User login
Bringing you the latest news, research and reviews, exclusive interviews, podcasts, quizzes, and more.
Powered by CHEST Physician, Clinician Reviews, MDedge Family Medicine, Internal Medicine News, and The Journal of Clinical Outcomes Management.
CDC activates Emergency Operations Center to investigate vaping-associated lung injury
This move allows the CDC “to provide increased operational support” to CDC staff to meet the evolving challenges of the outbreak of vaping-related injuries and deaths, says a statement from the CDC.
“CDC has made it a priority to find out what is causing this outbreak,” noted CDC Director Robert Redfield, MD, in the statement.
The agency “continues to work closely with the U.S. Food and Drug Administration to collect information about recent e-cigarette product use, or vaping, among patients and to test the substances or chemicals within e-cigarette products used by case patients,” according to the statement.
The CDC provided email addresses and site addresses for gathering information and communicating about e-cigarettes.
Information about the collection of e-cigarettes for possible testing by FDA can be obtained through contacting [email protected].
To communicate with CDC about this public health response, clinicians and health officials can contact [email protected].
More information on the current outbreak related to e-cigarettes is available at https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html.
General information on electronic cigarette products, can be found at www.cdc.gov/e-cigarettes.
Individuals concerned about health risks of vaping should consider refraining from e-cigarette use while the cases of lung injury are being investigated, the CDC said.
This move allows the CDC “to provide increased operational support” to CDC staff to meet the evolving challenges of the outbreak of vaping-related injuries and deaths, says a statement from the CDC.
“CDC has made it a priority to find out what is causing this outbreak,” noted CDC Director Robert Redfield, MD, in the statement.
The agency “continues to work closely with the U.S. Food and Drug Administration to collect information about recent e-cigarette product use, or vaping, among patients and to test the substances or chemicals within e-cigarette products used by case patients,” according to the statement.
The CDC provided email addresses and site addresses for gathering information and communicating about e-cigarettes.
Information about the collection of e-cigarettes for possible testing by FDA can be obtained through contacting [email protected].
To communicate with CDC about this public health response, clinicians and health officials can contact [email protected].
More information on the current outbreak related to e-cigarettes is available at https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html.
General information on electronic cigarette products, can be found at www.cdc.gov/e-cigarettes.
Individuals concerned about health risks of vaping should consider refraining from e-cigarette use while the cases of lung injury are being investigated, the CDC said.
This move allows the CDC “to provide increased operational support” to CDC staff to meet the evolving challenges of the outbreak of vaping-related injuries and deaths, says a statement from the CDC.
“CDC has made it a priority to find out what is causing this outbreak,” noted CDC Director Robert Redfield, MD, in the statement.
The agency “continues to work closely with the U.S. Food and Drug Administration to collect information about recent e-cigarette product use, or vaping, among patients and to test the substances or chemicals within e-cigarette products used by case patients,” according to the statement.
The CDC provided email addresses and site addresses for gathering information and communicating about e-cigarettes.
Information about the collection of e-cigarettes for possible testing by FDA can be obtained through contacting [email protected].
To communicate with CDC about this public health response, clinicians and health officials can contact [email protected].
More information on the current outbreak related to e-cigarettes is available at https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html.
General information on electronic cigarette products, can be found at www.cdc.gov/e-cigarettes.
Individuals concerned about health risks of vaping should consider refraining from e-cigarette use while the cases of lung injury are being investigated, the CDC said.
Pulegone levels in e-liquids, smokeless tobacco products exceed FDA limits
A group of mint- and menthol-flavored e-liquids and smokeless tobacco products contained significantly more pulegone – a known carcinogen that causes hepatic carcinomas, pulmonary metaplasia, and other neoplasms – than the Food and Drug Administration considers acceptable, according to new findings.
Pulegone, an oil extract from mint plants such as peppermint, spearmint, and pennyroyal, was banned as a food additive by the agency in 2018, and the tobacco industry has taken steps to minimize pulegone levels in cigarettes because of the toxicity concerns.
Studies from the Centers for Disease Control and Prevention, however, have indicated that mint- and menthol-flavored e-cigarette liquids and smokeless tobacco products marketed in the United States contain substantial amounts of the substance, Sairam V. Jabba, DVM, PhD, and Sven-Eric Jordt, PhD, said in a research letter published in JAMA Internal Medicine.
Dr. Jabba and Dr. Jordt, both with the department of anesthesiology at Duke University, Durham, N.C., calculated the margin of exposure in five e-liquids (V2 Menthol, V2 Peppermint, Premium Menthol, South Beach Smoke Menthol, and South Beach Smoke Peppermint) and one smokeless tobacco product (Skoal Xtra Mint snuff) by dividing the no–observed adverse event level (13.39 mg/kg of bodyweight per day) by the mean human exposure to e-liquids or smokeless tobacco. The FDA considers margin-of-exposure values of 10,000 or less to require mitigation strategies.
The six products included in the analysis had pulegone concentration levels ranging from 25.7 to 119.0 mcg/g (a menthol cigarette has a pulegone concentration of 0.037-0.290 mcg/g). Based on those levels, light daily use (5 mL e-liquid, 10 g smokeless tobacco, half a pack of cigarettes) exposed e-cigarette users to 44-198 times more pulegone, compared with menthol cigarettes, and exposed smokeless tobacco users to 168-1,319 times as much pulegone. The margin of exposure ranged from 1,298 to 6,012, all below 10,000 threshhold the FDA deems acceptable.
For heavy daily use (20 mL e-liquid, 30 g smokeless tobacco, two packs of cigarettes), e-cigarette users were exposed to 282-1,608 times more pulegone, compared with menthol cigarettes; smokeless tobacco users were exposed to 126-990 times more pulegone. The margin of exposure ranged from 325 to 1,503.
The study findings “appear to establish health risks associated with pulegone intake and concerns that the FDA should address before suggesting mint- and menthol-flavored e-cigarettes and smokeless tobacco products as alternatives for people who use combustible tobacco products,” Dr. Jabba and Dr. Jordt concluded.
The study was funded by a grant from the National Institute of Environmental Health Sciences. Dr. Jordt reported receiving grants from the NIEHS and the National Institute on Drug Abuse, personal fees from Hydra Biosciences and Sanofi, and nonfinancial support from GlaxoSmithKline. Dr. Jabba reported no disclosures.
SOURCE: Jabba SV, Jordt S-E. JAMA Intern Med. 2019 Sep 16. doi: 10.1001/jamainternmed.2019.3649.
A group of mint- and menthol-flavored e-liquids and smokeless tobacco products contained significantly more pulegone – a known carcinogen that causes hepatic carcinomas, pulmonary metaplasia, and other neoplasms – than the Food and Drug Administration considers acceptable, according to new findings.
Pulegone, an oil extract from mint plants such as peppermint, spearmint, and pennyroyal, was banned as a food additive by the agency in 2018, and the tobacco industry has taken steps to minimize pulegone levels in cigarettes because of the toxicity concerns.
Studies from the Centers for Disease Control and Prevention, however, have indicated that mint- and menthol-flavored e-cigarette liquids and smokeless tobacco products marketed in the United States contain substantial amounts of the substance, Sairam V. Jabba, DVM, PhD, and Sven-Eric Jordt, PhD, said in a research letter published in JAMA Internal Medicine.
Dr. Jabba and Dr. Jordt, both with the department of anesthesiology at Duke University, Durham, N.C., calculated the margin of exposure in five e-liquids (V2 Menthol, V2 Peppermint, Premium Menthol, South Beach Smoke Menthol, and South Beach Smoke Peppermint) and one smokeless tobacco product (Skoal Xtra Mint snuff) by dividing the no–observed adverse event level (13.39 mg/kg of bodyweight per day) by the mean human exposure to e-liquids or smokeless tobacco. The FDA considers margin-of-exposure values of 10,000 or less to require mitigation strategies.
The six products included in the analysis had pulegone concentration levels ranging from 25.7 to 119.0 mcg/g (a menthol cigarette has a pulegone concentration of 0.037-0.290 mcg/g). Based on those levels, light daily use (5 mL e-liquid, 10 g smokeless tobacco, half a pack of cigarettes) exposed e-cigarette users to 44-198 times more pulegone, compared with menthol cigarettes, and exposed smokeless tobacco users to 168-1,319 times as much pulegone. The margin of exposure ranged from 1,298 to 6,012, all below 10,000 threshhold the FDA deems acceptable.
For heavy daily use (20 mL e-liquid, 30 g smokeless tobacco, two packs of cigarettes), e-cigarette users were exposed to 282-1,608 times more pulegone, compared with menthol cigarettes; smokeless tobacco users were exposed to 126-990 times more pulegone. The margin of exposure ranged from 325 to 1,503.
The study findings “appear to establish health risks associated with pulegone intake and concerns that the FDA should address before suggesting mint- and menthol-flavored e-cigarettes and smokeless tobacco products as alternatives for people who use combustible tobacco products,” Dr. Jabba and Dr. Jordt concluded.
The study was funded by a grant from the National Institute of Environmental Health Sciences. Dr. Jordt reported receiving grants from the NIEHS and the National Institute on Drug Abuse, personal fees from Hydra Biosciences and Sanofi, and nonfinancial support from GlaxoSmithKline. Dr. Jabba reported no disclosures.
SOURCE: Jabba SV, Jordt S-E. JAMA Intern Med. 2019 Sep 16. doi: 10.1001/jamainternmed.2019.3649.
A group of mint- and menthol-flavored e-liquids and smokeless tobacco products contained significantly more pulegone – a known carcinogen that causes hepatic carcinomas, pulmonary metaplasia, and other neoplasms – than the Food and Drug Administration considers acceptable, according to new findings.
Pulegone, an oil extract from mint plants such as peppermint, spearmint, and pennyroyal, was banned as a food additive by the agency in 2018, and the tobacco industry has taken steps to minimize pulegone levels in cigarettes because of the toxicity concerns.
Studies from the Centers for Disease Control and Prevention, however, have indicated that mint- and menthol-flavored e-cigarette liquids and smokeless tobacco products marketed in the United States contain substantial amounts of the substance, Sairam V. Jabba, DVM, PhD, and Sven-Eric Jordt, PhD, said in a research letter published in JAMA Internal Medicine.
Dr. Jabba and Dr. Jordt, both with the department of anesthesiology at Duke University, Durham, N.C., calculated the margin of exposure in five e-liquids (V2 Menthol, V2 Peppermint, Premium Menthol, South Beach Smoke Menthol, and South Beach Smoke Peppermint) and one smokeless tobacco product (Skoal Xtra Mint snuff) by dividing the no–observed adverse event level (13.39 mg/kg of bodyweight per day) by the mean human exposure to e-liquids or smokeless tobacco. The FDA considers margin-of-exposure values of 10,000 or less to require mitigation strategies.
The six products included in the analysis had pulegone concentration levels ranging from 25.7 to 119.0 mcg/g (a menthol cigarette has a pulegone concentration of 0.037-0.290 mcg/g). Based on those levels, light daily use (5 mL e-liquid, 10 g smokeless tobacco, half a pack of cigarettes) exposed e-cigarette users to 44-198 times more pulegone, compared with menthol cigarettes, and exposed smokeless tobacco users to 168-1,319 times as much pulegone. The margin of exposure ranged from 1,298 to 6,012, all below 10,000 threshhold the FDA deems acceptable.
For heavy daily use (20 mL e-liquid, 30 g smokeless tobacco, two packs of cigarettes), e-cigarette users were exposed to 282-1,608 times more pulegone, compared with menthol cigarettes; smokeless tobacco users were exposed to 126-990 times more pulegone. The margin of exposure ranged from 325 to 1,503.
The study findings “appear to establish health risks associated with pulegone intake and concerns that the FDA should address before suggesting mint- and menthol-flavored e-cigarettes and smokeless tobacco products as alternatives for people who use combustible tobacco products,” Dr. Jabba and Dr. Jordt concluded.
The study was funded by a grant from the National Institute of Environmental Health Sciences. Dr. Jordt reported receiving grants from the NIEHS and the National Institute on Drug Abuse, personal fees from Hydra Biosciences and Sanofi, and nonfinancial support from GlaxoSmithKline. Dr. Jabba reported no disclosures.
SOURCE: Jabba SV, Jordt S-E. JAMA Intern Med. 2019 Sep 16. doi: 10.1001/jamainternmed.2019.3649.
FROM JAMA INTERNAL MEDICINE
Key clinical point: Mint- and menthol-flavored e-liquids and smokeless tobacco contain levels of pulegone that are much higher than those deemed acceptable by the Food and Drug Administration.
Major finding:
Study details: An assessment of pulegone in five e-liquids and one brand of smokeless tobacco.
Disclosures: The study was funded by a grant from the National Institute of Environmental Health Sciences. Dr. Jordt reported receiving grants from the NIEHS and the National Institute on Drug Abuse, personal fees from Hydra Biosciences and Sanofi, and nonfinancial support from GlaxoSmithKline. Dr. Jabba reported no disclosures.
Source: Jabba SV, Jordt S-E. JAMA Intern Med. 2019 Sep 16. doi: 10.1001/jamainternmed.2019.3649.
Peanut allergy pill gets thumbs-up from FDA advisory panel
A pill designed to desensitize peanut-allergic children and teenagers may be on the way.
aged 4-17 years old with a confirmed peanut allergy. Conditions for approval include stipulations that a black-box warning and medication use guide are included in the packaging, the panel said. The FDA usually follows the recommendations of its advisory panels.
The committee members voted 7-2 that the drug was effective and 8-1 that it was safe.
John Kelso, MD, the sole dissenter on safety, voiced concerns about the dearth of long-term follow-up in Aimmune Therapeutic’s body of research and the finding that children who received the treatment during the dose-escalation and maintenance periods had twice the number of allergic reactions requiring epinephrine, compared with those who received placebo. There are no long-term safety data to rely on yet, he added.
“Efficacy has not been demonstrated, except on the day the peanut challenge is administered,” said Dr. Kelso, an allergist at the Scripps Clinic, San Diego, adding that only long-term follow-up data would fully convince him that the drug’s benefits outweigh the risks.
In the discussion, however, other committee members pointed out that new drugs are often approved without long-term efficacy and safety data. Those data are extrapolated from clinical trials, and only real-world experience will confirm the data, they noted.
Company representatives did not explicitly address the potential cost of the therapy, but a recent review by the Institute for Clinical and Economic Review estimated the cost to be $4,200 a year. Palforzia would have to be taken every day, for an unknown amount of time, to maintain peanut tolerance.
“Using prices from analysts for AR101 ($4,200 a year), we estimated that only 41% of eligible patients could be treated in a given year without exceeding ICER’s budget impact threshold,” the institute concluded in a publicly released analysis.
Palforzia comes in individual packs of capsules filled with peanut protein, not flour. The capsules come in doses of 0.5, 1, 10, 20, and 100, and 300 mg. A single-dose sachet contains 300 mg. Treatment begins with 0.5-6 mg over 1 day and escalates every 2 weeks until 300 mg is reached or there is a reaction requiring epinephrine. Passing at least a 300-mg dose was the requirement for exiting the escalation phase and moving on to the daily, year-long maintenance phase.
The four efficacy studies presented showed that 96% of patients tolerated 300 mg, 84% tolerated 600 mg, and 63% 1,000 mg – about 10 times the reactive dose observed in the placebo controls.
“Only 125 mg of peanut protein – the amount in about half a peanut kernel – can be enough to provoke a reaction,” said Daniel Adelman, MD, chief medical officer of Aimmune. If patients can tolerate 600 mg of protein – the equivalent of two kernels, accidental ingestion will result in a “predictable, manageable” reaction.
“This is truly a clinically significant result for patients and families who report lives dictated by the allergy,” Dr. Adelman said.
Consistent manufacturing processes and positive safety data should reassure clinicians and patients that they are receiving a safe, effective, and well-regulated treatment, he added.
The capsule, however, is not a panacea. The company advises that families continue with the peanut avoidance diet. “It’s important to remember that reactive episodes can occur with dosing, and accidental exposures can occur at unpredictable times, away from home, and despite the best efforts at avoidance,” Dr. Adelman said. “This is not a drug for everyone, but it is an effective desensitization tool and would clearly be the first therapy to treat a food allergy, providing statistically significant and clinically important improvement. Outcomes align with patients’ goals.”
Safety was assessed in 709 treated patients who received the medication and 292 who received placebo. Treatment-related adverse events were most common in initial dosing: 89% of the treatment group and 58% of the placebo group experienced at least one adverse event during that time. Adverse events were mostly mild to moderate and decreased in severity over the study period. They included abdominal pain (45% active vs. 18% placebo), throat irritation (40% vs. 17%), pruritus (33% vs. 20%), vomiting (37% vs. 16%), cough (32% vs. 24%), nausea (32% vs. 14%), urticaria (28% vs. 19%), and upper abdominal pain (30% vs. 14%).
Discontinuations caused by these adverse events were infrequent, with only 1.8% of participants who were taking the active capsule and 1% of those taking placebo discontinuing the study product during initial dose escalation. Only the severe systemic allergic reactions were considered to be anaphylaxis, and they had to affect at least two body systems.
Respiratory events were more common in those in the active group, especially in children with asthma. These events included cough, wheezing, dyspnea, dysphonia, throat irritation and tightness, and exercise-induced asthma. There was, however, no “concerning change” in asthma control.
Systemic allergic reactions and anaphylaxis were more common in the active-dose group. Systemic reactions during dose escalation occurred in 9.4% of active patients and 3.8% those taking placebo. During the maintenance phase, they occurred in 8.7% and 1.7% of patients, respectively. Three patients in the active group had a serious systemic reaction – two during up-dosing and one during maintenance.
During initial dose escalation and up-dosing combined, 6.1% of patients in the active group and 3.1% in the placebo group had a systemic reaction requiring epinephrine. This was most often administered outside of the clinic.
There were 12 cases of eosinophilic esophagitis, all of which resolved after withdrawal from the study medication.
Aimmune submitted a risk-management proposal that includes the following:
- The first dose of each progressive dose must be administered in a facility that is equipped to treat systemic allergic reactions.
- Families must have a valid prescription for injectable epinephrine before treatment starts and must demonstrate that they know how to use it.
- There must be distribution controls in every pharmacy that dispenses the product.
- Packaging will be dose specific to ensure proper at-home administration.
- Pharmacologic questionnaires will be used as data collection instruments.
- Professional and patient-focused labeling will include a medication guide and educational material.
Palforzia is not the only peanut desensitization product in the works. DBC Technology has resubmitted its biologics license application to the FDA in the hope of getting approval for its peanut allergy treatment, the Viaskin Peanut patch.
The patch is designed to desensitize allergic children aged 4-11 years through a skin-patch method known as epicutaneous immunotherapy. Results from two controlled clinical trials were included in the submission. The company is also investigating the potential of this form of skin-patch therapy for milk and egg allergies.
Correction, 9/15/19: An earlier version of this article did not clearly state that the panel recommended approval rather than granted approval for the drug.
A pill designed to desensitize peanut-allergic children and teenagers may be on the way.
aged 4-17 years old with a confirmed peanut allergy. Conditions for approval include stipulations that a black-box warning and medication use guide are included in the packaging, the panel said. The FDA usually follows the recommendations of its advisory panels.
The committee members voted 7-2 that the drug was effective and 8-1 that it was safe.
John Kelso, MD, the sole dissenter on safety, voiced concerns about the dearth of long-term follow-up in Aimmune Therapeutic’s body of research and the finding that children who received the treatment during the dose-escalation and maintenance periods had twice the number of allergic reactions requiring epinephrine, compared with those who received placebo. There are no long-term safety data to rely on yet, he added.
“Efficacy has not been demonstrated, except on the day the peanut challenge is administered,” said Dr. Kelso, an allergist at the Scripps Clinic, San Diego, adding that only long-term follow-up data would fully convince him that the drug’s benefits outweigh the risks.
In the discussion, however, other committee members pointed out that new drugs are often approved without long-term efficacy and safety data. Those data are extrapolated from clinical trials, and only real-world experience will confirm the data, they noted.
Company representatives did not explicitly address the potential cost of the therapy, but a recent review by the Institute for Clinical and Economic Review estimated the cost to be $4,200 a year. Palforzia would have to be taken every day, for an unknown amount of time, to maintain peanut tolerance.
“Using prices from analysts for AR101 ($4,200 a year), we estimated that only 41% of eligible patients could be treated in a given year without exceeding ICER’s budget impact threshold,” the institute concluded in a publicly released analysis.
Palforzia comes in individual packs of capsules filled with peanut protein, not flour. The capsules come in doses of 0.5, 1, 10, 20, and 100, and 300 mg. A single-dose sachet contains 300 mg. Treatment begins with 0.5-6 mg over 1 day and escalates every 2 weeks until 300 mg is reached or there is a reaction requiring epinephrine. Passing at least a 300-mg dose was the requirement for exiting the escalation phase and moving on to the daily, year-long maintenance phase.
The four efficacy studies presented showed that 96% of patients tolerated 300 mg, 84% tolerated 600 mg, and 63% 1,000 mg – about 10 times the reactive dose observed in the placebo controls.
“Only 125 mg of peanut protein – the amount in about half a peanut kernel – can be enough to provoke a reaction,” said Daniel Adelman, MD, chief medical officer of Aimmune. If patients can tolerate 600 mg of protein – the equivalent of two kernels, accidental ingestion will result in a “predictable, manageable” reaction.
“This is truly a clinically significant result for patients and families who report lives dictated by the allergy,” Dr. Adelman said.
Consistent manufacturing processes and positive safety data should reassure clinicians and patients that they are receiving a safe, effective, and well-regulated treatment, he added.
The capsule, however, is not a panacea. The company advises that families continue with the peanut avoidance diet. “It’s important to remember that reactive episodes can occur with dosing, and accidental exposures can occur at unpredictable times, away from home, and despite the best efforts at avoidance,” Dr. Adelman said. “This is not a drug for everyone, but it is an effective desensitization tool and would clearly be the first therapy to treat a food allergy, providing statistically significant and clinically important improvement. Outcomes align with patients’ goals.”
Safety was assessed in 709 treated patients who received the medication and 292 who received placebo. Treatment-related adverse events were most common in initial dosing: 89% of the treatment group and 58% of the placebo group experienced at least one adverse event during that time. Adverse events were mostly mild to moderate and decreased in severity over the study period. They included abdominal pain (45% active vs. 18% placebo), throat irritation (40% vs. 17%), pruritus (33% vs. 20%), vomiting (37% vs. 16%), cough (32% vs. 24%), nausea (32% vs. 14%), urticaria (28% vs. 19%), and upper abdominal pain (30% vs. 14%).
Discontinuations caused by these adverse events were infrequent, with only 1.8% of participants who were taking the active capsule and 1% of those taking placebo discontinuing the study product during initial dose escalation. Only the severe systemic allergic reactions were considered to be anaphylaxis, and they had to affect at least two body systems.
Respiratory events were more common in those in the active group, especially in children with asthma. These events included cough, wheezing, dyspnea, dysphonia, throat irritation and tightness, and exercise-induced asthma. There was, however, no “concerning change” in asthma control.
Systemic allergic reactions and anaphylaxis were more common in the active-dose group. Systemic reactions during dose escalation occurred in 9.4% of active patients and 3.8% those taking placebo. During the maintenance phase, they occurred in 8.7% and 1.7% of patients, respectively. Three patients in the active group had a serious systemic reaction – two during up-dosing and one during maintenance.
During initial dose escalation and up-dosing combined, 6.1% of patients in the active group and 3.1% in the placebo group had a systemic reaction requiring epinephrine. This was most often administered outside of the clinic.
There were 12 cases of eosinophilic esophagitis, all of which resolved after withdrawal from the study medication.
Aimmune submitted a risk-management proposal that includes the following:
- The first dose of each progressive dose must be administered in a facility that is equipped to treat systemic allergic reactions.
- Families must have a valid prescription for injectable epinephrine before treatment starts and must demonstrate that they know how to use it.
- There must be distribution controls in every pharmacy that dispenses the product.
- Packaging will be dose specific to ensure proper at-home administration.
- Pharmacologic questionnaires will be used as data collection instruments.
- Professional and patient-focused labeling will include a medication guide and educational material.
Palforzia is not the only peanut desensitization product in the works. DBC Technology has resubmitted its biologics license application to the FDA in the hope of getting approval for its peanut allergy treatment, the Viaskin Peanut patch.
The patch is designed to desensitize allergic children aged 4-11 years through a skin-patch method known as epicutaneous immunotherapy. Results from two controlled clinical trials were included in the submission. The company is also investigating the potential of this form of skin-patch therapy for milk and egg allergies.
Correction, 9/15/19: An earlier version of this article did not clearly state that the panel recommended approval rather than granted approval for the drug.
A pill designed to desensitize peanut-allergic children and teenagers may be on the way.
aged 4-17 years old with a confirmed peanut allergy. Conditions for approval include stipulations that a black-box warning and medication use guide are included in the packaging, the panel said. The FDA usually follows the recommendations of its advisory panels.
The committee members voted 7-2 that the drug was effective and 8-1 that it was safe.
John Kelso, MD, the sole dissenter on safety, voiced concerns about the dearth of long-term follow-up in Aimmune Therapeutic’s body of research and the finding that children who received the treatment during the dose-escalation and maintenance periods had twice the number of allergic reactions requiring epinephrine, compared with those who received placebo. There are no long-term safety data to rely on yet, he added.
“Efficacy has not been demonstrated, except on the day the peanut challenge is administered,” said Dr. Kelso, an allergist at the Scripps Clinic, San Diego, adding that only long-term follow-up data would fully convince him that the drug’s benefits outweigh the risks.
In the discussion, however, other committee members pointed out that new drugs are often approved without long-term efficacy and safety data. Those data are extrapolated from clinical trials, and only real-world experience will confirm the data, they noted.
Company representatives did not explicitly address the potential cost of the therapy, but a recent review by the Institute for Clinical and Economic Review estimated the cost to be $4,200 a year. Palforzia would have to be taken every day, for an unknown amount of time, to maintain peanut tolerance.
“Using prices from analysts for AR101 ($4,200 a year), we estimated that only 41% of eligible patients could be treated in a given year without exceeding ICER’s budget impact threshold,” the institute concluded in a publicly released analysis.
Palforzia comes in individual packs of capsules filled with peanut protein, not flour. The capsules come in doses of 0.5, 1, 10, 20, and 100, and 300 mg. A single-dose sachet contains 300 mg. Treatment begins with 0.5-6 mg over 1 day and escalates every 2 weeks until 300 mg is reached or there is a reaction requiring epinephrine. Passing at least a 300-mg dose was the requirement for exiting the escalation phase and moving on to the daily, year-long maintenance phase.
The four efficacy studies presented showed that 96% of patients tolerated 300 mg, 84% tolerated 600 mg, and 63% 1,000 mg – about 10 times the reactive dose observed in the placebo controls.
“Only 125 mg of peanut protein – the amount in about half a peanut kernel – can be enough to provoke a reaction,” said Daniel Adelman, MD, chief medical officer of Aimmune. If patients can tolerate 600 mg of protein – the equivalent of two kernels, accidental ingestion will result in a “predictable, manageable” reaction.
“This is truly a clinically significant result for patients and families who report lives dictated by the allergy,” Dr. Adelman said.
Consistent manufacturing processes and positive safety data should reassure clinicians and patients that they are receiving a safe, effective, and well-regulated treatment, he added.
The capsule, however, is not a panacea. The company advises that families continue with the peanut avoidance diet. “It’s important to remember that reactive episodes can occur with dosing, and accidental exposures can occur at unpredictable times, away from home, and despite the best efforts at avoidance,” Dr. Adelman said. “This is not a drug for everyone, but it is an effective desensitization tool and would clearly be the first therapy to treat a food allergy, providing statistically significant and clinically important improvement. Outcomes align with patients’ goals.”
Safety was assessed in 709 treated patients who received the medication and 292 who received placebo. Treatment-related adverse events were most common in initial dosing: 89% of the treatment group and 58% of the placebo group experienced at least one adverse event during that time. Adverse events were mostly mild to moderate and decreased in severity over the study period. They included abdominal pain (45% active vs. 18% placebo), throat irritation (40% vs. 17%), pruritus (33% vs. 20%), vomiting (37% vs. 16%), cough (32% vs. 24%), nausea (32% vs. 14%), urticaria (28% vs. 19%), and upper abdominal pain (30% vs. 14%).
Discontinuations caused by these adverse events were infrequent, with only 1.8% of participants who were taking the active capsule and 1% of those taking placebo discontinuing the study product during initial dose escalation. Only the severe systemic allergic reactions were considered to be anaphylaxis, and they had to affect at least two body systems.
Respiratory events were more common in those in the active group, especially in children with asthma. These events included cough, wheezing, dyspnea, dysphonia, throat irritation and tightness, and exercise-induced asthma. There was, however, no “concerning change” in asthma control.
Systemic allergic reactions and anaphylaxis were more common in the active-dose group. Systemic reactions during dose escalation occurred in 9.4% of active patients and 3.8% those taking placebo. During the maintenance phase, they occurred in 8.7% and 1.7% of patients, respectively. Three patients in the active group had a serious systemic reaction – two during up-dosing and one during maintenance.
During initial dose escalation and up-dosing combined, 6.1% of patients in the active group and 3.1% in the placebo group had a systemic reaction requiring epinephrine. This was most often administered outside of the clinic.
There were 12 cases of eosinophilic esophagitis, all of which resolved after withdrawal from the study medication.
Aimmune submitted a risk-management proposal that includes the following:
- The first dose of each progressive dose must be administered in a facility that is equipped to treat systemic allergic reactions.
- Families must have a valid prescription for injectable epinephrine before treatment starts and must demonstrate that they know how to use it.
- There must be distribution controls in every pharmacy that dispenses the product.
- Packaging will be dose specific to ensure proper at-home administration.
- Pharmacologic questionnaires will be used as data collection instruments.
- Professional and patient-focused labeling will include a medication guide and educational material.
Palforzia is not the only peanut desensitization product in the works. DBC Technology has resubmitted its biologics license application to the FDA in the hope of getting approval for its peanut allergy treatment, the Viaskin Peanut patch.
The patch is designed to desensitize allergic children aged 4-11 years through a skin-patch method known as epicutaneous immunotherapy. Results from two controlled clinical trials were included in the submission. The company is also investigating the potential of this form of skin-patch therapy for milk and egg allergies.
Correction, 9/15/19: An earlier version of this article did not clearly state that the panel recommended approval rather than granted approval for the drug.
FROM THE FDA ALLERGENIC PRODUCTS ADVISORY COMMITTEE MEETING
FDA issues warning for CDK 4/6 inhibitors
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
FDA approves mepolizumab for severe eosinophilic asthma in younger kids
according to a release from GlaxoSmithKline, which developed the drug. This is the first targeted biologic approved for this condition in this age group.
The approval is supported by both an open-label study in children aged 6-11 years and evidence from other trials conducted in adults and adolescents. The 52-week, long-term study in these younger patients investigated pharmacokinetics, pharmacodynamics, and safety, the last of which was shown to be similar to that seen in older patients.
Hypersensitivity reactions, such as anaphylaxis, rash, and bronchospasm, have been associated with mepolizumab. It should not be used to treat acute bronchospasm or status asthmaticus, nor should systemic or inhaled corticosteroids be stopped abruptly after initiating mepolizumab treatment. Common adverse events include headache, injection-site reactions, back pain, and fatigue. Injection site reactions (such as pain, erythema, and itching) occurred in 8% of mepolizumab patients treated with 100 mg of the drug versus 3% of placebo patients.
The monoclonal antibody targeting interleukin-5 was first approved for severe eosinophilic asthma in 2015 for ages 12 years and older and in ages 6 years and older in the European Union in August 2018. It inhibits IL-5 from binding to eosinophils, which reduces the presence of eosinophils in blood without completely eliminating them.
according to a release from GlaxoSmithKline, which developed the drug. This is the first targeted biologic approved for this condition in this age group.
The approval is supported by both an open-label study in children aged 6-11 years and evidence from other trials conducted in adults and adolescents. The 52-week, long-term study in these younger patients investigated pharmacokinetics, pharmacodynamics, and safety, the last of which was shown to be similar to that seen in older patients.
Hypersensitivity reactions, such as anaphylaxis, rash, and bronchospasm, have been associated with mepolizumab. It should not be used to treat acute bronchospasm or status asthmaticus, nor should systemic or inhaled corticosteroids be stopped abruptly after initiating mepolizumab treatment. Common adverse events include headache, injection-site reactions, back pain, and fatigue. Injection site reactions (such as pain, erythema, and itching) occurred in 8% of mepolizumab patients treated with 100 mg of the drug versus 3% of placebo patients.
The monoclonal antibody targeting interleukin-5 was first approved for severe eosinophilic asthma in 2015 for ages 12 years and older and in ages 6 years and older in the European Union in August 2018. It inhibits IL-5 from binding to eosinophils, which reduces the presence of eosinophils in blood without completely eliminating them.
according to a release from GlaxoSmithKline, which developed the drug. This is the first targeted biologic approved for this condition in this age group.
The approval is supported by both an open-label study in children aged 6-11 years and evidence from other trials conducted in adults and adolescents. The 52-week, long-term study in these younger patients investigated pharmacokinetics, pharmacodynamics, and safety, the last of which was shown to be similar to that seen in older patients.
Hypersensitivity reactions, such as anaphylaxis, rash, and bronchospasm, have been associated with mepolizumab. It should not be used to treat acute bronchospasm or status asthmaticus, nor should systemic or inhaled corticosteroids be stopped abruptly after initiating mepolizumab treatment. Common adverse events include headache, injection-site reactions, back pain, and fatigue. Injection site reactions (such as pain, erythema, and itching) occurred in 8% of mepolizumab patients treated with 100 mg of the drug versus 3% of placebo patients.
The monoclonal antibody targeting interleukin-5 was first approved for severe eosinophilic asthma in 2015 for ages 12 years and older and in ages 6 years and older in the European Union in August 2018. It inhibits IL-5 from binding to eosinophils, which reduces the presence of eosinophils in blood without completely eliminating them.
Benralizumab trials cast doubt on eosinophil depletion’s role in COPD treatment
and eosinophilic inflammation, according to results from two phase 3 trials. The data were published in the New England Journal of Medicine.
Benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, is approved for the treatment of patients with severe eosinophilic asthma. To assess whether the treatment may prevent COPD exacerbations, Gerard J. Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia and colleagues conducted two randomized, double-blind, parallel-group studies: GALATHEA and TERRANOVA. Researchers enrolled patients with frequent moderate or severe COPD exacerbations and blood eosinophil counts of at least 220 per mm3.
A 56-week treatment period
“An eosinophil threshold of 220 per mm3 was selected on the basis of the phase 2 trial of benralizumab in patients with COPD, in which modeling of annual exacerbations according to baseline blood eosinophil count indicated that patients with eosinophil counts above a similar threshold were more likely to have a response to benralizumab,” the authors wrote. “The doses selected were 30 mg, the approved dose for asthma treatment; 100 mg, to inform the safety margin; and 10 mg (in TERRANOVA), to evaluate the dose-efficacy relationship.”
Patients received placebo or benralizumab via subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks for the rest of the 56-week treatment period. The primary end point was the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56.
The primary analysis populations included 1,120 patients in GALATHEA and 1,545 patients in TERRANOVA. Most patients were white men, and the average age was 65 years. The percentages of patients with current asthma (5.4% in GALATHEA and 3.3% in TERRANOVA) or past asthma (8.3% in GALATHEA and 6.1% in TERRANOVA) were low.
In GALATHEA, the estimated annualized exacerbation rates were 1.19 per year in the 30-mg benralizumab group, 1.03 per year in the 100-mg benralizumab group, and 1.24 per year in the placebo group. Compared with placebo, the rate ratio was 0.96 for 30 mg of benralizumab and 0.83 for 100 mg of benralizumab.
In TERRANOVA, the estimated annualized exacerbation rates for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year, 1.21 per year, 1.09 per year, and 1.17 per year, respectively. The corresponding rate ratios were 0.85, 1.04, and 0.93. “At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial,” the researchers said. “Types and frequencies of adverse events were similar with benralizumab and placebo.”
Depletion of eosinophils in blood and sputum
By week 4, benralizumab substantially depleted blood eosinophils. In addition, treatment substantially depleted sputum eosinophils by week 24. “However, in contrast to the results in benralizumab-treated patients with severe eosinophilic asthma, this eosinophil depletion did not correspond to a significant difference in the rate of exacerbations. This finding, together with the effect on eosinophils – with minimal effect on the COPD exacerbation rate – that was observed in the mepolizumab trials, suggests that eosinophil depletion is unlikely to ameliorate exacerbation outcomes for the majority of patients with COPD,” Dr. Criner and his coauthors concluded. “Future investigation is required to identify additional clinical factors or biomarkers that may characterize the patients with COPD who are most likely to benefit from anti–interleukin-5 receptor antibody therapy.”
The trials were sponsored by AstraZeneca, which manufactures benralizumab (Fasenra), and by Kyowa Hakko Kirin. One author is supported by the National Institute for Health Research Manchester Biomedical Research Centre. The authors’ disclosures included grants and personal fees from AstraZeneca and other pharmaceutical companies.
SOURCE: Criner GJ et al. N Engl J Med. 2019;382(11):1023-34. doi: 10.1056/NEJMoa1905248.
and eosinophilic inflammation, according to results from two phase 3 trials. The data were published in the New England Journal of Medicine.
Benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, is approved for the treatment of patients with severe eosinophilic asthma. To assess whether the treatment may prevent COPD exacerbations, Gerard J. Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia and colleagues conducted two randomized, double-blind, parallel-group studies: GALATHEA and TERRANOVA. Researchers enrolled patients with frequent moderate or severe COPD exacerbations and blood eosinophil counts of at least 220 per mm3.
A 56-week treatment period
“An eosinophil threshold of 220 per mm3 was selected on the basis of the phase 2 trial of benralizumab in patients with COPD, in which modeling of annual exacerbations according to baseline blood eosinophil count indicated that patients with eosinophil counts above a similar threshold were more likely to have a response to benralizumab,” the authors wrote. “The doses selected were 30 mg, the approved dose for asthma treatment; 100 mg, to inform the safety margin; and 10 mg (in TERRANOVA), to evaluate the dose-efficacy relationship.”
Patients received placebo or benralizumab via subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks for the rest of the 56-week treatment period. The primary end point was the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56.
The primary analysis populations included 1,120 patients in GALATHEA and 1,545 patients in TERRANOVA. Most patients were white men, and the average age was 65 years. The percentages of patients with current asthma (5.4% in GALATHEA and 3.3% in TERRANOVA) or past asthma (8.3% in GALATHEA and 6.1% in TERRANOVA) were low.
In GALATHEA, the estimated annualized exacerbation rates were 1.19 per year in the 30-mg benralizumab group, 1.03 per year in the 100-mg benralizumab group, and 1.24 per year in the placebo group. Compared with placebo, the rate ratio was 0.96 for 30 mg of benralizumab and 0.83 for 100 mg of benralizumab.
In TERRANOVA, the estimated annualized exacerbation rates for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year, 1.21 per year, 1.09 per year, and 1.17 per year, respectively. The corresponding rate ratios were 0.85, 1.04, and 0.93. “At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial,” the researchers said. “Types and frequencies of adverse events were similar with benralizumab and placebo.”
Depletion of eosinophils in blood and sputum
By week 4, benralizumab substantially depleted blood eosinophils. In addition, treatment substantially depleted sputum eosinophils by week 24. “However, in contrast to the results in benralizumab-treated patients with severe eosinophilic asthma, this eosinophil depletion did not correspond to a significant difference in the rate of exacerbations. This finding, together with the effect on eosinophils – with minimal effect on the COPD exacerbation rate – that was observed in the mepolizumab trials, suggests that eosinophil depletion is unlikely to ameliorate exacerbation outcomes for the majority of patients with COPD,” Dr. Criner and his coauthors concluded. “Future investigation is required to identify additional clinical factors or biomarkers that may characterize the patients with COPD who are most likely to benefit from anti–interleukin-5 receptor antibody therapy.”
The trials were sponsored by AstraZeneca, which manufactures benralizumab (Fasenra), and by Kyowa Hakko Kirin. One author is supported by the National Institute for Health Research Manchester Biomedical Research Centre. The authors’ disclosures included grants and personal fees from AstraZeneca and other pharmaceutical companies.
SOURCE: Criner GJ et al. N Engl J Med. 2019;382(11):1023-34. doi: 10.1056/NEJMoa1905248.
and eosinophilic inflammation, according to results from two phase 3 trials. The data were published in the New England Journal of Medicine.
Benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, is approved for the treatment of patients with severe eosinophilic asthma. To assess whether the treatment may prevent COPD exacerbations, Gerard J. Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia and colleagues conducted two randomized, double-blind, parallel-group studies: GALATHEA and TERRANOVA. Researchers enrolled patients with frequent moderate or severe COPD exacerbations and blood eosinophil counts of at least 220 per mm3.
A 56-week treatment period
“An eosinophil threshold of 220 per mm3 was selected on the basis of the phase 2 trial of benralizumab in patients with COPD, in which modeling of annual exacerbations according to baseline blood eosinophil count indicated that patients with eosinophil counts above a similar threshold were more likely to have a response to benralizumab,” the authors wrote. “The doses selected were 30 mg, the approved dose for asthma treatment; 100 mg, to inform the safety margin; and 10 mg (in TERRANOVA), to evaluate the dose-efficacy relationship.”
Patients received placebo or benralizumab via subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks for the rest of the 56-week treatment period. The primary end point was the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56.
The primary analysis populations included 1,120 patients in GALATHEA and 1,545 patients in TERRANOVA. Most patients were white men, and the average age was 65 years. The percentages of patients with current asthma (5.4% in GALATHEA and 3.3% in TERRANOVA) or past asthma (8.3% in GALATHEA and 6.1% in TERRANOVA) were low.
In GALATHEA, the estimated annualized exacerbation rates were 1.19 per year in the 30-mg benralizumab group, 1.03 per year in the 100-mg benralizumab group, and 1.24 per year in the placebo group. Compared with placebo, the rate ratio was 0.96 for 30 mg of benralizumab and 0.83 for 100 mg of benralizumab.
In TERRANOVA, the estimated annualized exacerbation rates for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year, 1.21 per year, 1.09 per year, and 1.17 per year, respectively. The corresponding rate ratios were 0.85, 1.04, and 0.93. “At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial,” the researchers said. “Types and frequencies of adverse events were similar with benralizumab and placebo.”
Depletion of eosinophils in blood and sputum
By week 4, benralizumab substantially depleted blood eosinophils. In addition, treatment substantially depleted sputum eosinophils by week 24. “However, in contrast to the results in benralizumab-treated patients with severe eosinophilic asthma, this eosinophil depletion did not correspond to a significant difference in the rate of exacerbations. This finding, together with the effect on eosinophils – with minimal effect on the COPD exacerbation rate – that was observed in the mepolizumab trials, suggests that eosinophil depletion is unlikely to ameliorate exacerbation outcomes for the majority of patients with COPD,” Dr. Criner and his coauthors concluded. “Future investigation is required to identify additional clinical factors or biomarkers that may characterize the patients with COPD who are most likely to benefit from anti–interleukin-5 receptor antibody therapy.”
The trials were sponsored by AstraZeneca, which manufactures benralizumab (Fasenra), and by Kyowa Hakko Kirin. One author is supported by the National Institute for Health Research Manchester Biomedical Research Centre. The authors’ disclosures included grants and personal fees from AstraZeneca and other pharmaceutical companies.
SOURCE: Criner GJ et al. N Engl J Med. 2019;382(11):1023-34. doi: 10.1056/NEJMoa1905248.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Trump administration finalizing ban on flavored e-cigarettes
The Food and Drug Administration is finalizing a compliance policy that will target flavored e-cigarettes and aim to clear the market of unauthorized, non–tobacco-flavored e-cigarette products, U.S. Department of Health & Human Services Secretary Alex M. Azar II announced Sept. 11.
“The Trump administration is making it clear that we intend to clear the market of flavored e-cigarettes to reverse the deeply concerning epidemic of youth e-cigarette use that is impacting children, families, schools, and communities,” Mr. Azar said in a statement. “We will not stand idly by as these products become an on-ramp to combustible cigarettes or nicotine addiction for a generation of youth.”
The announcement comes as the Centers for Disease Control and Prevention and state health departments track hundreds of lung-related illnesses that are linked to the use of e-cigarettes. At least 450 cases have been reported in 33 states and one jurisdiction. Diagnoses include lipoid pneumonia, alveolar hemorrhage, and cryptogenic organizing pneumonia, according to a Sept. 6 press briefing by Ileana Arias, PhD, CDC acting deputy director for non-infectious diseases. Six deaths associated with the illnesses have been reported thus far.
Details of new regulatory action will be forthcoming and will outline enforcement policy for non–tobacco-flavored e-cigarette products that lack premarket authorization, HHS officials said. According to federal rules, all electronic nicotine delivery system (ENDS) products must file premarket tobacco product applications with the FDA within 2 years. Many ENDS products currently on the market are not being legally marketed and are subject to government action, according to the Trump administration.
“Once finalized, this compliance policy will serve as a powerful tool that the FDA can use to combat the troubling trend of youth e-cigarette use,” Ned Sharpless, MD, acting FDA commissioner, said in the statement. “We must act swiftly against flavored e-cigarette products that are especially attractive to children. Moreover, if we see a migration to tobacco-flavored products by kids, we will take additional steps to address youth use of these products.”
Federal officials noted that preliminary numbers from the National Youth Tobacco Survey show a continued rise in youth e-cigarette use, with more than a quarter of high school students current e-cigarette users in 2019. The overwhelming majority of youth e-cigarette users cited the use of fruit, menthol, or mint flavors, according to the preliminary data, which have not yet been published.
According to 2018 survey data, e-cigarette use increased from 12% to 21% among high school students and from 3% to 5% among middle school students from 2017 to 2018. There were 1.5 million more youth e-cigarette users in 2018 than in 2017, and youth who were using e-cigarettes were using them more often, according to the survey.
The Food and Drug Administration is finalizing a compliance policy that will target flavored e-cigarettes and aim to clear the market of unauthorized, non–tobacco-flavored e-cigarette products, U.S. Department of Health & Human Services Secretary Alex M. Azar II announced Sept. 11.
“The Trump administration is making it clear that we intend to clear the market of flavored e-cigarettes to reverse the deeply concerning epidemic of youth e-cigarette use that is impacting children, families, schools, and communities,” Mr. Azar said in a statement. “We will not stand idly by as these products become an on-ramp to combustible cigarettes or nicotine addiction for a generation of youth.”
The announcement comes as the Centers for Disease Control and Prevention and state health departments track hundreds of lung-related illnesses that are linked to the use of e-cigarettes. At least 450 cases have been reported in 33 states and one jurisdiction. Diagnoses include lipoid pneumonia, alveolar hemorrhage, and cryptogenic organizing pneumonia, according to a Sept. 6 press briefing by Ileana Arias, PhD, CDC acting deputy director for non-infectious diseases. Six deaths associated with the illnesses have been reported thus far.
Details of new regulatory action will be forthcoming and will outline enforcement policy for non–tobacco-flavored e-cigarette products that lack premarket authorization, HHS officials said. According to federal rules, all electronic nicotine delivery system (ENDS) products must file premarket tobacco product applications with the FDA within 2 years. Many ENDS products currently on the market are not being legally marketed and are subject to government action, according to the Trump administration.
“Once finalized, this compliance policy will serve as a powerful tool that the FDA can use to combat the troubling trend of youth e-cigarette use,” Ned Sharpless, MD, acting FDA commissioner, said in the statement. “We must act swiftly against flavored e-cigarette products that are especially attractive to children. Moreover, if we see a migration to tobacco-flavored products by kids, we will take additional steps to address youth use of these products.”
Federal officials noted that preliminary numbers from the National Youth Tobacco Survey show a continued rise in youth e-cigarette use, with more than a quarter of high school students current e-cigarette users in 2019. The overwhelming majority of youth e-cigarette users cited the use of fruit, menthol, or mint flavors, according to the preliminary data, which have not yet been published.
According to 2018 survey data, e-cigarette use increased from 12% to 21% among high school students and from 3% to 5% among middle school students from 2017 to 2018. There were 1.5 million more youth e-cigarette users in 2018 than in 2017, and youth who were using e-cigarettes were using them more often, according to the survey.
The Food and Drug Administration is finalizing a compliance policy that will target flavored e-cigarettes and aim to clear the market of unauthorized, non–tobacco-flavored e-cigarette products, U.S. Department of Health & Human Services Secretary Alex M. Azar II announced Sept. 11.
“The Trump administration is making it clear that we intend to clear the market of flavored e-cigarettes to reverse the deeply concerning epidemic of youth e-cigarette use that is impacting children, families, schools, and communities,” Mr. Azar said in a statement. “We will not stand idly by as these products become an on-ramp to combustible cigarettes or nicotine addiction for a generation of youth.”
The announcement comes as the Centers for Disease Control and Prevention and state health departments track hundreds of lung-related illnesses that are linked to the use of e-cigarettes. At least 450 cases have been reported in 33 states and one jurisdiction. Diagnoses include lipoid pneumonia, alveolar hemorrhage, and cryptogenic organizing pneumonia, according to a Sept. 6 press briefing by Ileana Arias, PhD, CDC acting deputy director for non-infectious diseases. Six deaths associated with the illnesses have been reported thus far.
Details of new regulatory action will be forthcoming and will outline enforcement policy for non–tobacco-flavored e-cigarette products that lack premarket authorization, HHS officials said. According to federal rules, all electronic nicotine delivery system (ENDS) products must file premarket tobacco product applications with the FDA within 2 years. Many ENDS products currently on the market are not being legally marketed and are subject to government action, according to the Trump administration.
“Once finalized, this compliance policy will serve as a powerful tool that the FDA can use to combat the troubling trend of youth e-cigarette use,” Ned Sharpless, MD, acting FDA commissioner, said in the statement. “We must act swiftly against flavored e-cigarette products that are especially attractive to children. Moreover, if we see a migration to tobacco-flavored products by kids, we will take additional steps to address youth use of these products.”
Federal officials noted that preliminary numbers from the National Youth Tobacco Survey show a continued rise in youth e-cigarette use, with more than a quarter of high school students current e-cigarette users in 2019. The overwhelming majority of youth e-cigarette users cited the use of fruit, menthol, or mint flavors, according to the preliminary data, which have not yet been published.
According to 2018 survey data, e-cigarette use increased from 12% to 21% among high school students and from 3% to 5% among middle school students from 2017 to 2018. There were 1.5 million more youth e-cigarette users in 2018 than in 2017, and youth who were using e-cigarettes were using them more often, according to the survey.
FDA issues warning to JUUL on illegal marketing of e-cigarettes
, citing violation of the Federal Food, Drug, and Cosmetic Act.
According to the letter, JUUL has marketed its e-cigarettes and e-liquids as modified-risk tobacco products without receiving FDA authorization to do so. JUUL’s labeling, advertising, and other consumer-oriented activities to this effect could reasonably lead consumers to believe that JUUL products represent a lower risk of tobacco-related disease, compared with other tobacco products; that they contain a reduced level of a substance; and that they are free of a particular substance or substances.
As evidence, the letter cited testimony given at a July 2019 hearing held by the Subcommittee on Economic and Consumer Policy of the Committee on Oversight and Reform of the House of Representatives, in which a representative from JUUL, speaking to students at a school presentation, said that JUUL products were “much safer than cigarettes” and that the “FDA would approve it any day,” that JUUL products were “totally safe,” that a student “should mention JUUL to his [nicotine-addicted] friend ... because that’s a safer alternative than smoking cigarettes, and it would be better for the kid to use,” and that the FDA “was about to come out and say it [JUUL] was 99% safer than cigarettes ... and that ... would happen very soon.”
In addition, a “Letter from the CEO” that appeared on the JUUL website and was emailed to a parent in response to her complaint that the company sold JUUL products to her child stated that “[JUUL’s] simple and convenient system incorporates temperature regulation to heat nicotine liquid and deliver smokers the satisfaction that they want without the combustion and the harm associated with it.”
In a related press release, acting FDA Commissioner Ned Sharpless, MD, said that “regardless of where products like e-cigarettes fall on the continuum of tobacco product risk, the law is clear that, before marketing tobacco products for reduced risk, companies must demonstrate with scientific evidence that their specific product does in fact pose less risk or is less harmful. JUUL has ignored the law, and very concerningly, has made some of these statements in school to our nation’s youth.”
The FDA has requested a response from JUUL within 15 working days of the letter’s issue. Failure to comply with the Federal Food, Drug, and Cosmetic Act could result in the FDA’s initiating further actions such as civil money penalties, seizure, and/or injunction.
, citing violation of the Federal Food, Drug, and Cosmetic Act.
According to the letter, JUUL has marketed its e-cigarettes and e-liquids as modified-risk tobacco products without receiving FDA authorization to do so. JUUL’s labeling, advertising, and other consumer-oriented activities to this effect could reasonably lead consumers to believe that JUUL products represent a lower risk of tobacco-related disease, compared with other tobacco products; that they contain a reduced level of a substance; and that they are free of a particular substance or substances.
As evidence, the letter cited testimony given at a July 2019 hearing held by the Subcommittee on Economic and Consumer Policy of the Committee on Oversight and Reform of the House of Representatives, in which a representative from JUUL, speaking to students at a school presentation, said that JUUL products were “much safer than cigarettes” and that the “FDA would approve it any day,” that JUUL products were “totally safe,” that a student “should mention JUUL to his [nicotine-addicted] friend ... because that’s a safer alternative than smoking cigarettes, and it would be better for the kid to use,” and that the FDA “was about to come out and say it [JUUL] was 99% safer than cigarettes ... and that ... would happen very soon.”
In addition, a “Letter from the CEO” that appeared on the JUUL website and was emailed to a parent in response to her complaint that the company sold JUUL products to her child stated that “[JUUL’s] simple and convenient system incorporates temperature regulation to heat nicotine liquid and deliver smokers the satisfaction that they want without the combustion and the harm associated with it.”
In a related press release, acting FDA Commissioner Ned Sharpless, MD, said that “regardless of where products like e-cigarettes fall on the continuum of tobacco product risk, the law is clear that, before marketing tobacco products for reduced risk, companies must demonstrate with scientific evidence that their specific product does in fact pose less risk or is less harmful. JUUL has ignored the law, and very concerningly, has made some of these statements in school to our nation’s youth.”
The FDA has requested a response from JUUL within 15 working days of the letter’s issue. Failure to comply with the Federal Food, Drug, and Cosmetic Act could result in the FDA’s initiating further actions such as civil money penalties, seizure, and/or injunction.
, citing violation of the Federal Food, Drug, and Cosmetic Act.
According to the letter, JUUL has marketed its e-cigarettes and e-liquids as modified-risk tobacco products without receiving FDA authorization to do so. JUUL’s labeling, advertising, and other consumer-oriented activities to this effect could reasonably lead consumers to believe that JUUL products represent a lower risk of tobacco-related disease, compared with other tobacco products; that they contain a reduced level of a substance; and that they are free of a particular substance or substances.
As evidence, the letter cited testimony given at a July 2019 hearing held by the Subcommittee on Economic and Consumer Policy of the Committee on Oversight and Reform of the House of Representatives, in which a representative from JUUL, speaking to students at a school presentation, said that JUUL products were “much safer than cigarettes” and that the “FDA would approve it any day,” that JUUL products were “totally safe,” that a student “should mention JUUL to his [nicotine-addicted] friend ... because that’s a safer alternative than smoking cigarettes, and it would be better for the kid to use,” and that the FDA “was about to come out and say it [JUUL] was 99% safer than cigarettes ... and that ... would happen very soon.”
In addition, a “Letter from the CEO” that appeared on the JUUL website and was emailed to a parent in response to her complaint that the company sold JUUL products to her child stated that “[JUUL’s] simple and convenient system incorporates temperature regulation to heat nicotine liquid and deliver smokers the satisfaction that they want without the combustion and the harm associated with it.”
In a related press release, acting FDA Commissioner Ned Sharpless, MD, said that “regardless of where products like e-cigarettes fall on the continuum of tobacco product risk, the law is clear that, before marketing tobacco products for reduced risk, companies must demonstrate with scientific evidence that their specific product does in fact pose less risk or is less harmful. JUUL has ignored the law, and very concerningly, has made some of these statements in school to our nation’s youth.”
The FDA has requested a response from JUUL within 15 working days of the letter’s issue. Failure to comply with the Federal Food, Drug, and Cosmetic Act could result in the FDA’s initiating further actions such as civil money penalties, seizure, and/or injunction.
Can Vitamin D Prevent Acute Respiratory Infections?
Ms. M, a generally healthy 55-year-old woman, was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] level of 8 ng/mL). She presents with her second episode of acute viral bronchitis in the past 6 months. She has no history of significant smoking or exposure or history of asthma and does not take respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/wk in bolus dosing—but is that your best option for the patient?
ARTIs include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.1,2 In the United States, ARTIs strain the health care system and are the most common reason for ambulatory care visits, accounting for almost 120 million (about 10% of all) visits per year.3 In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.2,4
While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.
STUDY SUMMARY
Vitamin D is protective in smaller doses
This 2017 systematic review and meta-analysis of 25 trials (N = 10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk for bias. The Cochrane risk-for-bias tool was used to address threats to validity.
The study included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D3 or D2 supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.
Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI; and mortality (ARTI-related and all-cause).
Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR], 0.88; number needed to treat [NNT], 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR, 0.81), but bolus dosing (≥ 30,000 IU) was not (AOR, 0.97).
In 2-step analysis, patients benefited if they had baseline circulating 25(OH)D concentrations < 10 ng/mL (AOR, 0.30; NNT, 4); had baseline circulating 25(OH)D levels of 10 to 28 ng/mL (AOR, 0.75; NNT, 15); were ages 1.1 to 15.9 (AOR, 0.59); were ages 16 to 65 (AOR, 0.79); or had a BMI < 25 (AOR, 0.82).
Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25(OH)D ≥ 30 ng/mL did not appear to provide benefit (AOR, 0.96). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR, 0.98).
WHAT’S NEW
A more accurate snapshot
Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25(OH)D levels, and employed various methods to monitor ARTI symptoms/incidence.5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D3 or D2 that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.
CAVEATS
Only the most deficient benefit?
Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect was noted in those who were most severely vitamin D deficient (those with circulating 25(OH)D levels < 10 ng/mL [NNT, 4] and those with circulating 25(OH)D levels 10-28 ng/mL [NNT, 15]). There was no demonstrable effect once circulating 25(OH)D levels reached 30 ng/mL.
CHALLENGES TO IMPLEMENTATION
Breaking tradition
The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs. However, the doses studied were much lower than those commonly used (10,000 to 50,000 IU bolus), which were ineffective in reducing ARTIs in this meta-analysis. Changing from bolus dosing may prove challenging, a
In addition, the authors of the study suggest that one way to provide this level of vitamin D is through food fortification. But this method is often complicated by emotional and/or political issues that could thwart implementation.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[4]:230-231).
1. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.
2. Renati S, Linder JA. Necessity of office visits for acute respiratory infections in primary care. Fam Pract. 2016,33:312-317.
3. CDC National Center for Health Statistics. National Health Care Surveys. www.cdc.gov/nchs/dhcs.htm. Accessed September 5, 2019.
4. Grijalva CG, Nuorti JP, Griffin MR. Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings. JAMA. 2009;302:758-766.
5. Rees JR, Hendricks K, Barry EL, et al. Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial. Clin Infect Dis. 2013;57:1384-1392.
6. Murdoch DR, Slow S, Chambers ST, et al. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA. 2012;308:1333-1339.
7. Laaksi I, Ruohola J-P, Mattila V, et al. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. Infect Dis. 2010;202:809-814.
8. Bergman P, Norlin A-C, Hansen S, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open. 2012;2:e001663.
Ms. M, a generally healthy 55-year-old woman, was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] level of 8 ng/mL). She presents with her second episode of acute viral bronchitis in the past 6 months. She has no history of significant smoking or exposure or history of asthma and does not take respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/wk in bolus dosing—but is that your best option for the patient?
ARTIs include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.1,2 In the United States, ARTIs strain the health care system and are the most common reason for ambulatory care visits, accounting for almost 120 million (about 10% of all) visits per year.3 In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.2,4
While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.
STUDY SUMMARY
Vitamin D is protective in smaller doses
This 2017 systematic review and meta-analysis of 25 trials (N = 10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk for bias. The Cochrane risk-for-bias tool was used to address threats to validity.
The study included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D3 or D2 supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.
Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI; and mortality (ARTI-related and all-cause).
Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR], 0.88; number needed to treat [NNT], 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR, 0.81), but bolus dosing (≥ 30,000 IU) was not (AOR, 0.97).
In 2-step analysis, patients benefited if they had baseline circulating 25(OH)D concentrations < 10 ng/mL (AOR, 0.30; NNT, 4); had baseline circulating 25(OH)D levels of 10 to 28 ng/mL (AOR, 0.75; NNT, 15); were ages 1.1 to 15.9 (AOR, 0.59); were ages 16 to 65 (AOR, 0.79); or had a BMI < 25 (AOR, 0.82).
Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25(OH)D ≥ 30 ng/mL did not appear to provide benefit (AOR, 0.96). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR, 0.98).
WHAT’S NEW
A more accurate snapshot
Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25(OH)D levels, and employed various methods to monitor ARTI symptoms/incidence.5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D3 or D2 that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.
CAVEATS
Only the most deficient benefit?
Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect was noted in those who were most severely vitamin D deficient (those with circulating 25(OH)D levels < 10 ng/mL [NNT, 4] and those with circulating 25(OH)D levels 10-28 ng/mL [NNT, 15]). There was no demonstrable effect once circulating 25(OH)D levels reached 30 ng/mL.
CHALLENGES TO IMPLEMENTATION
Breaking tradition
The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs. However, the doses studied were much lower than those commonly used (10,000 to 50,000 IU bolus), which were ineffective in reducing ARTIs in this meta-analysis. Changing from bolus dosing may prove challenging, a
In addition, the authors of the study suggest that one way to provide this level of vitamin D is through food fortification. But this method is often complicated by emotional and/or political issues that could thwart implementation.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[4]:230-231).
Ms. M, a generally healthy 55-year-old woman, was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] level of 8 ng/mL). She presents with her second episode of acute viral bronchitis in the past 6 months. She has no history of significant smoking or exposure or history of asthma and does not take respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/wk in bolus dosing—but is that your best option for the patient?
ARTIs include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.1,2 In the United States, ARTIs strain the health care system and are the most common reason for ambulatory care visits, accounting for almost 120 million (about 10% of all) visits per year.3 In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.2,4
While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.
STUDY SUMMARY
Vitamin D is protective in smaller doses
This 2017 systematic review and meta-analysis of 25 trials (N = 10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk for bias. The Cochrane risk-for-bias tool was used to address threats to validity.
The study included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D3 or D2 supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.
Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI; and mortality (ARTI-related and all-cause).
Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR], 0.88; number needed to treat [NNT], 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR, 0.81), but bolus dosing (≥ 30,000 IU) was not (AOR, 0.97).
In 2-step analysis, patients benefited if they had baseline circulating 25(OH)D concentrations < 10 ng/mL (AOR, 0.30; NNT, 4); had baseline circulating 25(OH)D levels of 10 to 28 ng/mL (AOR, 0.75; NNT, 15); were ages 1.1 to 15.9 (AOR, 0.59); were ages 16 to 65 (AOR, 0.79); or had a BMI < 25 (AOR, 0.82).
Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25(OH)D ≥ 30 ng/mL did not appear to provide benefit (AOR, 0.96). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR, 0.98).
WHAT’S NEW
A more accurate snapshot
Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25(OH)D levels, and employed various methods to monitor ARTI symptoms/incidence.5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D3 or D2 that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.
CAVEATS
Only the most deficient benefit?
Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect was noted in those who were most severely vitamin D deficient (those with circulating 25(OH)D levels < 10 ng/mL [NNT, 4] and those with circulating 25(OH)D levels 10-28 ng/mL [NNT, 15]). There was no demonstrable effect once circulating 25(OH)D levels reached 30 ng/mL.
CHALLENGES TO IMPLEMENTATION
Breaking tradition
The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs. However, the doses studied were much lower than those commonly used (10,000 to 50,000 IU bolus), which were ineffective in reducing ARTIs in this meta-analysis. Changing from bolus dosing may prove challenging, a
In addition, the authors of the study suggest that one way to provide this level of vitamin D is through food fortification. But this method is often complicated by emotional and/or political issues that could thwart implementation.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[4]:230-231).
1. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.
2. Renati S, Linder JA. Necessity of office visits for acute respiratory infections in primary care. Fam Pract. 2016,33:312-317.
3. CDC National Center for Health Statistics. National Health Care Surveys. www.cdc.gov/nchs/dhcs.htm. Accessed September 5, 2019.
4. Grijalva CG, Nuorti JP, Griffin MR. Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings. JAMA. 2009;302:758-766.
5. Rees JR, Hendricks K, Barry EL, et al. Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial. Clin Infect Dis. 2013;57:1384-1392.
6. Murdoch DR, Slow S, Chambers ST, et al. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA. 2012;308:1333-1339.
7. Laaksi I, Ruohola J-P, Mattila V, et al. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. Infect Dis. 2010;202:809-814.
8. Bergman P, Norlin A-C, Hansen S, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open. 2012;2:e001663.
1. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.
2. Renati S, Linder JA. Necessity of office visits for acute respiratory infections in primary care. Fam Pract. 2016,33:312-317.
3. CDC National Center for Health Statistics. National Health Care Surveys. www.cdc.gov/nchs/dhcs.htm. Accessed September 5, 2019.
4. Grijalva CG, Nuorti JP, Griffin MR. Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings. JAMA. 2009;302:758-766.
5. Rees JR, Hendricks K, Barry EL, et al. Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial. Clin Infect Dis. 2013;57:1384-1392.
6. Murdoch DR, Slow S, Chambers ST, et al. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA. 2012;308:1333-1339.
7. Laaksi I, Ruohola J-P, Mattila V, et al. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. Infect Dis. 2010;202:809-814.
8. Bergman P, Norlin A-C, Hansen S, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open. 2012;2:e001663.
Less CPAP time linked to exacerbation in COPD/OSA overlap syndrome
and all‐cause mortality, according to a retrospective cohort study.
“These factors should be taken into account when considering the management and prognosis of these patients,” the researchers said in the Clinical Respiratory Journal.
Prior studies have found that patients with COPD and OSA – that is, with overlap syndrome – “have a substantially greater risk of morbidity and mortality, compared to those with either COPD or OSA alone,” said Philippe E. Jaoude, MD, and Ali A. El Solh, MD, both of the Veterans Affairs Western New York Healthcare System in Buffalo and the University at Buffalo.
To identify factors associated with COPD exacerbation and all‐cause mortality in patients with overlap syndrome, Dr. Jaoude and Dr. El Solh reviewed the electronic health records of patients with simultaneous COPD and OSA. They compared patients with overlap syndrome who had an acute exacerbation of COPD during a 42-month period with a control group of patients with overlap syndrome who did not have exacerbations during that time. Patients with exacerbations and controls were matched 1:1 by age and body mass index.
Eligible patients were aged 42-90 years, had objectively confirmed COPD, and had documented OSA by in-laboratory polysomnography (that is, at least five obstructive apneas and hypopneas per hour). The investigators defined a COPD exacerbation as a sustained worsening of a patient’s respiratory condition that warranted additional treatment.
Of 225 eligible patients, 92 had at least one COPD exacerbation between March 2014 and September 2017. Patients with COPD exacerbation and controls had a mean age of about 68 years. The group of patients with exacerbation had a higher percentage of active smokers (21% vs. 9%) and had poorer lung function (mean forced expiratory volume in 1 second percent predicted: 55.2% vs. 64.5%).
“Although the rate of CPAP adherence between the two groups was not significantly different, the average time of CPAP use was significantly higher in patients with no recorded exacerbation,” the researchers reported – 285.4 min/night versus 238.2 min/night.
In all, 146 patients (79.4%) survived, and 38 patients (20.6%) died during the study period. The crude mortality rate was significantly higher in the group with COPD exacerbations (14% vs. 7%).
“Multivariate logistic regression analysis identified the independent risk factors associated with COPD exacerbations as active smoking, worse airflow limitation, and lower CPAP utilization,” they said. “As for all-cause mortality, a higher burden of comorbidities, worse airflow limitation, and lower time of CPAP use were independently associated with poor outcome.”
The researchers noted that they cannot rule out the possibility that patients who were adherent to CPAP were systematically different from those who were not.
The authors had no conflicts of interest.
SOURCE: Jaoude P et al. Clin Respir J. 2019 Aug 22. doi: 10.1111/crj.13079.
and all‐cause mortality, according to a retrospective cohort study.
“These factors should be taken into account when considering the management and prognosis of these patients,” the researchers said in the Clinical Respiratory Journal.
Prior studies have found that patients with COPD and OSA – that is, with overlap syndrome – “have a substantially greater risk of morbidity and mortality, compared to those with either COPD or OSA alone,” said Philippe E. Jaoude, MD, and Ali A. El Solh, MD, both of the Veterans Affairs Western New York Healthcare System in Buffalo and the University at Buffalo.
To identify factors associated with COPD exacerbation and all‐cause mortality in patients with overlap syndrome, Dr. Jaoude and Dr. El Solh reviewed the electronic health records of patients with simultaneous COPD and OSA. They compared patients with overlap syndrome who had an acute exacerbation of COPD during a 42-month period with a control group of patients with overlap syndrome who did not have exacerbations during that time. Patients with exacerbations and controls were matched 1:1 by age and body mass index.
Eligible patients were aged 42-90 years, had objectively confirmed COPD, and had documented OSA by in-laboratory polysomnography (that is, at least five obstructive apneas and hypopneas per hour). The investigators defined a COPD exacerbation as a sustained worsening of a patient’s respiratory condition that warranted additional treatment.
Of 225 eligible patients, 92 had at least one COPD exacerbation between March 2014 and September 2017. Patients with COPD exacerbation and controls had a mean age of about 68 years. The group of patients with exacerbation had a higher percentage of active smokers (21% vs. 9%) and had poorer lung function (mean forced expiratory volume in 1 second percent predicted: 55.2% vs. 64.5%).
“Although the rate of CPAP adherence between the two groups was not significantly different, the average time of CPAP use was significantly higher in patients with no recorded exacerbation,” the researchers reported – 285.4 min/night versus 238.2 min/night.
In all, 146 patients (79.4%) survived, and 38 patients (20.6%) died during the study period. The crude mortality rate was significantly higher in the group with COPD exacerbations (14% vs. 7%).
“Multivariate logistic regression analysis identified the independent risk factors associated with COPD exacerbations as active smoking, worse airflow limitation, and lower CPAP utilization,” they said. “As for all-cause mortality, a higher burden of comorbidities, worse airflow limitation, and lower time of CPAP use were independently associated with poor outcome.”
The researchers noted that they cannot rule out the possibility that patients who were adherent to CPAP were systematically different from those who were not.
The authors had no conflicts of interest.
SOURCE: Jaoude P et al. Clin Respir J. 2019 Aug 22. doi: 10.1111/crj.13079.
and all‐cause mortality, according to a retrospective cohort study.
“These factors should be taken into account when considering the management and prognosis of these patients,” the researchers said in the Clinical Respiratory Journal.
Prior studies have found that patients with COPD and OSA – that is, with overlap syndrome – “have a substantially greater risk of morbidity and mortality, compared to those with either COPD or OSA alone,” said Philippe E. Jaoude, MD, and Ali A. El Solh, MD, both of the Veterans Affairs Western New York Healthcare System in Buffalo and the University at Buffalo.
To identify factors associated with COPD exacerbation and all‐cause mortality in patients with overlap syndrome, Dr. Jaoude and Dr. El Solh reviewed the electronic health records of patients with simultaneous COPD and OSA. They compared patients with overlap syndrome who had an acute exacerbation of COPD during a 42-month period with a control group of patients with overlap syndrome who did not have exacerbations during that time. Patients with exacerbations and controls were matched 1:1 by age and body mass index.
Eligible patients were aged 42-90 years, had objectively confirmed COPD, and had documented OSA by in-laboratory polysomnography (that is, at least five obstructive apneas and hypopneas per hour). The investigators defined a COPD exacerbation as a sustained worsening of a patient’s respiratory condition that warranted additional treatment.
Of 225 eligible patients, 92 had at least one COPD exacerbation between March 2014 and September 2017. Patients with COPD exacerbation and controls had a mean age of about 68 years. The group of patients with exacerbation had a higher percentage of active smokers (21% vs. 9%) and had poorer lung function (mean forced expiratory volume in 1 second percent predicted: 55.2% vs. 64.5%).
“Although the rate of CPAP adherence between the two groups was not significantly different, the average time of CPAP use was significantly higher in patients with no recorded exacerbation,” the researchers reported – 285.4 min/night versus 238.2 min/night.
In all, 146 patients (79.4%) survived, and 38 patients (20.6%) died during the study period. The crude mortality rate was significantly higher in the group with COPD exacerbations (14% vs. 7%).
“Multivariate logistic regression analysis identified the independent risk factors associated with COPD exacerbations as active smoking, worse airflow limitation, and lower CPAP utilization,” they said. “As for all-cause mortality, a higher burden of comorbidities, worse airflow limitation, and lower time of CPAP use were independently associated with poor outcome.”
The researchers noted that they cannot rule out the possibility that patients who were adherent to CPAP were systematically different from those who were not.
The authors had no conflicts of interest.
SOURCE: Jaoude P et al. Clin Respir J. 2019 Aug 22. doi: 10.1111/crj.13079.
FROM CLINICAL RESPIRATORY JOURNAL