Pulmonology

Sometimes we get what we pay for. Other times we pay too much. 

That’s the message of a study published in Annals of Internal Medicine, which finds that a generic maintenance inhaler is as effective at managing symptoms of chronic obstructive pulmonary disorder (COPD) as a pricier branded alternative. 

In 2019, the Food and Drug Administration approved Wixela Inhub (the combination corticosteroid/long-acting beta² adrenergic agonist fluticasone-salmeterol; Viatris) as a generic dry powder inhaler for managing symptoms of COPD. This approval was based on evidence of the generic’s effectiveness against asthma, although COPD also was on the product label. The study authors compared Wixela’s effectiveness in controlling symptoms of COPD with that of the brand name inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline), which uses the same active ingredients.

The result: “The generic looks to be as safe and effective as the brand name. I don’t see a clinical reason why one would ever need to get the brand name over the generic version,” said study author William Feldman, MD, DPhil, MPH, a health services researcher and pulmonologist at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
 

Same types of patients, different inhalers, same outcomes

Dr. Feldman and colleagues compared the medical records of 10,000 patients with COPD who began using the branded inhaler to the records of another 10,000 patients with COPD who opted for the generic alternative. Participants in the two groups were evenly matched by age, sex, race, and ethnicity, region, severity of COPD, and presence of other comorbidities, according to the researchers. Participants were all older than age 40, and the average age in both groups was 72 years.

The researchers looked for a difference in a first episode of a moderate exacerbation of COPD, defined as requiring a course of prednisone for 5-14 days. They also looked for cases of severe COPD exacerbation requiring hospitalization in the year after people began using either the generic or brand name inhaler. And they looked for differences across 1 year in rates of hospitalization for pneumonia.

For none of those outcomes, however, did the type of inhaler appear to matter. Compared with the brand-name drug, using the generic was associated with nearly identical rates of moderate or severe COPD exacerbation (hazard ratio, 0.97; 95% confidence interval, 0.90-1.04. The same was true for the proportion of people who went to the hospital for pneumonia at least once (HR, 0.99; 95% CI, 0.86-1.15).

“To get through the FDA as an interchangeable generic, the generic firms have to show that their product can be used in just the same way as the brand-name version,” Dr. Feldman said, which may explain why the generic and brand-name versions of the inhaler performed so similarly.

Dr. Feldman cautioned that the price savings for patients who opt for the generic over the branded product are hard to determine, given the vagaries of different insurance plans and potential rebates when using the branded project. As a general matter, having a single generic competitor will not lower costs much, Dr. Feldman noted, pointing to 2017 research from Harvard that found a profusion of generic competitors is needed to significantly lower health care costs.

“I don’t want to in any way underestimate the importance of getting that first generic onto the market, because it sets the stage for future generics,” Dr. Feldman said.  

“There are very few generic options for patients with COPD,” said Surya Bhatt, MD, director of the Pulmonary Function and Exercise Physiology Lab at the University of Alabama at Birmingham. Even the rescue inhalers that people with COPD use to manage acute episodes of the condition are usually branded at this time, Dr. Bhatt noted, with few generic options.*

“The results are quite compelling,” said Dr. Bhatt, who was not involved in the research. Although the trial was not randomized, he commended the researchers for stratifying participants in the two groups to be as comparable as possible.

Dr. Bhatt noted that the FDA’s 2019 approval – given that the agency requires bioequivalence studies between branded and generic products – was enough to cause him to begin prescribing the generic inhaler. The fact that this approval was based on asthma but not also COPD is not a concern.

“There are so many similarities between asthma, COPD, and some obstructive lung diseases,” Dr. Bhatt noted.

In his experience, the only time someone with COPD continues using the branded inhaler – now that a potentially cheaper generic is available – is when their insurance plan makes their out-of-pocket cost minimal. Otherwise, brand loyalty does not exist.

“Patients are generally okay with being on a generic for inhalers, just because of the high cost,” Dr. Bhatt said.

The study was primarily supported by the National Heart, Lung, and Blood Institute. Dr. Feldman reported funding from Arnold Ventures, the Commonwealth Fund, and the FDA, and consulting relationships with Alosa Health and Aetion. Dr. Bhatt reported no relevant financial relationships.

*Correction, 8/16/23: An earlier version of this article mischaracterized Dr. Bhatt's comments on the availability of generic options.

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

Sometimes we get what we pay for. Other times we pay too much. 

That’s the message of a study published in Annals of Internal Medicine, which finds that a generic maintenance inhaler is as effective at managing symptoms of chronic obstructive pulmonary disorder (COPD) as a pricier branded alternative. 

In 2019, the Food and Drug Administration approved Wixela Inhub (the combination corticosteroid/long-acting beta² adrenergic agonist fluticasone-salmeterol; Viatris) as a generic dry powder inhaler for managing symptoms of COPD. This approval was based on evidence of the generic’s effectiveness against asthma, although COPD also was on the product label. The study authors compared Wixela’s effectiveness in controlling symptoms of COPD with that of the brand name inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline), which uses the same active ingredients.

The result: “The generic looks to be as safe and effective as the brand name. I don’t see a clinical reason why one would ever need to get the brand name over the generic version,” said study author William Feldman, MD, DPhil, MPH, a health services researcher and pulmonologist at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
 

Same types of patients, different inhalers, same outcomes

Dr. Feldman and colleagues compared the medical records of 10,000 patients with COPD who began using the branded inhaler to the records of another 10,000 patients with COPD who opted for the generic alternative. Participants in the two groups were evenly matched by age, sex, race, and ethnicity, region, severity of COPD, and presence of other comorbidities, according to the researchers. Participants were all older than age 40, and the average age in both groups was 72 years.

The researchers looked for a difference in a first episode of a moderate exacerbation of COPD, defined as requiring a course of prednisone for 5-14 days. They also looked for cases of severe COPD exacerbation requiring hospitalization in the year after people began using either the generic or brand name inhaler. And they looked for differences across 1 year in rates of hospitalization for pneumonia.

For none of those outcomes, however, did the type of inhaler appear to matter. Compared with the brand-name drug, using the generic was associated with nearly identical rates of moderate or severe COPD exacerbation (hazard ratio, 0.97; 95% confidence interval, 0.90-1.04. The same was true for the proportion of people who went to the hospital for pneumonia at least once (HR, 0.99; 95% CI, 0.86-1.15).

“To get through the FDA as an interchangeable generic, the generic firms have to show that their product can be used in just the same way as the brand-name version,” Dr. Feldman said, which may explain why the generic and brand-name versions of the inhaler performed so similarly.

Dr. Feldman cautioned that the price savings for patients who opt for the generic over the branded product are hard to determine, given the vagaries of different insurance plans and potential rebates when using the branded project. As a general matter, having a single generic competitor will not lower costs much, Dr. Feldman noted, pointing to 2017 research from Harvard that found a profusion of generic competitors is needed to significantly lower health care costs.

“I don’t want to in any way underestimate the importance of getting that first generic onto the market, because it sets the stage for future generics,” Dr. Feldman said.  

“There are very few generic options for patients with COPD,” said Surya Bhatt, MD, director of the Pulmonary Function and Exercise Physiology Lab at the University of Alabama at Birmingham. Even the rescue inhalers that people with COPD use to manage acute episodes of the condition are usually branded at this time, Dr. Bhatt noted, with few generic options.*

“The results are quite compelling,” said Dr. Bhatt, who was not involved in the research. Although the trial was not randomized, he commended the researchers for stratifying participants in the two groups to be as comparable as possible.

Dr. Bhatt noted that the FDA’s 2019 approval – given that the agency requires bioequivalence studies between branded and generic products – was enough to cause him to begin prescribing the generic inhaler. The fact that this approval was based on asthma but not also COPD is not a concern.

“There are so many similarities between asthma, COPD, and some obstructive lung diseases,” Dr. Bhatt noted.

In his experience, the only time someone with COPD continues using the branded inhaler – now that a potentially cheaper generic is available – is when their insurance plan makes their out-of-pocket cost minimal. Otherwise, brand loyalty does not exist.

“Patients are generally okay with being on a generic for inhalers, just because of the high cost,” Dr. Bhatt said.

The study was primarily supported by the National Heart, Lung, and Blood Institute. Dr. Feldman reported funding from Arnold Ventures, the Commonwealth Fund, and the FDA, and consulting relationships with Alosa Health and Aetion. Dr. Bhatt reported no relevant financial relationships.

*Correction, 8/16/23: An earlier version of this article mischaracterized Dr. Bhatt's comments on the availability of generic options.

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

Sometimes we get what we pay for. Other times we pay too much. 

That’s the message of a study published in Annals of Internal Medicine, which finds that a generic maintenance inhaler is as effective at managing symptoms of chronic obstructive pulmonary disorder (COPD) as a pricier branded alternative. 

In 2019, the Food and Drug Administration approved Wixela Inhub (the combination corticosteroid/long-acting beta² adrenergic agonist fluticasone-salmeterol; Viatris) as a generic dry powder inhaler for managing symptoms of COPD. This approval was based on evidence of the generic’s effectiveness against asthma, although COPD also was on the product label. The study authors compared Wixela’s effectiveness in controlling symptoms of COPD with that of the brand name inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline), which uses the same active ingredients.

The result: “The generic looks to be as safe and effective as the brand name. I don’t see a clinical reason why one would ever need to get the brand name over the generic version,” said study author William Feldman, MD, DPhil, MPH, a health services researcher and pulmonologist at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
 

Same types of patients, different inhalers, same outcomes

Dr. Feldman and colleagues compared the medical records of 10,000 patients with COPD who began using the branded inhaler to the records of another 10,000 patients with COPD who opted for the generic alternative. Participants in the two groups were evenly matched by age, sex, race, and ethnicity, region, severity of COPD, and presence of other comorbidities, according to the researchers. Participants were all older than age 40, and the average age in both groups was 72 years.

The researchers looked for a difference in a first episode of a moderate exacerbation of COPD, defined as requiring a course of prednisone for 5-14 days. They also looked for cases of severe COPD exacerbation requiring hospitalization in the year after people began using either the generic or brand name inhaler. And they looked for differences across 1 year in rates of hospitalization for pneumonia.

For none of those outcomes, however, did the type of inhaler appear to matter. Compared with the brand-name drug, using the generic was associated with nearly identical rates of moderate or severe COPD exacerbation (hazard ratio, 0.97; 95% confidence interval, 0.90-1.04. The same was true for the proportion of people who went to the hospital for pneumonia at least once (HR, 0.99; 95% CI, 0.86-1.15).

“To get through the FDA as an interchangeable generic, the generic firms have to show that their product can be used in just the same way as the brand-name version,” Dr. Feldman said, which may explain why the generic and brand-name versions of the inhaler performed so similarly.

Dr. Feldman cautioned that the price savings for patients who opt for the generic over the branded product are hard to determine, given the vagaries of different insurance plans and potential rebates when using the branded project. As a general matter, having a single generic competitor will not lower costs much, Dr. Feldman noted, pointing to 2017 research from Harvard that found a profusion of generic competitors is needed to significantly lower health care costs.

“I don’t want to in any way underestimate the importance of getting that first generic onto the market, because it sets the stage for future generics,” Dr. Feldman said.  

“There are very few generic options for patients with COPD,” said Surya Bhatt, MD, director of the Pulmonary Function and Exercise Physiology Lab at the University of Alabama at Birmingham. Even the rescue inhalers that people with COPD use to manage acute episodes of the condition are usually branded at this time, Dr. Bhatt noted, with few generic options.*

“The results are quite compelling,” said Dr. Bhatt, who was not involved in the research. Although the trial was not randomized, he commended the researchers for stratifying participants in the two groups to be as comparable as possible.

Dr. Bhatt noted that the FDA’s 2019 approval – given that the agency requires bioequivalence studies between branded and generic products – was enough to cause him to begin prescribing the generic inhaler. The fact that this approval was based on asthma but not also COPD is not a concern.

“There are so many similarities between asthma, COPD, and some obstructive lung diseases,” Dr. Bhatt noted.

In his experience, the only time someone with COPD continues using the branded inhaler – now that a potentially cheaper generic is available – is when their insurance plan makes their out-of-pocket cost minimal. Otherwise, brand loyalty does not exist.

“Patients are generally okay with being on a generic for inhalers, just because of the high cost,” Dr. Bhatt said.

The study was primarily supported by the National Heart, Lung, and Blood Institute. Dr. Feldman reported funding from Arnold Ventures, the Commonwealth Fund, and the FDA, and consulting relationships with Alosa Health and Aetion. Dr. Bhatt reported no relevant financial relationships.

*Correction, 8/16/23: An earlier version of this article mischaracterized Dr. Bhatt's comments on the availability of generic options.

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

Chronic obstructive pulmonary disease and a new phenotype of lung function impairment predicted progression of frailty in older adults, based on data from more than 5,000 individuals.

COPD has been associated with frailty, but longitudinal data on the association of COPD with progression of frailty are limited, as are data on the potential association of preserved ratio impaired spirometry (PRISm) with frailty progression, wrote Di He, BS, of Zhejiang University, China, and colleagues. 

PRISm has been defined in recent studies as “proportional impairments in FEV1 and FVC, resulting in the normal ratio of FEV1 and FVC.” Individuals with PRISm may transition to normal spirometry or COPD over time, the researchers wrote.

In a study published in the journal Chest, the researchers reviewed data from 5,901 adults aged 50 years and older who were participating on the English Longitudinal Study of Ageing (ELSA), a prospective cohort study. Of these, 3,765 were included in an additional analysis of the association between transitions from normal spirometry to PRISm and the progression of frailty. The mean age of the participants was 65.5 years; 54.9% were women.

The median follow-up period for analysis with frailty progression was 9.5 years for PRISm and COPD and 5.8 years for PRISm transitions. Lung function data were collected at baseline. Based on spirometry data, participants were divided into three lung function groups – normal spirometry, PRISm, and COPD – and each of these was classified based on severity. Frailty was assessed using the frailty index (FI) during the follow-up period.

Frailty progression based on FI was significantly accelerated in patients with PRISm and COPD, compared with individuals with normal spirometry, with additional annual increases of 0.301 and 0.172, respectively (P < .001 for both). 

When stratified by severity, individuals with more severe PRISm and with more COPD had higher baseline FI and faster FI progression, compared with those with mild PRISm and COPD. 

PRISm transitions were assessed over a 4-year interval at the start of the ELSA. Individuals with normal spirometry who transitioned to PRISm during the study had accelerated progression of frailty, as did those with COPD who transitioned to PRISm. However, no significant frailty progression occurred in those who changed from PRISm to normal spirometry. 

The mechanisms behind the associations of PRISm and COPD with frailty remain unclear, but the results were consistent after controlling for multiple confounders, “suggesting PRISm and COPD had independent pathophysiological mechanisms for frailty,” the researchers write in their discussion. Other recent studies have identified sarcopenia as a complication for individuals with lung function impairment, they noted. “Therefore, another plausible explanation could be that PRISm and COPD caused sarcopenia, which accelerated frailty progression,” they say.

The findings were limited by several factors, including the observational design and the potential underestimation of lung function in participants with reversible airflow obstruction because of the use of prebronchodilator spirometry in the cohort study, the researchers noted. 

However, the results were strengthened by the large sample size and high-quality data from the ELSA, as well as by the repeat measures of FI and lung function. The results were consistent after controlling for multiple confounders, and support the need for more research to explore the causality behind the association of PRISm and COPD with frailty, the researchers concluded. 

The study was supported by the Zhejiang Provincial Basic Public Welfare Research Project, the Zhoushan Science and Technology Project, and the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province. The researchers report no relevant financial relationships.

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

Chronic obstructive pulmonary disease and a new phenotype of lung function impairment predicted progression of frailty in older adults, based on data from more than 5,000 individuals.

COPD has been associated with frailty, but longitudinal data on the association of COPD with progression of frailty are limited, as are data on the potential association of preserved ratio impaired spirometry (PRISm) with frailty progression, wrote Di He, BS, of Zhejiang University, China, and colleagues. 

PRISm has been defined in recent studies as “proportional impairments in FEV1 and FVC, resulting in the normal ratio of FEV1 and FVC.” Individuals with PRISm may transition to normal spirometry or COPD over time, the researchers wrote.

In a study published in the journal Chest, the researchers reviewed data from 5,901 adults aged 50 years and older who were participating on the English Longitudinal Study of Ageing (ELSA), a prospective cohort study. Of these, 3,765 were included in an additional analysis of the association between transitions from normal spirometry to PRISm and the progression of frailty. The mean age of the participants was 65.5 years; 54.9% were women.

The median follow-up period for analysis with frailty progression was 9.5 years for PRISm and COPD and 5.8 years for PRISm transitions. Lung function data were collected at baseline. Based on spirometry data, participants were divided into three lung function groups – normal spirometry, PRISm, and COPD – and each of these was classified based on severity. Frailty was assessed using the frailty index (FI) during the follow-up period.

Frailty progression based on FI was significantly accelerated in patients with PRISm and COPD, compared with individuals with normal spirometry, with additional annual increases of 0.301 and 0.172, respectively (P < .001 for both). 

When stratified by severity, individuals with more severe PRISm and with more COPD had higher baseline FI and faster FI progression, compared with those with mild PRISm and COPD. 

PRISm transitions were assessed over a 4-year interval at the start of the ELSA. Individuals with normal spirometry who transitioned to PRISm during the study had accelerated progression of frailty, as did those with COPD who transitioned to PRISm. However, no significant frailty progression occurred in those who changed from PRISm to normal spirometry. 

The mechanisms behind the associations of PRISm and COPD with frailty remain unclear, but the results were consistent after controlling for multiple confounders, “suggesting PRISm and COPD had independent pathophysiological mechanisms for frailty,” the researchers write in their discussion. Other recent studies have identified sarcopenia as a complication for individuals with lung function impairment, they noted. “Therefore, another plausible explanation could be that PRISm and COPD caused sarcopenia, which accelerated frailty progression,” they say.

The findings were limited by several factors, including the observational design and the potential underestimation of lung function in participants with reversible airflow obstruction because of the use of prebronchodilator spirometry in the cohort study, the researchers noted. 

However, the results were strengthened by the large sample size and high-quality data from the ELSA, as well as by the repeat measures of FI and lung function. The results were consistent after controlling for multiple confounders, and support the need for more research to explore the causality behind the association of PRISm and COPD with frailty, the researchers concluded. 

The study was supported by the Zhejiang Provincial Basic Public Welfare Research Project, the Zhoushan Science and Technology Project, and the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province. The researchers report no relevant financial relationships.

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

Chronic obstructive pulmonary disease and a new phenotype of lung function impairment predicted progression of frailty in older adults, based on data from more than 5,000 individuals.

COPD has been associated with frailty, but longitudinal data on the association of COPD with progression of frailty are limited, as are data on the potential association of preserved ratio impaired spirometry (PRISm) with frailty progression, wrote Di He, BS, of Zhejiang University, China, and colleagues. 

PRISm has been defined in recent studies as “proportional impairments in FEV1 and FVC, resulting in the normal ratio of FEV1 and FVC.” Individuals with PRISm may transition to normal spirometry or COPD over time, the researchers wrote.

In a study published in the journal Chest, the researchers reviewed data from 5,901 adults aged 50 years and older who were participating on the English Longitudinal Study of Ageing (ELSA), a prospective cohort study. Of these, 3,765 were included in an additional analysis of the association between transitions from normal spirometry to PRISm and the progression of frailty. The mean age of the participants was 65.5 years; 54.9% were women.

The median follow-up period for analysis with frailty progression was 9.5 years for PRISm and COPD and 5.8 years for PRISm transitions. Lung function data were collected at baseline. Based on spirometry data, participants were divided into three lung function groups – normal spirometry, PRISm, and COPD – and each of these was classified based on severity. Frailty was assessed using the frailty index (FI) during the follow-up period.

Frailty progression based on FI was significantly accelerated in patients with PRISm and COPD, compared with individuals with normal spirometry, with additional annual increases of 0.301 and 0.172, respectively (P < .001 for both). 

When stratified by severity, individuals with more severe PRISm and with more COPD had higher baseline FI and faster FI progression, compared with those with mild PRISm and COPD. 

PRISm transitions were assessed over a 4-year interval at the start of the ELSA. Individuals with normal spirometry who transitioned to PRISm during the study had accelerated progression of frailty, as did those with COPD who transitioned to PRISm. However, no significant frailty progression occurred in those who changed from PRISm to normal spirometry. 

The mechanisms behind the associations of PRISm and COPD with frailty remain unclear, but the results were consistent after controlling for multiple confounders, “suggesting PRISm and COPD had independent pathophysiological mechanisms for frailty,” the researchers write in their discussion. Other recent studies have identified sarcopenia as a complication for individuals with lung function impairment, they noted. “Therefore, another plausible explanation could be that PRISm and COPD caused sarcopenia, which accelerated frailty progression,” they say.

The findings were limited by several factors, including the observational design and the potential underestimation of lung function in participants with reversible airflow obstruction because of the use of prebronchodilator spirometry in the cohort study, the researchers noted. 

However, the results were strengthened by the large sample size and high-quality data from the ELSA, as well as by the repeat measures of FI and lung function. The results were consistent after controlling for multiple confounders, and support the need for more research to explore the causality behind the association of PRISm and COPD with frailty, the researchers concluded. 

The study was supported by the Zhejiang Provincial Basic Public Welfare Research Project, the Zhoushan Science and Technology Project, and the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province. The researchers report no relevant financial relationships.

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

Adults with exacerbations of chronic obstructive pulmonary disease (ECOPD) whose condition was classified as severe using the Rome criteria had a higher risk of death at 1 year than those who were classified as having moderate or mild disease, as determined from data from more than 300 individuals.

Patients hospitalized with severe exacerbations of ECOPD are at increased risk for worse clinical outcomes and death, so early identification is important, Ernesto Crisafulli, MD, of the University of Verona (Italy) and Azienda Ospedaliera Universitaria Integrata of Verona, and colleagues wrote.

To help predict prognosis for patients with ECOPD, an expert opinion group updated the definition of ECOPD using a new severity classification known as the Rome definition, which grades ECOPD as mild, moderate, or severe on the basis of more objective and disease-related aspects. However, data on the clinical usefulness of the Rome criteria are limited.

In a study published in the journal Chest, the researchers retrospectively categorized 347 adults hospitalized with ECOPD using the Rome severity classifications of mild, moderate, and severe.

Classifications were made using baseline, clinical and microbiological factors, as well as gas analysis and laboratory variables. The researchers also reviewed data on the length of hospital stay and mortality (in-hospital and over a follow-up of 6 months to 3 years).

Approximately one-third of the patients (39%) were classified as having mild disease, 31% as having moderate disease, and 30% as having severe illness. Overall, hospital stay was significantly longer for the patients with severe disease, although in-hospital mortality was similar across all three groups.

Patients classified as having severe disease also had a worse prognosis at all follow-up time points, and severe classification was significantly associated with worse cumulative survival at 1 year and 3 years (Gehan-Breslow-Wilson test, P = .032 and P = .004, respectively).

In a multivariate analysis, the risk of death at 1 year was significantly higher among patients classified as severe or moderate (hazard ratio, 1.99 and 1.47, respectively), compared with those classified as mild.

Mortality risk also was higher among patients aged 80 years and older and among those requiring long-term oxygen therapy or with a history of ECOPD episodes, the researchers noted. Body mass index in the range of 25-29 kg/m² was associated with lower risk.

The study was limited by several factors, including the replacement of dyspnea perception in the Rome classification with other objective measures, the researchers wrote. Other limitations include the retrospective design, small sample size, use of data from a single center, and lack of data on causes of mortality. Women were underrepresented in the study, and so additional research involving women is needed.

The results suggest that the Rome classification allows for the effective identification of patients with ECOPD who have a worse prognosis. The Rome classification may help guide disease management through targeted interventions and personalized care programs for this population, the researchers concluded.

The study received no outside funding. The researchers disclosed no relevant financial relationships.

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

Adults with exacerbations of chronic obstructive pulmonary disease (ECOPD) whose condition was classified as severe using the Rome criteria had a higher risk of death at 1 year than those who were classified as having moderate or mild disease, as determined from data from more than 300 individuals.

Patients hospitalized with severe exacerbations of ECOPD are at increased risk for worse clinical outcomes and death, so early identification is important, Ernesto Crisafulli, MD, of the University of Verona (Italy) and Azienda Ospedaliera Universitaria Integrata of Verona, and colleagues wrote.

To help predict prognosis for patients with ECOPD, an expert opinion group updated the definition of ECOPD using a new severity classification known as the Rome definition, which grades ECOPD as mild, moderate, or severe on the basis of more objective and disease-related aspects. However, data on the clinical usefulness of the Rome criteria are limited.

In a study published in the journal Chest, the researchers retrospectively categorized 347 adults hospitalized with ECOPD using the Rome severity classifications of mild, moderate, and severe.

Classifications were made using baseline, clinical and microbiological factors, as well as gas analysis and laboratory variables. The researchers also reviewed data on the length of hospital stay and mortality (in-hospital and over a follow-up of 6 months to 3 years).

Approximately one-third of the patients (39%) were classified as having mild disease, 31% as having moderate disease, and 30% as having severe illness. Overall, hospital stay was significantly longer for the patients with severe disease, although in-hospital mortality was similar across all three groups.

Patients classified as having severe disease also had a worse prognosis at all follow-up time points, and severe classification was significantly associated with worse cumulative survival at 1 year and 3 years (Gehan-Breslow-Wilson test, P = .032 and P = .004, respectively).

In a multivariate analysis, the risk of death at 1 year was significantly higher among patients classified as severe or moderate (hazard ratio, 1.99 and 1.47, respectively), compared with those classified as mild.

Mortality risk also was higher among patients aged 80 years and older and among those requiring long-term oxygen therapy or with a history of ECOPD episodes, the researchers noted. Body mass index in the range of 25-29 kg/m² was associated with lower risk.

The study was limited by several factors, including the replacement of dyspnea perception in the Rome classification with other objective measures, the researchers wrote. Other limitations include the retrospective design, small sample size, use of data from a single center, and lack of data on causes of mortality. Women were underrepresented in the study, and so additional research involving women is needed.

The results suggest that the Rome classification allows for the effective identification of patients with ECOPD who have a worse prognosis. The Rome classification may help guide disease management through targeted interventions and personalized care programs for this population, the researchers concluded.

The study received no outside funding. The researchers disclosed no relevant financial relationships.

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

Adults with exacerbations of chronic obstructive pulmonary disease (ECOPD) whose condition was classified as severe using the Rome criteria had a higher risk of death at 1 year than those who were classified as having moderate or mild disease, as determined from data from more than 300 individuals.

Patients hospitalized with severe exacerbations of ECOPD are at increased risk for worse clinical outcomes and death, so early identification is important, Ernesto Crisafulli, MD, of the University of Verona (Italy) and Azienda Ospedaliera Universitaria Integrata of Verona, and colleagues wrote.

To help predict prognosis for patients with ECOPD, an expert opinion group updated the definition of ECOPD using a new severity classification known as the Rome definition, which grades ECOPD as mild, moderate, or severe on the basis of more objective and disease-related aspects. However, data on the clinical usefulness of the Rome criteria are limited.

In a study published in the journal Chest, the researchers retrospectively categorized 347 adults hospitalized with ECOPD using the Rome severity classifications of mild, moderate, and severe.

Classifications were made using baseline, clinical and microbiological factors, as well as gas analysis and laboratory variables. The researchers also reviewed data on the length of hospital stay and mortality (in-hospital and over a follow-up of 6 months to 3 years).

Approximately one-third of the patients (39%) were classified as having mild disease, 31% as having moderate disease, and 30% as having severe illness. Overall, hospital stay was significantly longer for the patients with severe disease, although in-hospital mortality was similar across all three groups.

Patients classified as having severe disease also had a worse prognosis at all follow-up time points, and severe classification was significantly associated with worse cumulative survival at 1 year and 3 years (Gehan-Breslow-Wilson test, P = .032 and P = .004, respectively).

In a multivariate analysis, the risk of death at 1 year was significantly higher among patients classified as severe or moderate (hazard ratio, 1.99 and 1.47, respectively), compared with those classified as mild.

Mortality risk also was higher among patients aged 80 years and older and among those requiring long-term oxygen therapy or with a history of ECOPD episodes, the researchers noted. Body mass index in the range of 25-29 kg/m² was associated with lower risk.

The study was limited by several factors, including the replacement of dyspnea perception in the Rome classification with other objective measures, the researchers wrote. Other limitations include the retrospective design, small sample size, use of data from a single center, and lack of data on causes of mortality. Women were underrepresented in the study, and so additional research involving women is needed.

The results suggest that the Rome classification allows for the effective identification of patients with ECOPD who have a worse prognosis. The Rome classification may help guide disease management through targeted interventions and personalized care programs for this population, the researchers concluded.

The study received no outside funding. The researchers disclosed no relevant financial relationships.

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

COVID-19 hospitalizations continue their steady summer march upward, and now a new variant has perched atop the list of the most prevalent forms of the virus.

Called “Eris” among avid COVID trackers, the strain EG.5 now accounts for 17% of all U.S. COVID infections, according to the latest Centers for Disease Control and Prevention estimates. That’s up from 12% the week prior. 

EG.5 has been rising worldwide, just weeks after the World Health Organization added the strain to its official monitoring list. In the United Kingdom, it now accounts for 1 in 10 COVID cases, The Independent reported.

EG.5 is a descendant of the XBB strains that have dominated tracking lists in recent months. It has the same makeup as XBB.1.9.2 but carries an extra spike mutation, according to a summary published by the Center for Infectious Disease Research and Policy at the University of Minnesota. The spike protein is the part of the virus that allows it to enter human cells. But there’s no indication so far that EG.5 is more contagious or severe than other recent variants, according to the CIDRAP summary and a recent podcast from the American Medical Association. The CDC said that current vaccines protect against the variant.

U.S. hospitals saw a 12% increase in COVID admissions during the week ending on July 22, with 8,047 people being admitted because of the virus, up from an all-time low of 6,306 the week of June 24. In 17 states, the past-week increase in hospitalizations was 20% or greater. In Minnesota, the rate jumped by 50%, and in West Virginia, it jumped by 63%. Meanwhile, deaths reached their lowest weekly rate ever for the week of data ending July 29, with just 176 deaths reported by the CDC.

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

COVID-19 hospitalizations continue their steady summer march upward, and now a new variant has perched atop the list of the most prevalent forms of the virus.

Called “Eris” among avid COVID trackers, the strain EG.5 now accounts for 17% of all U.S. COVID infections, according to the latest Centers for Disease Control and Prevention estimates. That’s up from 12% the week prior. 

EG.5 has been rising worldwide, just weeks after the World Health Organization added the strain to its official monitoring list. In the United Kingdom, it now accounts for 1 in 10 COVID cases, The Independent reported.

EG.5 is a descendant of the XBB strains that have dominated tracking lists in recent months. It has the same makeup as XBB.1.9.2 but carries an extra spike mutation, according to a summary published by the Center for Infectious Disease Research and Policy at the University of Minnesota. The spike protein is the part of the virus that allows it to enter human cells. But there’s no indication so far that EG.5 is more contagious or severe than other recent variants, according to the CIDRAP summary and a recent podcast from the American Medical Association. The CDC said that current vaccines protect against the variant.

U.S. hospitals saw a 12% increase in COVID admissions during the week ending on July 22, with 8,047 people being admitted because of the virus, up from an all-time low of 6,306 the week of June 24. In 17 states, the past-week increase in hospitalizations was 20% or greater. In Minnesota, the rate jumped by 50%, and in West Virginia, it jumped by 63%. Meanwhile, deaths reached their lowest weekly rate ever for the week of data ending July 29, with just 176 deaths reported by the CDC.

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

COVID-19 hospitalizations continue their steady summer march upward, and now a new variant has perched atop the list of the most prevalent forms of the virus.

Called “Eris” among avid COVID trackers, the strain EG.5 now accounts for 17% of all U.S. COVID infections, according to the latest Centers for Disease Control and Prevention estimates. That’s up from 12% the week prior. 

EG.5 has been rising worldwide, just weeks after the World Health Organization added the strain to its official monitoring list. In the United Kingdom, it now accounts for 1 in 10 COVID cases, The Independent reported.

EG.5 is a descendant of the XBB strains that have dominated tracking lists in recent months. It has the same makeup as XBB.1.9.2 but carries an extra spike mutation, according to a summary published by the Center for Infectious Disease Research and Policy at the University of Minnesota. The spike protein is the part of the virus that allows it to enter human cells. But there’s no indication so far that EG.5 is more contagious or severe than other recent variants, according to the CIDRAP summary and a recent podcast from the American Medical Association. The CDC said that current vaccines protect against the variant.

U.S. hospitals saw a 12% increase in COVID admissions during the week ending on July 22, with 8,047 people being admitted because of the virus, up from an all-time low of 6,306 the week of June 24. In 17 states, the past-week increase in hospitalizations was 20% or greater. In Minnesota, the rate jumped by 50%, and in West Virginia, it jumped by 63%. Meanwhile, deaths reached their lowest weekly rate ever for the week of data ending July 29, with just 176 deaths reported by the CDC.

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

The recent statement on interpretive strategies for lung testing uses the acronym PRISm for preserved ratio impaired spirometry. PRISm identifies patients with a normal forced expiratory volume in 1 second/forced vital capacity ratio but abnormal FEV₁ and/or FVC (usually both). Most medical students are taught to call this a “restrictive pattern,” and every first-year pulmonary fellow orders full lung volumes when they see it. If total lung capacity (TLC) is normal, PRISm becomes the nonspecific pattern. If TLC is low, then the patient has “true” restriction, and if it’s elevated, then hyperinflation may be present.

The traditional classification scheme for basic spirometry interpretation (normal, restricted, obstructed, or mixed) is simple and conceptually clear. Because this simplicity is achieved at the expense of precision, the “restrictive pattern” label is due for retirement. It turns out that many with this pattern won’t have an abnormal TLC, so the name is, in some ways, a misnomer and can be misleading. Enter PRISm, a more descriptive and inclusive term. The phrase also lends itself to a phonetic acronym that is fun to say, easy to remember, and likely to catch on with learners.

Information on occurrence and clinical behavior comes from large cohorts with basic spirometry, but without full lung volumes because PRISm no longer applies once TLC is determined. As may be expected, prevalence varies by the population studied. Estimates for general populations have been in the 7%-12% range; however, one study examining a database of patients with clinical spirometry referrals found a prevalence of 22.3%. Rates may be far higher in low- and middle-income countries. Identified risk factors include sex, tobacco use, and body mass index; the presence of PRISm is associated with respiratory symptoms and mortality. Thus, PRISm is common and it matters.

Along with PRISm, the nonspecific pattern is a new addition, if not a new concept, to the 2022 interpretative strategies statement. As with PRISm, the title is necessarily broad, though far less imaginative. Defined by reductions in FEV₁ and FVC and a normal TLC, the nonspecific pattern has classically been considered a marker of early airway disease. The idea is that early, heterogeneous closure of distal segments of the bronchial tree can reduce total volume during a forced expiration before affecting the FEV₁/FVC. The fact that the TLC is not a forced maneuver means there is proportionately less effect from more collapsible/susceptible smaller units. More recent data suggest that there are additional causes.

Because the nonspecific pattern requires full lung volumes, we have less population-level data than for PRISm. Estimated prevalence is approximately 9.5% in patients with complete test results. The two most common causes are obesity and airway obstruction, and the pattern is relatively stable over time. Notably, an increase in specific airway resistance or TLC minus alveolar volume difference predicts progression to frank obstruction on spirometry.

The physiologic changes that obesity inflicts on the lung have been well described. Patients with obesity breathe at lower lung volumes and are therefore susceptible to small airway closure at rest and during forced expiration. There is no doubt that the increased recognition of PRISm and the nonspecific pattern is in part related to the worldwide rise in obesity rates.
 

Key takeaways

In summary, PRISm and the nonspecific pattern are now part of the classification scheme we use for spirometry and full lung volumes, respectively. They should be included in interpretations given their diagnostic and predictive value. Airway disease and obesity are common causes and often coexist with either pattern. Many will not have a true, restrictive lung deficit, and a reductionist approach to interpretation is likely to lead to erroneous diagnoses. There were many important updates included in the 2022 iteration on lung testing interpretation that should not fly under the radar.

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

A version of this article appeared on Medscape.com.

The recent statement on interpretive strategies for lung testing uses the acronym PRISm for preserved ratio impaired spirometry. PRISm identifies patients with a normal forced expiratory volume in 1 second/forced vital capacity ratio but abnormal FEV₁ and/or FVC (usually both). Most medical students are taught to call this a “restrictive pattern,” and every first-year pulmonary fellow orders full lung volumes when they see it. If total lung capacity (TLC) is normal, PRISm becomes the nonspecific pattern. If TLC is low, then the patient has “true” restriction, and if it’s elevated, then hyperinflation may be present.

The traditional classification scheme for basic spirometry interpretation (normal, restricted, obstructed, or mixed) is simple and conceptually clear. Because this simplicity is achieved at the expense of precision, the “restrictive pattern” label is due for retirement. It turns out that many with this pattern won’t have an abnormal TLC, so the name is, in some ways, a misnomer and can be misleading. Enter PRISm, a more descriptive and inclusive term. The phrase also lends itself to a phonetic acronym that is fun to say, easy to remember, and likely to catch on with learners.

Information on occurrence and clinical behavior comes from large cohorts with basic spirometry, but without full lung volumes because PRISm no longer applies once TLC is determined. As may be expected, prevalence varies by the population studied. Estimates for general populations have been in the 7%-12% range; however, one study examining a database of patients with clinical spirometry referrals found a prevalence of 22.3%. Rates may be far higher in low- and middle-income countries. Identified risk factors include sex, tobacco use, and body mass index; the presence of PRISm is associated with respiratory symptoms and mortality. Thus, PRISm is common and it matters.

Along with PRISm, the nonspecific pattern is a new addition, if not a new concept, to the 2022 interpretative strategies statement. As with PRISm, the title is necessarily broad, though far less imaginative. Defined by reductions in FEV₁ and FVC and a normal TLC, the nonspecific pattern has classically been considered a marker of early airway disease. The idea is that early, heterogeneous closure of distal segments of the bronchial tree can reduce total volume during a forced expiration before affecting the FEV₁/FVC. The fact that the TLC is not a forced maneuver means there is proportionately less effect from more collapsible/susceptible smaller units. More recent data suggest that there are additional causes.

Because the nonspecific pattern requires full lung volumes, we have less population-level data than for PRISm. Estimated prevalence is approximately 9.5% in patients with complete test results. The two most common causes are obesity and airway obstruction, and the pattern is relatively stable over time. Notably, an increase in specific airway resistance or TLC minus alveolar volume difference predicts progression to frank obstruction on spirometry.

The physiologic changes that obesity inflicts on the lung have been well described. Patients with obesity breathe at lower lung volumes and are therefore susceptible to small airway closure at rest and during forced expiration. There is no doubt that the increased recognition of PRISm and the nonspecific pattern is in part related to the worldwide rise in obesity rates.
 

Key takeaways

In summary, PRISm and the nonspecific pattern are now part of the classification scheme we use for spirometry and full lung volumes, respectively. They should be included in interpretations given their diagnostic and predictive value. Airway disease and obesity are common causes and often coexist with either pattern. Many will not have a true, restrictive lung deficit, and a reductionist approach to interpretation is likely to lead to erroneous diagnoses. There were many important updates included in the 2022 iteration on lung testing interpretation that should not fly under the radar.

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

A version of this article appeared on Medscape.com.

The recent statement on interpretive strategies for lung testing uses the acronym PRISm for preserved ratio impaired spirometry. PRISm identifies patients with a normal forced expiratory volume in 1 second/forced vital capacity ratio but abnormal FEV₁ and/or FVC (usually both). Most medical students are taught to call this a “restrictive pattern,” and every first-year pulmonary fellow orders full lung volumes when they see it. If total lung capacity (TLC) is normal, PRISm becomes the nonspecific pattern. If TLC is low, then the patient has “true” restriction, and if it’s elevated, then hyperinflation may be present.

The traditional classification scheme for basic spirometry interpretation (normal, restricted, obstructed, or mixed) is simple and conceptually clear. Because this simplicity is achieved at the expense of precision, the “restrictive pattern” label is due for retirement. It turns out that many with this pattern won’t have an abnormal TLC, so the name is, in some ways, a misnomer and can be misleading. Enter PRISm, a more descriptive and inclusive term. The phrase also lends itself to a phonetic acronym that is fun to say, easy to remember, and likely to catch on with learners.

Information on occurrence and clinical behavior comes from large cohorts with basic spirometry, but without full lung volumes because PRISm no longer applies once TLC is determined. As may be expected, prevalence varies by the population studied. Estimates for general populations have been in the 7%-12% range; however, one study examining a database of patients with clinical spirometry referrals found a prevalence of 22.3%. Rates may be far higher in low- and middle-income countries. Identified risk factors include sex, tobacco use, and body mass index; the presence of PRISm is associated with respiratory symptoms and mortality. Thus, PRISm is common and it matters.

Along with PRISm, the nonspecific pattern is a new addition, if not a new concept, to the 2022 interpretative strategies statement. As with PRISm, the title is necessarily broad, though far less imaginative. Defined by reductions in FEV₁ and FVC and a normal TLC, the nonspecific pattern has classically been considered a marker of early airway disease. The idea is that early, heterogeneous closure of distal segments of the bronchial tree can reduce total volume during a forced expiration before affecting the FEV₁/FVC. The fact that the TLC is not a forced maneuver means there is proportionately less effect from more collapsible/susceptible smaller units. More recent data suggest that there are additional causes.

Because the nonspecific pattern requires full lung volumes, we have less population-level data than for PRISm. Estimated prevalence is approximately 9.5% in patients with complete test results. The two most common causes are obesity and airway obstruction, and the pattern is relatively stable over time. Notably, an increase in specific airway resistance or TLC minus alveolar volume difference predicts progression to frank obstruction on spirometry.

The physiologic changes that obesity inflicts on the lung have been well described. Patients with obesity breathe at lower lung volumes and are therefore susceptible to small airway closure at rest and during forced expiration. There is no doubt that the increased recognition of PRISm and the nonspecific pattern is in part related to the worldwide rise in obesity rates.
 

Key takeaways

In summary, PRISm and the nonspecific pattern are now part of the classification scheme we use for spirometry and full lung volumes, respectively. They should be included in interpretations given their diagnostic and predictive value. Airway disease and obesity are common causes and often coexist with either pattern. Many will not have a true, restrictive lung deficit, and a reductionist approach to interpretation is likely to lead to erroneous diagnoses. There were many important updates included in the 2022 iteration on lung testing interpretation that should not fly under the radar.

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

A version of this article appeared on Medscape.com.

NEW YORK – When data were combined from two parallel phase 3 bronchiectasis treatment trials, inhaled colistimethate sodium failed to significantly reduce the rate of exacerbations associated with Pseudomonas aeruginosa infection, but the disparity in the findings from the two trials, presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023, strongly suggests that this therapy is effective after all.

“The totality of the evidence supports a consistent and clinically meaningful benefit [of this therapy] outside of pandemic conditions,” reported Charles Haworth, MD, director, Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, England.

The key phrase is “outside of pandemic conditions.” PROMIS I, which was fully enrolled before the COVID-19 pandemic descended, associated the inhaled therapy with highly significant benefits. PROMIS II, which was initiated later and enrolled 40% of its participants during the pandemic, did not.

The difference between these two trials, which were essentially identical, was the timing, according to Dr. Haworth. By starting later, PROMIS II caught the onset of the pandemic, which he believes introduced numerous problems that defeated the opportunity to show an advantage for the inhaled antibiotic.

Injectable colistimethate sodium, a decades-old formulation of colistin, is already approved in the United States for gram-negative infections and is considered helpful even in challenging diseases, such as cystic fibrosis. Positive results from a phase 2 trial with inhaled colistimethate sodium in bronchiectasis patients with P. aeruginosa infection provided the rationale for the phase 3 PROMIS program.

The key entry criterion of PROMIS I and PROMIS II, each with nearly 90 participating study sites, was a history of bronchiectasis and ≥ two P. aeruginosa infections requiring oral therapy or ≥ 1 infection requiring intravenous therapy in the prior 12 months. Patients were randomly assigned to receive colistimethate sodium delivered in the proprietary I-neb nebulizer (CMS I-neb) or a matching placebo.

On the primary endpoint of annualized rate of exacerbations, the figures per year were 0.58 for CMS I-neb and 0.95 for placebo in the PROMIS I trial. This produced a rate ratio of 0.65, signaling a significant 35% (P = .00101) reduction in risk. In PROMIS II, the annualized rates of exacerbation were essentially identical in the experimental and control arms (0.089 vs. 0.088; P = .97).

With “no signal of benefit” in the PROMIS II trial, the numerical advantage of CMS I-neb for the combined data did not reach statistical significance, Dr. Haworth reported.

Other endpoints told the same story. For example, the time to first exacerbation was reduced by 41% in PROMIS I (HR, 0.59; P = .0074) but was not reduced significantly (P = .603) in PROMIS II. In PROMIS I, there was a nearly 60% reduction in the risk of severe exacerbations associated with CMS I-neb, but the risk ratio of severe infections was slightly but not significantly higher on CMS I-neb in PROMIS II.

There were signals of benefit in PROMIS II. For example, the reductions in P. aeruginosa density were similar in the two studies (P < .00001 in both), and assessment with the Severe Exacerbations and Quality of Life (SQOL) tool associated CMS I-neb with end-of-study improvement in QOL for the experimental arm in both studies.

While Dr. Haworth acknowledged that he recognizes the “issues of post hoc analysis with any data,” he argued that there is compelling evidence that the pandemic “severely disrupted the conduct of the trial,” obscuring a benefit that would have been otherwise shown.

Besides the dramatic reduction in rates of hospitalization during the pandemic, an obstacle for showing differences in exacerbations, and other COVID-related factors with the potential to skew results, Dr. Haworth also provided several sets of objective data to make his point.

Most importantly, Dr. Haworth and his coinvestigators conducted a meta-analysis that combined data from the phase 2 trial, data from PROMIS I, and data from the patients enrolled in PROMIS II prior to the COVID pandemic. In this analysis the rate ratio for annualized exacerbations was a “pretty impressive” 0.65 favoring CMS I-neb. Moreover, in contrast to data from the PROMIS II patients enrolled during the COVID pandemic, the other three sets of data were “remarkably consistent.”

If PROMIS II data collected from patients enrolled during COVID are compared with the other sets of data, they are “the clear outlier,” he asserted.

Many guidelines in Europe, including those from the European Respiratory Society and the British Thoracic Society, already recommend inhaled colistin in patients with bronchiectasis for the treatment of P. aeruginosa. Although Dr. Haworth believes that the preponderance of controlled data now argue that CMS I-neb is effective as well as safe (adverse events in the experimental and placebo arms of PROMIS I and II were similar), he is not sure what steps will be taken to confirm a benefit to regulatory authorities. According to Dr. Haworth, there are no approved inhaled antibiotics in the United States.

Referring to Zambon, which funded the trials and is developing CMS I-neb, Dr. Haworth said, “This will be a company decision. There are some logistical hurdles to doing another trial.”

Not least of these hurdles is that clinicians and patients already consider inhalational antibiotics in general and inhaled colistin specifically to be effective for several types of infections, including P. aeruginosa, according to Eva Polverino, MD, PhD, a pulmonologist associated with the Hospital Clinic of Barcelona. She said that these drugs are already a standard of care in her own country as well as in many other countries in Europe.

“There has been a loss of equipoise needed to conduct a randomized placebo-controlled trial,” Dr. Polverino said. In her opinion, the U.S. FDA “should start thinking of other pathways to approval.” She thinks that enrollment in a placebo-controlled trial is no longer appropriate.

Dr. Haworth and Dr. Polverino have disclosed no relevant financial relationships.

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

NEW YORK – When data were combined from two parallel phase 3 bronchiectasis treatment trials, inhaled colistimethate sodium failed to significantly reduce the rate of exacerbations associated with Pseudomonas aeruginosa infection, but the disparity in the findings from the two trials, presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023, strongly suggests that this therapy is effective after all.

“The totality of the evidence supports a consistent and clinically meaningful benefit [of this therapy] outside of pandemic conditions,” reported Charles Haworth, MD, director, Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, England.

The key phrase is “outside of pandemic conditions.” PROMIS I, which was fully enrolled before the COVID-19 pandemic descended, associated the inhaled therapy with highly significant benefits. PROMIS II, which was initiated later and enrolled 40% of its participants during the pandemic, did not.

The difference between these two trials, which were essentially identical, was the timing, according to Dr. Haworth. By starting later, PROMIS II caught the onset of the pandemic, which he believes introduced numerous problems that defeated the opportunity to show an advantage for the inhaled antibiotic.

Injectable colistimethate sodium, a decades-old formulation of colistin, is already approved in the United States for gram-negative infections and is considered helpful even in challenging diseases, such as cystic fibrosis. Positive results from a phase 2 trial with inhaled colistimethate sodium in bronchiectasis patients with P. aeruginosa infection provided the rationale for the phase 3 PROMIS program.

The key entry criterion of PROMIS I and PROMIS II, each with nearly 90 participating study sites, was a history of bronchiectasis and ≥ two P. aeruginosa infections requiring oral therapy or ≥ 1 infection requiring intravenous therapy in the prior 12 months. Patients were randomly assigned to receive colistimethate sodium delivered in the proprietary I-neb nebulizer (CMS I-neb) or a matching placebo.

On the primary endpoint of annualized rate of exacerbations, the figures per year were 0.58 for CMS I-neb and 0.95 for placebo in the PROMIS I trial. This produced a rate ratio of 0.65, signaling a significant 35% (P = .00101) reduction in risk. In PROMIS II, the annualized rates of exacerbation were essentially identical in the experimental and control arms (0.089 vs. 0.088; P = .97).

With “no signal of benefit” in the PROMIS II trial, the numerical advantage of CMS I-neb for the combined data did not reach statistical significance, Dr. Haworth reported.

Other endpoints told the same story. For example, the time to first exacerbation was reduced by 41% in PROMIS I (HR, 0.59; P = .0074) but was not reduced significantly (P = .603) in PROMIS II. In PROMIS I, there was a nearly 60% reduction in the risk of severe exacerbations associated with CMS I-neb, but the risk ratio of severe infections was slightly but not significantly higher on CMS I-neb in PROMIS II.

There were signals of benefit in PROMIS II. For example, the reductions in P. aeruginosa density were similar in the two studies (P < .00001 in both), and assessment with the Severe Exacerbations and Quality of Life (SQOL) tool associated CMS I-neb with end-of-study improvement in QOL for the experimental arm in both studies.

While Dr. Haworth acknowledged that he recognizes the “issues of post hoc analysis with any data,” he argued that there is compelling evidence that the pandemic “severely disrupted the conduct of the trial,” obscuring a benefit that would have been otherwise shown.

Besides the dramatic reduction in rates of hospitalization during the pandemic, an obstacle for showing differences in exacerbations, and other COVID-related factors with the potential to skew results, Dr. Haworth also provided several sets of objective data to make his point.

Most importantly, Dr. Haworth and his coinvestigators conducted a meta-analysis that combined data from the phase 2 trial, data from PROMIS I, and data from the patients enrolled in PROMIS II prior to the COVID pandemic. In this analysis the rate ratio for annualized exacerbations was a “pretty impressive” 0.65 favoring CMS I-neb. Moreover, in contrast to data from the PROMIS II patients enrolled during the COVID pandemic, the other three sets of data were “remarkably consistent.”

If PROMIS II data collected from patients enrolled during COVID are compared with the other sets of data, they are “the clear outlier,” he asserted.

Many guidelines in Europe, including those from the European Respiratory Society and the British Thoracic Society, already recommend inhaled colistin in patients with bronchiectasis for the treatment of P. aeruginosa. Although Dr. Haworth believes that the preponderance of controlled data now argue that CMS I-neb is effective as well as safe (adverse events in the experimental and placebo arms of PROMIS I and II were similar), he is not sure what steps will be taken to confirm a benefit to regulatory authorities. According to Dr. Haworth, there are no approved inhaled antibiotics in the United States.

Referring to Zambon, which funded the trials and is developing CMS I-neb, Dr. Haworth said, “This will be a company decision. There are some logistical hurdles to doing another trial.”

Not least of these hurdles is that clinicians and patients already consider inhalational antibiotics in general and inhaled colistin specifically to be effective for several types of infections, including P. aeruginosa, according to Eva Polverino, MD, PhD, a pulmonologist associated with the Hospital Clinic of Barcelona. She said that these drugs are already a standard of care in her own country as well as in many other countries in Europe.

“There has been a loss of equipoise needed to conduct a randomized placebo-controlled trial,” Dr. Polverino said. In her opinion, the U.S. FDA “should start thinking of other pathways to approval.” She thinks that enrollment in a placebo-controlled trial is no longer appropriate.

Dr. Haworth and Dr. Polverino have disclosed no relevant financial relationships.

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

NEW YORK – When data were combined from two parallel phase 3 bronchiectasis treatment trials, inhaled colistimethate sodium failed to significantly reduce the rate of exacerbations associated with Pseudomonas aeruginosa infection, but the disparity in the findings from the two trials, presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023, strongly suggests that this therapy is effective after all.

“The totality of the evidence supports a consistent and clinically meaningful benefit [of this therapy] outside of pandemic conditions,” reported Charles Haworth, MD, director, Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, England.

The key phrase is “outside of pandemic conditions.” PROMIS I, which was fully enrolled before the COVID-19 pandemic descended, associated the inhaled therapy with highly significant benefits. PROMIS II, which was initiated later and enrolled 40% of its participants during the pandemic, did not.

The difference between these two trials, which were essentially identical, was the timing, according to Dr. Haworth. By starting later, PROMIS II caught the onset of the pandemic, which he believes introduced numerous problems that defeated the opportunity to show an advantage for the inhaled antibiotic.

Injectable colistimethate sodium, a decades-old formulation of colistin, is already approved in the United States for gram-negative infections and is considered helpful even in challenging diseases, such as cystic fibrosis. Positive results from a phase 2 trial with inhaled colistimethate sodium in bronchiectasis patients with P. aeruginosa infection provided the rationale for the phase 3 PROMIS program.

The key entry criterion of PROMIS I and PROMIS II, each with nearly 90 participating study sites, was a history of bronchiectasis and ≥ two P. aeruginosa infections requiring oral therapy or ≥ 1 infection requiring intravenous therapy in the prior 12 months. Patients were randomly assigned to receive colistimethate sodium delivered in the proprietary I-neb nebulizer (CMS I-neb) or a matching placebo.

On the primary endpoint of annualized rate of exacerbations, the figures per year were 0.58 for CMS I-neb and 0.95 for placebo in the PROMIS I trial. This produced a rate ratio of 0.65, signaling a significant 35% (P = .00101) reduction in risk. In PROMIS II, the annualized rates of exacerbation were essentially identical in the experimental and control arms (0.089 vs. 0.088; P = .97).

With “no signal of benefit” in the PROMIS II trial, the numerical advantage of CMS I-neb for the combined data did not reach statistical significance, Dr. Haworth reported.

Other endpoints told the same story. For example, the time to first exacerbation was reduced by 41% in PROMIS I (HR, 0.59; P = .0074) but was not reduced significantly (P = .603) in PROMIS II. In PROMIS I, there was a nearly 60% reduction in the risk of severe exacerbations associated with CMS I-neb, but the risk ratio of severe infections was slightly but not significantly higher on CMS I-neb in PROMIS II.

There were signals of benefit in PROMIS II. For example, the reductions in P. aeruginosa density were similar in the two studies (P < .00001 in both), and assessment with the Severe Exacerbations and Quality of Life (SQOL) tool associated CMS I-neb with end-of-study improvement in QOL for the experimental arm in both studies.

While Dr. Haworth acknowledged that he recognizes the “issues of post hoc analysis with any data,” he argued that there is compelling evidence that the pandemic “severely disrupted the conduct of the trial,” obscuring a benefit that would have been otherwise shown.

Besides the dramatic reduction in rates of hospitalization during the pandemic, an obstacle for showing differences in exacerbations, and other COVID-related factors with the potential to skew results, Dr. Haworth also provided several sets of objective data to make his point.

Most importantly, Dr. Haworth and his coinvestigators conducted a meta-analysis that combined data from the phase 2 trial, data from PROMIS I, and data from the patients enrolled in PROMIS II prior to the COVID pandemic. In this analysis the rate ratio for annualized exacerbations was a “pretty impressive” 0.65 favoring CMS I-neb. Moreover, in contrast to data from the PROMIS II patients enrolled during the COVID pandemic, the other three sets of data were “remarkably consistent.”

If PROMIS II data collected from patients enrolled during COVID are compared with the other sets of data, they are “the clear outlier,” he asserted.

Many guidelines in Europe, including those from the European Respiratory Society and the British Thoracic Society, already recommend inhaled colistin in patients with bronchiectasis for the treatment of P. aeruginosa. Although Dr. Haworth believes that the preponderance of controlled data now argue that CMS I-neb is effective as well as safe (adverse events in the experimental and placebo arms of PROMIS I and II were similar), he is not sure what steps will be taken to confirm a benefit to regulatory authorities. According to Dr. Haworth, there are no approved inhaled antibiotics in the United States.

Referring to Zambon, which funded the trials and is developing CMS I-neb, Dr. Haworth said, “This will be a company decision. There are some logistical hurdles to doing another trial.”

Not least of these hurdles is that clinicians and patients already consider inhalational antibiotics in general and inhaled colistin specifically to be effective for several types of infections, including P. aeruginosa, according to Eva Polverino, MD, PhD, a pulmonologist associated with the Hospital Clinic of Barcelona. She said that these drugs are already a standard of care in her own country as well as in many other countries in Europe.

“There has been a loss of equipoise needed to conduct a randomized placebo-controlled trial,” Dr. Polverino said. In her opinion, the U.S. FDA “should start thinking of other pathways to approval.” She thinks that enrollment in a placebo-controlled trial is no longer appropriate.

Dr. Haworth and Dr. Polverino have disclosed no relevant financial relationships.

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

Lower doses of initial vasopressin were associated with lower mortality when used as an adjunct in patients with septic shock, according to a review of three recent studies.

“Patients with septic shock require vasoactive agents to restore adequate tissue perfusion,” writes Gretchen L. Sacha, PharmD, of the Cleveland Clinic and colleagues.

Vasopressin is an attractive alternative to norepinephrine because it avoids the adverse effects associated with catecholamines, the researchers say. Although vasopressin is the recommended second-line adjunct after norepinephrine for patients with septic shock, findings to guide its use are inconsistent and data on the timing are limited, they note.

In a review published in the journal CHEST, the researchers summarize the three large, randomized trials to date examining the use of norepinephrine and vasopressin in patients with septic shock.

In the Vasopressin in Septic Shock Trial (VASST), 382 patients with septic shock were randomized to open-label norepinephrine with blinded norepinephrine, and 382 were randomized to open-label norepinephrine with blinded adjunctive vasopressin.

After initiation of the study drug, patients randomized to vasopressin had significantly lower requirements for open-label norepinephrine (P < .001). Although no differences occurred in the primary outcome of 28-day mortality, 90-day mortality was lower in the vasopressin group.

In the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock (VANISH) trial, 204 patients with septic shock were randomized to norepinephrine and 204 to vasopressin as an initial vasoactive agent. Although no differences appeared between the groups for the two primary outcomes of 28-day mortality and days free of kidney failure, the vasopressin group had a lower frequency of the use of kidney replacement therapy (absolute difference –9.9% vs. –0.6%).

The VANISH study was limited by the fact that 85% of the patients were receiving norepinephrine when they were randomized; “therefore, this study is best described as evaluating catecholamine-adjunctive vasopressin,” the researchers say.

The third clinical trial, published only as an abstract, randomized 387 patients with septic shock who were already receiving low doses of norepinephrine to either norepinephrine with adjunctive vasopressin or norepinephrine alone. Rates of 28-day mortality were significantly lower in the vasopressin group (34.0% vs. 42.3%; P = .03).

Several meta-analyses involving multiple vasopressin receptor agonists have shown an association between reduced mortality and their use. In addition, recent observational studies have shown an association between lower mortality and the initiation of vasopressors at a lower norepinephrine-equivalent dose or lower lactate concentration.

As for clinical implications, the 2021 version of the Surviving Sepsis Campaign (SSC) guidelines included a meta-analysis of 10 randomized, controlled trials that showed improved mortality associated with vasopressin use. This version of the guidelines was the first to address the timing of vasopressin initiation.

Because of insufficient evidence, the guidance was worded as “in our practice, vasopressin is usually started when the dose of norepinephrine is in the range of 0.25-0.5 mcg/kg/min,” the researchers write. “Although this is not a recommendation by the SSC for a specific threshold of catecholamine dose where vasopressin should be initiated, this statement represents clinician interest and the need for further research on the topic,” they note.

“Future studies of vasopressin should focus on the timing of its initiation at various clinical thresholds and patient selection for receipt of vasopressin,” they conclude.

The study was supported by the National Institutes of Health, National Institute of General Medical Sciences. Dr. Sacha has disclosed consulting for Wolters Kluwer.

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

Lower doses of initial vasopressin were associated with lower mortality when used as an adjunct in patients with septic shock, according to a review of three recent studies.

“Patients with septic shock require vasoactive agents to restore adequate tissue perfusion,” writes Gretchen L. Sacha, PharmD, of the Cleveland Clinic and colleagues.

Vasopressin is an attractive alternative to norepinephrine because it avoids the adverse effects associated with catecholamines, the researchers say. Although vasopressin is the recommended second-line adjunct after norepinephrine for patients with septic shock, findings to guide its use are inconsistent and data on the timing are limited, they note.

In a review published in the journal CHEST, the researchers summarize the three large, randomized trials to date examining the use of norepinephrine and vasopressin in patients with septic shock.

In the Vasopressin in Septic Shock Trial (VASST), 382 patients with septic shock were randomized to open-label norepinephrine with blinded norepinephrine, and 382 were randomized to open-label norepinephrine with blinded adjunctive vasopressin.

After initiation of the study drug, patients randomized to vasopressin had significantly lower requirements for open-label norepinephrine (P < .001). Although no differences occurred in the primary outcome of 28-day mortality, 90-day mortality was lower in the vasopressin group.

In the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock (VANISH) trial, 204 patients with septic shock were randomized to norepinephrine and 204 to vasopressin as an initial vasoactive agent. Although no differences appeared between the groups for the two primary outcomes of 28-day mortality and days free of kidney failure, the vasopressin group had a lower frequency of the use of kidney replacement therapy (absolute difference –9.9% vs. –0.6%).

The VANISH study was limited by the fact that 85% of the patients were receiving norepinephrine when they were randomized; “therefore, this study is best described as evaluating catecholamine-adjunctive vasopressin,” the researchers say.

The third clinical trial, published only as an abstract, randomized 387 patients with septic shock who were already receiving low doses of norepinephrine to either norepinephrine with adjunctive vasopressin or norepinephrine alone. Rates of 28-day mortality were significantly lower in the vasopressin group (34.0% vs. 42.3%; P = .03).

Several meta-analyses involving multiple vasopressin receptor agonists have shown an association between reduced mortality and their use. In addition, recent observational studies have shown an association between lower mortality and the initiation of vasopressors at a lower norepinephrine-equivalent dose or lower lactate concentration.

As for clinical implications, the 2021 version of the Surviving Sepsis Campaign (SSC) guidelines included a meta-analysis of 10 randomized, controlled trials that showed improved mortality associated with vasopressin use. This version of the guidelines was the first to address the timing of vasopressin initiation.

Because of insufficient evidence, the guidance was worded as “in our practice, vasopressin is usually started when the dose of norepinephrine is in the range of 0.25-0.5 mcg/kg/min,” the researchers write. “Although this is not a recommendation by the SSC for a specific threshold of catecholamine dose where vasopressin should be initiated, this statement represents clinician interest and the need for further research on the topic,” they note.

“Future studies of vasopressin should focus on the timing of its initiation at various clinical thresholds and patient selection for receipt of vasopressin,” they conclude.

The study was supported by the National Institutes of Health, National Institute of General Medical Sciences. Dr. Sacha has disclosed consulting for Wolters Kluwer.

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

Lower doses of initial vasopressin were associated with lower mortality when used as an adjunct in patients with septic shock, according to a review of three recent studies.

“Patients with septic shock require vasoactive agents to restore adequate tissue perfusion,” writes Gretchen L. Sacha, PharmD, of the Cleveland Clinic and colleagues.

Vasopressin is an attractive alternative to norepinephrine because it avoids the adverse effects associated with catecholamines, the researchers say. Although vasopressin is the recommended second-line adjunct after norepinephrine for patients with septic shock, findings to guide its use are inconsistent and data on the timing are limited, they note.

In a review published in the journal CHEST, the researchers summarize the three large, randomized trials to date examining the use of norepinephrine and vasopressin in patients with septic shock.

In the Vasopressin in Septic Shock Trial (VASST), 382 patients with septic shock were randomized to open-label norepinephrine with blinded norepinephrine, and 382 were randomized to open-label norepinephrine with blinded adjunctive vasopressin.

After initiation of the study drug, patients randomized to vasopressin had significantly lower requirements for open-label norepinephrine (P < .001). Although no differences occurred in the primary outcome of 28-day mortality, 90-day mortality was lower in the vasopressin group.

In the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock (VANISH) trial, 204 patients with septic shock were randomized to norepinephrine and 204 to vasopressin as an initial vasoactive agent. Although no differences appeared between the groups for the two primary outcomes of 28-day mortality and days free of kidney failure, the vasopressin group had a lower frequency of the use of kidney replacement therapy (absolute difference –9.9% vs. –0.6%).

The VANISH study was limited by the fact that 85% of the patients were receiving norepinephrine when they were randomized; “therefore, this study is best described as evaluating catecholamine-adjunctive vasopressin,” the researchers say.

The third clinical trial, published only as an abstract, randomized 387 patients with septic shock who were already receiving low doses of norepinephrine to either norepinephrine with adjunctive vasopressin or norepinephrine alone. Rates of 28-day mortality were significantly lower in the vasopressin group (34.0% vs. 42.3%; P = .03).

Several meta-analyses involving multiple vasopressin receptor agonists have shown an association between reduced mortality and their use. In addition, recent observational studies have shown an association between lower mortality and the initiation of vasopressors at a lower norepinephrine-equivalent dose or lower lactate concentration.

As for clinical implications, the 2021 version of the Surviving Sepsis Campaign (SSC) guidelines included a meta-analysis of 10 randomized, controlled trials that showed improved mortality associated with vasopressin use. This version of the guidelines was the first to address the timing of vasopressin initiation.

Because of insufficient evidence, the guidance was worded as “in our practice, vasopressin is usually started when the dose of norepinephrine is in the range of 0.25-0.5 mcg/kg/min,” the researchers write. “Although this is not a recommendation by the SSC for a specific threshold of catecholamine dose where vasopressin should be initiated, this statement represents clinician interest and the need for further research on the topic,” they note.

“Future studies of vasopressin should focus on the timing of its initiation at various clinical thresholds and patient selection for receipt of vasopressin,” they conclude.

The study was supported by the National Institutes of Health, National Institute of General Medical Sciences. Dr. Sacha has disclosed consulting for Wolters Kluwer.

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

Researchers in Texas are developing a “green light” technology they hope will solve a crucial problem highlighted by the pandemic: the limits of pulse oximeters in patients with darker skin.

A recent study adds weight to earlier findings that their device works. 

“It is a new, first-in-class technology,” said Sanjay Gokhale, MD, the bioengineer who is leading this research at the University of Texas at Arlington. “The team conducted extensive preclinical work and carried out phase 1 studies in human volunteers, demonstrating sensitivity and accuracy.”

It’s one of several projects underway to update pulse oximetry, a technology based on research in lighter-skinned people that has not changed much in 50 years. 

The pulse oximeter, or “pulse ox,” measures the saturation of oxygen in your hemoglobin (a protein in red blood cells). But it tends to overestimate the oxygen saturation in patients with darker skin by about 2%-3%. That may not sound like a lot, but it’s enough to delay major treatment for respiratory issues like COVID-19. 

“Falsely elevated readings from commercial oximeters have delayed treatment of Black COVID-19 patients for hours in some cases,” said Divya Chander, MD, PhD, an anesthesiologist in Oakland, Calif., and chair of neuroscience at The Singularity Group. (Dr. Chander was not involved in the UT Arlington research.)

Early research happening separately at Brown University and Tufts University aims to redesign the pulse oximeter to get accurate readings in patients of all skin tones. University of California, San Diego, researchers are looking into a method that measures blood oxygen using sound in combination with light.  Other solutions try to correct for skin tone with algorithms. 

The device from UT Arlington uses an algorithm too, but its main innovation is that it replaces red light with green light. 
 

Red light, green light

Traditional oximetry devices, which typically clip on to the patient’s fingertip, use LEDs to beam light through the skin at two wavelengths: one in the red part of the spectrum, the other in the infrared. The light transmits from one side of the clip to the other, passing through arterial blood as it pulses.

The device calculates a patient’s oxygenation based on how much light of each wavelength is absorbed by hemoglobin in the blood. Oxygenated hemoglobin absorbs the light differently than deoxygenated hemoglobin, so oxygenation can be represented as a percentage; 100% means all hemoglobin is completely oxygenated.  But the melanin in skin can interfere with the absorption of light and affect the results. 

The green light strategy measures not absorption but reflectance – how much of the light bounces back. As with traditional oximetry, the green-light method uses two wavelengths. Each is a different shade of green, and the two forms of hemoglobin reflect them differently. 

Using an algorithm developed by the researchers, the device can capture readings in patients of all skin tones, the researchers say. And because it works on the wrist rather than a finger, the device also eliminates issues with cold fingers and dark nail polish – both known to reduce accuracy in traditional oximetry.

In the latest experiments, the researchers tested the technology on synthetic skin samples with varying amounts of melanin, Dr. Gokhale said. The device picked up changes in blood oxygen saturation even in samples with high melanin levels. 

In a study published last year, the technology was tested in 16 people against an invasive handheld blood analyzer and a noninvasive commercial pulse oximeter, and found to be comparable to the invasive method. 
 

A drawback 

The green light approach could be “game changing,” Dr. Chander said. But there is a drawback. 

Since green light doesn’t penetrate as deeply, this approach measures blood oxygen saturation in capillary beds (small blood vessels very close to the skin surface). By contrast, traditional oximetry measures oxygen saturation in an artery as it pulses – thus the name pulse oximetry. 

Valuable information can be obtained from an arterial pulse.

Changes in arterial pulse, known as the waveforms, “can tell us about a patient’s hydration status [for instance],” Dr. Chander said. “In a mechanically ventilated patient, this variation with a patient’s respiratory cycle can give us feedback about how responsive the patient will be to fluid resuscitation if their blood pressure is too low.” 

Given such considerations, the green light method may be useful as an adjunct, not a full replacement, to a standard pulse ox, Dr. Chander noted.

A version of this article appeared on WebMD.com.

Researchers in Texas are developing a “green light” technology they hope will solve a crucial problem highlighted by the pandemic: the limits of pulse oximeters in patients with darker skin.

A recent study adds weight to earlier findings that their device works. 

“It is a new, first-in-class technology,” said Sanjay Gokhale, MD, the bioengineer who is leading this research at the University of Texas at Arlington. “The team conducted extensive preclinical work and carried out phase 1 studies in human volunteers, demonstrating sensitivity and accuracy.”

It’s one of several projects underway to update pulse oximetry, a technology based on research in lighter-skinned people that has not changed much in 50 years. 

The pulse oximeter, or “pulse ox,” measures the saturation of oxygen in your hemoglobin (a protein in red blood cells). But it tends to overestimate the oxygen saturation in patients with darker skin by about 2%-3%. That may not sound like a lot, but it’s enough to delay major treatment for respiratory issues like COVID-19. 

“Falsely elevated readings from commercial oximeters have delayed treatment of Black COVID-19 patients for hours in some cases,” said Divya Chander, MD, PhD, an anesthesiologist in Oakland, Calif., and chair of neuroscience at The Singularity Group. (Dr. Chander was not involved in the UT Arlington research.)

Early research happening separately at Brown University and Tufts University aims to redesign the pulse oximeter to get accurate readings in patients of all skin tones. University of California, San Diego, researchers are looking into a method that measures blood oxygen using sound in combination with light.  Other solutions try to correct for skin tone with algorithms. 

The device from UT Arlington uses an algorithm too, but its main innovation is that it replaces red light with green light. 
 

Red light, green light

Traditional oximetry devices, which typically clip on to the patient’s fingertip, use LEDs to beam light through the skin at two wavelengths: one in the red part of the spectrum, the other in the infrared. The light transmits from one side of the clip to the other, passing through arterial blood as it pulses.

The device calculates a patient’s oxygenation based on how much light of each wavelength is absorbed by hemoglobin in the blood. Oxygenated hemoglobin absorbs the light differently than deoxygenated hemoglobin, so oxygenation can be represented as a percentage; 100% means all hemoglobin is completely oxygenated.  But the melanin in skin can interfere with the absorption of light and affect the results. 

The green light strategy measures not absorption but reflectance – how much of the light bounces back. As with traditional oximetry, the green-light method uses two wavelengths. Each is a different shade of green, and the two forms of hemoglobin reflect them differently. 

Using an algorithm developed by the researchers, the device can capture readings in patients of all skin tones, the researchers say. And because it works on the wrist rather than a finger, the device also eliminates issues with cold fingers and dark nail polish – both known to reduce accuracy in traditional oximetry.

In the latest experiments, the researchers tested the technology on synthetic skin samples with varying amounts of melanin, Dr. Gokhale said. The device picked up changes in blood oxygen saturation even in samples with high melanin levels. 

In a study published last year, the technology was tested in 16 people against an invasive handheld blood analyzer and a noninvasive commercial pulse oximeter, and found to be comparable to the invasive method. 
 

A drawback 

The green light approach could be “game changing,” Dr. Chander said. But there is a drawback. 

Since green light doesn’t penetrate as deeply, this approach measures blood oxygen saturation in capillary beds (small blood vessels very close to the skin surface). By contrast, traditional oximetry measures oxygen saturation in an artery as it pulses – thus the name pulse oximetry. 

Valuable information can be obtained from an arterial pulse.

Changes in arterial pulse, known as the waveforms, “can tell us about a patient’s hydration status [for instance],” Dr. Chander said. “In a mechanically ventilated patient, this variation with a patient’s respiratory cycle can give us feedback about how responsive the patient will be to fluid resuscitation if their blood pressure is too low.” 

Given such considerations, the green light method may be useful as an adjunct, not a full replacement, to a standard pulse ox, Dr. Chander noted.

A version of this article appeared on WebMD.com.

Researchers in Texas are developing a “green light” technology they hope will solve a crucial problem highlighted by the pandemic: the limits of pulse oximeters in patients with darker skin.

A recent study adds weight to earlier findings that their device works. 

“It is a new, first-in-class technology,” said Sanjay Gokhale, MD, the bioengineer who is leading this research at the University of Texas at Arlington. “The team conducted extensive preclinical work and carried out phase 1 studies in human volunteers, demonstrating sensitivity and accuracy.”

It’s one of several projects underway to update pulse oximetry, a technology based on research in lighter-skinned people that has not changed much in 50 years. 

The pulse oximeter, or “pulse ox,” measures the saturation of oxygen in your hemoglobin (a protein in red blood cells). But it tends to overestimate the oxygen saturation in patients with darker skin by about 2%-3%. That may not sound like a lot, but it’s enough to delay major treatment for respiratory issues like COVID-19. 

“Falsely elevated readings from commercial oximeters have delayed treatment of Black COVID-19 patients for hours in some cases,” said Divya Chander, MD, PhD, an anesthesiologist in Oakland, Calif., and chair of neuroscience at The Singularity Group. (Dr. Chander was not involved in the UT Arlington research.)

Early research happening separately at Brown University and Tufts University aims to redesign the pulse oximeter to get accurate readings in patients of all skin tones. University of California, San Diego, researchers are looking into a method that measures blood oxygen using sound in combination with light.  Other solutions try to correct for skin tone with algorithms. 

The device from UT Arlington uses an algorithm too, but its main innovation is that it replaces red light with green light. 
 

Red light, green light

Traditional oximetry devices, which typically clip on to the patient’s fingertip, use LEDs to beam light through the skin at two wavelengths: one in the red part of the spectrum, the other in the infrared. The light transmits from one side of the clip to the other, passing through arterial blood as it pulses.

The device calculates a patient’s oxygenation based on how much light of each wavelength is absorbed by hemoglobin in the blood. Oxygenated hemoglobin absorbs the light differently than deoxygenated hemoglobin, so oxygenation can be represented as a percentage; 100% means all hemoglobin is completely oxygenated.  But the melanin in skin can interfere with the absorption of light and affect the results. 

The green light strategy measures not absorption but reflectance – how much of the light bounces back. As with traditional oximetry, the green-light method uses two wavelengths. Each is a different shade of green, and the two forms of hemoglobin reflect them differently. 

Using an algorithm developed by the researchers, the device can capture readings in patients of all skin tones, the researchers say. And because it works on the wrist rather than a finger, the device also eliminates issues with cold fingers and dark nail polish – both known to reduce accuracy in traditional oximetry.

In the latest experiments, the researchers tested the technology on synthetic skin samples with varying amounts of melanin, Dr. Gokhale said. The device picked up changes in blood oxygen saturation even in samples with high melanin levels. 

In a study published last year, the technology was tested in 16 people against an invasive handheld blood analyzer and a noninvasive commercial pulse oximeter, and found to be comparable to the invasive method. 
 

A drawback 

The green light approach could be “game changing,” Dr. Chander said. But there is a drawback. 

Since green light doesn’t penetrate as deeply, this approach measures blood oxygen saturation in capillary beds (small blood vessels very close to the skin surface). By contrast, traditional oximetry measures oxygen saturation in an artery as it pulses – thus the name pulse oximetry. 

Valuable information can be obtained from an arterial pulse.

Changes in arterial pulse, known as the waveforms, “can tell us about a patient’s hydration status [for instance],” Dr. Chander said. “In a mechanically ventilated patient, this variation with a patient’s respiratory cycle can give us feedback about how responsive the patient will be to fluid resuscitation if their blood pressure is too low.” 

Given such considerations, the green light method may be useful as an adjunct, not a full replacement, to a standard pulse ox, Dr. Chander noted.

A version of this article appeared on WebMD.com.

The combination of heat waves and poor air quality is associated with double the risk of fatal myocardial infarction (MI), with women and older adults at greatest risk, a study from China suggests.

rottadana/Thinkstock

The researchers estimate that up to 3% of all deaths due to MI could be attributed to the combination of extreme temperatures and high levels of ambient fine particulate matter (PM2.5).

“Our findings provide evidence that reducing exposure to both extreme temperatures and fine particulate pollution may be useful to prevent premature deaths from heart attack,” senior author Yuewei Liu, MD, PhD, with Sun Yat-sen University in Guangzhou, China, said in a statement.

There is “long-standing evidence” of the harmful cardiovascular effects of air pollution, Jonathan Newman, MD, MPH, cardiologist at NYU Langone Heart in New York, who wasn’t involved in the study, said in an interview.

The added value of this study was finding an interaction between extreme hot temperatures and air pollution, “which is worrisome with global warming,” said Dr. Newman, assistant professor, department of medicine, the Leon H. Charney Division of Cardiology at NYU Langone Health.

The study was published online in Circulation.
 

Intensity and duration matter

The researchers analyzed data on 202,678 adults (mean age, 77.6 years; 52% male) who suffered fatal MI between 2015 and 2020 in Jiangsu province, a region with four distinct seasons and a wide range of temperatures and ambient PM2.5.

They evaluated the association of exposure to extreme temperature events, including both hot and cold spells, and PM2.5 with MI mortality, and their interactive effects.

Among the key findings:

• The risk of fatal MI was 18% higher during 2-day heat waves with heat indexes at or above the 90th percentile (ranging from 82.6° to 97.9° F) and 74% higher during 4-day heat waves with heat indexes at or above the 97.5th percentile (ranging from 94.8° to 109.4° F), compared with control days.
• The risk of fatal MI was 4% higher during 2-day cold snaps with temperatures at or below the 10th percentile (ranging from 33.3° to 40.5° F) and 12% higher during 3-day cold snaps with temperatures at or below the 2.5th percentile (ranging from 27.0° to 37.2° F).
• The risk of fatal MI was twice as high during 4-day heat waves that had PM2.5 above 37.5 mcg/m³. Days with high levels of PM2.5 during cold snaps did not have an equivalent increase in the risk of fatal MI.
• Up to 2.8% of MI deaths during the 5-year study period may be attributable to the combination of extreme temperature exposure and PM2.5 at levels exceeding World Health Organization air quality guidelines (37.5 mcg/m³).
• The risk of fatal MI was generally higher among women than men during heat waves and was higher among adults 80 years old and older than in younger adults during heat waves, cold snaps, or days with high levels of PM2.5.

The finding that adults over age 80 are particularly susceptible to the effects of heat and air pollution and the interaction of the two is “notable and particularly relevant given the aging of the population,” Dr. Newman told this news organization.

Mitigating both extreme temperature events and PM2.5 exposures “may bring health cobenefits in preventing premature deaths from MI,” the researchers write.

“To improve public health, it is important to take fine particulate pollution into consideration when providing extreme temperature warnings to the public,” Dr. Liu adds in the statement.

In an earlier study, Dr. Liu and colleagues showed that exposure to both large and small particulate matter, as well as nitrogen dioxide, was significantly associated with increased odds of death from MI.

This study was funded by China’s Ministry of Science and Technology. The authors and Dr. Newman have disclosed no relevant financial relationships.

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

The combination of heat waves and poor air quality is associated with double the risk of fatal myocardial infarction (MI), with women and older adults at greatest risk, a study from China suggests.

rottadana/Thinkstock

The researchers estimate that up to 3% of all deaths due to MI could be attributed to the combination of extreme temperatures and high levels of ambient fine particulate matter (PM2.5).

“Our findings provide evidence that reducing exposure to both extreme temperatures and fine particulate pollution may be useful to prevent premature deaths from heart attack,” senior author Yuewei Liu, MD, PhD, with Sun Yat-sen University in Guangzhou, China, said in a statement.

There is “long-standing evidence” of the harmful cardiovascular effects of air pollution, Jonathan Newman, MD, MPH, cardiologist at NYU Langone Heart in New York, who wasn’t involved in the study, said in an interview.

The added value of this study was finding an interaction between extreme hot temperatures and air pollution, “which is worrisome with global warming,” said Dr. Newman, assistant professor, department of medicine, the Leon H. Charney Division of Cardiology at NYU Langone Health.

The study was published online in Circulation.
 

Intensity and duration matter

The researchers analyzed data on 202,678 adults (mean age, 77.6 years; 52% male) who suffered fatal MI between 2015 and 2020 in Jiangsu province, a region with four distinct seasons and a wide range of temperatures and ambient PM2.5.

They evaluated the association of exposure to extreme temperature events, including both hot and cold spells, and PM2.5 with MI mortality, and their interactive effects.

Among the key findings:

• The risk of fatal MI was 18% higher during 2-day heat waves with heat indexes at or above the 90th percentile (ranging from 82.6° to 97.9° F) and 74% higher during 4-day heat waves with heat indexes at or above the 97.5th percentile (ranging from 94.8° to 109.4° F), compared with control days.
• The risk of fatal MI was 4% higher during 2-day cold snaps with temperatures at or below the 10th percentile (ranging from 33.3° to 40.5° F) and 12% higher during 3-day cold snaps with temperatures at or below the 2.5th percentile (ranging from 27.0° to 37.2° F).
• The risk of fatal MI was twice as high during 4-day heat waves that had PM2.5 above 37.5 mcg/m³. Days with high levels of PM2.5 during cold snaps did not have an equivalent increase in the risk of fatal MI.
• Up to 2.8% of MI deaths during the 5-year study period may be attributable to the combination of extreme temperature exposure and PM2.5 at levels exceeding World Health Organization air quality guidelines (37.5 mcg/m³).
• The risk of fatal MI was generally higher among women than men during heat waves and was higher among adults 80 years old and older than in younger adults during heat waves, cold snaps, or days with high levels of PM2.5.

The finding that adults over age 80 are particularly susceptible to the effects of heat and air pollution and the interaction of the two is “notable and particularly relevant given the aging of the population,” Dr. Newman told this news organization.

Mitigating both extreme temperature events and PM2.5 exposures “may bring health cobenefits in preventing premature deaths from MI,” the researchers write.

“To improve public health, it is important to take fine particulate pollution into consideration when providing extreme temperature warnings to the public,” Dr. Liu adds in the statement.

In an earlier study, Dr. Liu and colleagues showed that exposure to both large and small particulate matter, as well as nitrogen dioxide, was significantly associated with increased odds of death from MI.

This study was funded by China’s Ministry of Science and Technology. The authors and Dr. Newman have disclosed no relevant financial relationships.

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

The combination of heat waves and poor air quality is associated with double the risk of fatal myocardial infarction (MI), with women and older adults at greatest risk, a study from China suggests.

rottadana/Thinkstock

The researchers estimate that up to 3% of all deaths due to MI could be attributed to the combination of extreme temperatures and high levels of ambient fine particulate matter (PM2.5).

“Our findings provide evidence that reducing exposure to both extreme temperatures and fine particulate pollution may be useful to prevent premature deaths from heart attack,” senior author Yuewei Liu, MD, PhD, with Sun Yat-sen University in Guangzhou, China, said in a statement.

There is “long-standing evidence” of the harmful cardiovascular effects of air pollution, Jonathan Newman, MD, MPH, cardiologist at NYU Langone Heart in New York, who wasn’t involved in the study, said in an interview.

The added value of this study was finding an interaction between extreme hot temperatures and air pollution, “which is worrisome with global warming,” said Dr. Newman, assistant professor, department of medicine, the Leon H. Charney Division of Cardiology at NYU Langone Health.

The study was published online in Circulation.
 

Intensity and duration matter

The researchers analyzed data on 202,678 adults (mean age, 77.6 years; 52% male) who suffered fatal MI between 2015 and 2020 in Jiangsu province, a region with four distinct seasons and a wide range of temperatures and ambient PM2.5.

They evaluated the association of exposure to extreme temperature events, including both hot and cold spells, and PM2.5 with MI mortality, and their interactive effects.

Among the key findings:

• The risk of fatal MI was 18% higher during 2-day heat waves with heat indexes at or above the 90th percentile (ranging from 82.6° to 97.9° F) and 74% higher during 4-day heat waves with heat indexes at or above the 97.5th percentile (ranging from 94.8° to 109.4° F), compared with control days.
• The risk of fatal MI was 4% higher during 2-day cold snaps with temperatures at or below the 10th percentile (ranging from 33.3° to 40.5° F) and 12% higher during 3-day cold snaps with temperatures at or below the 2.5th percentile (ranging from 27.0° to 37.2° F).
• The risk of fatal MI was twice as high during 4-day heat waves that had PM2.5 above 37.5 mcg/m³. Days with high levels of PM2.5 during cold snaps did not have an equivalent increase in the risk of fatal MI.
• Up to 2.8% of MI deaths during the 5-year study period may be attributable to the combination of extreme temperature exposure and PM2.5 at levels exceeding World Health Organization air quality guidelines (37.5 mcg/m³).
• The risk of fatal MI was generally higher among women than men during heat waves and was higher among adults 80 years old and older than in younger adults during heat waves, cold snaps, or days with high levels of PM2.5.

The finding that adults over age 80 are particularly susceptible to the effects of heat and air pollution and the interaction of the two is “notable and particularly relevant given the aging of the population,” Dr. Newman told this news organization.

Mitigating both extreme temperature events and PM2.5 exposures “may bring health cobenefits in preventing premature deaths from MI,” the researchers write.

“To improve public health, it is important to take fine particulate pollution into consideration when providing extreme temperature warnings to the public,” Dr. Liu adds in the statement.

In an earlier study, Dr. Liu and colleagues showed that exposure to both large and small particulate matter, as well as nitrogen dioxide, was significantly associated with increased odds of death from MI.

This study was funded by China’s Ministry of Science and Technology. The authors and Dr. Newman have disclosed no relevant financial relationships.

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

Family members with pulmonary fibrosis showed correlations for predicted forced vital capacity trajectories and computed tomography patterns, based on data from 101 individuals in 45 families.

Patients with familial pulmonary fibrosis (FPF), defined as fibrotic interstitial lung disease among two or more first-degree or second-degree relatives, have worse survival than that of patients with sporadic pulmonary fibrosis, wrote Tinne Goos, MD, of KU Leuven, Belgium, and colleagues. Diagnosis of FPF diagnosis is mainly based on family history, and data on intrafamilial correlations are lacking, they said.

In a study published in the journal Chest, the researchers identified FPF patients treated at a single center. The study population included 101 patients from 45 families; most of these (34) were siblings. Overall, 61.4% of the participants were men, 69.3% were ever-smokers, and 84.2% had idiopathic pulmonary fibrosis.

The analysis included data on computed tomography (CT) scanning and predicted forced vital capacity (FVC%), as well as age at diagnosis, treatment type, gender, smoking history, and date of diagnosis.

Overall, FVC%predicted was significantly correlated within families, with a correlation of 0.75. The annual change in FVC was –158.2 mL, and the annual change in FVC%predicted was –6.3%.

Sixty-five patients received antifibrotic treatment, and 18 received immunosuppressive treatment. Immunosuppressive treatment remained significantly correlated among families in a multivariate analysis, with a correlation of 0.77.

“Age at diagnosis correlated within a generation, while patients from a second generation were diagnosed younger,” the researchers noted. The current study findings and results from other studies suggest a genetic basis for FPF age of onset, and determining an age range for screening unaffected relatives based on the age at diagnosis of affected relatives might be useful, they said.

In addition, 42.2% of families showed concordance of CT scan patterns. Typical usual interstitial pneumonia (UIP) appeared in 35 patients, atypical UIP in 36 patients, UIP with emphysema in 9 patients, and findings incompatible with UIP in 21 patients.

The study findings were limited by several factors including the retrospective design and use of data from a single center, as well as by the changes in clinical practice guidelines between 2004 and 2019, with increases in genetic testing, the researchers noted.

However, the current study is the first known to report on FVC evolution within families in FPF, they said. Future studies of both intra- and interfamilial correlation and variability are needed to identify the genetic and environmental factors that may affect disease manifestation and progression, they concluded.

The study was supported by Research Foundation-Flanders. Dr. Goos had no financial conflicts to disclose.

Family members with pulmonary fibrosis showed correlations for predicted forced vital capacity trajectories and computed tomography patterns, based on data from 101 individuals in 45 families.

Patients with familial pulmonary fibrosis (FPF), defined as fibrotic interstitial lung disease among two or more first-degree or second-degree relatives, have worse survival than that of patients with sporadic pulmonary fibrosis, wrote Tinne Goos, MD, of KU Leuven, Belgium, and colleagues. Diagnosis of FPF diagnosis is mainly based on family history, and data on intrafamilial correlations are lacking, they said.

In a study published in the journal Chest, the researchers identified FPF patients treated at a single center. The study population included 101 patients from 45 families; most of these (34) were siblings. Overall, 61.4% of the participants were men, 69.3% were ever-smokers, and 84.2% had idiopathic pulmonary fibrosis.

The analysis included data on computed tomography (CT) scanning and predicted forced vital capacity (FVC%), as well as age at diagnosis, treatment type, gender, smoking history, and date of diagnosis.

Overall, FVC%predicted was significantly correlated within families, with a correlation of 0.75. The annual change in FVC was –158.2 mL, and the annual change in FVC%predicted was –6.3%.

Sixty-five patients received antifibrotic treatment, and 18 received immunosuppressive treatment. Immunosuppressive treatment remained significantly correlated among families in a multivariate analysis, with a correlation of 0.77.

“Age at diagnosis correlated within a generation, while patients from a second generation were diagnosed younger,” the researchers noted. The current study findings and results from other studies suggest a genetic basis for FPF age of onset, and determining an age range for screening unaffected relatives based on the age at diagnosis of affected relatives might be useful, they said.

In addition, 42.2% of families showed concordance of CT scan patterns. Typical usual interstitial pneumonia (UIP) appeared in 35 patients, atypical UIP in 36 patients, UIP with emphysema in 9 patients, and findings incompatible with UIP in 21 patients.

The study findings were limited by several factors including the retrospective design and use of data from a single center, as well as by the changes in clinical practice guidelines between 2004 and 2019, with increases in genetic testing, the researchers noted.

However, the current study is the first known to report on FVC evolution within families in FPF, they said. Future studies of both intra- and interfamilial correlation and variability are needed to identify the genetic and environmental factors that may affect disease manifestation and progression, they concluded.

The study was supported by Research Foundation-Flanders. Dr. Goos had no financial conflicts to disclose.

Family members with pulmonary fibrosis showed correlations for predicted forced vital capacity trajectories and computed tomography patterns, based on data from 101 individuals in 45 families.

Patients with familial pulmonary fibrosis (FPF), defined as fibrotic interstitial lung disease among two or more first-degree or second-degree relatives, have worse survival than that of patients with sporadic pulmonary fibrosis, wrote Tinne Goos, MD, of KU Leuven, Belgium, and colleagues. Diagnosis of FPF diagnosis is mainly based on family history, and data on intrafamilial correlations are lacking, they said.

In a study published in the journal Chest, the researchers identified FPF patients treated at a single center. The study population included 101 patients from 45 families; most of these (34) were siblings. Overall, 61.4% of the participants were men, 69.3% were ever-smokers, and 84.2% had idiopathic pulmonary fibrosis.

The analysis included data on computed tomography (CT) scanning and predicted forced vital capacity (FVC%), as well as age at diagnosis, treatment type, gender, smoking history, and date of diagnosis.

Overall, FVC%predicted was significantly correlated within families, with a correlation of 0.75. The annual change in FVC was –158.2 mL, and the annual change in FVC%predicted was –6.3%.

Sixty-five patients received antifibrotic treatment, and 18 received immunosuppressive treatment. Immunosuppressive treatment remained significantly correlated among families in a multivariate analysis, with a correlation of 0.77.

“Age at diagnosis correlated within a generation, while patients from a second generation were diagnosed younger,” the researchers noted. The current study findings and results from other studies suggest a genetic basis for FPF age of onset, and determining an age range for screening unaffected relatives based on the age at diagnosis of affected relatives might be useful, they said.

In addition, 42.2% of families showed concordance of CT scan patterns. Typical usual interstitial pneumonia (UIP) appeared in 35 patients, atypical UIP in 36 patients, UIP with emphysema in 9 patients, and findings incompatible with UIP in 21 patients.

The study findings were limited by several factors including the retrospective design and use of data from a single center, as well as by the changes in clinical practice guidelines between 2004 and 2019, with increases in genetic testing, the researchers noted.

However, the current study is the first known to report on FVC evolution within families in FPF, they said. Future studies of both intra- and interfamilial correlation and variability are needed to identify the genetic and environmental factors that may affect disease manifestation and progression, they concluded.

The study was supported by Research Foundation-Flanders. Dr. Goos had no financial conflicts to disclose.