Pulmonology

On July 13, the Food and Drug Administration approved the first over-the-counter (OTC) norgestrel birth control pill (Opill). The daily oral contraceptive was approved for prescription use 5 decades ago, providing regulators with a half-century of data to show that the progestin-only drug can be used safely without a prescription. 

The drug is the latest in a series of medications that have made the switch from behind the pharmacy counter to retail shelves. 

Experts say several more classes of drugs to treat high cholesterol, asthma, and other common health problems could be next.
 

Why switch?

When a drug manufacturer submits a proposal for a switch to OTC, the key question that the FDA considers is patient safety. Some risks can be mitigated by approving OTC drugs at lower doses than what is available as the prescription version. 

“There is no drug that doesn’t have risks,” said Almut G. Winterstein, RPh, PhD, a distinguished professor in pharmaceutical outcomes and policy and director of the Center for Drug Evaluation and Safety at the University of Florida, Gainesville. “Risks are mitigated by putting specific constraints around access to those medications.”

Dr. Winterstein, a former chair of the FDA’s Drug Safety and Risk Management Advisory Committee, said that nonprescription drugs are unnecessary in a functional health care system. 

Many patients may struggle with accessing health clinicians, so making medications available OTC fills gaps left by not being able to get a prescription, according to Dr. Winterstein. 

A 2012 paper funded by the Consumer Healthcare Products Association (CHPA), the organization representing manufacturers and distributors of OTC medications, estimated that one quarter of people who bought OTC drugs would not otherwise seek treatment if these treatments were available only via prescription. The CHPA notes that the number of those who experience allergies who use nonprescription antihistamines and allergy-relief drugs increased by about 10% between 2009 and 2015. 
 

Cholesterol drugs

Approximately 80 million U.S. adults are eligible for cholesterol-lowering medications, particularly statins, but nearly half don’t take them, according to the Centers for Disease Control and Prevention. 

Fear of side effects is the most common reason people might avoid taking these drugs. But eliminating the need for a refill may encourage uptake of the statins. 

“It’s refill, refill, refill,” said Allen J. Taylor, MD, chairman of cardiology at MedStar Heart and Vascular Institute, in Washington. “We spend a ton of time refilling statins and it’s a headache for patients, too.” 

The need to secure regular prescriptions for the drug, “doesn’t put enough trust and faith in pharmacists and doesn’t put enough trust and faith in patients,” Dr. Taylor said. 

Moving statins to the front end of a pharmacy might not be the best move given the potential for drug interactions, but a nonprescription behind-the-counter approach could work, according to Dr. Taylor. 

“The concerns are modest at most, to where they can be monitored by a pharmacist,” he said. “There’s probably more people that would take a statin if they had that kind of access.” 

Many statin manufacturers have attempted to make the prescription-to-OTC switch. In 2005, an FDA advisory panel rejected Merck’s proposal for OTC sales of lovastatin after reviewing a study that found only 55% of OTC purchases would have been medically appropriate. 

In 2015, Pfizer pulled its application to make the cholesterol drug atorvastatin available to patients OTC because patients were not using the drug correctly. AstraZeneca is investigating an online platform that would allow patients to self-assess their eligibility for rosuvastatin. 
 

Asthma inhalers 

Inhalers are the main rescue therapy for asthma aside from a visit to the ED. 

The only inhaler available OTC is epinephrine sold under the brand name Primatene Mist, but this type of medicine device is not recommended as a first-line therapy for acute asthma symptoms, according to the American Medical Association. 

“It’s been around for a long time and has stayed over the counter even though newer, safer agents have come onto the market which aren’t available over the counter,” said William B. Feldman, MD, DPhil, MPH, a pulmonologist at Brigham and Women’s Hospital, Boston. 

Patients who have a hard time getting to a doctor or patients who lack insurance often face barriers accessing albuterol inhalers and beta agonist–corticosteroid combinations, according to Dr. Feldman. A switch to OTC distribution would widen access. 

“What we’re advocating is, if they’re going to have access to Primatene Mist, wouldn’t it be sensible to have access to a safer and more effective therapy?” Dr. Feldman said. 
 

Triptans

Migraines affect an estimated 39 million people in the United States, according to the American Migraine Foundation. Several drugs to treat migraine are available OTC, including nonsteroidal anti-inflammatory drugs, aspirin, and acetaminophen. Triptans, drugs used for the short-term treatment of acute symptoms, are prescription-only in the United States. 

But in the United Kingdom, triptans first became available in retail stores in 2006, leading to reduced costs for patients, employers, and the government. One study found that government health expenditures would be reduced by $84 million annually if the OTC switch were made in six European countries. 

However, overuse of the drug and potential contraindications have been cited as concerns with OTC access. 

For Dr. Winterstein, the decision to switch isn’t just about the freedom to buy a drug; it comes down to weighing potential risks and benefits. 

“Drugs are only as good as if they’re used in the context of how they should be used,” Dr. Winterstein said. “It’s not candy.”
 

A version of this article first appeared on Medscape.com.

On July 13, the Food and Drug Administration approved the first over-the-counter (OTC) norgestrel birth control pill (Opill). The daily oral contraceptive was approved for prescription use 5 decades ago, providing regulators with a half-century of data to show that the progestin-only drug can be used safely without a prescription. 

The drug is the latest in a series of medications that have made the switch from behind the pharmacy counter to retail shelves. 

Experts say several more classes of drugs to treat high cholesterol, asthma, and other common health problems could be next.
 

Why switch?

When a drug manufacturer submits a proposal for a switch to OTC, the key question that the FDA considers is patient safety. Some risks can be mitigated by approving OTC drugs at lower doses than what is available as the prescription version. 

“There is no drug that doesn’t have risks,” said Almut G. Winterstein, RPh, PhD, a distinguished professor in pharmaceutical outcomes and policy and director of the Center for Drug Evaluation and Safety at the University of Florida, Gainesville. “Risks are mitigated by putting specific constraints around access to those medications.”

Dr. Winterstein, a former chair of the FDA’s Drug Safety and Risk Management Advisory Committee, said that nonprescription drugs are unnecessary in a functional health care system. 

Many patients may struggle with accessing health clinicians, so making medications available OTC fills gaps left by not being able to get a prescription, according to Dr. Winterstein. 

A 2012 paper funded by the Consumer Healthcare Products Association (CHPA), the organization representing manufacturers and distributors of OTC medications, estimated that one quarter of people who bought OTC drugs would not otherwise seek treatment if these treatments were available only via prescription. The CHPA notes that the number of those who experience allergies who use nonprescription antihistamines and allergy-relief drugs increased by about 10% between 2009 and 2015. 
 

Cholesterol drugs

Approximately 80 million U.S. adults are eligible for cholesterol-lowering medications, particularly statins, but nearly half don’t take them, according to the Centers for Disease Control and Prevention. 

Fear of side effects is the most common reason people might avoid taking these drugs. But eliminating the need for a refill may encourage uptake of the statins. 

“It’s refill, refill, refill,” said Allen J. Taylor, MD, chairman of cardiology at MedStar Heart and Vascular Institute, in Washington. “We spend a ton of time refilling statins and it’s a headache for patients, too.” 

The need to secure regular prescriptions for the drug, “doesn’t put enough trust and faith in pharmacists and doesn’t put enough trust and faith in patients,” Dr. Taylor said. 

Moving statins to the front end of a pharmacy might not be the best move given the potential for drug interactions, but a nonprescription behind-the-counter approach could work, according to Dr. Taylor. 

“The concerns are modest at most, to where they can be monitored by a pharmacist,” he said. “There’s probably more people that would take a statin if they had that kind of access.” 

Many statin manufacturers have attempted to make the prescription-to-OTC switch. In 2005, an FDA advisory panel rejected Merck’s proposal for OTC sales of lovastatin after reviewing a study that found only 55% of OTC purchases would have been medically appropriate. 

In 2015, Pfizer pulled its application to make the cholesterol drug atorvastatin available to patients OTC because patients were not using the drug correctly. AstraZeneca is investigating an online platform that would allow patients to self-assess their eligibility for rosuvastatin. 
 

Asthma inhalers 

Inhalers are the main rescue therapy for asthma aside from a visit to the ED. 

The only inhaler available OTC is epinephrine sold under the brand name Primatene Mist, but this type of medicine device is not recommended as a first-line therapy for acute asthma symptoms, according to the American Medical Association. 

“It’s been around for a long time and has stayed over the counter even though newer, safer agents have come onto the market which aren’t available over the counter,” said William B. Feldman, MD, DPhil, MPH, a pulmonologist at Brigham and Women’s Hospital, Boston. 

Patients who have a hard time getting to a doctor or patients who lack insurance often face barriers accessing albuterol inhalers and beta agonist–corticosteroid combinations, according to Dr. Feldman. A switch to OTC distribution would widen access. 

“What we’re advocating is, if they’re going to have access to Primatene Mist, wouldn’t it be sensible to have access to a safer and more effective therapy?” Dr. Feldman said. 
 

Triptans

Migraines affect an estimated 39 million people in the United States, according to the American Migraine Foundation. Several drugs to treat migraine are available OTC, including nonsteroidal anti-inflammatory drugs, aspirin, and acetaminophen. Triptans, drugs used for the short-term treatment of acute symptoms, are prescription-only in the United States. 

But in the United Kingdom, triptans first became available in retail stores in 2006, leading to reduced costs for patients, employers, and the government. One study found that government health expenditures would be reduced by $84 million annually if the OTC switch were made in six European countries. 

However, overuse of the drug and potential contraindications have been cited as concerns with OTC access. 

For Dr. Winterstein, the decision to switch isn’t just about the freedom to buy a drug; it comes down to weighing potential risks and benefits. 

“Drugs are only as good as if they’re used in the context of how they should be used,” Dr. Winterstein said. “It’s not candy.”
 

A version of this article first appeared on Medscape.com.

On July 13, the Food and Drug Administration approved the first over-the-counter (OTC) norgestrel birth control pill (Opill). The daily oral contraceptive was approved for prescription use 5 decades ago, providing regulators with a half-century of data to show that the progestin-only drug can be used safely without a prescription. 

The drug is the latest in a series of medications that have made the switch from behind the pharmacy counter to retail shelves. 

Experts say several more classes of drugs to treat high cholesterol, asthma, and other common health problems could be next.
 

Why switch?

When a drug manufacturer submits a proposal for a switch to OTC, the key question that the FDA considers is patient safety. Some risks can be mitigated by approving OTC drugs at lower doses than what is available as the prescription version. 

“There is no drug that doesn’t have risks,” said Almut G. Winterstein, RPh, PhD, a distinguished professor in pharmaceutical outcomes and policy and director of the Center for Drug Evaluation and Safety at the University of Florida, Gainesville. “Risks are mitigated by putting specific constraints around access to those medications.”

Dr. Winterstein, a former chair of the FDA’s Drug Safety and Risk Management Advisory Committee, said that nonprescription drugs are unnecessary in a functional health care system. 

Many patients may struggle with accessing health clinicians, so making medications available OTC fills gaps left by not being able to get a prescription, according to Dr. Winterstein. 

A 2012 paper funded by the Consumer Healthcare Products Association (CHPA), the organization representing manufacturers and distributors of OTC medications, estimated that one quarter of people who bought OTC drugs would not otherwise seek treatment if these treatments were available only via prescription. The CHPA notes that the number of those who experience allergies who use nonprescription antihistamines and allergy-relief drugs increased by about 10% between 2009 and 2015. 
 

Cholesterol drugs

Approximately 80 million U.S. adults are eligible for cholesterol-lowering medications, particularly statins, but nearly half don’t take them, according to the Centers for Disease Control and Prevention. 

Fear of side effects is the most common reason people might avoid taking these drugs. But eliminating the need for a refill may encourage uptake of the statins. 

“It’s refill, refill, refill,” said Allen J. Taylor, MD, chairman of cardiology at MedStar Heart and Vascular Institute, in Washington. “We spend a ton of time refilling statins and it’s a headache for patients, too.” 

The need to secure regular prescriptions for the drug, “doesn’t put enough trust and faith in pharmacists and doesn’t put enough trust and faith in patients,” Dr. Taylor said. 

Moving statins to the front end of a pharmacy might not be the best move given the potential for drug interactions, but a nonprescription behind-the-counter approach could work, according to Dr. Taylor. 

“The concerns are modest at most, to where they can be monitored by a pharmacist,” he said. “There’s probably more people that would take a statin if they had that kind of access.” 

Many statin manufacturers have attempted to make the prescription-to-OTC switch. In 2005, an FDA advisory panel rejected Merck’s proposal for OTC sales of lovastatin after reviewing a study that found only 55% of OTC purchases would have been medically appropriate. 

In 2015, Pfizer pulled its application to make the cholesterol drug atorvastatin available to patients OTC because patients were not using the drug correctly. AstraZeneca is investigating an online platform that would allow patients to self-assess their eligibility for rosuvastatin. 
 

Asthma inhalers 

Inhalers are the main rescue therapy for asthma aside from a visit to the ED. 

The only inhaler available OTC is epinephrine sold under the brand name Primatene Mist, but this type of medicine device is not recommended as a first-line therapy for acute asthma symptoms, according to the American Medical Association. 

“It’s been around for a long time and has stayed over the counter even though newer, safer agents have come onto the market which aren’t available over the counter,” said William B. Feldman, MD, DPhil, MPH, a pulmonologist at Brigham and Women’s Hospital, Boston. 

Patients who have a hard time getting to a doctor or patients who lack insurance often face barriers accessing albuterol inhalers and beta agonist–corticosteroid combinations, according to Dr. Feldman. A switch to OTC distribution would widen access. 

“What we’re advocating is, if they’re going to have access to Primatene Mist, wouldn’t it be sensible to have access to a safer and more effective therapy?” Dr. Feldman said. 
 

Triptans

Migraines affect an estimated 39 million people in the United States, according to the American Migraine Foundation. Several drugs to treat migraine are available OTC, including nonsteroidal anti-inflammatory drugs, aspirin, and acetaminophen. Triptans, drugs used for the short-term treatment of acute symptoms, are prescription-only in the United States. 

But in the United Kingdom, triptans first became available in retail stores in 2006, leading to reduced costs for patients, employers, and the government. One study found that government health expenditures would be reduced by $84 million annually if the OTC switch were made in six European countries. 

However, overuse of the drug and potential contraindications have been cited as concerns with OTC access. 

For Dr. Winterstein, the decision to switch isn’t just about the freedom to buy a drug; it comes down to weighing potential risks and benefits. 

“Drugs are only as good as if they’re used in the context of how they should be used,” Dr. Winterstein said. “It’s not candy.”
 

A version of this article first appeared on Medscape.com.

The presence of a positive fungal culture in patients with bronchiectasis does not appear to correlate with disease severity or any increased risk of an adverse outcome, according to data pulled from the Bronchiectasis and NTM Registry and presented at the 6th World Bronchiectasis & NTM Conference.

“The question we were asking is whether there is some signal that suggests we need to take care of these patients differently, and the answer is no,” reported Pamela J. McShane, MD, a pulmonologist on the faculty at the University of Texas Health Science Center at Tyler.

When compared for outcome over time, those with a positive fungal culture at initial evaluation did not have more exacerbations, more hospitalizations, or other signs of a more severe disease or more complex course than did those without a positive fungal culture.

When fungal infections are detected in an initial microbiologic evaluation of patients with bronchiectasis or other lung diseases, first-line clinicians generally assume that coverage is needed. Dr. McShane noted that many of the patients referred to her with bronchiectasis and a positive fungal culture were already on an antifungal.

These data are not supportive of treatment in the absence of fungal-related complications. Dr. McShane suggested they even raise questions about the value of culturing beyond bacterial pathogens in the absence of suspicion that fungal organisms are playing a role in symptoms. She cautioned, however, that more studies specifically studying this possibility are needed.
 

Study details

The data were drawn in December 2022 from the U.S.-based Bronchiectasis and NTM Registry, which at that time had 22 participating sites. Of the more than 5,000 patients enrolled, the study looked at 2,230 after several exclusions, such as a diagnosis of allergic bronchopulmonary aspergillosis (ABPA).

Of these 2,230 patients, 949 had a fungal infection at the time of diagnosis and 1,281 did not. Those with a fungal infection were further subdivided into those with an aspergillosis (331 patients) and those with a nonaspergillosis fungal infection (751 patients). The total of these two numbers is greater than the total number of fungal infections because these were not mutually exclusive.

At enrollment into the registry, there were no statistical differences between groups for age. Some statistical differences were observed among groups stratified by race, but Dr. McShane doubted that these were clinically significant with the exception of a potential disparity among Asians that might deserve further analysis.
 

Infection results

Of clinical features evaluated for their association with fungal infection, there was no correlation with either body mass index or history of asthma. Eosinophilia was associated significantly with positive fungal cultures.

Baseline FEV₁ was slightly lower among those with a positive fungal culture even if the difference was highly significant (P = .0006). Again, Dr. McShane questioned the clinical significance of values that varied by only a few percentage points, even though she was willing to acknowledge that higher is always preferable to a lower FEV₁.

In the context of other pathogens, “generally speaking, those with a positive bacterial culture were more likely to have a fungal infection,” Dr. McShane reported, although there was some variation when looking at pathogenicity of the bacteria and other variables.

“Whether this [higher rate of fungal infection] just involves the environment or our antibiotics are driving the opportunity to permit the fungi to exist, we do not have the answer,” she added.

Nontuberculosis mycobacteria (NTM) infection was similarly represented in those with or without a fungal infection, according to Dr. McShane. Noting the high use of antibiotics in an NTM population, Dr. McShane conceded that this challenges the theory that antibiotic use is driving the risk of fungal infection, but these are what the data say.  

Steroid use was associated with a statistically significant risk of fungal infection, but Dr. McShane said it is unclear whether steroid use drives the risk or is an epiphenomenon.

“We looked at this a lot of different ways: oral vs. inhaled and oral vs. inhaled and oral, and it did not make much difference. Generally speaking, the fungal cultures were more likely to be positive in patients on any kind of steroid,” she said.

Finally, with the exception of the slightly lower FEV₁ in patients with fungal infections, Dr. McShane said that there was no discernible relationship between the presence of a fungal infection and severity of bronchiectasis.

Because of this evidence, Dr. McShane concluded that the presence of fungus in the culture of patients with bronchiectasis does not appear to correlate with outcome or severity. Since completing the study, she said she is now using these data to reassure patients who have a positive fungal culture.

While these data do not affect the need to diagnosis fungal infections in patients who are not responding typically to therapy or otherwise have an abnormal course of bronchiectasis, raising suspicion that fungal infection is participating in the disease course, the data provide a basis for questioning whether routine cultures are needed, according to the discussion that followed Dr. McShane’s presentation.
 

Expert opinion

Several of the experts at the presentation provided an opinion. Some reported that they would continue to order fungal cultures on a routine basis, while others said that they now, on the basis of these data, plan to order cultures only at the first visit or when fungal infection is suspected of exacerbating the disease.

Of this latter group, which seemed to be dominant, Juzar Ali, MD, professor of medicine, Louisiana State University, New Orleans, said that he has not been ordering fungal cultures on every visit. Rather, he has been doing so selectively. Examples include those who are on steroids or those with an unusual pattern of exacerbations.

“The value of these data is that they have now provided some data to support this approach,” Dr. Ali said in an interview. Noting that this is the first large study to address this question in a systematic way, he considers this to be a valuable contribution for approaching a common clinical issue.

Dr. McShane reports no relevant financial relationships. Dr. Ali reports a financial relationship with Insmed.
 

A version of this article first appeared on Medscape.com.

The presence of a positive fungal culture in patients with bronchiectasis does not appear to correlate with disease severity or any increased risk of an adverse outcome, according to data pulled from the Bronchiectasis and NTM Registry and presented at the 6th World Bronchiectasis & NTM Conference.

“The question we were asking is whether there is some signal that suggests we need to take care of these patients differently, and the answer is no,” reported Pamela J. McShane, MD, a pulmonologist on the faculty at the University of Texas Health Science Center at Tyler.

When compared for outcome over time, those with a positive fungal culture at initial evaluation did not have more exacerbations, more hospitalizations, or other signs of a more severe disease or more complex course than did those without a positive fungal culture.

When fungal infections are detected in an initial microbiologic evaluation of patients with bronchiectasis or other lung diseases, first-line clinicians generally assume that coverage is needed. Dr. McShane noted that many of the patients referred to her with bronchiectasis and a positive fungal culture were already on an antifungal.

These data are not supportive of treatment in the absence of fungal-related complications. Dr. McShane suggested they even raise questions about the value of culturing beyond bacterial pathogens in the absence of suspicion that fungal organisms are playing a role in symptoms. She cautioned, however, that more studies specifically studying this possibility are needed.
 

Study details

The data were drawn in December 2022 from the U.S.-based Bronchiectasis and NTM Registry, which at that time had 22 participating sites. Of the more than 5,000 patients enrolled, the study looked at 2,230 after several exclusions, such as a diagnosis of allergic bronchopulmonary aspergillosis (ABPA).

Of these 2,230 patients, 949 had a fungal infection at the time of diagnosis and 1,281 did not. Those with a fungal infection were further subdivided into those with an aspergillosis (331 patients) and those with a nonaspergillosis fungal infection (751 patients). The total of these two numbers is greater than the total number of fungal infections because these were not mutually exclusive.

At enrollment into the registry, there were no statistical differences between groups for age. Some statistical differences were observed among groups stratified by race, but Dr. McShane doubted that these were clinically significant with the exception of a potential disparity among Asians that might deserve further analysis.
 

Infection results

Of clinical features evaluated for their association with fungal infection, there was no correlation with either body mass index or history of asthma. Eosinophilia was associated significantly with positive fungal cultures.

Baseline FEV₁ was slightly lower among those with a positive fungal culture even if the difference was highly significant (P = .0006). Again, Dr. McShane questioned the clinical significance of values that varied by only a few percentage points, even though she was willing to acknowledge that higher is always preferable to a lower FEV₁.

In the context of other pathogens, “generally speaking, those with a positive bacterial culture were more likely to have a fungal infection,” Dr. McShane reported, although there was some variation when looking at pathogenicity of the bacteria and other variables.

“Whether this [higher rate of fungal infection] just involves the environment or our antibiotics are driving the opportunity to permit the fungi to exist, we do not have the answer,” she added.

Nontuberculosis mycobacteria (NTM) infection was similarly represented in those with or without a fungal infection, according to Dr. McShane. Noting the high use of antibiotics in an NTM population, Dr. McShane conceded that this challenges the theory that antibiotic use is driving the risk of fungal infection, but these are what the data say.  

Steroid use was associated with a statistically significant risk of fungal infection, but Dr. McShane said it is unclear whether steroid use drives the risk or is an epiphenomenon.

“We looked at this a lot of different ways: oral vs. inhaled and oral vs. inhaled and oral, and it did not make much difference. Generally speaking, the fungal cultures were more likely to be positive in patients on any kind of steroid,” she said.

Finally, with the exception of the slightly lower FEV₁ in patients with fungal infections, Dr. McShane said that there was no discernible relationship between the presence of a fungal infection and severity of bronchiectasis.

Because of this evidence, Dr. McShane concluded that the presence of fungus in the culture of patients with bronchiectasis does not appear to correlate with outcome or severity. Since completing the study, she said she is now using these data to reassure patients who have a positive fungal culture.

While these data do not affect the need to diagnosis fungal infections in patients who are not responding typically to therapy or otherwise have an abnormal course of bronchiectasis, raising suspicion that fungal infection is participating in the disease course, the data provide a basis for questioning whether routine cultures are needed, according to the discussion that followed Dr. McShane’s presentation.
 

Expert opinion

Several of the experts at the presentation provided an opinion. Some reported that they would continue to order fungal cultures on a routine basis, while others said that they now, on the basis of these data, plan to order cultures only at the first visit or when fungal infection is suspected of exacerbating the disease.

Of this latter group, which seemed to be dominant, Juzar Ali, MD, professor of medicine, Louisiana State University, New Orleans, said that he has not been ordering fungal cultures on every visit. Rather, he has been doing so selectively. Examples include those who are on steroids or those with an unusual pattern of exacerbations.

“The value of these data is that they have now provided some data to support this approach,” Dr. Ali said in an interview. Noting that this is the first large study to address this question in a systematic way, he considers this to be a valuable contribution for approaching a common clinical issue.

Dr. McShane reports no relevant financial relationships. Dr. Ali reports a financial relationship with Insmed.
 

A version of this article first appeared on Medscape.com.

The presence of a positive fungal culture in patients with bronchiectasis does not appear to correlate with disease severity or any increased risk of an adverse outcome, according to data pulled from the Bronchiectasis and NTM Registry and presented at the 6th World Bronchiectasis & NTM Conference.

“The question we were asking is whether there is some signal that suggests we need to take care of these patients differently, and the answer is no,” reported Pamela J. McShane, MD, a pulmonologist on the faculty at the University of Texas Health Science Center at Tyler.

When compared for outcome over time, those with a positive fungal culture at initial evaluation did not have more exacerbations, more hospitalizations, or other signs of a more severe disease or more complex course than did those without a positive fungal culture.

When fungal infections are detected in an initial microbiologic evaluation of patients with bronchiectasis or other lung diseases, first-line clinicians generally assume that coverage is needed. Dr. McShane noted that many of the patients referred to her with bronchiectasis and a positive fungal culture were already on an antifungal.

These data are not supportive of treatment in the absence of fungal-related complications. Dr. McShane suggested they even raise questions about the value of culturing beyond bacterial pathogens in the absence of suspicion that fungal organisms are playing a role in symptoms. She cautioned, however, that more studies specifically studying this possibility are needed.
 

Study details

The data were drawn in December 2022 from the U.S.-based Bronchiectasis and NTM Registry, which at that time had 22 participating sites. Of the more than 5,000 patients enrolled, the study looked at 2,230 after several exclusions, such as a diagnosis of allergic bronchopulmonary aspergillosis (ABPA).

Of these 2,230 patients, 949 had a fungal infection at the time of diagnosis and 1,281 did not. Those with a fungal infection were further subdivided into those with an aspergillosis (331 patients) and those with a nonaspergillosis fungal infection (751 patients). The total of these two numbers is greater than the total number of fungal infections because these were not mutually exclusive.

At enrollment into the registry, there were no statistical differences between groups for age. Some statistical differences were observed among groups stratified by race, but Dr. McShane doubted that these were clinically significant with the exception of a potential disparity among Asians that might deserve further analysis.
 

Infection results

Of clinical features evaluated for their association with fungal infection, there was no correlation with either body mass index or history of asthma. Eosinophilia was associated significantly with positive fungal cultures.

Baseline FEV₁ was slightly lower among those with a positive fungal culture even if the difference was highly significant (P = .0006). Again, Dr. McShane questioned the clinical significance of values that varied by only a few percentage points, even though she was willing to acknowledge that higher is always preferable to a lower FEV₁.

In the context of other pathogens, “generally speaking, those with a positive bacterial culture were more likely to have a fungal infection,” Dr. McShane reported, although there was some variation when looking at pathogenicity of the bacteria and other variables.

“Whether this [higher rate of fungal infection] just involves the environment or our antibiotics are driving the opportunity to permit the fungi to exist, we do not have the answer,” she added.

Nontuberculosis mycobacteria (NTM) infection was similarly represented in those with or without a fungal infection, according to Dr. McShane. Noting the high use of antibiotics in an NTM population, Dr. McShane conceded that this challenges the theory that antibiotic use is driving the risk of fungal infection, but these are what the data say.  

Steroid use was associated with a statistically significant risk of fungal infection, but Dr. McShane said it is unclear whether steroid use drives the risk or is an epiphenomenon.

“We looked at this a lot of different ways: oral vs. inhaled and oral vs. inhaled and oral, and it did not make much difference. Generally speaking, the fungal cultures were more likely to be positive in patients on any kind of steroid,” she said.

Finally, with the exception of the slightly lower FEV₁ in patients with fungal infections, Dr. McShane said that there was no discernible relationship between the presence of a fungal infection and severity of bronchiectasis.

Because of this evidence, Dr. McShane concluded that the presence of fungus in the culture of patients with bronchiectasis does not appear to correlate with outcome or severity. Since completing the study, she said she is now using these data to reassure patients who have a positive fungal culture.

While these data do not affect the need to diagnosis fungal infections in patients who are not responding typically to therapy or otherwise have an abnormal course of bronchiectasis, raising suspicion that fungal infection is participating in the disease course, the data provide a basis for questioning whether routine cultures are needed, according to the discussion that followed Dr. McShane’s presentation.
 

Expert opinion

Several of the experts at the presentation provided an opinion. Some reported that they would continue to order fungal cultures on a routine basis, while others said that they now, on the basis of these data, plan to order cultures only at the first visit or when fungal infection is suspected of exacerbating the disease.

Of this latter group, which seemed to be dominant, Juzar Ali, MD, professor of medicine, Louisiana State University, New Orleans, said that he has not been ordering fungal cultures on every visit. Rather, he has been doing so selectively. Examples include those who are on steroids or those with an unusual pattern of exacerbations.

“The value of these data is that they have now provided some data to support this approach,” Dr. Ali said in an interview. Noting that this is the first large study to address this question in a systematic way, he considers this to be a valuable contribution for approaching a common clinical issue.

Dr. McShane reports no relevant financial relationships. Dr. Ali reports a financial relationship with Insmed.
 

A version of this article first appeared on Medscape.com.

Indigenous children or children with new abnormal auscultatory findings were significantly more likely than children in other categories to respond to oral antibiotics for exacerbations related to bronchiectasis, based on data from more than 200 individuals in New Zealand.

Children and adolescents with bronchiectasis are often treated with antibiotics for respiratory exacerbations, but the effects of antibiotics can vary among individuals, and phenotypic features associated with greater symptom resolution have not been identified, wrote Vikas Goyal, PhD, of the Centre for Children’s Health Research, Brisbane, Australia, and colleagues.

Previous studies have suggested that nearly half of exacerbations in children and adolescents resolve spontaneously after 14 days, and more data are needed to identify which patients are mostly likely to benefit from antibiotics, they noted.

In a study published in the journal Chest, the researchers reviewed secondary data from 217 children and adolescents aged 1-18 years with bronchiectasis enrolled in a pair of randomized, controlled trials comparing oral antibiotics with placebo (known as BEST-1 and BEST-2). The median age of the participants was 6.6 years, 52% were boys, and 41% were Indigenous (defined as Australian First Nations, New Zealand Maori, or Pacific Islander). All participants in the analysis received at least 14 days of oral antibiotics for treatment of nonhospitalized respiratory exacerbations.

Overall, 130 children had resolution of symptoms by day 14, and 87 were nonresponders.

In a multivariate analysis, children who were Indigenous or who had new abnormal auscultatory findings were significantly more likely to respond than children in other categories (odds ratios, 3.59 and 3.85, respectively).

Patients with multiple bronchiectatic lobes at the time of diagnosis and those with higher cough scores at the start of treatment were significantly less likely to respond to antibiotics than patients without these features (OR, 0.66 and 0.55, respectively).

The researchers conducted a further analysis to examine the association between Indigenous ethnicity and treatment response. They found no differences in the other response variables of number of affected lobes at diagnosis and cough scores at the start of treatment between Indigenous and non-Indigenous children.

Given the strong response to antibiotics among Indigenous children, the researchers also conducted a mediation analysis. “Respiratory bacterial pathogens were mediated by Indigenous ethnicity and associated with being an antibiotic ‘responder,’ ” they wrote. For new abnormal chest auscultatory findings, both direct and indirect effects on day 14 response to oral antibiotics were mediated by Indigenous ethnicity. However, neither cough scores at the start of treatment nor the number of affected lobes at diagnosis showed a mediation effect from Indigenous ethnicity.

Among the nonresponders, 59 of 87 resolved symptoms with continuing oral antibiotics over the next 2-4 weeks, and 21 improved without antibiotics.

Additionally, the detection of a respiratory virus at the start of an exacerbation was not associated with antibiotic failure at 14 days, the researchers noted.

The findings were limited by several factors including the use of data from randomized trials that were not designed to address the question in the current study, the researchers noted. Other limitations included incomplete clinical data and lack of data on inflammatory indices, potential antibiotic-resistant pathogens in nonresponders, and the follow-up period of only 14 days, they said.

However, the results suggest a role for patient and exacerbation phenotypes in management of bronchiectasis in clinical practice and promoting antimicrobial stewardship, the researchers wrote. “Although there is benefit in treating exacerbations early to avoid treatment failure and subsequent intravenous antibiotics, future research also needs to identify exacerbations that can be managed without antibiotics,” they concluded.

The BEST-1 and BEST-2 studies were supported by the Australian National Health and Medical Research Council and the NHMRC Centre for Research Excellence in Lung Health of Aboriginal and Torres Strait Islander Children. Dr. Goyal had no financial conflicts to disclose.
 

Indigenous children or children with new abnormal auscultatory findings were significantly more likely than children in other categories to respond to oral antibiotics for exacerbations related to bronchiectasis, based on data from more than 200 individuals in New Zealand.

Children and adolescents with bronchiectasis are often treated with antibiotics for respiratory exacerbations, but the effects of antibiotics can vary among individuals, and phenotypic features associated with greater symptom resolution have not been identified, wrote Vikas Goyal, PhD, of the Centre for Children’s Health Research, Brisbane, Australia, and colleagues.

Previous studies have suggested that nearly half of exacerbations in children and adolescents resolve spontaneously after 14 days, and more data are needed to identify which patients are mostly likely to benefit from antibiotics, they noted.

In a study published in the journal Chest, the researchers reviewed secondary data from 217 children and adolescents aged 1-18 years with bronchiectasis enrolled in a pair of randomized, controlled trials comparing oral antibiotics with placebo (known as BEST-1 and BEST-2). The median age of the participants was 6.6 years, 52% were boys, and 41% were Indigenous (defined as Australian First Nations, New Zealand Maori, or Pacific Islander). All participants in the analysis received at least 14 days of oral antibiotics for treatment of nonhospitalized respiratory exacerbations.

Overall, 130 children had resolution of symptoms by day 14, and 87 were nonresponders.

In a multivariate analysis, children who were Indigenous or who had new abnormal auscultatory findings were significantly more likely to respond than children in other categories (odds ratios, 3.59 and 3.85, respectively).

Patients with multiple bronchiectatic lobes at the time of diagnosis and those with higher cough scores at the start of treatment were significantly less likely to respond to antibiotics than patients without these features (OR, 0.66 and 0.55, respectively).

The researchers conducted a further analysis to examine the association between Indigenous ethnicity and treatment response. They found no differences in the other response variables of number of affected lobes at diagnosis and cough scores at the start of treatment between Indigenous and non-Indigenous children.

Given the strong response to antibiotics among Indigenous children, the researchers also conducted a mediation analysis. “Respiratory bacterial pathogens were mediated by Indigenous ethnicity and associated with being an antibiotic ‘responder,’ ” they wrote. For new abnormal chest auscultatory findings, both direct and indirect effects on day 14 response to oral antibiotics were mediated by Indigenous ethnicity. However, neither cough scores at the start of treatment nor the number of affected lobes at diagnosis showed a mediation effect from Indigenous ethnicity.

Among the nonresponders, 59 of 87 resolved symptoms with continuing oral antibiotics over the next 2-4 weeks, and 21 improved without antibiotics.

Additionally, the detection of a respiratory virus at the start of an exacerbation was not associated with antibiotic failure at 14 days, the researchers noted.

The findings were limited by several factors including the use of data from randomized trials that were not designed to address the question in the current study, the researchers noted. Other limitations included incomplete clinical data and lack of data on inflammatory indices, potential antibiotic-resistant pathogens in nonresponders, and the follow-up period of only 14 days, they said.

However, the results suggest a role for patient and exacerbation phenotypes in management of bronchiectasis in clinical practice and promoting antimicrobial stewardship, the researchers wrote. “Although there is benefit in treating exacerbations early to avoid treatment failure and subsequent intravenous antibiotics, future research also needs to identify exacerbations that can be managed without antibiotics,” they concluded.

The BEST-1 and BEST-2 studies were supported by the Australian National Health and Medical Research Council and the NHMRC Centre for Research Excellence in Lung Health of Aboriginal and Torres Strait Islander Children. Dr. Goyal had no financial conflicts to disclose.
 

Indigenous children or children with new abnormal auscultatory findings were significantly more likely than children in other categories to respond to oral antibiotics for exacerbations related to bronchiectasis, based on data from more than 200 individuals in New Zealand.

Children and adolescents with bronchiectasis are often treated with antibiotics for respiratory exacerbations, but the effects of antibiotics can vary among individuals, and phenotypic features associated with greater symptom resolution have not been identified, wrote Vikas Goyal, PhD, of the Centre for Children’s Health Research, Brisbane, Australia, and colleagues.

Previous studies have suggested that nearly half of exacerbations in children and adolescents resolve spontaneously after 14 days, and more data are needed to identify which patients are mostly likely to benefit from antibiotics, they noted.

In a study published in the journal Chest, the researchers reviewed secondary data from 217 children and adolescents aged 1-18 years with bronchiectasis enrolled in a pair of randomized, controlled trials comparing oral antibiotics with placebo (known as BEST-1 and BEST-2). The median age of the participants was 6.6 years, 52% were boys, and 41% were Indigenous (defined as Australian First Nations, New Zealand Maori, or Pacific Islander). All participants in the analysis received at least 14 days of oral antibiotics for treatment of nonhospitalized respiratory exacerbations.

Overall, 130 children had resolution of symptoms by day 14, and 87 were nonresponders.

In a multivariate analysis, children who were Indigenous or who had new abnormal auscultatory findings were significantly more likely to respond than children in other categories (odds ratios, 3.59 and 3.85, respectively).

Patients with multiple bronchiectatic lobes at the time of diagnosis and those with higher cough scores at the start of treatment were significantly less likely to respond to antibiotics than patients without these features (OR, 0.66 and 0.55, respectively).

The researchers conducted a further analysis to examine the association between Indigenous ethnicity and treatment response. They found no differences in the other response variables of number of affected lobes at diagnosis and cough scores at the start of treatment between Indigenous and non-Indigenous children.

Given the strong response to antibiotics among Indigenous children, the researchers also conducted a mediation analysis. “Respiratory bacterial pathogens were mediated by Indigenous ethnicity and associated with being an antibiotic ‘responder,’ ” they wrote. For new abnormal chest auscultatory findings, both direct and indirect effects on day 14 response to oral antibiotics were mediated by Indigenous ethnicity. However, neither cough scores at the start of treatment nor the number of affected lobes at diagnosis showed a mediation effect from Indigenous ethnicity.

Among the nonresponders, 59 of 87 resolved symptoms with continuing oral antibiotics over the next 2-4 weeks, and 21 improved without antibiotics.

Additionally, the detection of a respiratory virus at the start of an exacerbation was not associated with antibiotic failure at 14 days, the researchers noted.

The findings were limited by several factors including the use of data from randomized trials that were not designed to address the question in the current study, the researchers noted. Other limitations included incomplete clinical data and lack of data on inflammatory indices, potential antibiotic-resistant pathogens in nonresponders, and the follow-up period of only 14 days, they said.

However, the results suggest a role for patient and exacerbation phenotypes in management of bronchiectasis in clinical practice and promoting antimicrobial stewardship, the researchers wrote. “Although there is benefit in treating exacerbations early to avoid treatment failure and subsequent intravenous antibiotics, future research also needs to identify exacerbations that can be managed without antibiotics,” they concluded.

The BEST-1 and BEST-2 studies were supported by the Australian National Health and Medical Research Council and the NHMRC Centre for Research Excellence in Lung Health of Aboriginal and Torres Strait Islander Children. Dr. Goyal had no financial conflicts to disclose.
 

A potentially protective role for vitamin D in the pathogenesis of chronic obstructive pulmonary disease (COPD) is suggested by the finding that serum 25-hydroxyvitamin D (25[OH]D) concentrations are inversely associated with COPD incidence and mortality. COPD risk was 23% higher in people within the lowest quintile vs. the fourth quintile of 25(OH)D concentrations, according to research appearing in BMJ Open Respiratory Research.

While low vitamin D status has been linked to increased inflammatory diseases risk and to the regulation of pathogenic mechanisms in COPD, epidemiological evidence regarding the associations of 25(OH)D concentrations with COPD incidence and survival remains inconclusive, Zheng Zhu, MD, of Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China, and colleagues wrote.

From UK Biobank data recorded from 403,648 participants (mean age 56.4 years; 54% women) who were free of COPD at baseline and had 25(OH)D measurements, researchers estimated hazard ratios and 95% confidence intervals for the associations of 25(OH)D concentrations with COPD risk and survival. After median follow-up of 12.3 years (ending Sept. 30, 2021), with 11,008 COPD cases recorded, beyond the COPD and mortality increase (HR, 1.23; 95% CI, 1.16-1.31) in the lowest quintile of 25(OH)D concentrations, risk for overall death was 38% higher, as well (HR, 1.38; 95% CI, 1.22-1.56). Serum concentrations were greater than 64.6 nmol/L in the highest (quintile 5) and less than 31.7 nmol/L in the lowest (quintile 1). Also, men and current smokers had higher COPD and mortality risk (P interaction for both: < .05).

While event rates tracked generally inversely with 25(OH)D concentrations, overall the event curves were non-linear. Dr Zhu and associates reported that the decreasing risk of COPD appeared to be lowest at 55 nmol/L of 25(OH)D within quintile 4 (51.8 to < 64.6 nmol/L). Furthermore, lower prediagnostic 25(OH)D concentrations were associated with a significant decrease in overall and COPD-specific survival.

Smoking is the most commonly encountered risk factor for COPD, the researchers noted, and their findings indicated that 25(OH)D concentrations were inversely associated with COPD risk in both smokers and never-smokers. In a fully adjusted model, compared with quintile 4, the quintile 1 increase in COPD risk was 25% in never-smokers and 23% in smokers.

“Our findings imply that vitamin D might play a role in progression of COPD,” the authors stated. They added, “Whether lower concentrations of 25(OH)D are causal or contributory to COPD risk may spur future long-duration and large-scale RCTs.”

“Vitamin D has an important function in the immune system and lower serum levels have been implicated in a variety of inflammatory diseases,” commented associate professor of medicine Diego J. Maselli, MD, who is chief of the division of pulmonary diseases & critical care at UT Health San Antonio. “Patients with COPD often have lower levels of vitamin D compared to healthy individuals. COPD patients with low serum levels of vitamin D may have a higher risk of exacerbations and worse lung function.”

He added, “The research by Zhu and colleagues adds to the field of study and highlights the potential role of vitamin D in the pathophysiology of COPD. It is important to remember that these associations do not establish causality, as patients with chronic and debilitating diseases may have limited sunlight exposure, poor nutritional intake, and other behaviors that may affect vitamin D levels. There are mixed results in studies evaluating the role of supplementing vitamin D in COPD with regards to disease progression and exacerbation reduction. While there are some studies that report that supplementation of vitamin D can reduce COPD exacerbations, there is still a need for randomized controlled studies that explore if the supplementation of vitamin D can prevent the development of COPD, particularly in those who actively smoke. Yet, it is reasonable to evaluate the serum vitamin D levels in COPD patients who have had exacerbations and supplement when there is a severe deficiency.” 

Given that the majority of participants in this study were from the United Kingdom, the researchers stated, a study limitation is that findings might not apply to other populations.

No disclosures were reported by Dr. Zhu or by Dr. Maselli.

A potentially protective role for vitamin D in the pathogenesis of chronic obstructive pulmonary disease (COPD) is suggested by the finding that serum 25-hydroxyvitamin D (25[OH]D) concentrations are inversely associated with COPD incidence and mortality. COPD risk was 23% higher in people within the lowest quintile vs. the fourth quintile of 25(OH)D concentrations, according to research appearing in BMJ Open Respiratory Research.

While low vitamin D status has been linked to increased inflammatory diseases risk and to the regulation of pathogenic mechanisms in COPD, epidemiological evidence regarding the associations of 25(OH)D concentrations with COPD incidence and survival remains inconclusive, Zheng Zhu, MD, of Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China, and colleagues wrote.

From UK Biobank data recorded from 403,648 participants (mean age 56.4 years; 54% women) who were free of COPD at baseline and had 25(OH)D measurements, researchers estimated hazard ratios and 95% confidence intervals for the associations of 25(OH)D concentrations with COPD risk and survival. After median follow-up of 12.3 years (ending Sept. 30, 2021), with 11,008 COPD cases recorded, beyond the COPD and mortality increase (HR, 1.23; 95% CI, 1.16-1.31) in the lowest quintile of 25(OH)D concentrations, risk for overall death was 38% higher, as well (HR, 1.38; 95% CI, 1.22-1.56). Serum concentrations were greater than 64.6 nmol/L in the highest (quintile 5) and less than 31.7 nmol/L in the lowest (quintile 1). Also, men and current smokers had higher COPD and mortality risk (P interaction for both: < .05).

While event rates tracked generally inversely with 25(OH)D concentrations, overall the event curves were non-linear. Dr Zhu and associates reported that the decreasing risk of COPD appeared to be lowest at 55 nmol/L of 25(OH)D within quintile 4 (51.8 to < 64.6 nmol/L). Furthermore, lower prediagnostic 25(OH)D concentrations were associated with a significant decrease in overall and COPD-specific survival.

Smoking is the most commonly encountered risk factor for COPD, the researchers noted, and their findings indicated that 25(OH)D concentrations were inversely associated with COPD risk in both smokers and never-smokers. In a fully adjusted model, compared with quintile 4, the quintile 1 increase in COPD risk was 25% in never-smokers and 23% in smokers.

“Our findings imply that vitamin D might play a role in progression of COPD,” the authors stated. They added, “Whether lower concentrations of 25(OH)D are causal or contributory to COPD risk may spur future long-duration and large-scale RCTs.”

“Vitamin D has an important function in the immune system and lower serum levels have been implicated in a variety of inflammatory diseases,” commented associate professor of medicine Diego J. Maselli, MD, who is chief of the division of pulmonary diseases & critical care at UT Health San Antonio. “Patients with COPD often have lower levels of vitamin D compared to healthy individuals. COPD patients with low serum levels of vitamin D may have a higher risk of exacerbations and worse lung function.”

He added, “The research by Zhu and colleagues adds to the field of study and highlights the potential role of vitamin D in the pathophysiology of COPD. It is important to remember that these associations do not establish causality, as patients with chronic and debilitating diseases may have limited sunlight exposure, poor nutritional intake, and other behaviors that may affect vitamin D levels. There are mixed results in studies evaluating the role of supplementing vitamin D in COPD with regards to disease progression and exacerbation reduction. While there are some studies that report that supplementation of vitamin D can reduce COPD exacerbations, there is still a need for randomized controlled studies that explore if the supplementation of vitamin D can prevent the development of COPD, particularly in those who actively smoke. Yet, it is reasonable to evaluate the serum vitamin D levels in COPD patients who have had exacerbations and supplement when there is a severe deficiency.” 

Given that the majority of participants in this study were from the United Kingdom, the researchers stated, a study limitation is that findings might not apply to other populations.

No disclosures were reported by Dr. Zhu or by Dr. Maselli.

A potentially protective role for vitamin D in the pathogenesis of chronic obstructive pulmonary disease (COPD) is suggested by the finding that serum 25-hydroxyvitamin D (25[OH]D) concentrations are inversely associated with COPD incidence and mortality. COPD risk was 23% higher in people within the lowest quintile vs. the fourth quintile of 25(OH)D concentrations, according to research appearing in BMJ Open Respiratory Research.

While low vitamin D status has been linked to increased inflammatory diseases risk and to the regulation of pathogenic mechanisms in COPD, epidemiological evidence regarding the associations of 25(OH)D concentrations with COPD incidence and survival remains inconclusive, Zheng Zhu, MD, of Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China, and colleagues wrote.

From UK Biobank data recorded from 403,648 participants (mean age 56.4 years; 54% women) who were free of COPD at baseline and had 25(OH)D measurements, researchers estimated hazard ratios and 95% confidence intervals for the associations of 25(OH)D concentrations with COPD risk and survival. After median follow-up of 12.3 years (ending Sept. 30, 2021), with 11,008 COPD cases recorded, beyond the COPD and mortality increase (HR, 1.23; 95% CI, 1.16-1.31) in the lowest quintile of 25(OH)D concentrations, risk for overall death was 38% higher, as well (HR, 1.38; 95% CI, 1.22-1.56). Serum concentrations were greater than 64.6 nmol/L in the highest (quintile 5) and less than 31.7 nmol/L in the lowest (quintile 1). Also, men and current smokers had higher COPD and mortality risk (P interaction for both: < .05).

While event rates tracked generally inversely with 25(OH)D concentrations, overall the event curves were non-linear. Dr Zhu and associates reported that the decreasing risk of COPD appeared to be lowest at 55 nmol/L of 25(OH)D within quintile 4 (51.8 to < 64.6 nmol/L). Furthermore, lower prediagnostic 25(OH)D concentrations were associated with a significant decrease in overall and COPD-specific survival.

Smoking is the most commonly encountered risk factor for COPD, the researchers noted, and their findings indicated that 25(OH)D concentrations were inversely associated with COPD risk in both smokers and never-smokers. In a fully adjusted model, compared with quintile 4, the quintile 1 increase in COPD risk was 25% in never-smokers and 23% in smokers.

“Our findings imply that vitamin D might play a role in progression of COPD,” the authors stated. They added, “Whether lower concentrations of 25(OH)D are causal or contributory to COPD risk may spur future long-duration and large-scale RCTs.”

“Vitamin D has an important function in the immune system and lower serum levels have been implicated in a variety of inflammatory diseases,” commented associate professor of medicine Diego J. Maselli, MD, who is chief of the division of pulmonary diseases & critical care at UT Health San Antonio. “Patients with COPD often have lower levels of vitamin D compared to healthy individuals. COPD patients with low serum levels of vitamin D may have a higher risk of exacerbations and worse lung function.”

He added, “The research by Zhu and colleagues adds to the field of study and highlights the potential role of vitamin D in the pathophysiology of COPD. It is important to remember that these associations do not establish causality, as patients with chronic and debilitating diseases may have limited sunlight exposure, poor nutritional intake, and other behaviors that may affect vitamin D levels. There are mixed results in studies evaluating the role of supplementing vitamin D in COPD with regards to disease progression and exacerbation reduction. While there are some studies that report that supplementation of vitamin D can reduce COPD exacerbations, there is still a need for randomized controlled studies that explore if the supplementation of vitamin D can prevent the development of COPD, particularly in those who actively smoke. Yet, it is reasonable to evaluate the serum vitamin D levels in COPD patients who have had exacerbations and supplement when there is a severe deficiency.” 

Given that the majority of participants in this study were from the United Kingdom, the researchers stated, a study limitation is that findings might not apply to other populations.

No disclosures were reported by Dr. Zhu or by Dr. Maselli.

A U.S. Food and Drug Administration investigation of injection-site necrosis in some people who received the 23-valent pneumococcal vaccine has concluded that the benefits of the vaccine outweigh the risks.

No similar safety signal has been detected for the more recently approved 15-valent and 20-valent pneumococcal conjugate vaccines, explain the investigators, led by Brendan Day, MD, MPH, from the FDA’s Center for Biologics Evaluation and Research, in their report published online in JAMA Internal Medicine.

Reports of injection-site necrosis emerged after the vaccine (Pneumovax 23, Merck) had been approved by the FDA and was administered to a large, diverse, real-world population.

Rare safety events can emerge after FDA approval, as clinical trials may not be able to detect them in a study-group population.

Therefore, “postmarketing safety surveillance is critical to further characterize the safety profile of licensed vaccines,” the investigators point out.

The FDA and the Centers for Disease Control and Prevention monitor the postmarketing safety of licensed vaccines using the Vaccine Adverse Event Reporting System (VAERS), which relies on people who get the vaccines to report adverse events.
 

Real-world finding

After reports indicated a safety signal in 2020, the researchers conducted a case-series review, calculated the reporting rate, and did a PubMed search for similar reports.

They found that the reporting rate for injection-site necrosis was less than 0.2 cases per 1 million vaccine doses administered. The PubMed search yielded two cases of injection-site necrosis after the vaccine.

The 23-valent vaccine helps protect people from pneumococcus bacterial infection. The manufacturer reports that it is for people at least 50 years of age and for children who are at least 2 years of age with medical conditions that put them at elevated risk for infection.

The U.S. package insert has been updated, in the Post-Marketing Experience section, to include injection-site necrosis.

Of the 104 VAERS reports identified by the researchers, 48 met the case definition. Of those cases, most were for skin necrosis (n = 43), five of which also included fat necrosis. The remaining five cases of necrosis affected fascia (n = 2); fat and fascia (n = 1); fat, fascia, and muscle (n = 1); and muscle (n = 1).

In 23 of the 48 cases (47.9%), the reactions were serious and included one death (unrelated to vaccination).

Seventeen patients (35.4%) were hospitalized and 26 (54.2%) required surgery, most commonly debridement. Eight patients (16.7%) underwent multiple surgical procedures and three (6.3%) required a skin graft.

For patients with skin necrosis (n = 43), the median age was 67 years, and most patients were female (n = 36). Twelve patients were immunocompromised.

Concomitant vaccinations were reported in 10 patients, five of whom got the shot in the same arm as the 23-valent pneumococcal vaccine. A concurrent diagnosis of cellulitis was reported in 16 patients and an abscess was reported in three patients. There were too few cases of fat, fascia, or muscle necrosis to draw conclusions, the researchers report.

Often, skin necrosis was seen after a progression of symptoms, such as redness, pain, or swelling.

“These reports are consistent with published descriptions of injection-site necrosis, which has been reported as a rare complication for many vaccines and injectable drugs,” the investigators report.

Although the researchers couldn’t conclude from the VAERS reports alone that the vaccine injection caused the necrosis, “the timing and the location of reactions at the injection site suggest a possible causal association with the vaccine,” they explain. However, they add, patient comorbidities and poor injection technique may also be contributors.

A version of this article first appeared on Medscape.com.

A U.S. Food and Drug Administration investigation of injection-site necrosis in some people who received the 23-valent pneumococcal vaccine has concluded that the benefits of the vaccine outweigh the risks.

No similar safety signal has been detected for the more recently approved 15-valent and 20-valent pneumococcal conjugate vaccines, explain the investigators, led by Brendan Day, MD, MPH, from the FDA’s Center for Biologics Evaluation and Research, in their report published online in JAMA Internal Medicine.

Reports of injection-site necrosis emerged after the vaccine (Pneumovax 23, Merck) had been approved by the FDA and was administered to a large, diverse, real-world population.

Rare safety events can emerge after FDA approval, as clinical trials may not be able to detect them in a study-group population.

Therefore, “postmarketing safety surveillance is critical to further characterize the safety profile of licensed vaccines,” the investigators point out.

The FDA and the Centers for Disease Control and Prevention monitor the postmarketing safety of licensed vaccines using the Vaccine Adverse Event Reporting System (VAERS), which relies on people who get the vaccines to report adverse events.
 

Real-world finding

After reports indicated a safety signal in 2020, the researchers conducted a case-series review, calculated the reporting rate, and did a PubMed search for similar reports.

They found that the reporting rate for injection-site necrosis was less than 0.2 cases per 1 million vaccine doses administered. The PubMed search yielded two cases of injection-site necrosis after the vaccine.

The 23-valent vaccine helps protect people from pneumococcus bacterial infection. The manufacturer reports that it is for people at least 50 years of age and for children who are at least 2 years of age with medical conditions that put them at elevated risk for infection.

The U.S. package insert has been updated, in the Post-Marketing Experience section, to include injection-site necrosis.

Of the 104 VAERS reports identified by the researchers, 48 met the case definition. Of those cases, most were for skin necrosis (n = 43), five of which also included fat necrosis. The remaining five cases of necrosis affected fascia (n = 2); fat and fascia (n = 1); fat, fascia, and muscle (n = 1); and muscle (n = 1).

In 23 of the 48 cases (47.9%), the reactions were serious and included one death (unrelated to vaccination).

Seventeen patients (35.4%) were hospitalized and 26 (54.2%) required surgery, most commonly debridement. Eight patients (16.7%) underwent multiple surgical procedures and three (6.3%) required a skin graft.

For patients with skin necrosis (n = 43), the median age was 67 years, and most patients were female (n = 36). Twelve patients were immunocompromised.

Concomitant vaccinations were reported in 10 patients, five of whom got the shot in the same arm as the 23-valent pneumococcal vaccine. A concurrent diagnosis of cellulitis was reported in 16 patients and an abscess was reported in three patients. There were too few cases of fat, fascia, or muscle necrosis to draw conclusions, the researchers report.

Often, skin necrosis was seen after a progression of symptoms, such as redness, pain, or swelling.

“These reports are consistent with published descriptions of injection-site necrosis, which has been reported as a rare complication for many vaccines and injectable drugs,” the investigators report.

Although the researchers couldn’t conclude from the VAERS reports alone that the vaccine injection caused the necrosis, “the timing and the location of reactions at the injection site suggest a possible causal association with the vaccine,” they explain. However, they add, patient comorbidities and poor injection technique may also be contributors.

A version of this article first appeared on Medscape.com.

A U.S. Food and Drug Administration investigation of injection-site necrosis in some people who received the 23-valent pneumococcal vaccine has concluded that the benefits of the vaccine outweigh the risks.

No similar safety signal has been detected for the more recently approved 15-valent and 20-valent pneumococcal conjugate vaccines, explain the investigators, led by Brendan Day, MD, MPH, from the FDA’s Center for Biologics Evaluation and Research, in their report published online in JAMA Internal Medicine.

Reports of injection-site necrosis emerged after the vaccine (Pneumovax 23, Merck) had been approved by the FDA and was administered to a large, diverse, real-world population.

Rare safety events can emerge after FDA approval, as clinical trials may not be able to detect them in a study-group population.

Therefore, “postmarketing safety surveillance is critical to further characterize the safety profile of licensed vaccines,” the investigators point out.

The FDA and the Centers for Disease Control and Prevention monitor the postmarketing safety of licensed vaccines using the Vaccine Adverse Event Reporting System (VAERS), which relies on people who get the vaccines to report adverse events.
 

Real-world finding

After reports indicated a safety signal in 2020, the researchers conducted a case-series review, calculated the reporting rate, and did a PubMed search for similar reports.

They found that the reporting rate for injection-site necrosis was less than 0.2 cases per 1 million vaccine doses administered. The PubMed search yielded two cases of injection-site necrosis after the vaccine.

The 23-valent vaccine helps protect people from pneumococcus bacterial infection. The manufacturer reports that it is for people at least 50 years of age and for children who are at least 2 years of age with medical conditions that put them at elevated risk for infection.

The U.S. package insert has been updated, in the Post-Marketing Experience section, to include injection-site necrosis.

Of the 104 VAERS reports identified by the researchers, 48 met the case definition. Of those cases, most were for skin necrosis (n = 43), five of which also included fat necrosis. The remaining five cases of necrosis affected fascia (n = 2); fat and fascia (n = 1); fat, fascia, and muscle (n = 1); and muscle (n = 1).

In 23 of the 48 cases (47.9%), the reactions were serious and included one death (unrelated to vaccination).

Seventeen patients (35.4%) were hospitalized and 26 (54.2%) required surgery, most commonly debridement. Eight patients (16.7%) underwent multiple surgical procedures and three (6.3%) required a skin graft.

For patients with skin necrosis (n = 43), the median age was 67 years, and most patients were female (n = 36). Twelve patients were immunocompromised.

Concomitant vaccinations were reported in 10 patients, five of whom got the shot in the same arm as the 23-valent pneumococcal vaccine. A concurrent diagnosis of cellulitis was reported in 16 patients and an abscess was reported in three patients. There were too few cases of fat, fascia, or muscle necrosis to draw conclusions, the researchers report.

Often, skin necrosis was seen after a progression of symptoms, such as redness, pain, or swelling.

“These reports are consistent with published descriptions of injection-site necrosis, which has been reported as a rare complication for many vaccines and injectable drugs,” the investigators report.

Although the researchers couldn’t conclude from the VAERS reports alone that the vaccine injection caused the necrosis, “the timing and the location of reactions at the injection site suggest a possible causal association with the vaccine,” they explain. However, they add, patient comorbidities and poor injection technique may also be contributors.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved an injectable monoclonal antibody to protect newborns and infants against respiratory syncytial virus (RSV).

The monoclonal antibody Beyfortus (nirsevimab-alip), which already is approved for use in Europe and Canada, is indicated for newborns and infants born during or entering their first RSV season, and for children up to 24 months of age who are vulnerable to severe RSV through their second RSV season.

As many as 80,000 children under age 5 years are hospitalized with an RSV infection annually in the United States. Most cases are mild, but infants under 6 months, those born prematurely, and children with weakened immune systems or neuromuscular disorders are at an increased risk for severe illness, according to the Centers for Disease Control and Prevention.

The highly contagious virus is also a concern for immunocompromised adults and older people with underlying health conditions, who are at increased risk for severe disease.

Sanofi and AstraZeneca, which jointly developed the injectable agent, said in a press release that the companies plan to make it available by the fall of 2023. The long-acting antibody is given as a single intramuscular injection.

Beyfortus was approved in part based on data from the phase 3 MELODY trial, which found the shot reduced the incidence of medically attended lower respiratory tract infections associated with RSV by 74.9% versus placebo (95% confidence interval, 50.6-87.3; P < .001).

The phase 2/3 MEDLEY trial, conducted between July 2019 and May 2021, compared Beyfortus with palivizumab, another RSV antibody injection with more limited indications. The trial included more than 900 preterm infants less than 35 weeks’ gestational age and infants with congenital heart disease. Results were similar to the phase 3 MELODY trial, according to the manufacturers.

“Today’s approval marks an unprecedented moment for protecting infant health in the United States, following an RSV season that took a record toll on infants, their families, and the U.S. health care system,” said Thomas Triomphe, executive vice president for vaccines at Sanofi, in a press release about the FDA decision. “Beyfortus is the only monoclonal antibody approved for passive immunization to provide safe and effective protection for all infants during their first RSV season.”

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved an injectable monoclonal antibody to protect newborns and infants against respiratory syncytial virus (RSV).

The monoclonal antibody Beyfortus (nirsevimab-alip), which already is approved for use in Europe and Canada, is indicated for newborns and infants born during or entering their first RSV season, and for children up to 24 months of age who are vulnerable to severe RSV through their second RSV season.

As many as 80,000 children under age 5 years are hospitalized with an RSV infection annually in the United States. Most cases are mild, but infants under 6 months, those born prematurely, and children with weakened immune systems or neuromuscular disorders are at an increased risk for severe illness, according to the Centers for Disease Control and Prevention.

The highly contagious virus is also a concern for immunocompromised adults and older people with underlying health conditions, who are at increased risk for severe disease.

Sanofi and AstraZeneca, which jointly developed the injectable agent, said in a press release that the companies plan to make it available by the fall of 2023. The long-acting antibody is given as a single intramuscular injection.

Beyfortus was approved in part based on data from the phase 3 MELODY trial, which found the shot reduced the incidence of medically attended lower respiratory tract infections associated with RSV by 74.9% versus placebo (95% confidence interval, 50.6-87.3; P < .001).

The phase 2/3 MEDLEY trial, conducted between July 2019 and May 2021, compared Beyfortus with palivizumab, another RSV antibody injection with more limited indications. The trial included more than 900 preterm infants less than 35 weeks’ gestational age and infants with congenital heart disease. Results were similar to the phase 3 MELODY trial, according to the manufacturers.

“Today’s approval marks an unprecedented moment for protecting infant health in the United States, following an RSV season that took a record toll on infants, their families, and the U.S. health care system,” said Thomas Triomphe, executive vice president for vaccines at Sanofi, in a press release about the FDA decision. “Beyfortus is the only monoclonal antibody approved for passive immunization to provide safe and effective protection for all infants during their first RSV season.”

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved an injectable monoclonal antibody to protect newborns and infants against respiratory syncytial virus (RSV).

The monoclonal antibody Beyfortus (nirsevimab-alip), which already is approved for use in Europe and Canada, is indicated for newborns and infants born during or entering their first RSV season, and for children up to 24 months of age who are vulnerable to severe RSV through their second RSV season.

As many as 80,000 children under age 5 years are hospitalized with an RSV infection annually in the United States. Most cases are mild, but infants under 6 months, those born prematurely, and children with weakened immune systems or neuromuscular disorders are at an increased risk for severe illness, according to the Centers for Disease Control and Prevention.

The highly contagious virus is also a concern for immunocompromised adults and older people with underlying health conditions, who are at increased risk for severe disease.

Sanofi and AstraZeneca, which jointly developed the injectable agent, said in a press release that the companies plan to make it available by the fall of 2023. The long-acting antibody is given as a single intramuscular injection.

Beyfortus was approved in part based on data from the phase 3 MELODY trial, which found the shot reduced the incidence of medically attended lower respiratory tract infections associated with RSV by 74.9% versus placebo (95% confidence interval, 50.6-87.3; P < .001).

The phase 2/3 MEDLEY trial, conducted between July 2019 and May 2021, compared Beyfortus with palivizumab, another RSV antibody injection with more limited indications. The trial included more than 900 preterm infants less than 35 weeks’ gestational age and infants with congenital heart disease. Results were similar to the phase 3 MELODY trial, according to the manufacturers.

“Today’s approval marks an unprecedented moment for protecting infant health in the United States, following an RSV season that took a record toll on infants, their families, and the U.S. health care system,” said Thomas Triomphe, executive vice president for vaccines at Sanofi, in a press release about the FDA decision. “Beyfortus is the only monoclonal antibody approved for passive immunization to provide safe and effective protection for all infants during their first RSV season.”

A version of this article first appeared on Medscape.com.

Use of inhalers with long-acting muscarinic antagonists and long-acting beta-agonists reduced COPD exacerbations and pneumonia hospitalizations compared with inhalers with corticosteroids and long-acting beta-agonists, based on data from more than 30,000 individuals.

Current clinical guidelines for chronic obstructive pulmonary disease (COPD) patients recommend inhalers with long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs) over those with inhaled corticosteroids (ICSs) and LABAs, but data comparing the two formulations have been inconsistent, and concerns about generalizability persist, wrote William B. Feldman, MD, of Brigham and Women’s Hospital, Boston, and colleagues.

In a study published in JAMA Internal Medicine, the researchers reviewed data from a commercial insurance claims database of individuals diagnosed with COPD who filled a new prescription for a LAMA-LABA inhaler or ICS-LABA inhaler between Jan. 1, 2014, and Dec. 31, 2019. Patients with asthma and those younger than 40 years were excluded. The study population included 137,833 individuals with a mean age of 70.2 years; 50.4% were female. Of the 107,004 ICS-LABA users and 30,829 LAMA-LABA users, 30,216 matched pairs were included in a 1:1 propensity score matched study. The primary outcomes were effectiveness, based on the rate of first moderate or severe COPD exacerbation, and safety, based on the rate of first pneumonia hospitalization.

Use of LAMA-LABA inhalers was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation and a 20% reduction in the rate of first pneumonia hospitalization compared with use of ICS-LABA (hazard ratios 0.92 and 0.80, respectively). The absolute rate reductions with LAMA-LABA inhalers for first moderate or severe COPD exacerbations and for first pneumonia hospitalizations were was 43.0 events per 1,000 person-years and 91.8 events per person-years, respectively.

The overall rates of total moderate to severe COPD and pneumonia hospitalizations were 5% and 17% lower, respectively, among patients who used LAMA-LABA than those treated with ICS-LABA. The results were consistently robust in subgroup and sensitivity analyses, the researchers wrote in their discussion. However, the results must be interpreted cautiously in comparison to other large studies because of the significant differences in the cohorts of patients studied, notably that most patients in the current study had no received previous inhaler therapy.

The study findings were limited by several factors including the relatively short follow-up time and reliance on prescription fills as an indicator of medication use, the researchers noted. Other limitations included notable differences between the LAMA-LABA patients and ICS-LABA patients, such as more severe COPD and less access to respiratory care, they wrote.

Although the current study is not the definitive answer to conflicting results from previous trials, it is the largest know to date to compare LAMA-LABA with ICS-LABA, and the results support LAMA-LABA as the preferred therapy for COPD patients, the researchers concluded.
 

Findings clarify clinical practice guidelines

“This study was required to provide clarity regarding the optimal choice of treatment for COPD given conflicting data from other recent trials,” Suman Pal, MBBS, of the University of New Mexico, Albuquerque, said in an interview.

“The study findings reinforce the benefits of combined LAMA-LABA in improving clinical outcomes in COPD in a real-world setting,” and the data provide further support for choosing LAMA-LABA over ICS-LABA in COPD patients, said Dr. Pal, who was not involved in the study.

However, availability and affordability of LAMA-LABA inhalers may be barriers to expanding their use in clinical practice, he noted.

“Additional research is needed to accurately define which patient populations would benefit most from the therapy and whether patients who have previously been stabilized on ICS-LABA would derive additional benefit from a change in therapy,” Dr. Pal said.

The study was supported by the National Heart, Lung, and Blood Institute and funding from the Commonwealth Fund and Arnold Ventures.

Dr. Feldman disclosed receiving personal fees from Alosa Health and Aetion, serving as an expert witness in litigation against inhaler manufacturers, and receiving an honorarium for a presentation to Blue Cross Blue Shield of Massachusetts unrelated to the current study. Dr. Pal had no financial conflicts to disclose.

Use of inhalers with long-acting muscarinic antagonists and long-acting beta-agonists reduced COPD exacerbations and pneumonia hospitalizations compared with inhalers with corticosteroids and long-acting beta-agonists, based on data from more than 30,000 individuals.

Current clinical guidelines for chronic obstructive pulmonary disease (COPD) patients recommend inhalers with long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs) over those with inhaled corticosteroids (ICSs) and LABAs, but data comparing the two formulations have been inconsistent, and concerns about generalizability persist, wrote William B. Feldman, MD, of Brigham and Women’s Hospital, Boston, and colleagues.

In a study published in JAMA Internal Medicine, the researchers reviewed data from a commercial insurance claims database of individuals diagnosed with COPD who filled a new prescription for a LAMA-LABA inhaler or ICS-LABA inhaler between Jan. 1, 2014, and Dec. 31, 2019. Patients with asthma and those younger than 40 years were excluded. The study population included 137,833 individuals with a mean age of 70.2 years; 50.4% were female. Of the 107,004 ICS-LABA users and 30,829 LAMA-LABA users, 30,216 matched pairs were included in a 1:1 propensity score matched study. The primary outcomes were effectiveness, based on the rate of first moderate or severe COPD exacerbation, and safety, based on the rate of first pneumonia hospitalization.

Use of LAMA-LABA inhalers was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation and a 20% reduction in the rate of first pneumonia hospitalization compared with use of ICS-LABA (hazard ratios 0.92 and 0.80, respectively). The absolute rate reductions with LAMA-LABA inhalers for first moderate or severe COPD exacerbations and for first pneumonia hospitalizations were was 43.0 events per 1,000 person-years and 91.8 events per person-years, respectively.

The overall rates of total moderate to severe COPD and pneumonia hospitalizations were 5% and 17% lower, respectively, among patients who used LAMA-LABA than those treated with ICS-LABA. The results were consistently robust in subgroup and sensitivity analyses, the researchers wrote in their discussion. However, the results must be interpreted cautiously in comparison to other large studies because of the significant differences in the cohorts of patients studied, notably that most patients in the current study had no received previous inhaler therapy.

The study findings were limited by several factors including the relatively short follow-up time and reliance on prescription fills as an indicator of medication use, the researchers noted. Other limitations included notable differences between the LAMA-LABA patients and ICS-LABA patients, such as more severe COPD and less access to respiratory care, they wrote.

Although the current study is not the definitive answer to conflicting results from previous trials, it is the largest know to date to compare LAMA-LABA with ICS-LABA, and the results support LAMA-LABA as the preferred therapy for COPD patients, the researchers concluded.
 

Findings clarify clinical practice guidelines

“This study was required to provide clarity regarding the optimal choice of treatment for COPD given conflicting data from other recent trials,” Suman Pal, MBBS, of the University of New Mexico, Albuquerque, said in an interview.

“The study findings reinforce the benefits of combined LAMA-LABA in improving clinical outcomes in COPD in a real-world setting,” and the data provide further support for choosing LAMA-LABA over ICS-LABA in COPD patients, said Dr. Pal, who was not involved in the study.

However, availability and affordability of LAMA-LABA inhalers may be barriers to expanding their use in clinical practice, he noted.

“Additional research is needed to accurately define which patient populations would benefit most from the therapy and whether patients who have previously been stabilized on ICS-LABA would derive additional benefit from a change in therapy,” Dr. Pal said.

The study was supported by the National Heart, Lung, and Blood Institute and funding from the Commonwealth Fund and Arnold Ventures.

Dr. Feldman disclosed receiving personal fees from Alosa Health and Aetion, serving as an expert witness in litigation against inhaler manufacturers, and receiving an honorarium for a presentation to Blue Cross Blue Shield of Massachusetts unrelated to the current study. Dr. Pal had no financial conflicts to disclose.

Use of inhalers with long-acting muscarinic antagonists and long-acting beta-agonists reduced COPD exacerbations and pneumonia hospitalizations compared with inhalers with corticosteroids and long-acting beta-agonists, based on data from more than 30,000 individuals.

Current clinical guidelines for chronic obstructive pulmonary disease (COPD) patients recommend inhalers with long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs) over those with inhaled corticosteroids (ICSs) and LABAs, but data comparing the two formulations have been inconsistent, and concerns about generalizability persist, wrote William B. Feldman, MD, of Brigham and Women’s Hospital, Boston, and colleagues.

In a study published in JAMA Internal Medicine, the researchers reviewed data from a commercial insurance claims database of individuals diagnosed with COPD who filled a new prescription for a LAMA-LABA inhaler or ICS-LABA inhaler between Jan. 1, 2014, and Dec. 31, 2019. Patients with asthma and those younger than 40 years were excluded. The study population included 137,833 individuals with a mean age of 70.2 years; 50.4% were female. Of the 107,004 ICS-LABA users and 30,829 LAMA-LABA users, 30,216 matched pairs were included in a 1:1 propensity score matched study. The primary outcomes were effectiveness, based on the rate of first moderate or severe COPD exacerbation, and safety, based on the rate of first pneumonia hospitalization.

Use of LAMA-LABA inhalers was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation and a 20% reduction in the rate of first pneumonia hospitalization compared with use of ICS-LABA (hazard ratios 0.92 and 0.80, respectively). The absolute rate reductions with LAMA-LABA inhalers for first moderate or severe COPD exacerbations and for first pneumonia hospitalizations were was 43.0 events per 1,000 person-years and 91.8 events per person-years, respectively.

The overall rates of total moderate to severe COPD and pneumonia hospitalizations were 5% and 17% lower, respectively, among patients who used LAMA-LABA than those treated with ICS-LABA. The results were consistently robust in subgroup and sensitivity analyses, the researchers wrote in their discussion. However, the results must be interpreted cautiously in comparison to other large studies because of the significant differences in the cohorts of patients studied, notably that most patients in the current study had no received previous inhaler therapy.

The study findings were limited by several factors including the relatively short follow-up time and reliance on prescription fills as an indicator of medication use, the researchers noted. Other limitations included notable differences between the LAMA-LABA patients and ICS-LABA patients, such as more severe COPD and less access to respiratory care, they wrote.

Although the current study is not the definitive answer to conflicting results from previous trials, it is the largest know to date to compare LAMA-LABA with ICS-LABA, and the results support LAMA-LABA as the preferred therapy for COPD patients, the researchers concluded.
 

Findings clarify clinical practice guidelines

“This study was required to provide clarity regarding the optimal choice of treatment for COPD given conflicting data from other recent trials,” Suman Pal, MBBS, of the University of New Mexico, Albuquerque, said in an interview.

“The study findings reinforce the benefits of combined LAMA-LABA in improving clinical outcomes in COPD in a real-world setting,” and the data provide further support for choosing LAMA-LABA over ICS-LABA in COPD patients, said Dr. Pal, who was not involved in the study.

However, availability and affordability of LAMA-LABA inhalers may be barriers to expanding their use in clinical practice, he noted.

“Additional research is needed to accurately define which patient populations would benefit most from the therapy and whether patients who have previously been stabilized on ICS-LABA would derive additional benefit from a change in therapy,” Dr. Pal said.

The study was supported by the National Heart, Lung, and Blood Institute and funding from the Commonwealth Fund and Arnold Ventures.

Dr. Feldman disclosed receiving personal fees from Alosa Health and Aetion, serving as an expert witness in litigation against inhaler manufacturers, and receiving an honorarium for a presentation to Blue Cross Blue Shield of Massachusetts unrelated to the current study. Dr. Pal had no financial conflicts to disclose.

Among adults with type 2 diabetes, the presence of preserved ratio impaired spirometry (PRISm) was significantly associated with increased risk of mortality and both macro- and microvascular complications, as well as increased mortality, based on data from more than 20,000 individuals.

PRISm occurs in approximately 10% of the general population and has been identified as a predictor of adverse health outcomes including cardiorespiratory morbidity and mortality, Guochen Li, MD, of the Medical College of Soochow University, Suzhou, China, and colleagues wrote.

“A growing number of studies have demonstrated that impaired lung function and type 2 diabetes could trigger shared pathophysiological injuries, such as microangiopathy and chronic inflammation,” they said, but the potential role of PRISm as an early predictor of adverse outcomes in patients with type 2 diabetes has not been fully examined.

In a study published in the journal Chest, the researchers reviewed data from 20,047 individuals with type 2 diabetes in the UK Biobank, a population-based cohort of adults aged 37-73 years recruited between 2006 and 2010.

The main exposure was lung function based on spirometry. PRISm was defined as predicted forced expiratory volume per second (FEV1) less than 80%, with an FEV1/ forced vital capacity (FVC) ratio of at least 0.70. Individuals with normal spirometry (defined as predicted FEV1 ≥ 80% with an FEV1/FVC ratio ≥ 0.70) served as controls.

The primary outcomes were major complications of type 2 diabetes including macrovascular events (myocardial infarction, unstable angina, coronary heart disease [CHD], ischemic stroke, and any type of stroke), microvascular events (diabetic retinopathy and diabetic kidney disease) and mortality (all-cause, cardiovascular, and respiratory).

Overall, 16.9% of study participants (3385 patients) had obstructive spirometry and 22.6% (4521 patients) had PRISm. Compared with individuals with normal spirometry, those with PRISm were more likely to be current smokers, obese, and living in economically disadvantaged areas. Individuals with PRISm also were significantly more likely to be long-term patients with diabetes who were taking glucose-lowering or lipid-lowering drugs (P < .001 for all).

The median follow-up for each of the type 2 diabetes complications and mortality was approximately 12 years. Over this time, 5.0% of patients developed incident MI, 1.3% developed unstable angina, 15.6% had CHD, 3.5% had an ischemic stroke, and 4.7% had any type of stroke. As for microvascular events, 7.8% developed diabetic retinopathy and 6.7% developed diabetic kidney disease. A total of 2588 patients died during the study period (15.1%), including 544 from cardiovascular disease and 319 from respiratory disease.

PRISm was significantly associated with increased risk of each of the complications and mortality types. These associations persisted after adjusting for lifestyle and other factors. The fully adjusted hazard ratios for PRISm versus normal spirometry were 1.23 for MI, 1.23 for unstable angina, 1.21 for CHD, 1.38 for ischemic stroke, 1.41 for any type of stroke, 1.31 for diabetic retinopathy, and 1.38 for diabetic kidney disease. Adjusted HRs for mortality were 1.34, 1.60, and 1.56 for all-cause, cardiovascular, and respiratory mortality, respectively.

The researchers also found that adding PRISm to an office-based risk score significantly improved the risk classification and predictive power for type 2 diabetes complications with the exception of unstable angina and mortality. They found little evidence for an association with sex, smoking, or PRISm duration and any mortality types. However, in subgroup analyses by age, sex, and duration of diabetes, PRISm remained associated with increased risk of macrovascular and microvascular complications, as well as mortality.

Potential mechanisms for the association between PRISm and diabetes complications include the role of insulin resistance in the exacerbation of lung damage in patients with type 2 diabetes, the increased rate of supplemental oxygen use among individuals with PRISm, and the increased prevalence of pulmonary artery enlargement in the PRISm subjects, the researchers wrote.

The findings were limited by several factors including the prospective design, the homogeneous population of individuals primarily of British or Irish ancestry, and the exclusion of diabetic neuropathy from the analysis, the researchers noted.

However, the results were strengthened by the large cohort, use of professional spirometry, and relatively long follow-up. “The findings underscore the relevance of PRISm for prognostic classification in type 2 diabetes and its potential for optimizing prevention strategies in this condition,” they concluded.

The study was supported by the National Natural Science Foundation of China, Natural Science Foundation of Jiangsu Province, and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The researchers reported no relevant financial relationships.

A version of this article first appeared on Medscape.com

Among adults with type 2 diabetes, the presence of preserved ratio impaired spirometry (PRISm) was significantly associated with increased risk of mortality and both macro- and microvascular complications, as well as increased mortality, based on data from more than 20,000 individuals.

PRISm occurs in approximately 10% of the general population and has been identified as a predictor of adverse health outcomes including cardiorespiratory morbidity and mortality, Guochen Li, MD, of the Medical College of Soochow University, Suzhou, China, and colleagues wrote.

“A growing number of studies have demonstrated that impaired lung function and type 2 diabetes could trigger shared pathophysiological injuries, such as microangiopathy and chronic inflammation,” they said, but the potential role of PRISm as an early predictor of adverse outcomes in patients with type 2 diabetes has not been fully examined.

In a study published in the journal Chest, the researchers reviewed data from 20,047 individuals with type 2 diabetes in the UK Biobank, a population-based cohort of adults aged 37-73 years recruited between 2006 and 2010.

The main exposure was lung function based on spirometry. PRISm was defined as predicted forced expiratory volume per second (FEV1) less than 80%, with an FEV1/ forced vital capacity (FVC) ratio of at least 0.70. Individuals with normal spirometry (defined as predicted FEV1 ≥ 80% with an FEV1/FVC ratio ≥ 0.70) served as controls.

The primary outcomes were major complications of type 2 diabetes including macrovascular events (myocardial infarction, unstable angina, coronary heart disease [CHD], ischemic stroke, and any type of stroke), microvascular events (diabetic retinopathy and diabetic kidney disease) and mortality (all-cause, cardiovascular, and respiratory).

Overall, 16.9% of study participants (3385 patients) had obstructive spirometry and 22.6% (4521 patients) had PRISm. Compared with individuals with normal spirometry, those with PRISm were more likely to be current smokers, obese, and living in economically disadvantaged areas. Individuals with PRISm also were significantly more likely to be long-term patients with diabetes who were taking glucose-lowering or lipid-lowering drugs (P < .001 for all).

The median follow-up for each of the type 2 diabetes complications and mortality was approximately 12 years. Over this time, 5.0% of patients developed incident MI, 1.3% developed unstable angina, 15.6% had CHD, 3.5% had an ischemic stroke, and 4.7% had any type of stroke. As for microvascular events, 7.8% developed diabetic retinopathy and 6.7% developed diabetic kidney disease. A total of 2588 patients died during the study period (15.1%), including 544 from cardiovascular disease and 319 from respiratory disease.

PRISm was significantly associated with increased risk of each of the complications and mortality types. These associations persisted after adjusting for lifestyle and other factors. The fully adjusted hazard ratios for PRISm versus normal spirometry were 1.23 for MI, 1.23 for unstable angina, 1.21 for CHD, 1.38 for ischemic stroke, 1.41 for any type of stroke, 1.31 for diabetic retinopathy, and 1.38 for diabetic kidney disease. Adjusted HRs for mortality were 1.34, 1.60, and 1.56 for all-cause, cardiovascular, and respiratory mortality, respectively.

The researchers also found that adding PRISm to an office-based risk score significantly improved the risk classification and predictive power for type 2 diabetes complications with the exception of unstable angina and mortality. They found little evidence for an association with sex, smoking, or PRISm duration and any mortality types. However, in subgroup analyses by age, sex, and duration of diabetes, PRISm remained associated with increased risk of macrovascular and microvascular complications, as well as mortality.

Potential mechanisms for the association between PRISm and diabetes complications include the role of insulin resistance in the exacerbation of lung damage in patients with type 2 diabetes, the increased rate of supplemental oxygen use among individuals with PRISm, and the increased prevalence of pulmonary artery enlargement in the PRISm subjects, the researchers wrote.

The findings were limited by several factors including the prospective design, the homogeneous population of individuals primarily of British or Irish ancestry, and the exclusion of diabetic neuropathy from the analysis, the researchers noted.

However, the results were strengthened by the large cohort, use of professional spirometry, and relatively long follow-up. “The findings underscore the relevance of PRISm for prognostic classification in type 2 diabetes and its potential for optimizing prevention strategies in this condition,” they concluded.

The study was supported by the National Natural Science Foundation of China, Natural Science Foundation of Jiangsu Province, and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The researchers reported no relevant financial relationships.

A version of this article first appeared on Medscape.com

Among adults with type 2 diabetes, the presence of preserved ratio impaired spirometry (PRISm) was significantly associated with increased risk of mortality and both macro- and microvascular complications, as well as increased mortality, based on data from more than 20,000 individuals.

PRISm occurs in approximately 10% of the general population and has been identified as a predictor of adverse health outcomes including cardiorespiratory morbidity and mortality, Guochen Li, MD, of the Medical College of Soochow University, Suzhou, China, and colleagues wrote.

“A growing number of studies have demonstrated that impaired lung function and type 2 diabetes could trigger shared pathophysiological injuries, such as microangiopathy and chronic inflammation,” they said, but the potential role of PRISm as an early predictor of adverse outcomes in patients with type 2 diabetes has not been fully examined.

In a study published in the journal Chest, the researchers reviewed data from 20,047 individuals with type 2 diabetes in the UK Biobank, a population-based cohort of adults aged 37-73 years recruited between 2006 and 2010.

The main exposure was lung function based on spirometry. PRISm was defined as predicted forced expiratory volume per second (FEV1) less than 80%, with an FEV1/ forced vital capacity (FVC) ratio of at least 0.70. Individuals with normal spirometry (defined as predicted FEV1 ≥ 80% with an FEV1/FVC ratio ≥ 0.70) served as controls.

The primary outcomes were major complications of type 2 diabetes including macrovascular events (myocardial infarction, unstable angina, coronary heart disease [CHD], ischemic stroke, and any type of stroke), microvascular events (diabetic retinopathy and diabetic kidney disease) and mortality (all-cause, cardiovascular, and respiratory).

Overall, 16.9% of study participants (3385 patients) had obstructive spirometry and 22.6% (4521 patients) had PRISm. Compared with individuals with normal spirometry, those with PRISm were more likely to be current smokers, obese, and living in economically disadvantaged areas. Individuals with PRISm also were significantly more likely to be long-term patients with diabetes who were taking glucose-lowering or lipid-lowering drugs (P < .001 for all).

The median follow-up for each of the type 2 diabetes complications and mortality was approximately 12 years. Over this time, 5.0% of patients developed incident MI, 1.3% developed unstable angina, 15.6% had CHD, 3.5% had an ischemic stroke, and 4.7% had any type of stroke. As for microvascular events, 7.8% developed diabetic retinopathy and 6.7% developed diabetic kidney disease. A total of 2588 patients died during the study period (15.1%), including 544 from cardiovascular disease and 319 from respiratory disease.

PRISm was significantly associated with increased risk of each of the complications and mortality types. These associations persisted after adjusting for lifestyle and other factors. The fully adjusted hazard ratios for PRISm versus normal spirometry were 1.23 for MI, 1.23 for unstable angina, 1.21 for CHD, 1.38 for ischemic stroke, 1.41 for any type of stroke, 1.31 for diabetic retinopathy, and 1.38 for diabetic kidney disease. Adjusted HRs for mortality were 1.34, 1.60, and 1.56 for all-cause, cardiovascular, and respiratory mortality, respectively.

The researchers also found that adding PRISm to an office-based risk score significantly improved the risk classification and predictive power for type 2 diabetes complications with the exception of unstable angina and mortality. They found little evidence for an association with sex, smoking, or PRISm duration and any mortality types. However, in subgroup analyses by age, sex, and duration of diabetes, PRISm remained associated with increased risk of macrovascular and microvascular complications, as well as mortality.

Potential mechanisms for the association between PRISm and diabetes complications include the role of insulin resistance in the exacerbation of lung damage in patients with type 2 diabetes, the increased rate of supplemental oxygen use among individuals with PRISm, and the increased prevalence of pulmonary artery enlargement in the PRISm subjects, the researchers wrote.

The findings were limited by several factors including the prospective design, the homogeneous population of individuals primarily of British or Irish ancestry, and the exclusion of diabetic neuropathy from the analysis, the researchers noted.

However, the results were strengthened by the large cohort, use of professional spirometry, and relatively long follow-up. “The findings underscore the relevance of PRISm for prognostic classification in type 2 diabetes and its potential for optimizing prevention strategies in this condition,” they concluded.

The study was supported by the National Natural Science Foundation of China, Natural Science Foundation of Jiangsu Province, and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The researchers reported no relevant financial relationships.

A version of this article first appeared on Medscape.com

It’s tough to keep up with the proliferation of monoclonal antibodies. Seems every day I’m confronted by a patient who’s using a new drug with a name ending in “mab.” That drug blocks a cellular receptor I haven’t heard of that’s involved in a cascade of interactions I haven’t thought about since medical school. The resulting disruption reduces disease burden, typically at great expense to the medical system, the patient, or both. We’ve truly entered the era of precision medicine. It’s not enough to understand disease; you also must know its heterogeneous expression so that you can prescribe the ‘mab that targets the biology responsible for variants in behavior. All diseases are, in fact, syndromes. This isn’t a bad thing, but it’s a challenge.

A series of ‘mabs have been approved for treating type 2 high (TH2) or eosinophilic asthma. We refer to this group of ‘mabs generically as biologics. The group includes omalizumab, mepolizumab, dupilumab, benralizumab, reslizumab, and tezepelumab. While mechanism of action varies slightly across drugs, the biologics all target a specific arm of the immune system. Efficacy is linearly related to serum eosinophil count and there’s little clinically or pharmacologically to distinguish one from another. Of course, no head-to-head comparisons of efficacy are available and there’s no financial incentive for them to be performed.
 

Latest research

A new randomized controlled trial (RCT) of dupilumab for chronic obstructive pulmonary disease (COPD) adds to the aforementioned biologic knowledge base. Turns out it works as long as the patients are carefully selected. Researchers enrolled GOLD D (or E depending on which iteration of the GOLD Statement you use) patients on triple inhaler therapy (inhaled corticosteroids [ICS]/long-acting beta-agonist [LABA]/long-acting muscarinic antagonist [LAMA]) with two moderate exacerbations or one exacerbation requiring hospitalization in the past year. Blood eosinophil counts were > 300 cells/mcL and chronic bronchitis was present clinically. The primary and multiple secondary outcomes were improved with dupilumab.

This is welcome news. I’ve treated countless patients with severe COPD who have repeated exacerbations despite my efforts to prevent them. These patients are on ICS/LABA/LAMA and azithromycin or roflumilast, and occasionally both. While every COPD guideline known to man forbids using chronic oral corticosteroids (OCS), I’ve prescribed them repeatedly because the benefits to keeping a recalcitrant, exacerbating patient out of the hospital seem to outweigh OCS risks. It would be nice to have a better option. Although we were taught that they were immutably distinct in medical school, every first-year pulmonary fellow knows that asthma and COPD share more similarities than differences, so it makes sense that proven asthma therapies would work for some patients with COPD.

However, the dupilumab study must be placed in context. Past studies haven’t been as positive. In 2017, two separate RCTs found that mepolizumab reduced the annual rate of moderate to severe exacerbations (primary outcome) in one trial but not the other. Interpretation gets more complicated when broken down by intention to treat (ITT) vs. modified ITT and when secondary outcomes are considered. Sparing you those details, this trial does not instill confidence, leading the Food and Drug Administration to refuse approval for mepolizumab for COPD. A second RCT of benralizumab for COPD was published in 2019. Much less cognitive load was required to interpret this one; it was negative. FDA approval was not requested.

Looking through the trial designs for the three RCTs of biologics for COPD, I couldn’t find major differences that could explain the discordant results. Sample size and enrollment criteria were similar. As stated, I don’t believe that the biologic data in asthma allow for predicting efficacy in one eosinophilic patient vs. another and I assume the same would be true for COPD. All three trials found that eosinophils were eliminated, so responses were biologically equivalent.
 

Key takeaways

If trial design and pharmacology don’t account for the disparate outcomes, how do we explain them? More important, how do we translate these trials into clinical practice? I looked for a review or editorial by a scientist-clinician smarter than I so I could steal their ideas and express them as pedantic euphemisms here. I found it curious that I was unable to find one. A recent publication in the American Journal of Respiratory and Critical Care Medicine suggests that the answer lies within the complex lattice of eosinophil subtypes, but I’m unqualified to judge the veracity of this “phenotype within a phenotype” theory.

For now, there will be no biologics prescribed for COPD – at least not by me. More trials in COPD are being done. We should have results on tezepelumab, that great savior that may cover noneosinophilic asthma phenotypes, within the next few years. Until then, we’re stuck defying guidelines with the anachronistic use of OCS for the COPD patient who exacerbates through ICS/LABA/LAMA, roflumilast, and azithromycin.

Dr. Holley is professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington. He reported receiving income from CHEST College, Metapharm, and WebMD.

A version of this article first appeared on Medscape.com.

It’s tough to keep up with the proliferation of monoclonal antibodies. Seems every day I’m confronted by a patient who’s using a new drug with a name ending in “mab.” That drug blocks a cellular receptor I haven’t heard of that’s involved in a cascade of interactions I haven’t thought about since medical school. The resulting disruption reduces disease burden, typically at great expense to the medical system, the patient, or both. We’ve truly entered the era of precision medicine. It’s not enough to understand disease; you also must know its heterogeneous expression so that you can prescribe the ‘mab that targets the biology responsible for variants in behavior. All diseases are, in fact, syndromes. This isn’t a bad thing, but it’s a challenge.

A series of ‘mabs have been approved for treating type 2 high (TH2) or eosinophilic asthma. We refer to this group of ‘mabs generically as biologics. The group includes omalizumab, mepolizumab, dupilumab, benralizumab, reslizumab, and tezepelumab. While mechanism of action varies slightly across drugs, the biologics all target a specific arm of the immune system. Efficacy is linearly related to serum eosinophil count and there’s little clinically or pharmacologically to distinguish one from another. Of course, no head-to-head comparisons of efficacy are available and there’s no financial incentive for them to be performed.
 

Latest research

A new randomized controlled trial (RCT) of dupilumab for chronic obstructive pulmonary disease (COPD) adds to the aforementioned biologic knowledge base. Turns out it works as long as the patients are carefully selected. Researchers enrolled GOLD D (or E depending on which iteration of the GOLD Statement you use) patients on triple inhaler therapy (inhaled corticosteroids [ICS]/long-acting beta-agonist [LABA]/long-acting muscarinic antagonist [LAMA]) with two moderate exacerbations or one exacerbation requiring hospitalization in the past year. Blood eosinophil counts were > 300 cells/mcL and chronic bronchitis was present clinically. The primary and multiple secondary outcomes were improved with dupilumab.

This is welcome news. I’ve treated countless patients with severe COPD who have repeated exacerbations despite my efforts to prevent them. These patients are on ICS/LABA/LAMA and azithromycin or roflumilast, and occasionally both. While every COPD guideline known to man forbids using chronic oral corticosteroids (OCS), I’ve prescribed them repeatedly because the benefits to keeping a recalcitrant, exacerbating patient out of the hospital seem to outweigh OCS risks. It would be nice to have a better option. Although we were taught that they were immutably distinct in medical school, every first-year pulmonary fellow knows that asthma and COPD share more similarities than differences, so it makes sense that proven asthma therapies would work for some patients with COPD.

However, the dupilumab study must be placed in context. Past studies haven’t been as positive. In 2017, two separate RCTs found that mepolizumab reduced the annual rate of moderate to severe exacerbations (primary outcome) in one trial but not the other. Interpretation gets more complicated when broken down by intention to treat (ITT) vs. modified ITT and when secondary outcomes are considered. Sparing you those details, this trial does not instill confidence, leading the Food and Drug Administration to refuse approval for mepolizumab for COPD. A second RCT of benralizumab for COPD was published in 2019. Much less cognitive load was required to interpret this one; it was negative. FDA approval was not requested.

Looking through the trial designs for the three RCTs of biologics for COPD, I couldn’t find major differences that could explain the discordant results. Sample size and enrollment criteria were similar. As stated, I don’t believe that the biologic data in asthma allow for predicting efficacy in one eosinophilic patient vs. another and I assume the same would be true for COPD. All three trials found that eosinophils were eliminated, so responses were biologically equivalent.
 

Key takeaways

If trial design and pharmacology don’t account for the disparate outcomes, how do we explain them? More important, how do we translate these trials into clinical practice? I looked for a review or editorial by a scientist-clinician smarter than I so I could steal their ideas and express them as pedantic euphemisms here. I found it curious that I was unable to find one. A recent publication in the American Journal of Respiratory and Critical Care Medicine suggests that the answer lies within the complex lattice of eosinophil subtypes, but I’m unqualified to judge the veracity of this “phenotype within a phenotype” theory.

For now, there will be no biologics prescribed for COPD – at least not by me. More trials in COPD are being done. We should have results on tezepelumab, that great savior that may cover noneosinophilic asthma phenotypes, within the next few years. Until then, we’re stuck defying guidelines with the anachronistic use of OCS for the COPD patient who exacerbates through ICS/LABA/LAMA, roflumilast, and azithromycin.

Dr. Holley is professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington. He reported receiving income from CHEST College, Metapharm, and WebMD.

A version of this article first appeared on Medscape.com.

It’s tough to keep up with the proliferation of monoclonal antibodies. Seems every day I’m confronted by a patient who’s using a new drug with a name ending in “mab.” That drug blocks a cellular receptor I haven’t heard of that’s involved in a cascade of interactions I haven’t thought about since medical school. The resulting disruption reduces disease burden, typically at great expense to the medical system, the patient, or both. We’ve truly entered the era of precision medicine. It’s not enough to understand disease; you also must know its heterogeneous expression so that you can prescribe the ‘mab that targets the biology responsible for variants in behavior. All diseases are, in fact, syndromes. This isn’t a bad thing, but it’s a challenge.

A series of ‘mabs have been approved for treating type 2 high (TH2) or eosinophilic asthma. We refer to this group of ‘mabs generically as biologics. The group includes omalizumab, mepolizumab, dupilumab, benralizumab, reslizumab, and tezepelumab. While mechanism of action varies slightly across drugs, the biologics all target a specific arm of the immune system. Efficacy is linearly related to serum eosinophil count and there’s little clinically or pharmacologically to distinguish one from another. Of course, no head-to-head comparisons of efficacy are available and there’s no financial incentive for them to be performed.
 

Latest research

A new randomized controlled trial (RCT) of dupilumab for chronic obstructive pulmonary disease (COPD) adds to the aforementioned biologic knowledge base. Turns out it works as long as the patients are carefully selected. Researchers enrolled GOLD D (or E depending on which iteration of the GOLD Statement you use) patients on triple inhaler therapy (inhaled corticosteroids [ICS]/long-acting beta-agonist [LABA]/long-acting muscarinic antagonist [LAMA]) with two moderate exacerbations or one exacerbation requiring hospitalization in the past year. Blood eosinophil counts were > 300 cells/mcL and chronic bronchitis was present clinically. The primary and multiple secondary outcomes were improved with dupilumab.

This is welcome news. I’ve treated countless patients with severe COPD who have repeated exacerbations despite my efforts to prevent them. These patients are on ICS/LABA/LAMA and azithromycin or roflumilast, and occasionally both. While every COPD guideline known to man forbids using chronic oral corticosteroids (OCS), I’ve prescribed them repeatedly because the benefits to keeping a recalcitrant, exacerbating patient out of the hospital seem to outweigh OCS risks. It would be nice to have a better option. Although we were taught that they were immutably distinct in medical school, every first-year pulmonary fellow knows that asthma and COPD share more similarities than differences, so it makes sense that proven asthma therapies would work for some patients with COPD.

However, the dupilumab study must be placed in context. Past studies haven’t been as positive. In 2017, two separate RCTs found that mepolizumab reduced the annual rate of moderate to severe exacerbations (primary outcome) in one trial but not the other. Interpretation gets more complicated when broken down by intention to treat (ITT) vs. modified ITT and when secondary outcomes are considered. Sparing you those details, this trial does not instill confidence, leading the Food and Drug Administration to refuse approval for mepolizumab for COPD. A second RCT of benralizumab for COPD was published in 2019. Much less cognitive load was required to interpret this one; it was negative. FDA approval was not requested.

Looking through the trial designs for the three RCTs of biologics for COPD, I couldn’t find major differences that could explain the discordant results. Sample size and enrollment criteria were similar. As stated, I don’t believe that the biologic data in asthma allow for predicting efficacy in one eosinophilic patient vs. another and I assume the same would be true for COPD. All three trials found that eosinophils were eliminated, so responses were biologically equivalent.
 

Key takeaways

If trial design and pharmacology don’t account for the disparate outcomes, how do we explain them? More important, how do we translate these trials into clinical practice? I looked for a review or editorial by a scientist-clinician smarter than I so I could steal their ideas and express them as pedantic euphemisms here. I found it curious that I was unable to find one. A recent publication in the American Journal of Respiratory and Critical Care Medicine suggests that the answer lies within the complex lattice of eosinophil subtypes, but I’m unqualified to judge the veracity of this “phenotype within a phenotype” theory.

For now, there will be no biologics prescribed for COPD – at least not by me. More trials in COPD are being done. We should have results on tezepelumab, that great savior that may cover noneosinophilic asthma phenotypes, within the next few years. Until then, we’re stuck defying guidelines with the anachronistic use of OCS for the COPD patient who exacerbates through ICS/LABA/LAMA, roflumilast, and azithromycin.

Dr. Holley is professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington. He reported receiving income from CHEST College, Metapharm, and WebMD.

A version of this article first appeared on Medscape.com.

Baseball legend Leroy “Satchel” Paige famously said that “age is a question of mind over matter: If you don’t mind, it doesn’t matter.”

But even the strongest and most supple minds can’t avoid the effects of advanced age and accompanying physical frailty, and for community-dwelling elderly with pulmonary diseases frailty is a predictor of both hospitalization and death, investigators have found.

For example, among 1,188 community-dwelling older adults enrolled in the Toledo (Spain) Study for Healthy Aging, declining pulmonary function measured by forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) was associated with increased risk for frailty and hospitalization, and a more than twofold greater risk for death in participants both with and without respiratory diseases. These findings were reported by Walter Sepulveda-Loyola, PT, MSC, PhD, from the Faculty of Health and Social Sciences at Universidad de Las Americas in Santiago, Chile, and colleagues in the journal Heart & Lung.

Similarly, results of a meta-analysis performed by investigators at Jiangsu (China) University showed that among 13,203 patients with chronic obstructive pulmonary disease (COPD), frailty was associated with a more than 2.6-fold relative increase in risk for death from any cause, and “prefrailty,” an intermediate state between frailty and “robustness,” was associated with a 48% relative increase in all-cause mortality. Frailty was also associated with a 2.2-fold risk for COPD exacerbations of any severity, the authors reported in JAMDA: The Journal of Post-Acute and Long-Term Care Medicine.

The good (old) USA

In June 2023 the U.S. Census Bureau announced that the median age of the U.S. population is now 38.9 years, and according to a 2016 Census Bureau report funded by the National Institutes of Health, “America’s 65-and-over population is projected to nearly double over the next three decades, from 48 million to 88 million by 2050.”

With the graying of the U.S. population the burden on pulmonary and critical care experts will almost inevitably increase, as evidenced by research from Julien Cobert, MD, from the University of California, San Francisco, and colleagues.

The investigators looked at trends over time in older adults admitted to ICUs from 1988 through 2015 using data from the Health and Retirement Study (HRS), a nationally representative, longitudinal study of older adults. They found that rates of preexisting frailty, disability, and multimorbidity increased over the study period.

“Our findings suggest a growing prevalence of geriatric conditions among older adults admitted to the ICU, suggesting a pressing need to integrate geriatric principles into critical care medicine. Further research could examine if early interventions emphasizing physical, cognitive, mental health, delirium prevention, advance care planning, and rehabilitation individualized to critically ill elderly patients with preexisting geriatric conditions could improve ICU outcomes and post-ICU recovery,” they wrote in a study published in the journal CHEST.

In an editorial accompanying the study by Dr. Cobert and colleagues, Nathan E. Brummel, MD, from The Ohio State University College of Medicine and Davis Heart and Lung Research Institute in Columbus, said “the finding that nearly 30% of overall HRS participants were admitted to the ICU provides novel data about the extent to which older Americans are affected by critical illness. Because the number of older Americans is projected to continue to increase for the next 30 years or more, these data make clear the ongoing importance of aging-focused research and clinical care.”

Dr. Brummel also noted that older adults who are admitted to the ICU today are at greater risk for poor outcomes than those admitted in prior years, as evidenced by the increased prevalence of disability, frailty, and multimorbidity.

“Moreover, because the average age of those admitted to the ICU only changed by 1 year during the study, these data show that increases in vulnerability are not simply due to chronological age, and they suggest that to identify those with greater baseline vulnerability, screening for geriatric syndromes at ICU admission may be warranted,” he wrote.
 

Geriatric principles in the ICU

“I think what’s most important is that we think about patients from a geriatric principles standpoint, not just when they’re admitted to the hospital but especially when they’re admitted to the ICU,” Dr. Cobert said in an interview.

“The first step is ensuring that we’re asking questions about their underlying comorbidities, especially around frailty, hearing, vision loss, falls, multimorbidities, polypharmacy – things that are primarily done on the outpatient side in geriatric clinics, but things that we should probably be a little bit more cognizant of, given that we’re starting to see higher rates of patients coming in with these issues,” he said.

Critical care specialists need to take a more holistic approach and try to understand as best they can each patients’ goals and then determine whether the ICU staff are acting in concordance with those goals, he emphasized.

For example, ICU clinicians should try to understand whether patients were losing function or having mobility difficulties before hospital and ICU admission, and what they hope to retain when or if they are discharged. ICU staff can then try as much as reasonably possible to minimize interventions that could contribute to impairment after discharge.
 

Frailty and COPD in the ICU

There are special considerations for frail elderly with obstructive airway disease, Dr. Cobert noted.

Patients with advanced COPD, for example, are likely to be on home oxygen.

“Home oxygen is a big deal,” he said. “It can definitely help with functioning and there’s potentially a mortality benefit in certain populations. But that said, it’s a flammable object that they have to carry around and lug with them all the time. It contributes to falls, it’s tethering, it’s life-limiting in many ways.”

In addition, many patients with COPD have multiple re-hospitalizations, and for clinicians the challenge is “understanding what their goals are, what their motivations are, especially when they live with dyspnea, with advanced lung disease. Is intubation within their goals of care? Has their functional status been declining over time? Are there things that we can optimize holistically and globally as their COPD advances over time?”

Another important component of critical care for the frail elderly is consideration of patients’ palliative care needs and what their symptoms and symptom burdens were like prior to hospitalizations.

“The ICU experience and the critical illness experience may serve as an inflexion point – more likely a downward inflection point – whereby their needs increase, their symptoms can worsen, and their health, especially their global health, worsens. Their preexisting geriatric conditions might be a moving target after another hit and another traumatic stressor like the ICU setting,” Dr. Cobert said.

The study by Dr. Cobert and colleagues was supported by the National Institute on Aging. Dr. Cobert had no reported conflicts of interest.

Baseball legend Leroy “Satchel” Paige famously said that “age is a question of mind over matter: If you don’t mind, it doesn’t matter.”

But even the strongest and most supple minds can’t avoid the effects of advanced age and accompanying physical frailty, and for community-dwelling elderly with pulmonary diseases frailty is a predictor of both hospitalization and death, investigators have found.

For example, among 1,188 community-dwelling older adults enrolled in the Toledo (Spain) Study for Healthy Aging, declining pulmonary function measured by forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) was associated with increased risk for frailty and hospitalization, and a more than twofold greater risk for death in participants both with and without respiratory diseases. These findings were reported by Walter Sepulveda-Loyola, PT, MSC, PhD, from the Faculty of Health and Social Sciences at Universidad de Las Americas in Santiago, Chile, and colleagues in the journal Heart & Lung.

Similarly, results of a meta-analysis performed by investigators at Jiangsu (China) University showed that among 13,203 patients with chronic obstructive pulmonary disease (COPD), frailty was associated with a more than 2.6-fold relative increase in risk for death from any cause, and “prefrailty,” an intermediate state between frailty and “robustness,” was associated with a 48% relative increase in all-cause mortality. Frailty was also associated with a 2.2-fold risk for COPD exacerbations of any severity, the authors reported in JAMDA: The Journal of Post-Acute and Long-Term Care Medicine.

The good (old) USA

In June 2023 the U.S. Census Bureau announced that the median age of the U.S. population is now 38.9 years, and according to a 2016 Census Bureau report funded by the National Institutes of Health, “America’s 65-and-over population is projected to nearly double over the next three decades, from 48 million to 88 million by 2050.”

With the graying of the U.S. population the burden on pulmonary and critical care experts will almost inevitably increase, as evidenced by research from Julien Cobert, MD, from the University of California, San Francisco, and colleagues.

The investigators looked at trends over time in older adults admitted to ICUs from 1988 through 2015 using data from the Health and Retirement Study (HRS), a nationally representative, longitudinal study of older adults. They found that rates of preexisting frailty, disability, and multimorbidity increased over the study period.

“Our findings suggest a growing prevalence of geriatric conditions among older adults admitted to the ICU, suggesting a pressing need to integrate geriatric principles into critical care medicine. Further research could examine if early interventions emphasizing physical, cognitive, mental health, delirium prevention, advance care planning, and rehabilitation individualized to critically ill elderly patients with preexisting geriatric conditions could improve ICU outcomes and post-ICU recovery,” they wrote in a study published in the journal CHEST.

In an editorial accompanying the study by Dr. Cobert and colleagues, Nathan E. Brummel, MD, from The Ohio State University College of Medicine and Davis Heart and Lung Research Institute in Columbus, said “the finding that nearly 30% of overall HRS participants were admitted to the ICU provides novel data about the extent to which older Americans are affected by critical illness. Because the number of older Americans is projected to continue to increase for the next 30 years or more, these data make clear the ongoing importance of aging-focused research and clinical care.”

Dr. Brummel also noted that older adults who are admitted to the ICU today are at greater risk for poor outcomes than those admitted in prior years, as evidenced by the increased prevalence of disability, frailty, and multimorbidity.

“Moreover, because the average age of those admitted to the ICU only changed by 1 year during the study, these data show that increases in vulnerability are not simply due to chronological age, and they suggest that to identify those with greater baseline vulnerability, screening for geriatric syndromes at ICU admission may be warranted,” he wrote.
 

Geriatric principles in the ICU

“I think what’s most important is that we think about patients from a geriatric principles standpoint, not just when they’re admitted to the hospital but especially when they’re admitted to the ICU,” Dr. Cobert said in an interview.

“The first step is ensuring that we’re asking questions about their underlying comorbidities, especially around frailty, hearing, vision loss, falls, multimorbidities, polypharmacy – things that are primarily done on the outpatient side in geriatric clinics, but things that we should probably be a little bit more cognizant of, given that we’re starting to see higher rates of patients coming in with these issues,” he said.

Critical care specialists need to take a more holistic approach and try to understand as best they can each patients’ goals and then determine whether the ICU staff are acting in concordance with those goals, he emphasized.

For example, ICU clinicians should try to understand whether patients were losing function or having mobility difficulties before hospital and ICU admission, and what they hope to retain when or if they are discharged. ICU staff can then try as much as reasonably possible to minimize interventions that could contribute to impairment after discharge.
 

Frailty and COPD in the ICU

There are special considerations for frail elderly with obstructive airway disease, Dr. Cobert noted.

Patients with advanced COPD, for example, are likely to be on home oxygen.

“Home oxygen is a big deal,” he said. “It can definitely help with functioning and there’s potentially a mortality benefit in certain populations. But that said, it’s a flammable object that they have to carry around and lug with them all the time. It contributes to falls, it’s tethering, it’s life-limiting in many ways.”

In addition, many patients with COPD have multiple re-hospitalizations, and for clinicians the challenge is “understanding what their goals are, what their motivations are, especially when they live with dyspnea, with advanced lung disease. Is intubation within their goals of care? Has their functional status been declining over time? Are there things that we can optimize holistically and globally as their COPD advances over time?”

Another important component of critical care for the frail elderly is consideration of patients’ palliative care needs and what their symptoms and symptom burdens were like prior to hospitalizations.

“The ICU experience and the critical illness experience may serve as an inflexion point – more likely a downward inflection point – whereby their needs increase, their symptoms can worsen, and their health, especially their global health, worsens. Their preexisting geriatric conditions might be a moving target after another hit and another traumatic stressor like the ICU setting,” Dr. Cobert said.

The study by Dr. Cobert and colleagues was supported by the National Institute on Aging. Dr. Cobert had no reported conflicts of interest.

Baseball legend Leroy “Satchel” Paige famously said that “age is a question of mind over matter: If you don’t mind, it doesn’t matter.”

But even the strongest and most supple minds can’t avoid the effects of advanced age and accompanying physical frailty, and for community-dwelling elderly with pulmonary diseases frailty is a predictor of both hospitalization and death, investigators have found.

For example, among 1,188 community-dwelling older adults enrolled in the Toledo (Spain) Study for Healthy Aging, declining pulmonary function measured by forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) was associated with increased risk for frailty and hospitalization, and a more than twofold greater risk for death in participants both with and without respiratory diseases. These findings were reported by Walter Sepulveda-Loyola, PT, MSC, PhD, from the Faculty of Health and Social Sciences at Universidad de Las Americas in Santiago, Chile, and colleagues in the journal Heart & Lung.

Similarly, results of a meta-analysis performed by investigators at Jiangsu (China) University showed that among 13,203 patients with chronic obstructive pulmonary disease (COPD), frailty was associated with a more than 2.6-fold relative increase in risk for death from any cause, and “prefrailty,” an intermediate state between frailty and “robustness,” was associated with a 48% relative increase in all-cause mortality. Frailty was also associated with a 2.2-fold risk for COPD exacerbations of any severity, the authors reported in JAMDA: The Journal of Post-Acute and Long-Term Care Medicine.

The good (old) USA

In June 2023 the U.S. Census Bureau announced that the median age of the U.S. population is now 38.9 years, and according to a 2016 Census Bureau report funded by the National Institutes of Health, “America’s 65-and-over population is projected to nearly double over the next three decades, from 48 million to 88 million by 2050.”

With the graying of the U.S. population the burden on pulmonary and critical care experts will almost inevitably increase, as evidenced by research from Julien Cobert, MD, from the University of California, San Francisco, and colleagues.

The investigators looked at trends over time in older adults admitted to ICUs from 1988 through 2015 using data from the Health and Retirement Study (HRS), a nationally representative, longitudinal study of older adults. They found that rates of preexisting frailty, disability, and multimorbidity increased over the study period.

“Our findings suggest a growing prevalence of geriatric conditions among older adults admitted to the ICU, suggesting a pressing need to integrate geriatric principles into critical care medicine. Further research could examine if early interventions emphasizing physical, cognitive, mental health, delirium prevention, advance care planning, and rehabilitation individualized to critically ill elderly patients with preexisting geriatric conditions could improve ICU outcomes and post-ICU recovery,” they wrote in a study published in the journal CHEST.

In an editorial accompanying the study by Dr. Cobert and colleagues, Nathan E. Brummel, MD, from The Ohio State University College of Medicine and Davis Heart and Lung Research Institute in Columbus, said “the finding that nearly 30% of overall HRS participants were admitted to the ICU provides novel data about the extent to which older Americans are affected by critical illness. Because the number of older Americans is projected to continue to increase for the next 30 years or more, these data make clear the ongoing importance of aging-focused research and clinical care.”

Dr. Brummel also noted that older adults who are admitted to the ICU today are at greater risk for poor outcomes than those admitted in prior years, as evidenced by the increased prevalence of disability, frailty, and multimorbidity.

“Moreover, because the average age of those admitted to the ICU only changed by 1 year during the study, these data show that increases in vulnerability are not simply due to chronological age, and they suggest that to identify those with greater baseline vulnerability, screening for geriatric syndromes at ICU admission may be warranted,” he wrote.
 

Geriatric principles in the ICU

“I think what’s most important is that we think about patients from a geriatric principles standpoint, not just when they’re admitted to the hospital but especially when they’re admitted to the ICU,” Dr. Cobert said in an interview.

“The first step is ensuring that we’re asking questions about their underlying comorbidities, especially around frailty, hearing, vision loss, falls, multimorbidities, polypharmacy – things that are primarily done on the outpatient side in geriatric clinics, but things that we should probably be a little bit more cognizant of, given that we’re starting to see higher rates of patients coming in with these issues,” he said.

Critical care specialists need to take a more holistic approach and try to understand as best they can each patients’ goals and then determine whether the ICU staff are acting in concordance with those goals, he emphasized.

For example, ICU clinicians should try to understand whether patients were losing function or having mobility difficulties before hospital and ICU admission, and what they hope to retain when or if they are discharged. ICU staff can then try as much as reasonably possible to minimize interventions that could contribute to impairment after discharge.
 

Frailty and COPD in the ICU

There are special considerations for frail elderly with obstructive airway disease, Dr. Cobert noted.

Patients with advanced COPD, for example, are likely to be on home oxygen.

“Home oxygen is a big deal,” he said. “It can definitely help with functioning and there’s potentially a mortality benefit in certain populations. But that said, it’s a flammable object that they have to carry around and lug with them all the time. It contributes to falls, it’s tethering, it’s life-limiting in many ways.”

In addition, many patients with COPD have multiple re-hospitalizations, and for clinicians the challenge is “understanding what their goals are, what their motivations are, especially when they live with dyspnea, with advanced lung disease. Is intubation within their goals of care? Has their functional status been declining over time? Are there things that we can optimize holistically and globally as their COPD advances over time?”

Another important component of critical care for the frail elderly is consideration of patients’ palliative care needs and what their symptoms and symptom burdens were like prior to hospitalizations.

“The ICU experience and the critical illness experience may serve as an inflexion point – more likely a downward inflection point – whereby their needs increase, their symptoms can worsen, and their health, especially their global health, worsens. Their preexisting geriatric conditions might be a moving target after another hit and another traumatic stressor like the ICU setting,” Dr. Cobert said.

The study by Dr. Cobert and colleagues was supported by the National Institute on Aging. Dr. Cobert had no reported conflicts of interest.