inhalers, it requires a priming spray before the inhalation dose, Dr. Michele noted in her online column.

“The inhaler also needs to be shaken and then sprayed once into the air before each use. It may seem strange to shake and spray the inhaler into the air each time before using it. But these two steps are critical to ensure that the medicine is properly mixed before each dose,” Dr. Michele wrote.

A public statement by FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, asserted that the inhaler fills a clinical gap for patients with mild to moderate intermittent asthma.

“The scientific information we reviewed to approve the new version of OTC Primatene Mist shows there is a narrow population of those diagnosed with asthma that may benefit from having access to this type of OTC asthma inhaler. But the product has certain cautions. Making sure that patients can understand and apply the instructions for use was a critical consideration for the FDA. The new product is only appropriate for those with a diagnosis of mild, intermittent asthma. Patients with more severe asthma should not rely on it. Instead, they should be working with their health care provider to ensure an appropriate treatment plan for their condition.”

Before this approval, Amphastar had unsuccessfully brought the reformulated Primatene before FDA several times. The move to finally reinstate it comes after a long, and sometimes contentious, debate among patients and FDA’s Nonprescription Drugs and Pulmonary-Allergy Drugs advisory committee. A quick Internet or Facebook search brings up dozens of stories from patients who say they effectively managed their mild to moderate asthma for years with Primatene. Typically, the stories describe changing to prescription asthma medications that, for some, run into the hundreds of dollars per month. Supporters often negatively compare decades of using the inexpensive Primatene with no ill effects to their recent experiences using prescription corticosteroid inhalers.

It was 4 years ago when Amphastar first appeared before the advisory committee with the reformulated inhaler and positive safety and efficacy data. Although agreeing with the efficacy data, the advisory committee voted against approval, because some felt that asthma should always be managed by a physician; an OTC bronchodilator encouraged self-medicating and discouraged patients from seeking medical care, they said.

“On the one hand, it has been stated that a quick-relief medication available OTC is needed for use in low-income, elderly, and uninsured individuals who might otherwise not have access to treatment or be able to see a health care practitioner,” FDA documents noted. “In contrast, there is also a concern that because asthma is a potentially life-threatening condition that should be diagnosed and treated by a health care professional, availability of an OTC bronchodilator product may discourage consumers from seeking appropriate care, resulting in worse asthma outcomes.”

Two years later, the company received another blow to Primatene program. FDA’s Complete Response Letter required Amphastar to make additional changes to the packaging and run a consumer product safety study, intended to show that people could learn to use the metered-dose inhaler correctly.

In Amphastar’s 2018 first-quarter report, however, company CEO Jack Zhang, PhD, finally shared some good news. “We are pleased to announce that we have resubmitted our NDA for Primatene Mist after receiving good results from our recent human factors study. While we don’t have a Prescription Free User Drug Act [PDUFA] date yet, we plan to begin producing inventory in preparation for a launch.”

That day arrived on Nov. 8, when the PDUFA was granted. In their public letter, Dr. Gottlieb and Dr. Woodcock acknowledged the long and difficult approval path and offered reassurance that Primatene is safe and effective.

“For the right patient, our analysis of the data, including new information that was developed since this product was previously on the market, shows that there are no serious safety concerns when Primatene Mist is used as directed. The product is appropriate for mild symptoms of intermittent asthma, however, even patients with mild asthma can have severe exacerbations – so it’s still important to consult a health care provider about appropriate care and have their condition reassessed. And, of course, all patients who experience severe exacerbations should go to the emergency room right away.”

Primatene Mist HFA is intended for the temporary relief of mild symptoms of intermittent asthma (wheezing, tightness of chest, shortness of breath) in patients aged 12 years and older. It should not be considered a replacement for prescription asthma medications. It should be available in stores early next year.
 

[email protected]

After a long absence, Primatene Mist, an over-the-counter asthma inhaler removed from the market in 2011, is being reintroduced in a metered-dose inhaler with a new, environmentally friendly propellant.

Wikimedia Commons/FitzColinGerald/Creative Commons License

But the inhaler’s comeback may prove as controversial as its removal. Respiratory medicine associations have taken issue with the Food and Drug Administration’s decision, warning patients that asthma is not a “do-it-yourself” disease that can be managed with over-the-counter medications.

The American College of Allergy, Asthma, and Immunology, American College of Chest Physicians, American Lung Association, American Thoracic Society, and the American Association of Asthma Educators have each individually protested the decision, and together sent a joint resolution to FDA decrying it. At the core of their protest are the facts that epinephrine is a symptomatic, not therapeutic, asthma treatment and that racemic epinephrine is not a not a recommended asthma treatment under the National Institutes of Health’s “Guidelines for the Diagnosis and Management of Asthma.”

CHEST has published the following statement: “The American College of Chest Physicians (CHEST) is disappointed with the FDA’s decision to approve over-the counter epinephrine (Primatene® Mist HFA) for the treatment of asthma. CHEST is a nonprofit organization dedicated to advancing best patient outcomes. Our membership of more than 19,000 members from around the world provides patient care in pulmonary, critical care, and sleep medicine.

Asthma is a serious and chronic condition with associated high health-care burden. Care for ALL patients with asthma should be under the guidance of a health-care provider. The majority of asthma patients requires treatment with a controller medication, which is only available by prescription. Frequent rescue inhaler use has been associated with increased morbidity and mortality. Over the counter availability of a reliever medication like Primatene Mist can endanger a patient’s wellbeing by providing temporary relief in symptoms, resulting in delay in seeking medical care.”

The inhaler was pulled from sales as part of an international pact to reduce ozone-depleting substances. The 1989 Montreal Protocol of Substances that Deplete the Ozone Layer and the Clean Air Act of 1990 targeted chlorofluorocarbons among those substances, and epinephrine inhalers that contained CFCs were phased out.

The new Primatene Mist HFA (Amphastar Pharmaceuticals) contains hydrofluoroalkane (HFA) propellants, which are permitted under current international and U.S. law. This puts Primatene in the same category with other inhalers, including albuterol and levalbuterol, which also use HFAs as propellants. Each dose delivers 125 mcg of epinephrine.

The inhaler itself has also been redesigned, according to Theresa Michele, MD, director of the FDA’s Division of Nonprescription Drug Products in the Center for Drug Evaluation and Research. The active ingredient is still epinephrine, albeit a smaller dose than found in the original 200-mcg mist. However, the inhaler needs to be activated before first use and cleaned every day after use to prevent a medication buildup. Like other metered-dose inhalers, it requires a priming spray before the inhalation dose, Dr. Michele noted in her online column.

“The inhaler also needs to be shaken and then sprayed once into the air before each use. It may seem strange to shake and spray the inhaler into the air each time before using it. But these two steps are critical to ensure that the medicine is properly mixed before each dose,” Dr. Michele wrote.

A public statement by FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, asserted that the inhaler fills a clinical gap for patients with mild to moderate intermittent asthma.

“The scientific information we reviewed to approve the new version of OTC Primatene Mist shows there is a narrow population of those diagnosed with asthma that may benefit from having access to this type of OTC asthma inhaler. But the product has certain cautions. Making sure that patients can understand and apply the instructions for use was a critical consideration for the FDA. The new product is only appropriate for those with a diagnosis of mild, intermittent asthma. Patients with more severe asthma should not rely on it. Instead, they should be working with their health care provider to ensure an appropriate treatment plan for their condition.”

Before this approval, Amphastar had unsuccessfully brought the reformulated Primatene before FDA several times. The move to finally reinstate it comes after a long, and sometimes contentious, debate among patients and FDA’s Nonprescription Drugs and Pulmonary-Allergy Drugs advisory committee. A quick Internet or Facebook search brings up dozens of stories from patients who say they effectively managed their mild to moderate asthma for years with Primatene. Typically, the stories describe changing to prescription asthma medications that, for some, run into the hundreds of dollars per month. Supporters often negatively compare decades of using the inexpensive Primatene with no ill effects to their recent experiences using prescription corticosteroid inhalers.

It was 4 years ago when Amphastar first appeared before the advisory committee with the reformulated inhaler and positive safety and efficacy data. Although agreeing with the efficacy data, the advisory committee voted against approval, because some felt that asthma should always be managed by a physician; an OTC bronchodilator encouraged self-medicating and discouraged patients from seeking medical care, they said.

“On the one hand, it has been stated that a quick-relief medication available OTC is needed for use in low-income, elderly, and uninsured individuals who might otherwise not have access to treatment or be able to see a health care practitioner,” FDA documents noted. “In contrast, there is also a concern that because asthma is a potentially life-threatening condition that should be diagnosed and treated by a health care professional, availability of an OTC bronchodilator product may discourage consumers from seeking appropriate care, resulting in worse asthma outcomes.”

Two years later, the company received another blow to Primatene program. FDA’s Complete Response Letter required Amphastar to make additional changes to the packaging and run a consumer product safety study, intended to show that people could learn to use the metered-dose inhaler correctly.

In Amphastar’s 2018 first-quarter report, however, company CEO Jack Zhang, PhD, finally shared some good news. “We are pleased to announce that we have resubmitted our NDA for Primatene Mist after receiving good results from our recent human factors study. While we don’t have a Prescription Free User Drug Act [PDUFA] date yet, we plan to begin producing inventory in preparation for a launch.”

That day arrived on Nov. 8, when the PDUFA was granted. In their public letter, Dr. Gottlieb and Dr. Woodcock acknowledged the long and difficult approval path and offered reassurance that Primatene is safe and effective.

“For the right patient, our analysis of the data, including new information that was developed since this product was previously on the market, shows that there are no serious safety concerns when Primatene Mist is used as directed. The product is appropriate for mild symptoms of intermittent asthma, however, even patients with mild asthma can have severe exacerbations – so it’s still important to consult a health care provider about appropriate care and have their condition reassessed. And, of course, all patients who experience severe exacerbations should go to the emergency room right away.”

Primatene Mist HFA is intended for the temporary relief of mild symptoms of intermittent asthma (wheezing, tightness of chest, shortness of breath) in patients aged 12 years and older. It should not be considered a replacement for prescription asthma medications. It should be available in stores early next year.
 

[email protected]

SAN DIEGO – Emergency care–sensitive conditions – those for which timely access to high-quality emergency care impact morbidity and mortality—account for 14% of all ED visits, results from a large analysis of national data showed.

Doug Brunk/MDedge News

In previously published work, an eight-member expert panel identified 51 condition groups as emergency care–sensitive conditions (ECSCs), including asthma, cardiac arrest, cerebral infarction, and pneumonia. The purpose of the current study, published in Annals of Emergency Medicine and presented by Anita Vashi, MD, MPH, at the annual meeting of the American College of Emergency Physicians, was to provide the first national estimates of acute care utilization and the demographic characteristics of adults experiencing ECSCs, compare ECSC and non-ECSC ED visits, and assess patient- and hospital-level characteristics predictive of an ECSC-related ED visit.

Using the Nationwide Emergency Department Sample data set, Dr. Vashi, a physician investigator at the Center for Innovation to Implementation at the VA Palo Alto Health Care System, and her colleagues retrospectively evaluated all ED visits for patients aged 18 years and older from 2009 to 2014. The researchers used summary statistics to compare population characteristics across groups and multivariable logistic regression models to assess the odds of an ECSC-related ED visit with patient- and hospital-level characteristics.

Of the 622,725,542 estimated ED visits evaluated during the study period, 86,577,041 (14%) were ECSCs. Among these ECSC visits, 58% of patients were admitted for an average length of 3.2 days and an average charge of $2,240. The most frequent ECSC-related visits were for pneumonia (9%), chronic obstructive pulmonary disease (9%), asthma (7%), heart failure (7%), and sepsis (5%), but varied by age group.

Dr. Vashi and her colleagues found that ECSCs were more common among older adults, males, those who reside in low-income areas, those who reside in the South, and among metropolitan-based hospitals and nontrauma center hospitals. ECSCs also accounted for about 45% of all inpatient admissions.

Multivariate logistic regression analysis revealed that the odds of having an ECSC-related visit was highest among patients aged 65 years and older (odds ratio, 3.84), those on Medicare (OR, 1.37), those who resided in rural counties (OR, 1.21), and those who reside in the Western portion of the United States (OR, 1.11). Significant hospital-related factors related to ECSC visits included trauma centers (OR, 1.09), nonteaching hospitals (OR, 1.04), and EDs located in the wealthiest counties (OR, 1.02).

The researchers also found that 40% of patients who made ECSC-related ED visits were treated and discharged back to the community. “There is evidence of regional variability, suggesting the need for future research,” said Dr. Vashi, who also holds a faculty position in the department of emergency medicine at Stanford (Calif.) University. “We found no consistent relationship between insurance, income, and ED use for ECSC-related conditions. This suggests that ECSCs are not significantly influenced by socioeconomic factor and can serve as a reliable marker for acuity.”

The next steps in this research area, she added, are to create condition-specific measures related to morbidity, mortality, and posthospital events, as well as to analyze regional and hospital variations including correlation across conditions, and to compare performance across conditions and hospitals.

Dr. Vashi reported having no financial disclosures.

[email protected]

Source: Vashi A et al. Ann Emerg Med. 2018 Oct;72;4:S38. doi. 10.1016/j.annemergmed.2018.08.091.




 

SAN DIEGO – Emergency care–sensitive conditions – those for which timely access to high-quality emergency care impact morbidity and mortality—account for 14% of all ED visits, results from a large analysis of national data showed.

Doug Brunk/MDedge News

In previously published work, an eight-member expert panel identified 51 condition groups as emergency care–sensitive conditions (ECSCs), including asthma, cardiac arrest, cerebral infarction, and pneumonia. The purpose of the current study, published in Annals of Emergency Medicine and presented by Anita Vashi, MD, MPH, at the annual meeting of the American College of Emergency Physicians, was to provide the first national estimates of acute care utilization and the demographic characteristics of adults experiencing ECSCs, compare ECSC and non-ECSC ED visits, and assess patient- and hospital-level characteristics predictive of an ECSC-related ED visit.

Using the Nationwide Emergency Department Sample data set, Dr. Vashi, a physician investigator at the Center for Innovation to Implementation at the VA Palo Alto Health Care System, and her colleagues retrospectively evaluated all ED visits for patients aged 18 years and older from 2009 to 2014. The researchers used summary statistics to compare population characteristics across groups and multivariable logistic regression models to assess the odds of an ECSC-related ED visit with patient- and hospital-level characteristics.

Of the 622,725,542 estimated ED visits evaluated during the study period, 86,577,041 (14%) were ECSCs. Among these ECSC visits, 58% of patients were admitted for an average length of 3.2 days and an average charge of $2,240. The most frequent ECSC-related visits were for pneumonia (9%), chronic obstructive pulmonary disease (9%), asthma (7%), heart failure (7%), and sepsis (5%), but varied by age group.

Dr. Vashi and her colleagues found that ECSCs were more common among older adults, males, those who reside in low-income areas, those who reside in the South, and among metropolitan-based hospitals and nontrauma center hospitals. ECSCs also accounted for about 45% of all inpatient admissions.

Multivariate logistic regression analysis revealed that the odds of having an ECSC-related visit was highest among patients aged 65 years and older (odds ratio, 3.84), those on Medicare (OR, 1.37), those who resided in rural counties (OR, 1.21), and those who reside in the Western portion of the United States (OR, 1.11). Significant hospital-related factors related to ECSC visits included trauma centers (OR, 1.09), nonteaching hospitals (OR, 1.04), and EDs located in the wealthiest counties (OR, 1.02).

The researchers also found that 40% of patients who made ECSC-related ED visits were treated and discharged back to the community. “There is evidence of regional variability, suggesting the need for future research,” said Dr. Vashi, who also holds a faculty position in the department of emergency medicine at Stanford (Calif.) University. “We found no consistent relationship between insurance, income, and ED use for ECSC-related conditions. This suggests that ECSCs are not significantly influenced by socioeconomic factor and can serve as a reliable marker for acuity.”

The next steps in this research area, she added, are to create condition-specific measures related to morbidity, mortality, and posthospital events, as well as to analyze regional and hospital variations including correlation across conditions, and to compare performance across conditions and hospitals.

Dr. Vashi reported having no financial disclosures.

[email protected]

Source: Vashi A et al. Ann Emerg Med. 2018 Oct;72;4:S38. doi. 10.1016/j.annemergmed.2018.08.091.




 

SAN DIEGO – Emergency care–sensitive conditions – those for which timely access to high-quality emergency care impact morbidity and mortality—account for 14% of all ED visits, results from a large analysis of national data showed.

Doug Brunk/MDedge News

In previously published work, an eight-member expert panel identified 51 condition groups as emergency care–sensitive conditions (ECSCs), including asthma, cardiac arrest, cerebral infarction, and pneumonia. The purpose of the current study, published in Annals of Emergency Medicine and presented by Anita Vashi, MD, MPH, at the annual meeting of the American College of Emergency Physicians, was to provide the first national estimates of acute care utilization and the demographic characteristics of adults experiencing ECSCs, compare ECSC and non-ECSC ED visits, and assess patient- and hospital-level characteristics predictive of an ECSC-related ED visit.

Using the Nationwide Emergency Department Sample data set, Dr. Vashi, a physician investigator at the Center for Innovation to Implementation at the VA Palo Alto Health Care System, and her colleagues retrospectively evaluated all ED visits for patients aged 18 years and older from 2009 to 2014. The researchers used summary statistics to compare population characteristics across groups and multivariable logistic regression models to assess the odds of an ECSC-related ED visit with patient- and hospital-level characteristics.

Of the 622,725,542 estimated ED visits evaluated during the study period, 86,577,041 (14%) were ECSCs. Among these ECSC visits, 58% of patients were admitted for an average length of 3.2 days and an average charge of $2,240. The most frequent ECSC-related visits were for pneumonia (9%), chronic obstructive pulmonary disease (9%), asthma (7%), heart failure (7%), and sepsis (5%), but varied by age group.

Dr. Vashi and her colleagues found that ECSCs were more common among older adults, males, those who reside in low-income areas, those who reside in the South, and among metropolitan-based hospitals and nontrauma center hospitals. ECSCs also accounted for about 45% of all inpatient admissions.

Multivariate logistic regression analysis revealed that the odds of having an ECSC-related visit was highest among patients aged 65 years and older (odds ratio, 3.84), those on Medicare (OR, 1.37), those who resided in rural counties (OR, 1.21), and those who reside in the Western portion of the United States (OR, 1.11). Significant hospital-related factors related to ECSC visits included trauma centers (OR, 1.09), nonteaching hospitals (OR, 1.04), and EDs located in the wealthiest counties (OR, 1.02).

The researchers also found that 40% of patients who made ECSC-related ED visits were treated and discharged back to the community. “There is evidence of regional variability, suggesting the need for future research,” said Dr. Vashi, who also holds a faculty position in the department of emergency medicine at Stanford (Calif.) University. “We found no consistent relationship between insurance, income, and ED use for ECSC-related conditions. This suggests that ECSCs are not significantly influenced by socioeconomic factor and can serve as a reliable marker for acuity.”

The next steps in this research area, she added, are to create condition-specific measures related to morbidity, mortality, and posthospital events, as well as to analyze regional and hospital variations including correlation across conditions, and to compare performance across conditions and hospitals.

Dr. Vashi reported having no financial disclosures.

[email protected]

Source: Vashi A et al. Ann Emerg Med. 2018 Oct;72;4:S38. doi. 10.1016/j.annemergmed.2018.08.091.