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New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Meijer_Onno_C_NETHERLANDS_web.jpg

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Meijer_Onno_C_NETHERLANDS_web.jpg

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Meijer_Onno_C_NETHERLANDS_web.jpg

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Metra_Marco_ITALY_web.jpg

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

[embed:render:related:node:256467]

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Metra_Marco_ITALY_web.jpg

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

[embed:render:related:node:256467]

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Metra_Marco_ITALY_web.jpg

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

[embed:render:related:node:256467]

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

metformin_tablets_web.jpg

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

[embed:render:related:node:234901]

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

metformin_tablets_web.jpg

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

[embed:render:related:node:234901]

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

metformin_tablets_web.jpg

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

[embed:render:related:node:234901]

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Adults with hypertension who were vaccinated for COVID-19 with at least one booster were more than twice as likely as vaccinated and boosted individuals without hypertension to be hospitalized for severe COVID-19, according to data from more than 900 individuals.

“We were surprised to learn that many people who were hospitalized with COVID-19 had hypertension and no other risk factors,” said Susan Cheng, MD, MPH, director of the Institute for Research on Healthy Aging in the department of cardiology at the Smidt Heart Institute, Los Angeles, and a senior author of the study. “This is concerning when you consider that almost half of American adults have high blood pressure.”

blood_pressure_illustration_web.jpg

COVID-19 vaccines demonstrated ability to reduce death and some of the most severe side effects from the infection in the early stages of the pandemic. Although the Omicron surge prompted recommendations for a third mRNA vaccine dose, “a proportion of individuals who received three mRNA vaccine doses still required hospitalization for COVID-19 during the Omicron surge,” and the characteristics associated with severe illness in vaccinated and boosted patients have not been explored, Joseph Ebinger, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues wrote.

Previous research has shown an association between high blood pressure an increased risk for developing severe COVID-19 compared to several other chronic health conditions, including kidney disease, type 2 diabetes, chronic obstructive pulmonary disease, and heart failure, the researchers noted.

In a study published in Hypertension, the researchers identified 912 adults who received at least three doses of mRNA COVID-19 vaccine and were later diagnosed with COVID-19 during the surge in infections from the Omicron variant between December 2021 and April 2022.

A total of 145 of the individuals were hospitalized (16%); of these, 125 (86%) had hypertension.

Patients with hypertension were the most likely to be hospitalized, with an odds ratio of 2.9. In addition to high blood pressure, factors including older age (OR, 1.3), chronic kidney disease (OR, 2.2), prior myocardial infarction or heart failure (OR, 2.2), and longer time since the last vaccination and COVID-19 infection were associated with increased risk of hospitalization in a multivariate analysis.

However, the increased risk of severe illness and hospitalization associated with high blood pressure persisted, with an OR of 2.6, in the absence of comorbid conditions such as type 2 diabetes, kidney disease, and heart failure, the researchers emphasized.

“Although the mechanism for hypertension-associated COVID-19 risk remains unclear, prior studies have identified delayed SARS-CoV-2 viral clearance and prolonged inflammatory response among hypertensive patients, which may contribute to greater disease severity,” they wrote.

The findings were limited by several factors, including the use of data from a single center and lack of information on which Omicron variants and subvariants were behind the infections, the researchers noted.

However, the results highlight the need for more research on how to reduce the risks of severe COVID-19 in vulnerable populations, and on the mechanism for a potential connection between high blood pressure and severe COVID-19, they said.

Given the high prevalence of hypertension worldwide, increased understanding of the hypertension-specific risks and identification of individual and population-level risk reduction strategies will be important to the transition of COVID-19 from pandemic to endemic, they concluded.
 

Omicron changes the game

“When the pandemic initially started, many conditions were seen to increase risk for more severe COVID illness, and hypertension was one of those factors – and then things changed,” lead author Dr. Ebinger said in an interview. “First, vaccines arrived on the scene and substantially reduced risk of severe COVID for everyone who received them. Second, Omicron arrived and, while more transmissible, this variant has been less likely to cause severe COVID. On the one hand, we have vaccines and boosters that we want to think of as ‘the great equalizer’ when it comes to preexisting conditions. On the other hand, we have a dominant set of SARS-CoV-2 subvariants that seem less virulent in most people.

“Taken together, we have been hoping and even assuming that we have been doing pretty well with minimizing risks. Unfortunately, our study results indicate this is not exactly the case,” he said.

“Although vaccines and boosters appear to have equalized or minimized the risks of severe COVID for some people, this has not happened for others – even in the setting of the milder Omicron variant. Of individuals who were fully vaccinated and boosted, having hypertension increased the odds of needing to be hospitalized after getting infected with Omicron by 2.6-fold, even when accounting for or in the absence of having any major chronic disease that might otherwise predispose to more severe COVID-19 illness,” Dr. Ebinger added.

“So, while the originally seen risks of having obesity or diabetes seem to have been minimized during this current era of pandemic, the risk of having hypertension has persisted. We found this both surprising and concerning, because hypertension is very common and present in over half of people over age 50.”

Surprisingly, “we found that a fair number of people, even after being fully vaccinated plus a having gotten a booster, will not only catch Omicron but get sick enough to need hospital care,” Dr. Ebinger emphasized. “Moreover, it is not just older adults with major comorbid conditions who are vulnerable. Our data show that this can happen to an adult of any age and especially if a person has only hypertension and otherwise no major chronic disease.”

The first takeaway message for clinicians at this time is to raise awareness, Dr. Ebinger stressed in the interview. “We need to raise understanding around the fact that receiving three doses of vaccine may not prevent severe COVID-19 illness in everyone, even when the circulating viral variant is presumed to be causing only mild disease in most people. Moreover, the people who are most at risk are not whom we might think they are. They are not the sickest of the sick. They include people who might not have major conditions such as heart disease or kidney disease, but they do have hypertension.”

Second, “we need more research to understand out why there is this link between hypertension and excess risk for the more severe forms of COVID-19, despite it arising from a supposedly milder variant,” said Dr. Ebinger.

“Third, we need to determine how to reduce these risks, whether through more tailored vaccine regimens or novel therapeutics or a combination approach,” he said.

Looking ahead, “the biological mechanism underpinning the association between hypertension and severe COVID-19 remains underexplored. Future work should focus on understanding the factors linking hypertension to severe COVID-19, as this may elucidate both information on how SARS-CoV-2 effects the body and potential targets for intervention,” Dr. Ebinger added.

The study was supported in part by Cedars-Sinai Medical Center, the Erika J. Glazer Family Foundation and the National Institutes of Health. The researchers had no financial conflicts to disclose.

Adults with hypertension who were vaccinated for COVID-19 with at least one booster were more than twice as likely as vaccinated and boosted individuals without hypertension to be hospitalized for severe COVID-19, according to data from more than 900 individuals.

“We were surprised to learn that many people who were hospitalized with COVID-19 had hypertension and no other risk factors,” said Susan Cheng, MD, MPH, director of the Institute for Research on Healthy Aging in the department of cardiology at the Smidt Heart Institute, Los Angeles, and a senior author of the study. “This is concerning when you consider that almost half of American adults have high blood pressure.”

blood_pressure_illustration_web.jpg

COVID-19 vaccines demonstrated ability to reduce death and some of the most severe side effects from the infection in the early stages of the pandemic. Although the Omicron surge prompted recommendations for a third mRNA vaccine dose, “a proportion of individuals who received three mRNA vaccine doses still required hospitalization for COVID-19 during the Omicron surge,” and the characteristics associated with severe illness in vaccinated and boosted patients have not been explored, Joseph Ebinger, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues wrote.

Previous research has shown an association between high blood pressure an increased risk for developing severe COVID-19 compared to several other chronic health conditions, including kidney disease, type 2 diabetes, chronic obstructive pulmonary disease, and heart failure, the researchers noted.

In a study published in Hypertension, the researchers identified 912 adults who received at least three doses of mRNA COVID-19 vaccine and were later diagnosed with COVID-19 during the surge in infections from the Omicron variant between December 2021 and April 2022.

A total of 145 of the individuals were hospitalized (16%); of these, 125 (86%) had hypertension.

Patients with hypertension were the most likely to be hospitalized, with an odds ratio of 2.9. In addition to high blood pressure, factors including older age (OR, 1.3), chronic kidney disease (OR, 2.2), prior myocardial infarction or heart failure (OR, 2.2), and longer time since the last vaccination and COVID-19 infection were associated with increased risk of hospitalization in a multivariate analysis.

However, the increased risk of severe illness and hospitalization associated with high blood pressure persisted, with an OR of 2.6, in the absence of comorbid conditions such as type 2 diabetes, kidney disease, and heart failure, the researchers emphasized.

“Although the mechanism for hypertension-associated COVID-19 risk remains unclear, prior studies have identified delayed SARS-CoV-2 viral clearance and prolonged inflammatory response among hypertensive patients, which may contribute to greater disease severity,” they wrote.

The findings were limited by several factors, including the use of data from a single center and lack of information on which Omicron variants and subvariants were behind the infections, the researchers noted.

However, the results highlight the need for more research on how to reduce the risks of severe COVID-19 in vulnerable populations, and on the mechanism for a potential connection between high blood pressure and severe COVID-19, they said.

Given the high prevalence of hypertension worldwide, increased understanding of the hypertension-specific risks and identification of individual and population-level risk reduction strategies will be important to the transition of COVID-19 from pandemic to endemic, they concluded.
 

Omicron changes the game

“When the pandemic initially started, many conditions were seen to increase risk for more severe COVID illness, and hypertension was one of those factors – and then things changed,” lead author Dr. Ebinger said in an interview. “First, vaccines arrived on the scene and substantially reduced risk of severe COVID for everyone who received them. Second, Omicron arrived and, while more transmissible, this variant has been less likely to cause severe COVID. On the one hand, we have vaccines and boosters that we want to think of as ‘the great equalizer’ when it comes to preexisting conditions. On the other hand, we have a dominant set of SARS-CoV-2 subvariants that seem less virulent in most people.

“Taken together, we have been hoping and even assuming that we have been doing pretty well with minimizing risks. Unfortunately, our study results indicate this is not exactly the case,” he said.

“Although vaccines and boosters appear to have equalized or minimized the risks of severe COVID for some people, this has not happened for others – even in the setting of the milder Omicron variant. Of individuals who were fully vaccinated and boosted, having hypertension increased the odds of needing to be hospitalized after getting infected with Omicron by 2.6-fold, even when accounting for or in the absence of having any major chronic disease that might otherwise predispose to more severe COVID-19 illness,” Dr. Ebinger added.

“So, while the originally seen risks of having obesity or diabetes seem to have been minimized during this current era of pandemic, the risk of having hypertension has persisted. We found this both surprising and concerning, because hypertension is very common and present in over half of people over age 50.”

Surprisingly, “we found that a fair number of people, even after being fully vaccinated plus a having gotten a booster, will not only catch Omicron but get sick enough to need hospital care,” Dr. Ebinger emphasized. “Moreover, it is not just older adults with major comorbid conditions who are vulnerable. Our data show that this can happen to an adult of any age and especially if a person has only hypertension and otherwise no major chronic disease.”

The first takeaway message for clinicians at this time is to raise awareness, Dr. Ebinger stressed in the interview. “We need to raise understanding around the fact that receiving three doses of vaccine may not prevent severe COVID-19 illness in everyone, even when the circulating viral variant is presumed to be causing only mild disease in most people. Moreover, the people who are most at risk are not whom we might think they are. They are not the sickest of the sick. They include people who might not have major conditions such as heart disease or kidney disease, but they do have hypertension.”

Second, “we need more research to understand out why there is this link between hypertension and excess risk for the more severe forms of COVID-19, despite it arising from a supposedly milder variant,” said Dr. Ebinger.

“Third, we need to determine how to reduce these risks, whether through more tailored vaccine regimens or novel therapeutics or a combination approach,” he said.

Looking ahead, “the biological mechanism underpinning the association between hypertension and severe COVID-19 remains underexplored. Future work should focus on understanding the factors linking hypertension to severe COVID-19, as this may elucidate both information on how SARS-CoV-2 effects the body and potential targets for intervention,” Dr. Ebinger added.

The study was supported in part by Cedars-Sinai Medical Center, the Erika J. Glazer Family Foundation and the National Institutes of Health. The researchers had no financial conflicts to disclose.

Adults with hypertension who were vaccinated for COVID-19 with at least one booster were more than twice as likely as vaccinated and boosted individuals without hypertension to be hospitalized for severe COVID-19, according to data from more than 900 individuals.

“We were surprised to learn that many people who were hospitalized with COVID-19 had hypertension and no other risk factors,” said Susan Cheng, MD, MPH, director of the Institute for Research on Healthy Aging in the department of cardiology at the Smidt Heart Institute, Los Angeles, and a senior author of the study. “This is concerning when you consider that almost half of American adults have high blood pressure.”

blood_pressure_illustration_web.jpg

COVID-19 vaccines demonstrated ability to reduce death and some of the most severe side effects from the infection in the early stages of the pandemic. Although the Omicron surge prompted recommendations for a third mRNA vaccine dose, “a proportion of individuals who received three mRNA vaccine doses still required hospitalization for COVID-19 during the Omicron surge,” and the characteristics associated with severe illness in vaccinated and boosted patients have not been explored, Joseph Ebinger, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues wrote.

Previous research has shown an association between high blood pressure an increased risk for developing severe COVID-19 compared to several other chronic health conditions, including kidney disease, type 2 diabetes, chronic obstructive pulmonary disease, and heart failure, the researchers noted.

In a study published in Hypertension, the researchers identified 912 adults who received at least three doses of mRNA COVID-19 vaccine and were later diagnosed with COVID-19 during the surge in infections from the Omicron variant between December 2021 and April 2022.

A total of 145 of the individuals were hospitalized (16%); of these, 125 (86%) had hypertension.

Patients with hypertension were the most likely to be hospitalized, with an odds ratio of 2.9. In addition to high blood pressure, factors including older age (OR, 1.3), chronic kidney disease (OR, 2.2), prior myocardial infarction or heart failure (OR, 2.2), and longer time since the last vaccination and COVID-19 infection were associated with increased risk of hospitalization in a multivariate analysis.

However, the increased risk of severe illness and hospitalization associated with high blood pressure persisted, with an OR of 2.6, in the absence of comorbid conditions such as type 2 diabetes, kidney disease, and heart failure, the researchers emphasized.

“Although the mechanism for hypertension-associated COVID-19 risk remains unclear, prior studies have identified delayed SARS-CoV-2 viral clearance and prolonged inflammatory response among hypertensive patients, which may contribute to greater disease severity,” they wrote.

The findings were limited by several factors, including the use of data from a single center and lack of information on which Omicron variants and subvariants were behind the infections, the researchers noted.

However, the results highlight the need for more research on how to reduce the risks of severe COVID-19 in vulnerable populations, and on the mechanism for a potential connection between high blood pressure and severe COVID-19, they said.

Given the high prevalence of hypertension worldwide, increased understanding of the hypertension-specific risks and identification of individual and population-level risk reduction strategies will be important to the transition of COVID-19 from pandemic to endemic, they concluded.
 

Omicron changes the game

“When the pandemic initially started, many conditions were seen to increase risk for more severe COVID illness, and hypertension was one of those factors – and then things changed,” lead author Dr. Ebinger said in an interview. “First, vaccines arrived on the scene and substantially reduced risk of severe COVID for everyone who received them. Second, Omicron arrived and, while more transmissible, this variant has been less likely to cause severe COVID. On the one hand, we have vaccines and boosters that we want to think of as ‘the great equalizer’ when it comes to preexisting conditions. On the other hand, we have a dominant set of SARS-CoV-2 subvariants that seem less virulent in most people.

“Taken together, we have been hoping and even assuming that we have been doing pretty well with minimizing risks. Unfortunately, our study results indicate this is not exactly the case,” he said.

“Although vaccines and boosters appear to have equalized or minimized the risks of severe COVID for some people, this has not happened for others – even in the setting of the milder Omicron variant. Of individuals who were fully vaccinated and boosted, having hypertension increased the odds of needing to be hospitalized after getting infected with Omicron by 2.6-fold, even when accounting for or in the absence of having any major chronic disease that might otherwise predispose to more severe COVID-19 illness,” Dr. Ebinger added.

“So, while the originally seen risks of having obesity or diabetes seem to have been minimized during this current era of pandemic, the risk of having hypertension has persisted. We found this both surprising and concerning, because hypertension is very common and present in over half of people over age 50.”

Surprisingly, “we found that a fair number of people, even after being fully vaccinated plus a having gotten a booster, will not only catch Omicron but get sick enough to need hospital care,” Dr. Ebinger emphasized. “Moreover, it is not just older adults with major comorbid conditions who are vulnerable. Our data show that this can happen to an adult of any age and especially if a person has only hypertension and otherwise no major chronic disease.”

The first takeaway message for clinicians at this time is to raise awareness, Dr. Ebinger stressed in the interview. “We need to raise understanding around the fact that receiving three doses of vaccine may not prevent severe COVID-19 illness in everyone, even when the circulating viral variant is presumed to be causing only mild disease in most people. Moreover, the people who are most at risk are not whom we might think they are. They are not the sickest of the sick. They include people who might not have major conditions such as heart disease or kidney disease, but they do have hypertension.”

Second, “we need more research to understand out why there is this link between hypertension and excess risk for the more severe forms of COVID-19, despite it arising from a supposedly milder variant,” said Dr. Ebinger.

“Third, we need to determine how to reduce these risks, whether through more tailored vaccine regimens or novel therapeutics or a combination approach,” he said.

Looking ahead, “the biological mechanism underpinning the association between hypertension and severe COVID-19 remains underexplored. Future work should focus on understanding the factors linking hypertension to severe COVID-19, as this may elucidate both information on how SARS-CoV-2 effects the body and potential targets for intervention,” Dr. Ebinger added.

The study was supported in part by Cedars-Sinai Medical Center, the Erika J. Glazer Family Foundation and the National Institutes of Health. The researchers had no financial conflicts to disclose.

An overreliance on spirometry to identify emphysema led to missed cases in Black individuals, particularly men, based on a secondary data analysis of 2,674 people.

“Over the last few years, there has been growing debate around the use of race adjustment in diagnostic algorithms and equations commonly used in medicine,” lead author Gabrielle Yi-Hui Liu, MD, said in an interview. “Whereas, previously it was common to accept racial or ethnic differences in clinical measures and outcomes as inherent differences among populations, there is now more recognition of how racism, socioeconomic status, and environmental exposures can cause these racial differences. Our initial interest in this study was to examine how the use of race-specific spirometry reference equations, and the use of spirometry in general, may be contributing to racial disparities.”

“Previous studies have suggested that the use of race-specific equations in spirometry can exacerbate racial inequities in healthcare outcomes by under-recognition of early disease in Black adults, and this study adds to that evidence,” said Suman Pal, MBBS, of the University of New Mexico, Albuquerque, in an interview.
“By examining the crucial ways in which systemic factors in medicine, such as race-specific equations, exacerbate racial inequities in healthcare, this study is a timely analysis in a moment of national reckoning of structural racism,” said Dr. Pal, who was not involved in the study.

spirometry2_web.jpg

In a study published in Annals of Internal Medicine, Dr. Liu and colleagues at Northwestern University, Chicago, conducted a secondary analysis of data from the CARDIA Lung study (Coronary Artery Risk Development In Young Adults).

The primary outcome of the study was the prevalence of emphysema among participants with various measures of normal spirometry results, stratified by sex and race. The normal results included an forced expiratory volume in 1 second (FEV₁₎–forced vital capacity (FVC) ratio greater than or equal to 0.7 or greater than or equal to the lower limit of normal. The participants also were stratified by FEV₁ percent predicted, using race-specific reference equations, for FEV₁ between 80% and 99% of predicted, or an FEV₁ between 100% and 120% of predicted.

The study population included 485 Black men, 762 Black women, 659 White men, and 768 White women who received both a CT scan (in 2010-2011) and spirometry (obtained in 2015-2016) in the CARDIA study. The mean age of the participants at the spirometry exam was 55 years.

A total of 5.3% of the participants had emphysema after stratifying by FEV₁-FVC ratio. The prevalence was significantly higher for Black men, compared with White men (12.3% vs. 4.0%; relative risk, 3.0), and for Black women, compared with White women (5.0% vs. 2.6%; RR, 1.9).

The association between Black race and emphysema risk persisted but decreased when the researchers used a race-neutral estimate.

When the participants were stratified by race-specific FEV₁ percent predicted, 6.5% of individuals with a race-specific FEV₁ between 80% and 99% had emphysema. After controlling for factors including age and smoking, emphysema was significantly more prevalent in Black men versus White men (15.5% vs. 4.0%) and in Black women, compared with White women (6.6% vs. 3.4%).

The racial difference persisted in men with a race-specific FEV₁ between 100% and 120% of predicted. Of these, 4.0% had emphysema. The prevalence was significantly higher in Black men, compared with White men (13.9% vs. 2.2%), but similar between Black women and White women (2.6% vs. 2.0%).

The use of race-neutral equations reduced, but did not eliminate, these disparities, the researchers said.

The findings were limited by the lack of CT imaging data from the same visit as the final spirometry collection, the researchers noted. “Given that imaging was obtained 5 years before spirometry and emphysema is an irreversible finding, this may have led to an overall underestimation of the prevalence of emphysema.”
 

Spirometry alone misses cases

“We were surprised by the substantial rates of emphysema we saw among Black men in our cohort with normal spirometry,” Dr. Liu said in an interview. “We did not expect to find than more than one in eight Black men with an FEV₁ between 100% and 120% predicted would have emphysema – a rate more than six times higher than White men with the same range of FEV₁.”

“One takeaway is that we are likely missing a lot of people with impaired respiratory health or true lung disease by only using spirometry to diagnose COPD,” said Dr. Liu. In clinical practice, “physicians should consider ordering CT scans on patients with normal spirometry who have respiratory symptoms such as cough or shortness of breath. If emphysema is found, physicians should discuss mitigating any potential risk factors and consider the use of COPD medications such as inhalers.

“Our findings also support using race-neutral reference equations to interpret spirometry instead of race-specific equations. Racial disparities in rates of emphysema among those with ‘normal’ FEV₁ [between 80% and 120% predicted], were attenuated or eliminated when race-neutral equations were used to calculate FEV₁. This suggests that race-specific equations are normalizing worse lung health in Black adults,” Dr. Liu explained.

“We need to continue research into additional tools that can be used to assess respiratory health and diagnose COPD, while keeping in mind how these tools may affect racial disparities,” said Dr. Liu. “Our study suggests that our reliance on spirometry measures such as FEV₁/FVC ratio and FEV₁ is missing a number of people with respiratory symptoms and CT evidence of lung disease, and that this is disproportionately affecting Black adults in the United States.” Looking ahead, “it is important to find better tools to identify people with impaired respiratory health or early manifestations of disease so we can intercept chronic lung disease before it becomes clinically apparent and patients have sustained significant lung damage.”

The CARDIA study was supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Dr. Liu was supported by a grant from the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Pal had no financial conflicts to disclose.

*This article was updated 7/22/2022.

An overreliance on spirometry to identify emphysema led to missed cases in Black individuals, particularly men, based on a secondary data analysis of 2,674 people.

“Over the last few years, there has been growing debate around the use of race adjustment in diagnostic algorithms and equations commonly used in medicine,” lead author Gabrielle Yi-Hui Liu, MD, said in an interview. “Whereas, previously it was common to accept racial or ethnic differences in clinical measures and outcomes as inherent differences among populations, there is now more recognition of how racism, socioeconomic status, and environmental exposures can cause these racial differences. Our initial interest in this study was to examine how the use of race-specific spirometry reference equations, and the use of spirometry in general, may be contributing to racial disparities.”

“Previous studies have suggested that the use of race-specific equations in spirometry can exacerbate racial inequities in healthcare outcomes by under-recognition of early disease in Black adults, and this study adds to that evidence,” said Suman Pal, MBBS, of the University of New Mexico, Albuquerque, in an interview.
“By examining the crucial ways in which systemic factors in medicine, such as race-specific equations, exacerbate racial inequities in healthcare, this study is a timely analysis in a moment of national reckoning of structural racism,” said Dr. Pal, who was not involved in the study.

spirometry2_web.jpg

In a study published in Annals of Internal Medicine, Dr. Liu and colleagues at Northwestern University, Chicago, conducted a secondary analysis of data from the CARDIA Lung study (Coronary Artery Risk Development In Young Adults).

The primary outcome of the study was the prevalence of emphysema among participants with various measures of normal spirometry results, stratified by sex and race. The normal results included an forced expiratory volume in 1 second (FEV₁₎–forced vital capacity (FVC) ratio greater than or equal to 0.7 or greater than or equal to the lower limit of normal. The participants also were stratified by FEV₁ percent predicted, using race-specific reference equations, for FEV₁ between 80% and 99% of predicted, or an FEV₁ between 100% and 120% of predicted.

The study population included 485 Black men, 762 Black women, 659 White men, and 768 White women who received both a CT scan (in 2010-2011) and spirometry (obtained in 2015-2016) in the CARDIA study. The mean age of the participants at the spirometry exam was 55 years.

A total of 5.3% of the participants had emphysema after stratifying by FEV₁-FVC ratio. The prevalence was significantly higher for Black men, compared with White men (12.3% vs. 4.0%; relative risk, 3.0), and for Black women, compared with White women (5.0% vs. 2.6%; RR, 1.9).

The association between Black race and emphysema risk persisted but decreased when the researchers used a race-neutral estimate.

When the participants were stratified by race-specific FEV₁ percent predicted, 6.5% of individuals with a race-specific FEV₁ between 80% and 99% had emphysema. After controlling for factors including age and smoking, emphysema was significantly more prevalent in Black men versus White men (15.5% vs. 4.0%) and in Black women, compared with White women (6.6% vs. 3.4%).

The racial difference persisted in men with a race-specific FEV₁ between 100% and 120% of predicted. Of these, 4.0% had emphysema. The prevalence was significantly higher in Black men, compared with White men (13.9% vs. 2.2%), but similar between Black women and White women (2.6% vs. 2.0%).

The use of race-neutral equations reduced, but did not eliminate, these disparities, the researchers said.

The findings were limited by the lack of CT imaging data from the same visit as the final spirometry collection, the researchers noted. “Given that imaging was obtained 5 years before spirometry and emphysema is an irreversible finding, this may have led to an overall underestimation of the prevalence of emphysema.”
 

Spirometry alone misses cases

“We were surprised by the substantial rates of emphysema we saw among Black men in our cohort with normal spirometry,” Dr. Liu said in an interview. “We did not expect to find than more than one in eight Black men with an FEV₁ between 100% and 120% predicted would have emphysema – a rate more than six times higher than White men with the same range of FEV₁.”

“One takeaway is that we are likely missing a lot of people with impaired respiratory health or true lung disease by only using spirometry to diagnose COPD,” said Dr. Liu. In clinical practice, “physicians should consider ordering CT scans on patients with normal spirometry who have respiratory symptoms such as cough or shortness of breath. If emphysema is found, physicians should discuss mitigating any potential risk factors and consider the use of COPD medications such as inhalers.

“Our findings also support using race-neutral reference equations to interpret spirometry instead of race-specific equations. Racial disparities in rates of emphysema among those with ‘normal’ FEV₁ [between 80% and 120% predicted], were attenuated or eliminated when race-neutral equations were used to calculate FEV₁. This suggests that race-specific equations are normalizing worse lung health in Black adults,” Dr. Liu explained.

“We need to continue research into additional tools that can be used to assess respiratory health and diagnose COPD, while keeping in mind how these tools may affect racial disparities,” said Dr. Liu. “Our study suggests that our reliance on spirometry measures such as FEV₁/FVC ratio and FEV₁ is missing a number of people with respiratory symptoms and CT evidence of lung disease, and that this is disproportionately affecting Black adults in the United States.” Looking ahead, “it is important to find better tools to identify people with impaired respiratory health or early manifestations of disease so we can intercept chronic lung disease before it becomes clinically apparent and patients have sustained significant lung damage.”

The CARDIA study was supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Dr. Liu was supported by a grant from the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Pal had no financial conflicts to disclose.

*This article was updated 7/22/2022.

An overreliance on spirometry to identify emphysema led to missed cases in Black individuals, particularly men, based on a secondary data analysis of 2,674 people.

“Over the last few years, there has been growing debate around the use of race adjustment in diagnostic algorithms and equations commonly used in medicine,” lead author Gabrielle Yi-Hui Liu, MD, said in an interview. “Whereas, previously it was common to accept racial or ethnic differences in clinical measures and outcomes as inherent differences among populations, there is now more recognition of how racism, socioeconomic status, and environmental exposures can cause these racial differences. Our initial interest in this study was to examine how the use of race-specific spirometry reference equations, and the use of spirometry in general, may be contributing to racial disparities.”

“Previous studies have suggested that the use of race-specific equations in spirometry can exacerbate racial inequities in healthcare outcomes by under-recognition of early disease in Black adults, and this study adds to that evidence,” said Suman Pal, MBBS, of the University of New Mexico, Albuquerque, in an interview.
“By examining the crucial ways in which systemic factors in medicine, such as race-specific equations, exacerbate racial inequities in healthcare, this study is a timely analysis in a moment of national reckoning of structural racism,” said Dr. Pal, who was not involved in the study.

spirometry2_web.jpg

In a study published in Annals of Internal Medicine, Dr. Liu and colleagues at Northwestern University, Chicago, conducted a secondary analysis of data from the CARDIA Lung study (Coronary Artery Risk Development In Young Adults).

The primary outcome of the study was the prevalence of emphysema among participants with various measures of normal spirometry results, stratified by sex and race. The normal results included an forced expiratory volume in 1 second (FEV₁₎–forced vital capacity (FVC) ratio greater than or equal to 0.7 or greater than or equal to the lower limit of normal. The participants also were stratified by FEV₁ percent predicted, using race-specific reference equations, for FEV₁ between 80% and 99% of predicted, or an FEV₁ between 100% and 120% of predicted.

The study population included 485 Black men, 762 Black women, 659 White men, and 768 White women who received both a CT scan (in 2010-2011) and spirometry (obtained in 2015-2016) in the CARDIA study. The mean age of the participants at the spirometry exam was 55 years.

A total of 5.3% of the participants had emphysema after stratifying by FEV₁-FVC ratio. The prevalence was significantly higher for Black men, compared with White men (12.3% vs. 4.0%; relative risk, 3.0), and for Black women, compared with White women (5.0% vs. 2.6%; RR, 1.9).

The association between Black race and emphysema risk persisted but decreased when the researchers used a race-neutral estimate.

When the participants were stratified by race-specific FEV₁ percent predicted, 6.5% of individuals with a race-specific FEV₁ between 80% and 99% had emphysema. After controlling for factors including age and smoking, emphysema was significantly more prevalent in Black men versus White men (15.5% vs. 4.0%) and in Black women, compared with White women (6.6% vs. 3.4%).

The racial difference persisted in men with a race-specific FEV₁ between 100% and 120% of predicted. Of these, 4.0% had emphysema. The prevalence was significantly higher in Black men, compared with White men (13.9% vs. 2.2%), but similar between Black women and White women (2.6% vs. 2.0%).

The use of race-neutral equations reduced, but did not eliminate, these disparities, the researchers said.

The findings were limited by the lack of CT imaging data from the same visit as the final spirometry collection, the researchers noted. “Given that imaging was obtained 5 years before spirometry and emphysema is an irreversible finding, this may have led to an overall underestimation of the prevalence of emphysema.”
 

Spirometry alone misses cases

“We were surprised by the substantial rates of emphysema we saw among Black men in our cohort with normal spirometry,” Dr. Liu said in an interview. “We did not expect to find than more than one in eight Black men with an FEV₁ between 100% and 120% predicted would have emphysema – a rate more than six times higher than White men with the same range of FEV₁.”

“One takeaway is that we are likely missing a lot of people with impaired respiratory health or true lung disease by only using spirometry to diagnose COPD,” said Dr. Liu. In clinical practice, “physicians should consider ordering CT scans on patients with normal spirometry who have respiratory symptoms such as cough or shortness of breath. If emphysema is found, physicians should discuss mitigating any potential risk factors and consider the use of COPD medications such as inhalers.

“Our findings also support using race-neutral reference equations to interpret spirometry instead of race-specific equations. Racial disparities in rates of emphysema among those with ‘normal’ FEV₁ [between 80% and 120% predicted], were attenuated or eliminated when race-neutral equations were used to calculate FEV₁. This suggests that race-specific equations are normalizing worse lung health in Black adults,” Dr. Liu explained.

“We need to continue research into additional tools that can be used to assess respiratory health and diagnose COPD, while keeping in mind how these tools may affect racial disparities,” said Dr. Liu. “Our study suggests that our reliance on spirometry measures such as FEV₁/FVC ratio and FEV₁ is missing a number of people with respiratory symptoms and CT evidence of lung disease, and that this is disproportionately affecting Black adults in the United States.” Looking ahead, “it is important to find better tools to identify people with impaired respiratory health or early manifestations of disease so we can intercept chronic lung disease before it becomes clinically apparent and patients have sustained significant lung damage.”

The CARDIA study was supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Dr. Liu was supported by a grant from the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Pal had no financial conflicts to disclose.

*This article was updated 7/22/2022.

Most COVID-19 long-haulers continue to have brain fog, fatigue, and compromised quality of life more than a year after the initial infection, results from the most extensive follow-up to date of a group of long COVID patients show.

Most patients continue to experience debilitating neurologic symptoms an average of 15 months from symptom onset, Igor Koralnik, MD, who oversees the Neuro COVID-19 Clinic at Northwestern Medicine in Chicago, said during a press briefing.

Surprisingly, in some cases, new symptoms appear that didn’t exist before, including variation of heart rate and blood pressure, and gastrointestinal symptoms, indicating there may be a late appearance in dysfunction of the autonomic nervous system in those patients, Dr. Koralnik said.

The study was published online in Annals of Clinical and Translational Neurology.
 

Evolving symptoms

The investigators evaluated the evolution of neurologic symptoms in 52 adults who had mild COVID-19 symptoms and were not admitted to the hospital.

Their mean age was 43 years, 73% were women and 77% had received a COVID-19 vaccine. These patients have now been followed for between 11 and 18 months since their initial infection.

Overall, between first and follow-up evaluations, there was no significant change in the frequency of most neurologic symptoms, including brain fog (81% vs. 71%), numbness/tingling (69% vs. 65%), headache (67% vs. 54%), dizziness (50% vs. 54%), blurred vision (34% vs. 44%), tinnitus (33% vs. 42%), and fatigue (87% vs. 81%).

The only neurologic symptoms that decreased over time were loss of taste (63% vs. 27%) and smell (58% vs. 21%).

Conversely, heart rate and blood pressure variation (35% vs. 56%) and gastrointestinal symptoms (27% vs. 48%; P = .04) increased at follow-up evaluations.

Patients reported subjective improvements in their recovery, cognitive function and fatigue, but quality of life measures remained lower than the average population of the United States.

There was a neutral effect of COVID vaccination on long COVID symptoms – it didn’t cure long COVID or make long COVID worse, which is a reason given by some long-haulers for not getting vaccinated, Dr. Koralnik told the briefing.

Therefore, “we continue to encourage our patients to get vaccinated and boosted according to the Centers for Disease Control and Prevention recommendation,” he said.
 

Escape from the ‘pit of despair’

To date, the Northwestern Medicine Neuro COVID-19 Clinic has treated nearly 1,400 COVID long-haulers from across the United States.

Emily Caffee, a physical therapist from Wheaton, Ill., is one of them.

Speaking at the briefing, the 36-year-old described her saga and roller coaster of recovering from long COVID in three acts: her initial infection, followed by a descent into a pit of physical and emotional despair, followed by her eventual escape from that pit more than two years later.

Following a fairly mild case of COVID, Ms. Caffee said worsening neurologic symptoms forced her to take medical leave from her very physical and cognitively demanding job. 

Ms. Caffee said she experienced crushing fatigue and brain fog, as well as rapid heart rate and blood pressure changes going from sitting to standing position.

She went from being a competitive athlete to someone who could barely get off the couch or empty the dishwasher.

With the ongoing help of her medical team, she slowly returned to daily activities and eventually to work on a limited basis.

Today, Ms. Caffee says she’s 90%-95% better but still she has some lingering symptoms and does not yet feel like her pre-COVID self.

It’s been a very slow climb out of the pit, Ms. Caffee said.

This study has no specific funding. The authors disclosed no relevant conflicts of interest.

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

Most COVID-19 long-haulers continue to have brain fog, fatigue, and compromised quality of life more than a year after the initial infection, results from the most extensive follow-up to date of a group of long COVID patients show.

Most patients continue to experience debilitating neurologic symptoms an average of 15 months from symptom onset, Igor Koralnik, MD, who oversees the Neuro COVID-19 Clinic at Northwestern Medicine in Chicago, said during a press briefing.

Surprisingly, in some cases, new symptoms appear that didn’t exist before, including variation of heart rate and blood pressure, and gastrointestinal symptoms, indicating there may be a late appearance in dysfunction of the autonomic nervous system in those patients, Dr. Koralnik said.

The study was published online in Annals of Clinical and Translational Neurology.
 

Evolving symptoms

The investigators evaluated the evolution of neurologic symptoms in 52 adults who had mild COVID-19 symptoms and were not admitted to the hospital.

Their mean age was 43 years, 73% were women and 77% had received a COVID-19 vaccine. These patients have now been followed for between 11 and 18 months since their initial infection.

Overall, between first and follow-up evaluations, there was no significant change in the frequency of most neurologic symptoms, including brain fog (81% vs. 71%), numbness/tingling (69% vs. 65%), headache (67% vs. 54%), dizziness (50% vs. 54%), blurred vision (34% vs. 44%), tinnitus (33% vs. 42%), and fatigue (87% vs. 81%).

The only neurologic symptoms that decreased over time were loss of taste (63% vs. 27%) and smell (58% vs. 21%).

Conversely, heart rate and blood pressure variation (35% vs. 56%) and gastrointestinal symptoms (27% vs. 48%; P = .04) increased at follow-up evaluations.

Patients reported subjective improvements in their recovery, cognitive function and fatigue, but quality of life measures remained lower than the average population of the United States.

There was a neutral effect of COVID vaccination on long COVID symptoms – it didn’t cure long COVID or make long COVID worse, which is a reason given by some long-haulers for not getting vaccinated, Dr. Koralnik told the briefing.

Therefore, “we continue to encourage our patients to get vaccinated and boosted according to the Centers for Disease Control and Prevention recommendation,” he said.
 

Escape from the ‘pit of despair’

To date, the Northwestern Medicine Neuro COVID-19 Clinic has treated nearly 1,400 COVID long-haulers from across the United States.

Emily Caffee, a physical therapist from Wheaton, Ill., is one of them.

Speaking at the briefing, the 36-year-old described her saga and roller coaster of recovering from long COVID in three acts: her initial infection, followed by a descent into a pit of physical and emotional despair, followed by her eventual escape from that pit more than two years later.

Following a fairly mild case of COVID, Ms. Caffee said worsening neurologic symptoms forced her to take medical leave from her very physical and cognitively demanding job. 

Ms. Caffee said she experienced crushing fatigue and brain fog, as well as rapid heart rate and blood pressure changes going from sitting to standing position.

She went from being a competitive athlete to someone who could barely get off the couch or empty the dishwasher.

With the ongoing help of her medical team, she slowly returned to daily activities and eventually to work on a limited basis.

Today, Ms. Caffee says she’s 90%-95% better but still she has some lingering symptoms and does not yet feel like her pre-COVID self.

It’s been a very slow climb out of the pit, Ms. Caffee said.

This study has no specific funding. The authors disclosed no relevant conflicts of interest.

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

Most COVID-19 long-haulers continue to have brain fog, fatigue, and compromised quality of life more than a year after the initial infection, results from the most extensive follow-up to date of a group of long COVID patients show.

Most patients continue to experience debilitating neurologic symptoms an average of 15 months from symptom onset, Igor Koralnik, MD, who oversees the Neuro COVID-19 Clinic at Northwestern Medicine in Chicago, said during a press briefing.

Surprisingly, in some cases, new symptoms appear that didn’t exist before, including variation of heart rate and blood pressure, and gastrointestinal symptoms, indicating there may be a late appearance in dysfunction of the autonomic nervous system in those patients, Dr. Koralnik said.

The study was published online in Annals of Clinical and Translational Neurology.
 

Evolving symptoms

The investigators evaluated the evolution of neurologic symptoms in 52 adults who had mild COVID-19 symptoms and were not admitted to the hospital.

Their mean age was 43 years, 73% were women and 77% had received a COVID-19 vaccine. These patients have now been followed for between 11 and 18 months since their initial infection.

Overall, between first and follow-up evaluations, there was no significant change in the frequency of most neurologic symptoms, including brain fog (81% vs. 71%), numbness/tingling (69% vs. 65%), headache (67% vs. 54%), dizziness (50% vs. 54%), blurred vision (34% vs. 44%), tinnitus (33% vs. 42%), and fatigue (87% vs. 81%).

The only neurologic symptoms that decreased over time were loss of taste (63% vs. 27%) and smell (58% vs. 21%).

Conversely, heart rate and blood pressure variation (35% vs. 56%) and gastrointestinal symptoms (27% vs. 48%; P = .04) increased at follow-up evaluations.

Patients reported subjective improvements in their recovery, cognitive function and fatigue, but quality of life measures remained lower than the average population of the United States.

There was a neutral effect of COVID vaccination on long COVID symptoms – it didn’t cure long COVID or make long COVID worse, which is a reason given by some long-haulers for not getting vaccinated, Dr. Koralnik told the briefing.

Therefore, “we continue to encourage our patients to get vaccinated and boosted according to the Centers for Disease Control and Prevention recommendation,” he said.
 

Escape from the ‘pit of despair’

To date, the Northwestern Medicine Neuro COVID-19 Clinic has treated nearly 1,400 COVID long-haulers from across the United States.

Emily Caffee, a physical therapist from Wheaton, Ill., is one of them.

Speaking at the briefing, the 36-year-old described her saga and roller coaster of recovering from long COVID in three acts: her initial infection, followed by a descent into a pit of physical and emotional despair, followed by her eventual escape from that pit more than two years later.

Following a fairly mild case of COVID, Ms. Caffee said worsening neurologic symptoms forced her to take medical leave from her very physical and cognitively demanding job. 

Ms. Caffee said she experienced crushing fatigue and brain fog, as well as rapid heart rate and blood pressure changes going from sitting to standing position.

She went from being a competitive athlete to someone who could barely get off the couch or empty the dishwasher.

With the ongoing help of her medical team, she slowly returned to daily activities and eventually to work on a limited basis.

Today, Ms. Caffee says she’s 90%-95% better but still she has some lingering symptoms and does not yet feel like her pre-COVID self.

It’s been a very slow climb out of the pit, Ms. Caffee said.

This study has no specific funding. The authors disclosed no relevant conflicts of interest.

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

Sildenafil (Viagra, Pfizer), a phosphodieterase-5 (PDE-5) inhibitor and a pulmonary-selective vasodilator, may reduce mortality in patients with idiopathic pulmonary fibrosis (IPF), compared with placebo or standard of care but it does not reduce hospitalizations or acute exacerbations from the disorder, a small meta-analysis suggests.

“There have only been four trials investigating sildenafil [in IPF] and the results were very close to being statistically significant so the addition of a few events would cause that to be true,” Tyler Pitre, MD, McMaster University, Hamilton, Ont., and Dena Zeraatkar, PhD, Harvard Medical School, Boston, told this news organization in a joint email.

“So lack of statistical significance does not preclude benefit,” they added, “and we think these results warrant additional trials and, if results remain consistent, [we] suspect the next update of the analysis may demonstrate statistical significance.”

The study was published online in Pulmonary Pharmacology & Therapeutics.
 

Reanalysis necessary

As the investigators pointed out, the most recent international guidelines have a conditional recommendation against the use of sildenafil in IPF patients so reanalysis of the data was felt to be necessary in order to inform upcoming guidelines. The purpose of the review was to provide an update of the evidence as to whether sildenafil not only provides mortality benefit in this patient population but also whether it improves overall lung function, reduces exacerbations and hospitalizations along with adverse events (AEs) leading to drug discontinuation.

The four studies included in the meta-analysis were all randomized, controlled trials in which either standalone PDE-5 inhibitors were compared with placebo or with standard IPF care with either pirfenidone (Esbroef ) or nintedanib (Ofev). The age of participants across the trials ranged from 68.6 years to 70.4 years and participants were predominantly male.

Follow-up ranged from just 12 weeks to 52 weeks. “Four trials including 659 patients and 88 deaths, reported on mortality,” the investigators noted. At a relative risk reduction of 0.73 (95% confidence interval, 0.51-1.04), the investigators concluded with moderate certainty that sildenafil probably reduces mortality in IPF patients.

Four trials including 659 patients reported on acute exacerbations and hospitalizations. At a RR of 1.10 (95% CI, 0.61-1.67), pooled results showed sildenafil may not reduce hospitalizations or acute exacerbations, compared with controls, although this conclusion was reached with low certainty. Four trials containing slightly more patients at 661 participants reported on AEs leading to drug discontinuation.

Again with moderate certainty, the authors concluded there is probably no difference in drug discontinuation rates because of AEs when comparing sildenafil to controls, at a RR of 0.79 (95% CI, 0.56-1.10). Four trials including 602 patients reported on lung function changes while diffusion capacity of carbon monoxide (DLCO) results were available for 487 patients. Based on these four trials, sildenafil may not change the decline of forced vital capacity (FVC) at a mean difference of 0.61% (95% CI, –0.29 to 1.59), compared with standard of care or placebo.

Nor may it change the rate of DLCO decline at a MD of 0.97 (95% CI, 0.04-1.90), both outcomes again being rated with moderate certainty. Asked if the combination of either nintedanib plus sildenafil or pirfenidone plus sildenafil led to a mortality benefit in IPF patients, Dr. Pitre and Dr. Zeraatkar noted that there was no mortality benefit in either the INSTAGE trial or in another recent study published in Lancet Respiratory Medicine.

“However, both of these trials were quite small and therefore unlikely to detect a mortality benefit,” Dr. Pitre and Dr. Zeraatkar noted. Indeed, the benefit of doing a systematic review is the ability to pool event rates across trials to see if a benefit emerges as well as to evaluate the consistency of the direction of these effects.

“Our review presented the most up-to-date and comprehensive summary of the evidence on sildenafil therapy for IPF patients,” the authors stated.

While they did acknowledge that the mortality benefit seen with sildenafil over placebo or standard of care did not reach statistical significance, this was likely because of too few patients and events. For example, in a systematic review published in the New England Journal of Medicine in 1988, the authors were able to show a statistically significant benefit on 5-year mortality risk with the combination of tamoxifen and cytotoxic therapy whereas none of the individual trials analyzed were able to detect a mortality benefit because they were underpowered.

“Similarly, we suggest that something like this is possible with sildenafil, as the three major trials addressing sildenafil show the same direction toward benefit with little inconsistency,” Dr. Pitre and Dr. Zeraatkar noted.

“We should not exclude benefits based on P values alone,” they said, adding: “Clearly out systematic review is not going to change clinical practice given the uncertainty of the results but I do think that in a disease such as IPF, further research is warranted in targeted patient populations [and] for clinicians, we suggest they keep an open mind to sildenafil.”

Commentary

Asked to comment on the findings, Krishna Thavarajah, MD, director of the interstitial lung disease program at Henry Ford Hospital and clinical assistant professor at Wayne State University, both in Detroit, agreed with the authors that the lack of a statistically significant mortality benefit seen in the meta-analysis does not necessarily translate into a lack of benefit from the use of sildenafil in IPF patients. “As the authors point out, there are simply not enough data available to know if there is a mortality benefit, limited by the variable follow-up times and IPF patients targeted with or without pulmonary hypertension.”

Indeed, Dr. Thavarajah felt that a mortality benefit might be difficult to show in IPF patients, especially those on antifibrotics, given the duration of the studies analyzed and the number of patients needed to be able to show a statistically significant difference. “I myself have not prescribed sildenafil for IPF patients given the lack of clear data,” Dr. Thavarajah acknowledged.

“[But] the meta-analysis shows that sildenafil could have a mortality benefit in IPF patients without evidence of a benefit in FVC, DLCO, or acute exacerbations,” she confirmed, agreeing that further study would be helpful in assessing the potential for sildenafil to provide a mortality benefit in IPF patients.

No funding for the study was reported. Neither the authors nor Dr. Thavarajah had any conflicts of interest to declare.

Sildenafil (Viagra, Pfizer), a phosphodieterase-5 (PDE-5) inhibitor and a pulmonary-selective vasodilator, may reduce mortality in patients with idiopathic pulmonary fibrosis (IPF), compared with placebo or standard of care but it does not reduce hospitalizations or acute exacerbations from the disorder, a small meta-analysis suggests.

“There have only been four trials investigating sildenafil [in IPF] and the results were very close to being statistically significant so the addition of a few events would cause that to be true,” Tyler Pitre, MD, McMaster University, Hamilton, Ont., and Dena Zeraatkar, PhD, Harvard Medical School, Boston, told this news organization in a joint email.

“So lack of statistical significance does not preclude benefit,” they added, “and we think these results warrant additional trials and, if results remain consistent, [we] suspect the next update of the analysis may demonstrate statistical significance.”

The study was published online in Pulmonary Pharmacology & Therapeutics.
 

Reanalysis necessary

As the investigators pointed out, the most recent international guidelines have a conditional recommendation against the use of sildenafil in IPF patients so reanalysis of the data was felt to be necessary in order to inform upcoming guidelines. The purpose of the review was to provide an update of the evidence as to whether sildenafil not only provides mortality benefit in this patient population but also whether it improves overall lung function, reduces exacerbations and hospitalizations along with adverse events (AEs) leading to drug discontinuation.

The four studies included in the meta-analysis were all randomized, controlled trials in which either standalone PDE-5 inhibitors were compared with placebo or with standard IPF care with either pirfenidone (Esbroef ) or nintedanib (Ofev). The age of participants across the trials ranged from 68.6 years to 70.4 years and participants were predominantly male.

Follow-up ranged from just 12 weeks to 52 weeks. “Four trials including 659 patients and 88 deaths, reported on mortality,” the investigators noted. At a relative risk reduction of 0.73 (95% confidence interval, 0.51-1.04), the investigators concluded with moderate certainty that sildenafil probably reduces mortality in IPF patients.

Four trials including 659 patients reported on acute exacerbations and hospitalizations. At a RR of 1.10 (95% CI, 0.61-1.67), pooled results showed sildenafil may not reduce hospitalizations or acute exacerbations, compared with controls, although this conclusion was reached with low certainty. Four trials containing slightly more patients at 661 participants reported on AEs leading to drug discontinuation.

Again with moderate certainty, the authors concluded there is probably no difference in drug discontinuation rates because of AEs when comparing sildenafil to controls, at a RR of 0.79 (95% CI, 0.56-1.10). Four trials including 602 patients reported on lung function changes while diffusion capacity of carbon monoxide (DLCO) results were available for 487 patients. Based on these four trials, sildenafil may not change the decline of forced vital capacity (FVC) at a mean difference of 0.61% (95% CI, –0.29 to 1.59), compared with standard of care or placebo.

Nor may it change the rate of DLCO decline at a MD of 0.97 (95% CI, 0.04-1.90), both outcomes again being rated with moderate certainty. Asked if the combination of either nintedanib plus sildenafil or pirfenidone plus sildenafil led to a mortality benefit in IPF patients, Dr. Pitre and Dr. Zeraatkar noted that there was no mortality benefit in either the INSTAGE trial or in another recent study published in Lancet Respiratory Medicine.

“However, both of these trials were quite small and therefore unlikely to detect a mortality benefit,” Dr. Pitre and Dr. Zeraatkar noted. Indeed, the benefit of doing a systematic review is the ability to pool event rates across trials to see if a benefit emerges as well as to evaluate the consistency of the direction of these effects.

“Our review presented the most up-to-date and comprehensive summary of the evidence on sildenafil therapy for IPF patients,” the authors stated.

While they did acknowledge that the mortality benefit seen with sildenafil over placebo or standard of care did not reach statistical significance, this was likely because of too few patients and events. For example, in a systematic review published in the New England Journal of Medicine in 1988, the authors were able to show a statistically significant benefit on 5-year mortality risk with the combination of tamoxifen and cytotoxic therapy whereas none of the individual trials analyzed were able to detect a mortality benefit because they were underpowered.

“Similarly, we suggest that something like this is possible with sildenafil, as the three major trials addressing sildenafil show the same direction toward benefit with little inconsistency,” Dr. Pitre and Dr. Zeraatkar noted.

“We should not exclude benefits based on P values alone,” they said, adding: “Clearly out systematic review is not going to change clinical practice given the uncertainty of the results but I do think that in a disease such as IPF, further research is warranted in targeted patient populations [and] for clinicians, we suggest they keep an open mind to sildenafil.”

Commentary

Asked to comment on the findings, Krishna Thavarajah, MD, director of the interstitial lung disease program at Henry Ford Hospital and clinical assistant professor at Wayne State University, both in Detroit, agreed with the authors that the lack of a statistically significant mortality benefit seen in the meta-analysis does not necessarily translate into a lack of benefit from the use of sildenafil in IPF patients. “As the authors point out, there are simply not enough data available to know if there is a mortality benefit, limited by the variable follow-up times and IPF patients targeted with or without pulmonary hypertension.”

Indeed, Dr. Thavarajah felt that a mortality benefit might be difficult to show in IPF patients, especially those on antifibrotics, given the duration of the studies analyzed and the number of patients needed to be able to show a statistically significant difference. “I myself have not prescribed sildenafil for IPF patients given the lack of clear data,” Dr. Thavarajah acknowledged.

“[But] the meta-analysis shows that sildenafil could have a mortality benefit in IPF patients without evidence of a benefit in FVC, DLCO, or acute exacerbations,” she confirmed, agreeing that further study would be helpful in assessing the potential for sildenafil to provide a mortality benefit in IPF patients.

No funding for the study was reported. Neither the authors nor Dr. Thavarajah had any conflicts of interest to declare.

Sildenafil (Viagra, Pfizer), a phosphodieterase-5 (PDE-5) inhibitor and a pulmonary-selective vasodilator, may reduce mortality in patients with idiopathic pulmonary fibrosis (IPF), compared with placebo or standard of care but it does not reduce hospitalizations or acute exacerbations from the disorder, a small meta-analysis suggests.

“There have only been four trials investigating sildenafil [in IPF] and the results were very close to being statistically significant so the addition of a few events would cause that to be true,” Tyler Pitre, MD, McMaster University, Hamilton, Ont., and Dena Zeraatkar, PhD, Harvard Medical School, Boston, told this news organization in a joint email.

“So lack of statistical significance does not preclude benefit,” they added, “and we think these results warrant additional trials and, if results remain consistent, [we] suspect the next update of the analysis may demonstrate statistical significance.”

The study was published online in Pulmonary Pharmacology & Therapeutics.
 

Reanalysis necessary

As the investigators pointed out, the most recent international guidelines have a conditional recommendation against the use of sildenafil in IPF patients so reanalysis of the data was felt to be necessary in order to inform upcoming guidelines. The purpose of the review was to provide an update of the evidence as to whether sildenafil not only provides mortality benefit in this patient population but also whether it improves overall lung function, reduces exacerbations and hospitalizations along with adverse events (AEs) leading to drug discontinuation.

The four studies included in the meta-analysis were all randomized, controlled trials in which either standalone PDE-5 inhibitors were compared with placebo or with standard IPF care with either pirfenidone (Esbroef ) or nintedanib (Ofev). The age of participants across the trials ranged from 68.6 years to 70.4 years and participants were predominantly male.

Follow-up ranged from just 12 weeks to 52 weeks. “Four trials including 659 patients and 88 deaths, reported on mortality,” the investigators noted. At a relative risk reduction of 0.73 (95% confidence interval, 0.51-1.04), the investigators concluded with moderate certainty that sildenafil probably reduces mortality in IPF patients.

Four trials including 659 patients reported on acute exacerbations and hospitalizations. At a RR of 1.10 (95% CI, 0.61-1.67), pooled results showed sildenafil may not reduce hospitalizations or acute exacerbations, compared with controls, although this conclusion was reached with low certainty. Four trials containing slightly more patients at 661 participants reported on AEs leading to drug discontinuation.

Again with moderate certainty, the authors concluded there is probably no difference in drug discontinuation rates because of AEs when comparing sildenafil to controls, at a RR of 0.79 (95% CI, 0.56-1.10). Four trials including 602 patients reported on lung function changes while diffusion capacity of carbon monoxide (DLCO) results were available for 487 patients. Based on these four trials, sildenafil may not change the decline of forced vital capacity (FVC) at a mean difference of 0.61% (95% CI, –0.29 to 1.59), compared with standard of care or placebo.

Nor may it change the rate of DLCO decline at a MD of 0.97 (95% CI, 0.04-1.90), both outcomes again being rated with moderate certainty. Asked if the combination of either nintedanib plus sildenafil or pirfenidone plus sildenafil led to a mortality benefit in IPF patients, Dr. Pitre and Dr. Zeraatkar noted that there was no mortality benefit in either the INSTAGE trial or in another recent study published in Lancet Respiratory Medicine.

“However, both of these trials were quite small and therefore unlikely to detect a mortality benefit,” Dr. Pitre and Dr. Zeraatkar noted. Indeed, the benefit of doing a systematic review is the ability to pool event rates across trials to see if a benefit emerges as well as to evaluate the consistency of the direction of these effects.

“Our review presented the most up-to-date and comprehensive summary of the evidence on sildenafil therapy for IPF patients,” the authors stated.

While they did acknowledge that the mortality benefit seen with sildenafil over placebo or standard of care did not reach statistical significance, this was likely because of too few patients and events. For example, in a systematic review published in the New England Journal of Medicine in 1988, the authors were able to show a statistically significant benefit on 5-year mortality risk with the combination of tamoxifen and cytotoxic therapy whereas none of the individual trials analyzed were able to detect a mortality benefit because they were underpowered.

“Similarly, we suggest that something like this is possible with sildenafil, as the three major trials addressing sildenafil show the same direction toward benefit with little inconsistency,” Dr. Pitre and Dr. Zeraatkar noted.

“We should not exclude benefits based on P values alone,” they said, adding: “Clearly out systematic review is not going to change clinical practice given the uncertainty of the results but I do think that in a disease such as IPF, further research is warranted in targeted patient populations [and] for clinicians, we suggest they keep an open mind to sildenafil.”

Commentary

Asked to comment on the findings, Krishna Thavarajah, MD, director of the interstitial lung disease program at Henry Ford Hospital and clinical assistant professor at Wayne State University, both in Detroit, agreed with the authors that the lack of a statistically significant mortality benefit seen in the meta-analysis does not necessarily translate into a lack of benefit from the use of sildenafil in IPF patients. “As the authors point out, there are simply not enough data available to know if there is a mortality benefit, limited by the variable follow-up times and IPF patients targeted with or without pulmonary hypertension.”

Indeed, Dr. Thavarajah felt that a mortality benefit might be difficult to show in IPF patients, especially those on antifibrotics, given the duration of the studies analyzed and the number of patients needed to be able to show a statistically significant difference. “I myself have not prescribed sildenafil for IPF patients given the lack of clear data,” Dr. Thavarajah acknowledged.

“[But] the meta-analysis shows that sildenafil could have a mortality benefit in IPF patients without evidence of a benefit in FVC, DLCO, or acute exacerbations,” she confirmed, agreeing that further study would be helpful in assessing the potential for sildenafil to provide a mortality benefit in IPF patients.

No funding for the study was reported. Neither the authors nor Dr. Thavarajah had any conflicts of interest to declare.

The diverse effects of obesity on lung health and disease are increasingly being teased apart, with researchers honing in on the impact of metabolic dysfunction, circulating inflammatory factors produced by adipose tissue, lipid handling, and other factors – in addition to body mass index – that are associated with the obese state.

“The bird’s eye view is that obesity completely changes lung health. It’s something we’ve only recently begun to appreciate,” said Anne E. Dixon, MA, BM, BCh, director of the Vermont Lung Center at the University of Vermont, Burlington, who is focused on the research field of obesity and lung disease.

157468_Dixon_Anne_BMBCH_web.jpg

OSA and OHS

“With sleep apnea we tend to focus on anatomic considerations, but there may be relationships or interactions between obesity and neuromuscular function and neuroventilatory control,” Susheel P. Patil, MD, PhD, director of the sleep medicine program for University Hospitals and assistant professor at Case Western Reserve University, Cleveland, said in an interview.

Patil_Susheel_OHIO_web.jpg

Some studies suggest, for instance, that TNF-alpha can increase obstructive sleep apnea (OSA) susceptibility and severity through its neuroventilatory modulating properties during sleep. And the potential for additional proinflammatory cytokines produced by adipose tissue to similarly affect upper airway neuroventilatory control is an “intriguing line” of inquiry for researchers in the sleep apnea space, he said.

Leptin is of interest particularly in obesity hypoventilation syndrome (OHS), which is characterized by chronic daytime hypercapnia. Best known as a satiety hormone, leptin is produced by adipose tissue and suppresses appetite at the central nervous system level. But it has long been known that leptin also affects ventilation and the control of breathing.

When transported across the blood-brain barrier, leptin increases the hypercapnic ventilatory response, Babak Mokhlesi, MD, MSc, codirector of the Rush Lung Center and chief of pulmonary, critical care, and sleep medicine at Rush University Medical Center in Chicago, said in an interview.

Research suggests that patients with OHS may have resistance to leptin at the central nervous system level – with leptin not reaching the sites of ventilatory control. This is a “prevailing theory” and could explain why these patients “do not augment their ventilation to maintain homeostasis, normal levels of CO₂,” Dr. Mokhlesi said.

Mokhlesi_Babak_MD_web.jpg

“Why some patients with severe obesity develop CO₂ retention while others do not is not fully understood,” he said, noting that patients with OHS can normalize their CO₂ quickly when instructed to take deep breaths. “What we know is that the centers in the brain responsible for augmenting ventilation when CO₂ goes up are somehow blunted.”

In a study of obese mice led by Vsevolod Y. Polotsky, MD, PhD, of Johns Hopkins University, Baltimore – and highlighted by Dr. Mokhlesi as an example of important, recent research – leptin delivered intranasally alleviated hypoventilation (and upper-airway obstruction), while intraperitoneally administered leptin did not, seemingly overcoming “central leptin deficiency.” (Am J Respir Crit Care Med. 2019;199[6]:773-83).

“This proved that there is some level of resistance in this animal model ... and has potential for therapeutics in the future,” Dr. Mokhlesi said.

Understanding the role of insulin resistance in OSA is another research focus. Some data suggest that insulin resistance, which is more common in obesity, is more prevalent in populations with OSA, Dr. Patil said. Researchers have discussed a bidirectional relationship for years, but it’s likely that insulin resistance is a precursor, he said.

In a mechanistic study published in 2016, Dr. Patil and his coinvestigators found that obese individuals with insulin resistance but without frank diabetes or sleep apnea demonstrated preclinical elevations in pharyngeal collapsibility during sleep. The findings suggest that insulin resistance could play a causal role in OSA pathogenesis by “generating requisite elevations in pharyngeal collapsibility,” they wrote (Eur. Respir J. 2016;47[6]:1718-26).

More recently, Dr. Patil noted in the interview, there is increasing appreciation in academia that the type of fat may be important to predicting OSA. “Visceral fat has a completely different cytokine-secretion profile than subcutaneous fat ... it is the more metabolically active fat that may secondarily impact upper airway function though a neuroinflammatory mechanism,” he said. “That is one of the working hypotheses today.”
 

Asthma

Research has so roundly suggested that metabolic dysfunction contributes to severe, poorly controlled asthma that there’s recent and growing interest in targeting metabolic dysfunction as part of the treatment of obese asthma, said Dr. Dixon, whose own research in obesity and lung disease has focused on asthma.

Data from animal models and some epidemiologic studies have suggested that drugs used to treat type 2 diabetes mellitus, such as glucagon-like peptide receptor-1 (GLPR-1) agonists and metformin, may help control asthma. In one recent study – cited by Dr. Dixon in a 2022 review of obesity and asthma – people with obesity and asthma who were prescribed GLPR-1 agonists for diabetes had fewer asthma exacerbations compared with those who took other medications for diabetes (Semin Respir Crit Care Med. 2022 Feb 17. doi: 10.1055/s-0042-1742384).

There is also research interest in targeting the pro-inflammatory adipokine interleukin 6 (IL-6), since increased circulating levels of IL-6 correlate with asthma severity, and in addressing oxidative stress in asthma through treatment with a mitochondrially targeted antioxidant, she said. Oxidative stress is increased in the airways of people with obesity, and researchers believe it may contribute to the pathophysiology of obese asthma through effects on airway nitric oxide levels.

(Her own research work at the University of Vermont has found associations between poor asthma control and high levels of leptin, and similar associations involving low levels of adiponectin, an anti-inflammatory adipokine that has been shown to downregulate eosinophil recruitment in the airways.)

Weight loss has been shown in mostly small, single-center studies to improve asthma control, but short of weight loss, researchers are also investigating the role of poor dietary quality. Thus far, data suggest that it’s the composition of the diet, and not just its contribution to weight gain, that could be impactful, Dr. Dixon said.

More basic research questions cited by Dr. Dixon include the extent to which adipose tissue inflammation causes inflammation in the lungs. “It’s a little unclear whether all the metabolic dysfunction associated with poor asthma control is causing inflammation in the lungs,” she said, though “we’ve done some work here that shows mediators produced by the adipose tissue could be impacting production of inflammatory mediators by the airway epithelium.”

Overall, she said, “the big questions [in asthma] are, how does adipose tissue affect the airway? Is it through direct effects? Through effects on the immune system? And obesity is affected by diet and the gut microbiome – how can these be [impacting] the airway?”

Obesity “is associated with so many changes – the gut, the immune system, and metabolic dysfunction, in addition to airway mechanics,” she said, “that I no longer think, as I did when I came to this, that it’s just one thing. It’s probably all of these things together.”

In the meantime, questions about potential shared pathways for the development of obesity and asthma remain. “Obesity is a risk factor for developing asthma, but it’s also entirely possible that asthma is a risk factor for developing obesity,” she said. (Some data from pediatric populations, she noted, suggest that nonobese children with asthma are at increased risk of developing obesity.)

Also important, Dr. Dixon said, is “emerging literature in the last 5-10 years” that suggests that people with obesity are more susceptible to the effects of air pollution. Research involving inner-city schoolchildren with asthma, for instance, has shown that those with obesity had worse symptoms with air pollution exposure than did those who were not obese.
 

Pulmonary arterial hypertension

Some research has looked at adipose tissue–produced substances in PAH, but the most well-established association in obesity and PAH involves insulin resistance.

“I don’t think we’re certain as a community that obesity [in general] is the problem – it’s not itself considered a risk factor for PAH,” Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn., said in an interview. She noted that it’s “hard to dissect obesity” apart.

Researchers are “more confident,” she said, “that insulin resistance – one feature of obesity [in some people] – is associated with worse outcomes in PAH.” Metabolic disease resembling insulin resistance is common in PAH and is believed to contribute to pulmonary vascular disease and right ventricular (RV) failure – the main cause of mortality in PAH – at least in part because of increased oxidative stress.

Dr. Hemnes led a mechanistic phase II clinical trial of metformin in PAH in which the drug was associated with improved RV fractional area change and reduced RV lipid deposition (J Am Heart Assoc. 2020;9[22]:e018349), and she’s now leading a National Institutes of Health–funded multicenter trial looking at the impact of metformin and an exercise intervention on 6-minute walk distance and World Health Organization functional class in PAH.

At the Rush Lung Center, in the meantime, Dr. Mokhlesi is utilizing animal models of OSA and OHS to explore the effect of hypoxia and nighttime hypercapnia on the development of PAH. “I think the jury is still out as to whether obesity itself is a major risk factor, but if so, by what mechanism?” he said. “Is it worsening [sleep-disordered breathing], which then worsens PAH?”
 

COPD

The focus in COPD has traditionally been on underweight, but the relationship between obesity and COPD has increasingly been recognized in the last 10-15 years, said Frits M. E. Franssen, MD, PhD, of CIRO, a research institute in Horn, the Netherlands, that treats COPD and other chronic lung diseases, and of the department of respiratory medicine at Maastricht University.

Researchers like Dr. Franssen are trying, for one, to understand obesity’s impact on COPD pathophysiology and to tease apart the impact of both conditions on disease severity and patient-related outcomes such as exercise capacity and exercise-related symptoms.

When Dr. Franssen’s group compared responses to weight-bearing exercise (6-min. walk test) and weight-supported exercise (cycling) in obese and normal weight COPD patients matched for age, gender, and degree of airflow limitation, the researchers found that walking capacity was significantly reduced while cycling capacity was preserved in the obese group (Respirology. 2016;21[3]:483-8).

Exercise-related symptoms (dyspnea and leg fatigue) were largely comparable between the obese and normal-weight COPD patients in both exercise modalities. However, in other studies, dyspnea ratings during cycling – at any given level of ventilation – have been lower in obese patients, indicating that “additional fat mass may have a beneficial effect on lung functioning [in non–weight-bearing exercise],” he said in an interview.

Dr. Franssen’s group also has assessed body composition in overweight and obese patients with COPD and found that a significant number have low muscle mass. These patients had worse lung function, exercise tolerance, and muscle strength compared to patients with comparable BMI and normal muscle mass (Respir Res. 2021 Mar 25. doi: 10.1186/s12931-021-01689-w).

“We’d always thought that obese patients have normal muscle mass ... but now we know it can be dramatically low,” he said. In assessing obesity and formulating any weight loss plans, “we’re now interested not only in weight but in the distribution of fat mass and fat-free mass ... and in maintaining muscle mass in patients who are [prescribed dietary interventions].”

Paradoxically, in patients with severe COPD, obesity is associated with prolonged survival, while in patients with mild to moderate COPD, obesity is associated with increased mortality risk, he noted.

The impact of adipose tissue and the chronic inflammation and metabolic disturbances that characterize obesity are currently largely unexplored, he said. Researchers have not yet studied what optimal weights may be for patients with COPD. “And we’re interested in the questions, are body weight and body composition the result of the disease, or [are they] determining the type of COPD one will get?” Dr. Franssen said.

Patients with COPD who are obese have “more of the phenotype of chronic bronchitis,” he noted, “while typical emphysema patients are normally underweight.”

The diverse effects of obesity on lung health and disease are increasingly being teased apart, with researchers honing in on the impact of metabolic dysfunction, circulating inflammatory factors produced by adipose tissue, lipid handling, and other factors – in addition to body mass index – that are associated with the obese state.

“The bird’s eye view is that obesity completely changes lung health. It’s something we’ve only recently begun to appreciate,” said Anne E. Dixon, MA, BM, BCh, director of the Vermont Lung Center at the University of Vermont, Burlington, who is focused on the research field of obesity and lung disease.

157468_Dixon_Anne_BMBCH_web.jpg

OSA and OHS

“With sleep apnea we tend to focus on anatomic considerations, but there may be relationships or interactions between obesity and neuromuscular function and neuroventilatory control,” Susheel P. Patil, MD, PhD, director of the sleep medicine program for University Hospitals and assistant professor at Case Western Reserve University, Cleveland, said in an interview.

Patil_Susheel_OHIO_web.jpg

Some studies suggest, for instance, that TNF-alpha can increase obstructive sleep apnea (OSA) susceptibility and severity through its neuroventilatory modulating properties during sleep. And the potential for additional proinflammatory cytokines produced by adipose tissue to similarly affect upper airway neuroventilatory control is an “intriguing line” of inquiry for researchers in the sleep apnea space, he said.

Leptin is of interest particularly in obesity hypoventilation syndrome (OHS), which is characterized by chronic daytime hypercapnia. Best known as a satiety hormone, leptin is produced by adipose tissue and suppresses appetite at the central nervous system level. But it has long been known that leptin also affects ventilation and the control of breathing.

When transported across the blood-brain barrier, leptin increases the hypercapnic ventilatory response, Babak Mokhlesi, MD, MSc, codirector of the Rush Lung Center and chief of pulmonary, critical care, and sleep medicine at Rush University Medical Center in Chicago, said in an interview.

Research suggests that patients with OHS may have resistance to leptin at the central nervous system level – with leptin not reaching the sites of ventilatory control. This is a “prevailing theory” and could explain why these patients “do not augment their ventilation to maintain homeostasis, normal levels of CO₂,” Dr. Mokhlesi said.

Mokhlesi_Babak_MD_web.jpg

“Why some patients with severe obesity develop CO₂ retention while others do not is not fully understood,” he said, noting that patients with OHS can normalize their CO₂ quickly when instructed to take deep breaths. “What we know is that the centers in the brain responsible for augmenting ventilation when CO₂ goes up are somehow blunted.”

In a study of obese mice led by Vsevolod Y. Polotsky, MD, PhD, of Johns Hopkins University, Baltimore – and highlighted by Dr. Mokhlesi as an example of important, recent research – leptin delivered intranasally alleviated hypoventilation (and upper-airway obstruction), while intraperitoneally administered leptin did not, seemingly overcoming “central leptin deficiency.” (Am J Respir Crit Care Med. 2019;199[6]:773-83).

“This proved that there is some level of resistance in this animal model ... and has potential for therapeutics in the future,” Dr. Mokhlesi said.

Understanding the role of insulin resistance in OSA is another research focus. Some data suggest that insulin resistance, which is more common in obesity, is more prevalent in populations with OSA, Dr. Patil said. Researchers have discussed a bidirectional relationship for years, but it’s likely that insulin resistance is a precursor, he said.

In a mechanistic study published in 2016, Dr. Patil and his coinvestigators found that obese individuals with insulin resistance but without frank diabetes or sleep apnea demonstrated preclinical elevations in pharyngeal collapsibility during sleep. The findings suggest that insulin resistance could play a causal role in OSA pathogenesis by “generating requisite elevations in pharyngeal collapsibility,” they wrote (Eur. Respir J. 2016;47[6]:1718-26).

More recently, Dr. Patil noted in the interview, there is increasing appreciation in academia that the type of fat may be important to predicting OSA. “Visceral fat has a completely different cytokine-secretion profile than subcutaneous fat ... it is the more metabolically active fat that may secondarily impact upper airway function though a neuroinflammatory mechanism,” he said. “That is one of the working hypotheses today.”
 

Asthma

Research has so roundly suggested that metabolic dysfunction contributes to severe, poorly controlled asthma that there’s recent and growing interest in targeting metabolic dysfunction as part of the treatment of obese asthma, said Dr. Dixon, whose own research in obesity and lung disease has focused on asthma.

Data from animal models and some epidemiologic studies have suggested that drugs used to treat type 2 diabetes mellitus, such as glucagon-like peptide receptor-1 (GLPR-1) agonists and metformin, may help control asthma. In one recent study – cited by Dr. Dixon in a 2022 review of obesity and asthma – people with obesity and asthma who were prescribed GLPR-1 agonists for diabetes had fewer asthma exacerbations compared with those who took other medications for diabetes (Semin Respir Crit Care Med. 2022 Feb 17. doi: 10.1055/s-0042-1742384).

There is also research interest in targeting the pro-inflammatory adipokine interleukin 6 (IL-6), since increased circulating levels of IL-6 correlate with asthma severity, and in addressing oxidative stress in asthma through treatment with a mitochondrially targeted antioxidant, she said. Oxidative stress is increased in the airways of people with obesity, and researchers believe it may contribute to the pathophysiology of obese asthma through effects on airway nitric oxide levels.

(Her own research work at the University of Vermont has found associations between poor asthma control and high levels of leptin, and similar associations involving low levels of adiponectin, an anti-inflammatory adipokine that has been shown to downregulate eosinophil recruitment in the airways.)

Weight loss has been shown in mostly small, single-center studies to improve asthma control, but short of weight loss, researchers are also investigating the role of poor dietary quality. Thus far, data suggest that it’s the composition of the diet, and not just its contribution to weight gain, that could be impactful, Dr. Dixon said.

More basic research questions cited by Dr. Dixon include the extent to which adipose tissue inflammation causes inflammation in the lungs. “It’s a little unclear whether all the metabolic dysfunction associated with poor asthma control is causing inflammation in the lungs,” she said, though “we’ve done some work here that shows mediators produced by the adipose tissue could be impacting production of inflammatory mediators by the airway epithelium.”

Overall, she said, “the big questions [in asthma] are, how does adipose tissue affect the airway? Is it through direct effects? Through effects on the immune system? And obesity is affected by diet and the gut microbiome – how can these be [impacting] the airway?”

Obesity “is associated with so many changes – the gut, the immune system, and metabolic dysfunction, in addition to airway mechanics,” she said, “that I no longer think, as I did when I came to this, that it’s just one thing. It’s probably all of these things together.”

In the meantime, questions about potential shared pathways for the development of obesity and asthma remain. “Obesity is a risk factor for developing asthma, but it’s also entirely possible that asthma is a risk factor for developing obesity,” she said. (Some data from pediatric populations, she noted, suggest that nonobese children with asthma are at increased risk of developing obesity.)

Also important, Dr. Dixon said, is “emerging literature in the last 5-10 years” that suggests that people with obesity are more susceptible to the effects of air pollution. Research involving inner-city schoolchildren with asthma, for instance, has shown that those with obesity had worse symptoms with air pollution exposure than did those who were not obese.
 

Pulmonary arterial hypertension

Some research has looked at adipose tissue–produced substances in PAH, but the most well-established association in obesity and PAH involves insulin resistance.

“I don’t think we’re certain as a community that obesity [in general] is the problem – it’s not itself considered a risk factor for PAH,” Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn., said in an interview. She noted that it’s “hard to dissect obesity” apart.

Researchers are “more confident,” she said, “that insulin resistance – one feature of obesity [in some people] – is associated with worse outcomes in PAH.” Metabolic disease resembling insulin resistance is common in PAH and is believed to contribute to pulmonary vascular disease and right ventricular (RV) failure – the main cause of mortality in PAH – at least in part because of increased oxidative stress.

Dr. Hemnes led a mechanistic phase II clinical trial of metformin in PAH in which the drug was associated with improved RV fractional area change and reduced RV lipid deposition (J Am Heart Assoc. 2020;9[22]:e018349), and she’s now leading a National Institutes of Health–funded multicenter trial looking at the impact of metformin and an exercise intervention on 6-minute walk distance and World Health Organization functional class in PAH.

At the Rush Lung Center, in the meantime, Dr. Mokhlesi is utilizing animal models of OSA and OHS to explore the effect of hypoxia and nighttime hypercapnia on the development of PAH. “I think the jury is still out as to whether obesity itself is a major risk factor, but if so, by what mechanism?” he said. “Is it worsening [sleep-disordered breathing], which then worsens PAH?”
 

COPD

The focus in COPD has traditionally been on underweight, but the relationship between obesity and COPD has increasingly been recognized in the last 10-15 years, said Frits M. E. Franssen, MD, PhD, of CIRO, a research institute in Horn, the Netherlands, that treats COPD and other chronic lung diseases, and of the department of respiratory medicine at Maastricht University.

Researchers like Dr. Franssen are trying, for one, to understand obesity’s impact on COPD pathophysiology and to tease apart the impact of both conditions on disease severity and patient-related outcomes such as exercise capacity and exercise-related symptoms.

When Dr. Franssen’s group compared responses to weight-bearing exercise (6-min. walk test) and weight-supported exercise (cycling) in obese and normal weight COPD patients matched for age, gender, and degree of airflow limitation, the researchers found that walking capacity was significantly reduced while cycling capacity was preserved in the obese group (Respirology. 2016;21[3]:483-8).

Exercise-related symptoms (dyspnea and leg fatigue) were largely comparable between the obese and normal-weight COPD patients in both exercise modalities. However, in other studies, dyspnea ratings during cycling – at any given level of ventilation – have been lower in obese patients, indicating that “additional fat mass may have a beneficial effect on lung functioning [in non–weight-bearing exercise],” he said in an interview.

Dr. Franssen’s group also has assessed body composition in overweight and obese patients with COPD and found that a significant number have low muscle mass. These patients had worse lung function, exercise tolerance, and muscle strength compared to patients with comparable BMI and normal muscle mass (Respir Res. 2021 Mar 25. doi: 10.1186/s12931-021-01689-w).

“We’d always thought that obese patients have normal muscle mass ... but now we know it can be dramatically low,” he said. In assessing obesity and formulating any weight loss plans, “we’re now interested not only in weight but in the distribution of fat mass and fat-free mass ... and in maintaining muscle mass in patients who are [prescribed dietary interventions].”

Paradoxically, in patients with severe COPD, obesity is associated with prolonged survival, while in patients with mild to moderate COPD, obesity is associated with increased mortality risk, he noted.

The impact of adipose tissue and the chronic inflammation and metabolic disturbances that characterize obesity are currently largely unexplored, he said. Researchers have not yet studied what optimal weights may be for patients with COPD. “And we’re interested in the questions, are body weight and body composition the result of the disease, or [are they] determining the type of COPD one will get?” Dr. Franssen said.

Patients with COPD who are obese have “more of the phenotype of chronic bronchitis,” he noted, “while typical emphysema patients are normally underweight.”

The diverse effects of obesity on lung health and disease are increasingly being teased apart, with researchers honing in on the impact of metabolic dysfunction, circulating inflammatory factors produced by adipose tissue, lipid handling, and other factors – in addition to body mass index – that are associated with the obese state.

“The bird’s eye view is that obesity completely changes lung health. It’s something we’ve only recently begun to appreciate,” said Anne E. Dixon, MA, BM, BCh, director of the Vermont Lung Center at the University of Vermont, Burlington, who is focused on the research field of obesity and lung disease.

157468_Dixon_Anne_BMBCH_web.jpg

OSA and OHS

“With sleep apnea we tend to focus on anatomic considerations, but there may be relationships or interactions between obesity and neuromuscular function and neuroventilatory control,” Susheel P. Patil, MD, PhD, director of the sleep medicine program for University Hospitals and assistant professor at Case Western Reserve University, Cleveland, said in an interview.

Patil_Susheel_OHIO_web.jpg

Some studies suggest, for instance, that TNF-alpha can increase obstructive sleep apnea (OSA) susceptibility and severity through its neuroventilatory modulating properties during sleep. And the potential for additional proinflammatory cytokines produced by adipose tissue to similarly affect upper airway neuroventilatory control is an “intriguing line” of inquiry for researchers in the sleep apnea space, he said.

Leptin is of interest particularly in obesity hypoventilation syndrome (OHS), which is characterized by chronic daytime hypercapnia. Best known as a satiety hormone, leptin is produced by adipose tissue and suppresses appetite at the central nervous system level. But it has long been known that leptin also affects ventilation and the control of breathing.

When transported across the blood-brain barrier, leptin increases the hypercapnic ventilatory response, Babak Mokhlesi, MD, MSc, codirector of the Rush Lung Center and chief of pulmonary, critical care, and sleep medicine at Rush University Medical Center in Chicago, said in an interview.

Research suggests that patients with OHS may have resistance to leptin at the central nervous system level – with leptin not reaching the sites of ventilatory control. This is a “prevailing theory” and could explain why these patients “do not augment their ventilation to maintain homeostasis, normal levels of CO₂,” Dr. Mokhlesi said.

Mokhlesi_Babak_MD_web.jpg

“Why some patients with severe obesity develop CO₂ retention while others do not is not fully understood,” he said, noting that patients with OHS can normalize their CO₂ quickly when instructed to take deep breaths. “What we know is that the centers in the brain responsible for augmenting ventilation when CO₂ goes up are somehow blunted.”

In a study of obese mice led by Vsevolod Y. Polotsky, MD, PhD, of Johns Hopkins University, Baltimore – and highlighted by Dr. Mokhlesi as an example of important, recent research – leptin delivered intranasally alleviated hypoventilation (and upper-airway obstruction), while intraperitoneally administered leptin did not, seemingly overcoming “central leptin deficiency.” (Am J Respir Crit Care Med. 2019;199[6]:773-83).

“This proved that there is some level of resistance in this animal model ... and has potential for therapeutics in the future,” Dr. Mokhlesi said.

Understanding the role of insulin resistance in OSA is another research focus. Some data suggest that insulin resistance, which is more common in obesity, is more prevalent in populations with OSA, Dr. Patil said. Researchers have discussed a bidirectional relationship for years, but it’s likely that insulin resistance is a precursor, he said.

In a mechanistic study published in 2016, Dr. Patil and his coinvestigators found that obese individuals with insulin resistance but without frank diabetes or sleep apnea demonstrated preclinical elevations in pharyngeal collapsibility during sleep. The findings suggest that insulin resistance could play a causal role in OSA pathogenesis by “generating requisite elevations in pharyngeal collapsibility,” they wrote (Eur. Respir J. 2016;47[6]:1718-26).

More recently, Dr. Patil noted in the interview, there is increasing appreciation in academia that the type of fat may be important to predicting OSA. “Visceral fat has a completely different cytokine-secretion profile than subcutaneous fat ... it is the more metabolically active fat that may secondarily impact upper airway function though a neuroinflammatory mechanism,” he said. “That is one of the working hypotheses today.”
 

Asthma

Research has so roundly suggested that metabolic dysfunction contributes to severe, poorly controlled asthma that there’s recent and growing interest in targeting metabolic dysfunction as part of the treatment of obese asthma, said Dr. Dixon, whose own research in obesity and lung disease has focused on asthma.

Data from animal models and some epidemiologic studies have suggested that drugs used to treat type 2 diabetes mellitus, such as glucagon-like peptide receptor-1 (GLPR-1) agonists and metformin, may help control asthma. In one recent study – cited by Dr. Dixon in a 2022 review of obesity and asthma – people with obesity and asthma who were prescribed GLPR-1 agonists for diabetes had fewer asthma exacerbations compared with those who took other medications for diabetes (Semin Respir Crit Care Med. 2022 Feb 17. doi: 10.1055/s-0042-1742384).

There is also research interest in targeting the pro-inflammatory adipokine interleukin 6 (IL-6), since increased circulating levels of IL-6 correlate with asthma severity, and in addressing oxidative stress in asthma through treatment with a mitochondrially targeted antioxidant, she said. Oxidative stress is increased in the airways of people with obesity, and researchers believe it may contribute to the pathophysiology of obese asthma through effects on airway nitric oxide levels.

(Her own research work at the University of Vermont has found associations between poor asthma control and high levels of leptin, and similar associations involving low levels of adiponectin, an anti-inflammatory adipokine that has been shown to downregulate eosinophil recruitment in the airways.)

Weight loss has been shown in mostly small, single-center studies to improve asthma control, but short of weight loss, researchers are also investigating the role of poor dietary quality. Thus far, data suggest that it’s the composition of the diet, and not just its contribution to weight gain, that could be impactful, Dr. Dixon said.

More basic research questions cited by Dr. Dixon include the extent to which adipose tissue inflammation causes inflammation in the lungs. “It’s a little unclear whether all the metabolic dysfunction associated with poor asthma control is causing inflammation in the lungs,” she said, though “we’ve done some work here that shows mediators produced by the adipose tissue could be impacting production of inflammatory mediators by the airway epithelium.”

Overall, she said, “the big questions [in asthma] are, how does adipose tissue affect the airway? Is it through direct effects? Through effects on the immune system? And obesity is affected by diet and the gut microbiome – how can these be [impacting] the airway?”

Obesity “is associated with so many changes – the gut, the immune system, and metabolic dysfunction, in addition to airway mechanics,” she said, “that I no longer think, as I did when I came to this, that it’s just one thing. It’s probably all of these things together.”

In the meantime, questions about potential shared pathways for the development of obesity and asthma remain. “Obesity is a risk factor for developing asthma, but it’s also entirely possible that asthma is a risk factor for developing obesity,” she said. (Some data from pediatric populations, she noted, suggest that nonobese children with asthma are at increased risk of developing obesity.)

Also important, Dr. Dixon said, is “emerging literature in the last 5-10 years” that suggests that people with obesity are more susceptible to the effects of air pollution. Research involving inner-city schoolchildren with asthma, for instance, has shown that those with obesity had worse symptoms with air pollution exposure than did those who were not obese.
 

Pulmonary arterial hypertension

Some research has looked at adipose tissue–produced substances in PAH, but the most well-established association in obesity and PAH involves insulin resistance.

“I don’t think we’re certain as a community that obesity [in general] is the problem – it’s not itself considered a risk factor for PAH,” Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn., said in an interview. She noted that it’s “hard to dissect obesity” apart.

Researchers are “more confident,” she said, “that insulin resistance – one feature of obesity [in some people] – is associated with worse outcomes in PAH.” Metabolic disease resembling insulin resistance is common in PAH and is believed to contribute to pulmonary vascular disease and right ventricular (RV) failure – the main cause of mortality in PAH – at least in part because of increased oxidative stress.

Dr. Hemnes led a mechanistic phase II clinical trial of metformin in PAH in which the drug was associated with improved RV fractional area change and reduced RV lipid deposition (J Am Heart Assoc. 2020;9[22]:e018349), and she’s now leading a National Institutes of Health–funded multicenter trial looking at the impact of metformin and an exercise intervention on 6-minute walk distance and World Health Organization functional class in PAH.

At the Rush Lung Center, in the meantime, Dr. Mokhlesi is utilizing animal models of OSA and OHS to explore the effect of hypoxia and nighttime hypercapnia on the development of PAH. “I think the jury is still out as to whether obesity itself is a major risk factor, but if so, by what mechanism?” he said. “Is it worsening [sleep-disordered breathing], which then worsens PAH?”
 

COPD

The focus in COPD has traditionally been on underweight, but the relationship between obesity and COPD has increasingly been recognized in the last 10-15 years, said Frits M. E. Franssen, MD, PhD, of CIRO, a research institute in Horn, the Netherlands, that treats COPD and other chronic lung diseases, and of the department of respiratory medicine at Maastricht University.

Researchers like Dr. Franssen are trying, for one, to understand obesity’s impact on COPD pathophysiology and to tease apart the impact of both conditions on disease severity and patient-related outcomes such as exercise capacity and exercise-related symptoms.

When Dr. Franssen’s group compared responses to weight-bearing exercise (6-min. walk test) and weight-supported exercise (cycling) in obese and normal weight COPD patients matched for age, gender, and degree of airflow limitation, the researchers found that walking capacity was significantly reduced while cycling capacity was preserved in the obese group (Respirology. 2016;21[3]:483-8).

Exercise-related symptoms (dyspnea and leg fatigue) were largely comparable between the obese and normal-weight COPD patients in both exercise modalities. However, in other studies, dyspnea ratings during cycling – at any given level of ventilation – have been lower in obese patients, indicating that “additional fat mass may have a beneficial effect on lung functioning [in non–weight-bearing exercise],” he said in an interview.

Dr. Franssen’s group also has assessed body composition in overweight and obese patients with COPD and found that a significant number have low muscle mass. These patients had worse lung function, exercise tolerance, and muscle strength compared to patients with comparable BMI and normal muscle mass (Respir Res. 2021 Mar 25. doi: 10.1186/s12931-021-01689-w).

“We’d always thought that obese patients have normal muscle mass ... but now we know it can be dramatically low,” he said. In assessing obesity and formulating any weight loss plans, “we’re now interested not only in weight but in the distribution of fat mass and fat-free mass ... and in maintaining muscle mass in patients who are [prescribed dietary interventions].”

Paradoxically, in patients with severe COPD, obesity is associated with prolonged survival, while in patients with mild to moderate COPD, obesity is associated with increased mortality risk, he noted.

The impact of adipose tissue and the chronic inflammation and metabolic disturbances that characterize obesity are currently largely unexplored, he said. Researchers have not yet studied what optimal weights may be for patients with COPD. “And we’re interested in the questions, are body weight and body composition the result of the disease, or [are they] determining the type of COPD one will get?” Dr. Franssen said.

Patients with COPD who are obese have “more of the phenotype of chronic bronchitis,” he noted, “while typical emphysema patients are normally underweight.”

SAN FRANCISCO – It may be time to move beyond relying largely on spirometry to distinguish between healthy and abnormal lung function in diverse populations.

That conclusion comes from investigators who looked at patients with ostensibly normal spirometry values in a large population-based study and found that using standard equations to adjust for racial differences in lung-function measures appeared to miss emphysema in a significant proportion of Black patients.

“Our traditional measures of lung health based on spirometry may be under-recognizing impaired respiratory health in Black adults and particularly Black men,” said lead author Gabrielle Liu, MD, a fellow in the division of pulmonary and critical care medicine at the Northwestern University Feinberg School of Medicine, Chicago.

“CT imaging may be useful in the evaluation of those with suspected impaired respiratory health and normal spirometry,” she said in an oral abstract session at the American Thoracic Society International Conference 2022.

Dr. Liu and colleagues studied the association between self-identified race and visually identified emphysema among 2,674 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The patients had CT scans at a mean age of 50 and spirometry at a mean age of 55.
 

Racial differences

The investigators found that among men with forced expiratory volume in 1 second (FEV1) ranging from 100% to 120% of predicted according to race-adjusted formulas, 14.6% of Black men had emphysema, compared with only 1.7% of White men (P < .001). Respective emphysema rates in Black women and White women were 3.8% and 1.9%; this difference was not statistically significant.

Among patients with FEV1 80% to 99% of predicted according to race-specific measures, 15.5% of Black men had emphysema, compared with 4% of White men (P < .001). Respective rates of emphysema were 6.9% for Black women versus 3.2% for White women (P = .025).

When the investigators applied race-neutral spirometry reference equations to the same population, they found that it attenuated but did not completely eliminate the racial disparity in emphysema prevalence among patients with FEV1, ranging from 80% to 120% of predicted.
 

Relic of the past

The results suggest that race-based adjustments of spirometry measures are a relic of less enlightened times, said Adam Gaffney, MD, MPH, assistant professor of medicine at Harvard Medical School, Boston, and a pulmonologist and critical care physician at Cambridge Health Alliance, Massachusetts.

“If the average lower lung function of Black people is being driven by adversity, structural racism, and deprivation, that means that race-specific equations are normalizing that adversity,” he said in an interview.

“In my opinion, it is time to move beyond race-based equations in clinical pulmonary medicine, particularly in the context of patients with established lung disease in whom use of race-based equations might actually lead to undertreatment,” said Dr. Gaffney, who was not involved in the study.

Dr. Liu agreed that it’s time to move to race-neutral measures and that the whole concept of race-based differences is flawed.

“The long-standing structural inequities in health likely made the reference populations have lower lung function than among Whites,” she told this news organization.

Dr. Liu said that evaluation of lung function should not rely on spirometry alone, but should also include – when appropriate – CT scans, as well as improved understanding of how symptoms may be predictive for poor outcomes.

The study was supported by grants from the National Institutes of Health. Dr. Liu and Dr. Gaffney have disclosed no relevant financial relationships.

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

SAN FRANCISCO – It may be time to move beyond relying largely on spirometry to distinguish between healthy and abnormal lung function in diverse populations.

That conclusion comes from investigators who looked at patients with ostensibly normal spirometry values in a large population-based study and found that using standard equations to adjust for racial differences in lung-function measures appeared to miss emphysema in a significant proportion of Black patients.

“Our traditional measures of lung health based on spirometry may be under-recognizing impaired respiratory health in Black adults and particularly Black men,” said lead author Gabrielle Liu, MD, a fellow in the division of pulmonary and critical care medicine at the Northwestern University Feinberg School of Medicine, Chicago.

“CT imaging may be useful in the evaluation of those with suspected impaired respiratory health and normal spirometry,” she said in an oral abstract session at the American Thoracic Society International Conference 2022.

Dr. Liu and colleagues studied the association between self-identified race and visually identified emphysema among 2,674 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The patients had CT scans at a mean age of 50 and spirometry at a mean age of 55.
 

Racial differences

The investigators found that among men with forced expiratory volume in 1 second (FEV1) ranging from 100% to 120% of predicted according to race-adjusted formulas, 14.6% of Black men had emphysema, compared with only 1.7% of White men (P < .001). Respective emphysema rates in Black women and White women were 3.8% and 1.9%; this difference was not statistically significant.

Among patients with FEV1 80% to 99% of predicted according to race-specific measures, 15.5% of Black men had emphysema, compared with 4% of White men (P < .001). Respective rates of emphysema were 6.9% for Black women versus 3.2% for White women (P = .025).

When the investigators applied race-neutral spirometry reference equations to the same population, they found that it attenuated but did not completely eliminate the racial disparity in emphysema prevalence among patients with FEV1, ranging from 80% to 120% of predicted.
 

Relic of the past

The results suggest that race-based adjustments of spirometry measures are a relic of less enlightened times, said Adam Gaffney, MD, MPH, assistant professor of medicine at Harvard Medical School, Boston, and a pulmonologist and critical care physician at Cambridge Health Alliance, Massachusetts.

“If the average lower lung function of Black people is being driven by adversity, structural racism, and deprivation, that means that race-specific equations are normalizing that adversity,” he said in an interview.

“In my opinion, it is time to move beyond race-based equations in clinical pulmonary medicine, particularly in the context of patients with established lung disease in whom use of race-based equations might actually lead to undertreatment,” said Dr. Gaffney, who was not involved in the study.

Dr. Liu agreed that it’s time to move to race-neutral measures and that the whole concept of race-based differences is flawed.

“The long-standing structural inequities in health likely made the reference populations have lower lung function than among Whites,” she told this news organization.

Dr. Liu said that evaluation of lung function should not rely on spirometry alone, but should also include – when appropriate – CT scans, as well as improved understanding of how symptoms may be predictive for poor outcomes.

The study was supported by grants from the National Institutes of Health. Dr. Liu and Dr. Gaffney have disclosed no relevant financial relationships.

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

SAN FRANCISCO – It may be time to move beyond relying largely on spirometry to distinguish between healthy and abnormal lung function in diverse populations.

That conclusion comes from investigators who looked at patients with ostensibly normal spirometry values in a large population-based study and found that using standard equations to adjust for racial differences in lung-function measures appeared to miss emphysema in a significant proportion of Black patients.

“Our traditional measures of lung health based on spirometry may be under-recognizing impaired respiratory health in Black adults and particularly Black men,” said lead author Gabrielle Liu, MD, a fellow in the division of pulmonary and critical care medicine at the Northwestern University Feinberg School of Medicine, Chicago.

“CT imaging may be useful in the evaluation of those with suspected impaired respiratory health and normal spirometry,” she said in an oral abstract session at the American Thoracic Society International Conference 2022.

Dr. Liu and colleagues studied the association between self-identified race and visually identified emphysema among 2,674 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The patients had CT scans at a mean age of 50 and spirometry at a mean age of 55.
 

Racial differences

The investigators found that among men with forced expiratory volume in 1 second (FEV1) ranging from 100% to 120% of predicted according to race-adjusted formulas, 14.6% of Black men had emphysema, compared with only 1.7% of White men (P < .001). Respective emphysema rates in Black women and White women were 3.8% and 1.9%; this difference was not statistically significant.

Among patients with FEV1 80% to 99% of predicted according to race-specific measures, 15.5% of Black men had emphysema, compared with 4% of White men (P < .001). Respective rates of emphysema were 6.9% for Black women versus 3.2% for White women (P = .025).

When the investigators applied race-neutral spirometry reference equations to the same population, they found that it attenuated but did not completely eliminate the racial disparity in emphysema prevalence among patients with FEV1, ranging from 80% to 120% of predicted.
 

Relic of the past

The results suggest that race-based adjustments of spirometry measures are a relic of less enlightened times, said Adam Gaffney, MD, MPH, assistant professor of medicine at Harvard Medical School, Boston, and a pulmonologist and critical care physician at Cambridge Health Alliance, Massachusetts.

“If the average lower lung function of Black people is being driven by adversity, structural racism, and deprivation, that means that race-specific equations are normalizing that adversity,” he said in an interview.

“In my opinion, it is time to move beyond race-based equations in clinical pulmonary medicine, particularly in the context of patients with established lung disease in whom use of race-based equations might actually lead to undertreatment,” said Dr. Gaffney, who was not involved in the study.

Dr. Liu agreed that it’s time to move to race-neutral measures and that the whole concept of race-based differences is flawed.

“The long-standing structural inequities in health likely made the reference populations have lower lung function than among Whites,” she told this news organization.

Dr. Liu said that evaluation of lung function should not rely on spirometry alone, but should also include – when appropriate – CT scans, as well as improved understanding of how symptoms may be predictive for poor outcomes.

The study was supported by grants from the National Institutes of Health. Dr. Liu and Dr. Gaffney have disclosed no relevant financial relationships.

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

Researchers in Scotland have developed a risk calculator using a large electronic health records database that has shown a high reliability in predicting the risk of death for patients hospitalized for chronic occlusive pulmonary disease (COPD), providing another potential tool for improving postdischarge survival in these patients.

In a study published online in the journal Pharmacological Research, Pierpalo Pellicori, MD, and colleagues reported that a few variables, including prescriptions and laboratory data in routine EHRs, could help predict a patient’s risk of dying within 90 days after a hospital stay for COPD. Dr. Pellicori is a clinical cardiologist and research fellow at the Robertson Center for Biostatistics at the University of Glasgow.

“Identification of patients at high risk is valuable information for multidisciplinary teams,” Dr. Pellicori said in a written comment. “It allows the most vulnerable patients to be highlighted and prioritized for consideration of optimized value-based care, and for anticipatory care plan discussions.”

The retrospective cohort study analyzed EHR records of 17,973 patients who had an unplanned hospitalization for COPD in the Glasgow area from 2011 to 2017. The risk calculator model achieved a potential accuracy of 80%.

The study noted that, while a number of models have been developed to calculate the risk of exacerbations, inpatient death and prognosis in patients hospitalized for COPD, most of those models were based on cohorts of 1000 patients or less.

“Older age, male sex, and a longer hospital stay were important predictors of mortality in patients with COPD,” Dr. Pellicori said. “We also found that use of commonly prescribed medications such as digoxin identify patients with COPD more likely to die, perhaps because many have underlying heart failure, a highly prevalent but frequently missed diagnosis.”

He noted that heart failure and COPD share many risk factors, signs, and symptoms, such as smoking history, peripheral edema, and breathlessness. “Distinguishing between COPD and heart failure can be difficult, but is very important, as appropriate treatment for heart failure can improve a patient’s quality of life and survival substantially in many cases.”

The study also found that routinely collected and inexpensive blood markers – such as hemoglobin, neutrophil/lymphocyte ratio, serum chloride, urea, creatinine, and albumin – can also improve predictability of outcomes.

For example, the study found a linear increase in mortality of blood hemoglobin concentration less than 14 g/dL, but higher levels posed no greater risk. Higher white blood cell and neutrophil counts and lower lymphocyte and eosinophil counts were associated with a worse prognosis.

The study also found a linear increase in mortality with serum sodium less than 140 mmol/L or serum chloride less than 105 mmol/L –  but that higher concentrations of each were associated with a worse outcome.

“Interestingly,” Pellicori added, “social deprivation was not associated with mortality in this cohort.”

The final predictive model included age, sex, length of stay, and just nine other variables. “The model can be applied easily in clinical practice, even if electronic records are not available, because there are only 12 variables,” Dr. Pellicori said. “These could easily be entered manually into the risk calculator that we provide.”

“What is notable about this risk calculator is that it uses some of the techniques of machine learning, although it’s not specifically machine learning,” Angel Coz, MD, a pulmonologist at the Cleveland Clinic Respiratory Institute, said in an interview. “But it’s a retrospective data analysis, and actually by doing that it may catch some factors that we may not have necessarily paid attention to on a regular basis.”

While he called it a “well-done study,” Dr. Coz cautioned that “we have to be conservative in how to interpret and apply this because it is retrospective,” adding that future research should also use a prospective cohort.

For future consideration, Dr. Pellicori said that, while EHRs provide a “rich source” of data for such risk calculators, systems differ greatly across hospitals and health care systems and don’t link easily.

Future research would focus on validating the model in other large national datasets and seeing if machine learning can improve its predictability, Dr. Pellicori said. “Whether such models can provide a real-time, refined risk assessment for all patients in both primary or secondary care settings and improve the efficacy, efficiency, and quality of health care is our long-term goal.”

Dr. Pellicori and Dr. Coz disclosed no relevant financial relationships.

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

Researchers in Scotland have developed a risk calculator using a large electronic health records database that has shown a high reliability in predicting the risk of death for patients hospitalized for chronic occlusive pulmonary disease (COPD), providing another potential tool for improving postdischarge survival in these patients.

In a study published online in the journal Pharmacological Research, Pierpalo Pellicori, MD, and colleagues reported that a few variables, including prescriptions and laboratory data in routine EHRs, could help predict a patient’s risk of dying within 90 days after a hospital stay for COPD. Dr. Pellicori is a clinical cardiologist and research fellow at the Robertson Center for Biostatistics at the University of Glasgow.

“Identification of patients at high risk is valuable information for multidisciplinary teams,” Dr. Pellicori said in a written comment. “It allows the most vulnerable patients to be highlighted and prioritized for consideration of optimized value-based care, and for anticipatory care plan discussions.”

The retrospective cohort study analyzed EHR records of 17,973 patients who had an unplanned hospitalization for COPD in the Glasgow area from 2011 to 2017. The risk calculator model achieved a potential accuracy of 80%.

The study noted that, while a number of models have been developed to calculate the risk of exacerbations, inpatient death and prognosis in patients hospitalized for COPD, most of those models were based on cohorts of 1000 patients or less.

“Older age, male sex, and a longer hospital stay were important predictors of mortality in patients with COPD,” Dr. Pellicori said. “We also found that use of commonly prescribed medications such as digoxin identify patients with COPD more likely to die, perhaps because many have underlying heart failure, a highly prevalent but frequently missed diagnosis.”

He noted that heart failure and COPD share many risk factors, signs, and symptoms, such as smoking history, peripheral edema, and breathlessness. “Distinguishing between COPD and heart failure can be difficult, but is very important, as appropriate treatment for heart failure can improve a patient’s quality of life and survival substantially in many cases.”

The study also found that routinely collected and inexpensive blood markers – such as hemoglobin, neutrophil/lymphocyte ratio, serum chloride, urea, creatinine, and albumin – can also improve predictability of outcomes.

For example, the study found a linear increase in mortality of blood hemoglobin concentration less than 14 g/dL, but higher levels posed no greater risk. Higher white blood cell and neutrophil counts and lower lymphocyte and eosinophil counts were associated with a worse prognosis.

The study also found a linear increase in mortality with serum sodium less than 140 mmol/L or serum chloride less than 105 mmol/L –  but that higher concentrations of each were associated with a worse outcome.

“Interestingly,” Pellicori added, “social deprivation was not associated with mortality in this cohort.”

The final predictive model included age, sex, length of stay, and just nine other variables. “The model can be applied easily in clinical practice, even if electronic records are not available, because there are only 12 variables,” Dr. Pellicori said. “These could easily be entered manually into the risk calculator that we provide.”

“What is notable about this risk calculator is that it uses some of the techniques of machine learning, although it’s not specifically machine learning,” Angel Coz, MD, a pulmonologist at the Cleveland Clinic Respiratory Institute, said in an interview. “But it’s a retrospective data analysis, and actually by doing that it may catch some factors that we may not have necessarily paid attention to on a regular basis.”

While he called it a “well-done study,” Dr. Coz cautioned that “we have to be conservative in how to interpret and apply this because it is retrospective,” adding that future research should also use a prospective cohort.

For future consideration, Dr. Pellicori said that, while EHRs provide a “rich source” of data for such risk calculators, systems differ greatly across hospitals and health care systems and don’t link easily.

Future research would focus on validating the model in other large national datasets and seeing if machine learning can improve its predictability, Dr. Pellicori said. “Whether such models can provide a real-time, refined risk assessment for all patients in both primary or secondary care settings and improve the efficacy, efficiency, and quality of health care is our long-term goal.”

Dr. Pellicori and Dr. Coz disclosed no relevant financial relationships.

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

Researchers in Scotland have developed a risk calculator using a large electronic health records database that has shown a high reliability in predicting the risk of death for patients hospitalized for chronic occlusive pulmonary disease (COPD), providing another potential tool for improving postdischarge survival in these patients.

In a study published online in the journal Pharmacological Research, Pierpalo Pellicori, MD, and colleagues reported that a few variables, including prescriptions and laboratory data in routine EHRs, could help predict a patient’s risk of dying within 90 days after a hospital stay for COPD. Dr. Pellicori is a clinical cardiologist and research fellow at the Robertson Center for Biostatistics at the University of Glasgow.

“Identification of patients at high risk is valuable information for multidisciplinary teams,” Dr. Pellicori said in a written comment. “It allows the most vulnerable patients to be highlighted and prioritized for consideration of optimized value-based care, and for anticipatory care plan discussions.”

The retrospective cohort study analyzed EHR records of 17,973 patients who had an unplanned hospitalization for COPD in the Glasgow area from 2011 to 2017. The risk calculator model achieved a potential accuracy of 80%.

The study noted that, while a number of models have been developed to calculate the risk of exacerbations, inpatient death and prognosis in patients hospitalized for COPD, most of those models were based on cohorts of 1000 patients or less.

“Older age, male sex, and a longer hospital stay were important predictors of mortality in patients with COPD,” Dr. Pellicori said. “We also found that use of commonly prescribed medications such as digoxin identify patients with COPD more likely to die, perhaps because many have underlying heart failure, a highly prevalent but frequently missed diagnosis.”

He noted that heart failure and COPD share many risk factors, signs, and symptoms, such as smoking history, peripheral edema, and breathlessness. “Distinguishing between COPD and heart failure can be difficult, but is very important, as appropriate treatment for heart failure can improve a patient’s quality of life and survival substantially in many cases.”

The study also found that routinely collected and inexpensive blood markers – such as hemoglobin, neutrophil/lymphocyte ratio, serum chloride, urea, creatinine, and albumin – can also improve predictability of outcomes.

For example, the study found a linear increase in mortality of blood hemoglobin concentration less than 14 g/dL, but higher levels posed no greater risk. Higher white blood cell and neutrophil counts and lower lymphocyte and eosinophil counts were associated with a worse prognosis.

The study also found a linear increase in mortality with serum sodium less than 140 mmol/L or serum chloride less than 105 mmol/L –  but that higher concentrations of each were associated with a worse outcome.

“Interestingly,” Pellicori added, “social deprivation was not associated with mortality in this cohort.”

The final predictive model included age, sex, length of stay, and just nine other variables. “The model can be applied easily in clinical practice, even if electronic records are not available, because there are only 12 variables,” Dr. Pellicori said. “These could easily be entered manually into the risk calculator that we provide.”

“What is notable about this risk calculator is that it uses some of the techniques of machine learning, although it’s not specifically machine learning,” Angel Coz, MD, a pulmonologist at the Cleveland Clinic Respiratory Institute, said in an interview. “But it’s a retrospective data analysis, and actually by doing that it may catch some factors that we may not have necessarily paid attention to on a regular basis.”

While he called it a “well-done study,” Dr. Coz cautioned that “we have to be conservative in how to interpret and apply this because it is retrospective,” adding that future research should also use a prospective cohort.

For future consideration, Dr. Pellicori said that, while EHRs provide a “rich source” of data for such risk calculators, systems differ greatly across hospitals and health care systems and don’t link easily.

Future research would focus on validating the model in other large national datasets and seeing if machine learning can improve its predictability, Dr. Pellicori said. “Whether such models can provide a real-time, refined risk assessment for all patients in both primary or secondary care settings and improve the efficacy, efficiency, and quality of health care is our long-term goal.”

Dr. Pellicori and Dr. Coz disclosed no relevant financial relationships.

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