Pulmonology

Younger and older patients with severe chronic obstructive pulmonary disease have similar pulmonary and physical health limitations, based on data from 1,058 adults.

Although chronic obstructive pulmonary disease (COPD) generally appears in older patients, the prevalence among adults aged 45-55 years was 6.5% in 2014-2015, wrote Rosanne J.H.C.G. Beijers, PhD, of Maastricht (the Netherlands) University Medical Center, and colleagues. However, data on the early-onset COPD phenotype are limited. In particular, the extent to which younger patients with early-onset severe COPD experienced the same physical and mental health problems as older patients with similar degree of airflow limitation has not been examined, they said.

In a study published in Clinical Nutrition, the researchers analyzed data from adults with COPD who were referred for pulmonary rehabilitation at a single center between July 2013 and August 2018. Severe disease was defined as FEV1< 50%, and early onset was defined as younger than 55 years. The mean age difference between older and younger patient groups was 15.8 years.

The study population included 79 individuals with early-onset severe disease, 54 with early-onset mild to moderate disease, 158 older adults with severe disease, and 103 older adults with mild to moderate disease. The researchers compared disease markers including body composition, physical performance, and mental health between the groups. A significantly greater proportion of the early-onset group were women, compared to the older group (64% vs. 44%).

In comparing early-onset and older patients with severe COPD, the researchers found that clinical characteristics were similar for body composition, skeletal muscle index, fat percentage, and bone mineral content, and for physical performance factors including the percent predicted maximal work capacity (Wmax), 6-minute walk test, and isokinetic strength. However, a higher prevalence of depression appeared in the early-onset severe-disease patients, compared with the older severe-disease patients (51.9% vs. 32.7%; P = .029).

Although the prevalence of depression was not based on a clinical diagnosis, this finding should prompt health care professionals to pay more attention to psychosocial and emotional well-being in early-onset severe COPD patients, the researchers noted.

In comparing early-onset severe-disease patients and early-onset patients with mild to moderate disease, patients with early-onset severe COPD had significantly lower exercise performance, based on a 6-minute walk test and percent predicted Wmax. However, body composition and isokinetic muscle strength were not significantly different between both early-onset groups.

The findings were limited by several factors including the relatively small number of early-onset patients and the lack of data on whether older patients were diagnosed with severe COPD at a younger age, and more research using age and lung function at the time of diagnosis is needed, the researchers noted. However, the results highlight the importance of early identification of patients at risk for early-onset severe COPD, they said. “Within these individuals at risk, special attention should also be paid to the development of extrapulmonary disease manifestations such as exercise limitations, impaired body composition, and psychological and emotional problems,” the researchers said. “Subsequently, intervention strategies need to be applied that not only focus on the regular advice of quitting smoking but also include decreasing the exposure to air pollutants and promoting a healthy lifestyle including physical activity and a healthy diet,” they added.

The study received no outside funding. Lead author Dr. Beijers had no financial conflicts to disclose.

Younger and older patients with severe chronic obstructive pulmonary disease have similar pulmonary and physical health limitations, based on data from 1,058 adults.

Although chronic obstructive pulmonary disease (COPD) generally appears in older patients, the prevalence among adults aged 45-55 years was 6.5% in 2014-2015, wrote Rosanne J.H.C.G. Beijers, PhD, of Maastricht (the Netherlands) University Medical Center, and colleagues. However, data on the early-onset COPD phenotype are limited. In particular, the extent to which younger patients with early-onset severe COPD experienced the same physical and mental health problems as older patients with similar degree of airflow limitation has not been examined, they said.

In a study published in Clinical Nutrition, the researchers analyzed data from adults with COPD who were referred for pulmonary rehabilitation at a single center between July 2013 and August 2018. Severe disease was defined as FEV1< 50%, and early onset was defined as younger than 55 years. The mean age difference between older and younger patient groups was 15.8 years.

The study population included 79 individuals with early-onset severe disease, 54 with early-onset mild to moderate disease, 158 older adults with severe disease, and 103 older adults with mild to moderate disease. The researchers compared disease markers including body composition, physical performance, and mental health between the groups. A significantly greater proportion of the early-onset group were women, compared to the older group (64% vs. 44%).

In comparing early-onset and older patients with severe COPD, the researchers found that clinical characteristics were similar for body composition, skeletal muscle index, fat percentage, and bone mineral content, and for physical performance factors including the percent predicted maximal work capacity (Wmax), 6-minute walk test, and isokinetic strength. However, a higher prevalence of depression appeared in the early-onset severe-disease patients, compared with the older severe-disease patients (51.9% vs. 32.7%; P = .029).

Although the prevalence of depression was not based on a clinical diagnosis, this finding should prompt health care professionals to pay more attention to psychosocial and emotional well-being in early-onset severe COPD patients, the researchers noted.

In comparing early-onset severe-disease patients and early-onset patients with mild to moderate disease, patients with early-onset severe COPD had significantly lower exercise performance, based on a 6-minute walk test and percent predicted Wmax. However, body composition and isokinetic muscle strength were not significantly different between both early-onset groups.

The findings were limited by several factors including the relatively small number of early-onset patients and the lack of data on whether older patients were diagnosed with severe COPD at a younger age, and more research using age and lung function at the time of diagnosis is needed, the researchers noted. However, the results highlight the importance of early identification of patients at risk for early-onset severe COPD, they said. “Within these individuals at risk, special attention should also be paid to the development of extrapulmonary disease manifestations such as exercise limitations, impaired body composition, and psychological and emotional problems,” the researchers said. “Subsequently, intervention strategies need to be applied that not only focus on the regular advice of quitting smoking but also include decreasing the exposure to air pollutants and promoting a healthy lifestyle including physical activity and a healthy diet,” they added.

The study received no outside funding. Lead author Dr. Beijers had no financial conflicts to disclose.

Younger and older patients with severe chronic obstructive pulmonary disease have similar pulmonary and physical health limitations, based on data from 1,058 adults.

Although chronic obstructive pulmonary disease (COPD) generally appears in older patients, the prevalence among adults aged 45-55 years was 6.5% in 2014-2015, wrote Rosanne J.H.C.G. Beijers, PhD, of Maastricht (the Netherlands) University Medical Center, and colleagues. However, data on the early-onset COPD phenotype are limited. In particular, the extent to which younger patients with early-onset severe COPD experienced the same physical and mental health problems as older patients with similar degree of airflow limitation has not been examined, they said.

In a study published in Clinical Nutrition, the researchers analyzed data from adults with COPD who were referred for pulmonary rehabilitation at a single center between July 2013 and August 2018. Severe disease was defined as FEV1< 50%, and early onset was defined as younger than 55 years. The mean age difference between older and younger patient groups was 15.8 years.

The study population included 79 individuals with early-onset severe disease, 54 with early-onset mild to moderate disease, 158 older adults with severe disease, and 103 older adults with mild to moderate disease. The researchers compared disease markers including body composition, physical performance, and mental health between the groups. A significantly greater proportion of the early-onset group were women, compared to the older group (64% vs. 44%).

In comparing early-onset and older patients with severe COPD, the researchers found that clinical characteristics were similar for body composition, skeletal muscle index, fat percentage, and bone mineral content, and for physical performance factors including the percent predicted maximal work capacity (Wmax), 6-minute walk test, and isokinetic strength. However, a higher prevalence of depression appeared in the early-onset severe-disease patients, compared with the older severe-disease patients (51.9% vs. 32.7%; P = .029).

Although the prevalence of depression was not based on a clinical diagnosis, this finding should prompt health care professionals to pay more attention to psychosocial and emotional well-being in early-onset severe COPD patients, the researchers noted.

In comparing early-onset severe-disease patients and early-onset patients with mild to moderate disease, patients with early-onset severe COPD had significantly lower exercise performance, based on a 6-minute walk test and percent predicted Wmax. However, body composition and isokinetic muscle strength were not significantly different between both early-onset groups.

The findings were limited by several factors including the relatively small number of early-onset patients and the lack of data on whether older patients were diagnosed with severe COPD at a younger age, and more research using age and lung function at the time of diagnosis is needed, the researchers noted. However, the results highlight the importance of early identification of patients at risk for early-onset severe COPD, they said. “Within these individuals at risk, special attention should also be paid to the development of extrapulmonary disease manifestations such as exercise limitations, impaired body composition, and psychological and emotional problems,” the researchers said. “Subsequently, intervention strategies need to be applied that not only focus on the regular advice of quitting smoking but also include decreasing the exposure to air pollutants and promoting a healthy lifestyle including physical activity and a healthy diet,” they added.

The study received no outside funding. Lead author Dr. Beijers had no financial conflicts to disclose.

In a specialty clinic, dupilumab (Dupixent) injections significantly improved symptoms for patients with chronic rhinosinusitis with nasal polyps, based on provisional data from more than 100 adults.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a significant burden among working-age adults. Symptom control remains a challenge for many of these patients, and the cost in lost productivity and health care consumption can be substantial, write Rik J.L. van der Lans, MD, of the University of Amsterdam, and colleagues.

Dupilumab, a biologic that targets components of the type 2 inflammatory pathway, represents a new option that has shown effectiveness in clinical trials for regulatory approval, they said.

A new observational study tests dupilumab in patients who met criteria for biological treatment proposed in a recent major systematic review. The findings were published in the journal Allergy.

In the study, the researchers identified 131 adults older than 18 years (mean age 51.7) with CRSwNP treated at a single tertiary care center. Participants received 300 mg of dupilumab subcutaneous injection every 2 weeks for at least 12 weeks.

The primary outcomes were scores on several measures, including the SinoNasal Outcome Test-22 (SNOT-22, scale of 0-110), the bilateral Nasal Polyp Score (NPS, scale of 0-8), and the Sniffin’ Sticks-12 identification test (SSIT-12, scale of 0-6 anosmia, 7-10 hyposmia, 11-12 normosmia).

The mean scores on all three outcomes improved significantly from baseline to both 24 weeks and 48 weeks. Scores on the SNOT-22 improved from 52.4 at baseline to 18.5 and 16.8 at weeks 24 and 48, respectively. NPS improved from 5.4 at baseline to 1.6 and 1.0, respectively. SSIT-12 scores improved from 3.6 at baseline to 7.3 and 8.3, respectively.

At baseline, 95.8% of the patients had uncontrolled chronic rhinosinusitis, but at 24 and 48 weeks, respectively, 24.3% and 6.2% were uncontrolled.

Approximately half of the patients experienced treatment-emergent adverse events, but these were “mild and decreased in occurrence and intensity throughout treatment,” the researchers say.

For patients with a strong response, the researchers also tested an extension of the interval between doses to 4 weeks and 6 weeks, in a provisional indication of continued established control at these timepoints.

The study findings were limited by several factors, including the potential for selection bias, and data from only the first patient cohort, the researchers noted. However, the results were strengthened by the real-life context, standardized indications, and long-term follow up for almost a year, they said.

More research is needed on nonacademic patient cohorts, but the current data confirm the effectiveness of dupilumab as an add-on for difficult-to-treat CRSwNP, they concluded. The findings also validate the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) inclusion criteria for biologic treatment, they said.

The new study is important because of the need for verification of results from randomized controlled trials using real-world data, Dr. Van der Lans told this news organization.

“For example, differences in treatment efficacy might result from differing indication criteria, and the inclusion/exclusion criteria in the RCTs might have excluded patients one would encounter in daily practice,” he said. “With our prospective observational cohort, we are seeking to verify efficacy, monitor pharmacovigilance, and evaluate and advance the indication criteria and positioning of biologicals registered for CRSwNP, such as dupilumab.”

These cross-sectional results suggest dupilumab is more effective in preventing possibly harmful escape treatments, such as oral corticosteroids and/or surgery, than reported by the registration trials.

“Additionally, it appears possible to maintain established CRS-control during response-dependent, stepwise, interdose interval prolongation of up to 6 weeks, which is officially an off-label dosing interval,” he said. “This would greatly benefit patients’ treatment burden and direct costs,” he said. However, both findings require corroboration by anticipated longitudinal results in 2022, he noted.

The key message for clinicians in practice: “Biologicals like dupilumab are a potent and promising treatment for severe CRSwNP when conventional medical and surgical therapy fails,” he emphasized.

Looking ahead, important research objectives include head-on comparison studies of the diverse biological agents, establishing biomarkers to guide preferential therapy, and evaluating the economics of biologics compared with conventional therapy, Dr. Van der Lans added. Such research is vital not only for improving patient-centered care but to sustain the use of biologicals in a health-economic perspective.

One of the greatest criticisms of biologic therapy for CRSwNP is cost, particularly in a setting of ever-increasing health care costs. A recent review noted the average cost per year is greater than $30,000.
 

Real-life study verifies effectiveness

“As the authors pointed out, this is a real-life, prospective observational cohort with a decently large size, evaluating the therapeutic efficacy of add-on dupilumab,” said Seong H. Cho, MD, of the University of South Florida, Tampa, in an interview.

“Dupilumab is the first FDA-approved biologic to treat severe chronic rhinosinusitis with nasal polyps based on two phase 3 clinical trials,” said Dr. Cho, who was not involved with the study. “It has been more than 2 years since dupilumab was approved for severe CRSwNP by the FDA and EMA. This real-life, prospective, observational study with a decent size verified the efficacy of dupilumab as an add-on treatment when used with a proper indication such as EPOS2020 indication criteria.

“I am not surprised by the efficacy of dupilumab on severe CRSwNP, based on my clinical experience. My clinical observation is similar to the results of this study. This study verifies that dupilumab is highly efficacious in treating refractory and severe CRSwNP in a real-life setting by improving all subjective and objective clinical outcomes such as SNOT-22, NPS, and smell test score,” he said. The study also confirms that a stepwise, interdose interval prolongation from every 2-4 weeks for CRSwNP patients with good response should be a consideration for clinical practice, he added. 

The cost-effectiveness of dupilumab is the main barrier to more consistent use, Dr. Cho said. “There is no evidence that dupilumab can change the course of the disease, and we don’t know how long patients need to be on this drug. Therefore, nasal polyps need to be refractory and severe enough to use dupilumab and other biologics,” he explained.

Consequently, proper indication criteria, such as the EPOS2020 indication criteria for biologics, should be established before initiating dupilumab, Dr. Cho noted.

“Generally, endoscopic sinus surgery would be preferred in sinus-surgery naive CRSwNP patients, unless surgery is contraindicated or refused by patients because of cost-effectiveness rather than the superior efficacy,” he said. “If surgery fails, then dupilumab can be considered. In addition, proper evaluation of nasal polyp severity would be important.”

“One should establish an objective NPS by endoscopic exam before initiation of dupilumab. This baseline score would be an important marker to assess the efficacy of dupilumab in the course of treatment.”

Monitoring of the NPS together with the patient’s symptom improvement would be essential to implementing a stepwise, interdose interval prolongation to reduce the cost, he emphasized. 

“The most crucial additional research is establishing suitable biomarkers for the response of dupilumab and other biologics,” said Dr. Cho. “Overall, the performance of dupilumab seems to be good. But there are patients unresponsive to dupilumab, even more to other recently FDA-approved biologics for CRSwNP.”

Blood eosinophils and exhaled nitric oxide can be a good biomarker for type 2 asthma, Dr. Cho added. “Still, there is no evidence that these biomarkers are decent for CRSwNP, even though CRSwNP is mostly considered as type 2 disease. Therefore, it would be essential to find promising biomarkers for severe CRSwNP.”

Dr. Van der Lans disclosed serving as a consultant for GlaxoSmithKline, and several coauthors disclosed relationships with companies including Sanofi and Novartis. The patient registry from which the study population was drawn is cofunded by Sanofi and Novartis. Dr. Cho has disclosed no relevant financial relationships.

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

In a specialty clinic, dupilumab (Dupixent) injections significantly improved symptoms for patients with chronic rhinosinusitis with nasal polyps, based on provisional data from more than 100 adults.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a significant burden among working-age adults. Symptom control remains a challenge for many of these patients, and the cost in lost productivity and health care consumption can be substantial, write Rik J.L. van der Lans, MD, of the University of Amsterdam, and colleagues.

Dupilumab, a biologic that targets components of the type 2 inflammatory pathway, represents a new option that has shown effectiveness in clinical trials for regulatory approval, they said.

A new observational study tests dupilumab in patients who met criteria for biological treatment proposed in a recent major systematic review. The findings were published in the journal Allergy.

In the study, the researchers identified 131 adults older than 18 years (mean age 51.7) with CRSwNP treated at a single tertiary care center. Participants received 300 mg of dupilumab subcutaneous injection every 2 weeks for at least 12 weeks.

The primary outcomes were scores on several measures, including the SinoNasal Outcome Test-22 (SNOT-22, scale of 0-110), the bilateral Nasal Polyp Score (NPS, scale of 0-8), and the Sniffin’ Sticks-12 identification test (SSIT-12, scale of 0-6 anosmia, 7-10 hyposmia, 11-12 normosmia).

The mean scores on all three outcomes improved significantly from baseline to both 24 weeks and 48 weeks. Scores on the SNOT-22 improved from 52.4 at baseline to 18.5 and 16.8 at weeks 24 and 48, respectively. NPS improved from 5.4 at baseline to 1.6 and 1.0, respectively. SSIT-12 scores improved from 3.6 at baseline to 7.3 and 8.3, respectively.

At baseline, 95.8% of the patients had uncontrolled chronic rhinosinusitis, but at 24 and 48 weeks, respectively, 24.3% and 6.2% were uncontrolled.

Approximately half of the patients experienced treatment-emergent adverse events, but these were “mild and decreased in occurrence and intensity throughout treatment,” the researchers say.

For patients with a strong response, the researchers also tested an extension of the interval between doses to 4 weeks and 6 weeks, in a provisional indication of continued established control at these timepoints.

The study findings were limited by several factors, including the potential for selection bias, and data from only the first patient cohort, the researchers noted. However, the results were strengthened by the real-life context, standardized indications, and long-term follow up for almost a year, they said.

More research is needed on nonacademic patient cohorts, but the current data confirm the effectiveness of dupilumab as an add-on for difficult-to-treat CRSwNP, they concluded. The findings also validate the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) inclusion criteria for biologic treatment, they said.

The new study is important because of the need for verification of results from randomized controlled trials using real-world data, Dr. Van der Lans told this news organization.

“For example, differences in treatment efficacy might result from differing indication criteria, and the inclusion/exclusion criteria in the RCTs might have excluded patients one would encounter in daily practice,” he said. “With our prospective observational cohort, we are seeking to verify efficacy, monitor pharmacovigilance, and evaluate and advance the indication criteria and positioning of biologicals registered for CRSwNP, such as dupilumab.”

These cross-sectional results suggest dupilumab is more effective in preventing possibly harmful escape treatments, such as oral corticosteroids and/or surgery, than reported by the registration trials.

“Additionally, it appears possible to maintain established CRS-control during response-dependent, stepwise, interdose interval prolongation of up to 6 weeks, which is officially an off-label dosing interval,” he said. “This would greatly benefit patients’ treatment burden and direct costs,” he said. However, both findings require corroboration by anticipated longitudinal results in 2022, he noted.

The key message for clinicians in practice: “Biologicals like dupilumab are a potent and promising treatment for severe CRSwNP when conventional medical and surgical therapy fails,” he emphasized.

Looking ahead, important research objectives include head-on comparison studies of the diverse biological agents, establishing biomarkers to guide preferential therapy, and evaluating the economics of biologics compared with conventional therapy, Dr. Van der Lans added. Such research is vital not only for improving patient-centered care but to sustain the use of biologicals in a health-economic perspective.

One of the greatest criticisms of biologic therapy for CRSwNP is cost, particularly in a setting of ever-increasing health care costs. A recent review noted the average cost per year is greater than $30,000.
 

Real-life study verifies effectiveness

“As the authors pointed out, this is a real-life, prospective observational cohort with a decently large size, evaluating the therapeutic efficacy of add-on dupilumab,” said Seong H. Cho, MD, of the University of South Florida, Tampa, in an interview.

“Dupilumab is the first FDA-approved biologic to treat severe chronic rhinosinusitis with nasal polyps based on two phase 3 clinical trials,” said Dr. Cho, who was not involved with the study. “It has been more than 2 years since dupilumab was approved for severe CRSwNP by the FDA and EMA. This real-life, prospective, observational study with a decent size verified the efficacy of dupilumab as an add-on treatment when used with a proper indication such as EPOS2020 indication criteria.

“I am not surprised by the efficacy of dupilumab on severe CRSwNP, based on my clinical experience. My clinical observation is similar to the results of this study. This study verifies that dupilumab is highly efficacious in treating refractory and severe CRSwNP in a real-life setting by improving all subjective and objective clinical outcomes such as SNOT-22, NPS, and smell test score,” he said. The study also confirms that a stepwise, interdose interval prolongation from every 2-4 weeks for CRSwNP patients with good response should be a consideration for clinical practice, he added. 

The cost-effectiveness of dupilumab is the main barrier to more consistent use, Dr. Cho said. “There is no evidence that dupilumab can change the course of the disease, and we don’t know how long patients need to be on this drug. Therefore, nasal polyps need to be refractory and severe enough to use dupilumab and other biologics,” he explained.

Consequently, proper indication criteria, such as the EPOS2020 indication criteria for biologics, should be established before initiating dupilumab, Dr. Cho noted.

“Generally, endoscopic sinus surgery would be preferred in sinus-surgery naive CRSwNP patients, unless surgery is contraindicated or refused by patients because of cost-effectiveness rather than the superior efficacy,” he said. “If surgery fails, then dupilumab can be considered. In addition, proper evaluation of nasal polyp severity would be important.”

“One should establish an objective NPS by endoscopic exam before initiation of dupilumab. This baseline score would be an important marker to assess the efficacy of dupilumab in the course of treatment.”

Monitoring of the NPS together with the patient’s symptom improvement would be essential to implementing a stepwise, interdose interval prolongation to reduce the cost, he emphasized. 

“The most crucial additional research is establishing suitable biomarkers for the response of dupilumab and other biologics,” said Dr. Cho. “Overall, the performance of dupilumab seems to be good. But there are patients unresponsive to dupilumab, even more to other recently FDA-approved biologics for CRSwNP.”

Blood eosinophils and exhaled nitric oxide can be a good biomarker for type 2 asthma, Dr. Cho added. “Still, there is no evidence that these biomarkers are decent for CRSwNP, even though CRSwNP is mostly considered as type 2 disease. Therefore, it would be essential to find promising biomarkers for severe CRSwNP.”

Dr. Van der Lans disclosed serving as a consultant for GlaxoSmithKline, and several coauthors disclosed relationships with companies including Sanofi and Novartis. The patient registry from which the study population was drawn is cofunded by Sanofi and Novartis. Dr. Cho has disclosed no relevant financial relationships.

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

In a specialty clinic, dupilumab (Dupixent) injections significantly improved symptoms for patients with chronic rhinosinusitis with nasal polyps, based on provisional data from more than 100 adults.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a significant burden among working-age adults. Symptom control remains a challenge for many of these patients, and the cost in lost productivity and health care consumption can be substantial, write Rik J.L. van der Lans, MD, of the University of Amsterdam, and colleagues.

Dupilumab, a biologic that targets components of the type 2 inflammatory pathway, represents a new option that has shown effectiveness in clinical trials for regulatory approval, they said.

A new observational study tests dupilumab in patients who met criteria for biological treatment proposed in a recent major systematic review. The findings were published in the journal Allergy.

In the study, the researchers identified 131 adults older than 18 years (mean age 51.7) with CRSwNP treated at a single tertiary care center. Participants received 300 mg of dupilumab subcutaneous injection every 2 weeks for at least 12 weeks.

The primary outcomes were scores on several measures, including the SinoNasal Outcome Test-22 (SNOT-22, scale of 0-110), the bilateral Nasal Polyp Score (NPS, scale of 0-8), and the Sniffin’ Sticks-12 identification test (SSIT-12, scale of 0-6 anosmia, 7-10 hyposmia, 11-12 normosmia).

The mean scores on all three outcomes improved significantly from baseline to both 24 weeks and 48 weeks. Scores on the SNOT-22 improved from 52.4 at baseline to 18.5 and 16.8 at weeks 24 and 48, respectively. NPS improved from 5.4 at baseline to 1.6 and 1.0, respectively. SSIT-12 scores improved from 3.6 at baseline to 7.3 and 8.3, respectively.

At baseline, 95.8% of the patients had uncontrolled chronic rhinosinusitis, but at 24 and 48 weeks, respectively, 24.3% and 6.2% were uncontrolled.

Approximately half of the patients experienced treatment-emergent adverse events, but these were “mild and decreased in occurrence and intensity throughout treatment,” the researchers say.

For patients with a strong response, the researchers also tested an extension of the interval between doses to 4 weeks and 6 weeks, in a provisional indication of continued established control at these timepoints.

The study findings were limited by several factors, including the potential for selection bias, and data from only the first patient cohort, the researchers noted. However, the results were strengthened by the real-life context, standardized indications, and long-term follow up for almost a year, they said.

More research is needed on nonacademic patient cohorts, but the current data confirm the effectiveness of dupilumab as an add-on for difficult-to-treat CRSwNP, they concluded. The findings also validate the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) inclusion criteria for biologic treatment, they said.

The new study is important because of the need for verification of results from randomized controlled trials using real-world data, Dr. Van der Lans told this news organization.

“For example, differences in treatment efficacy might result from differing indication criteria, and the inclusion/exclusion criteria in the RCTs might have excluded patients one would encounter in daily practice,” he said. “With our prospective observational cohort, we are seeking to verify efficacy, monitor pharmacovigilance, and evaluate and advance the indication criteria and positioning of biologicals registered for CRSwNP, such as dupilumab.”

These cross-sectional results suggest dupilumab is more effective in preventing possibly harmful escape treatments, such as oral corticosteroids and/or surgery, than reported by the registration trials.

“Additionally, it appears possible to maintain established CRS-control during response-dependent, stepwise, interdose interval prolongation of up to 6 weeks, which is officially an off-label dosing interval,” he said. “This would greatly benefit patients’ treatment burden and direct costs,” he said. However, both findings require corroboration by anticipated longitudinal results in 2022, he noted.

The key message for clinicians in practice: “Biologicals like dupilumab are a potent and promising treatment for severe CRSwNP when conventional medical and surgical therapy fails,” he emphasized.

Looking ahead, important research objectives include head-on comparison studies of the diverse biological agents, establishing biomarkers to guide preferential therapy, and evaluating the economics of biologics compared with conventional therapy, Dr. Van der Lans added. Such research is vital not only for improving patient-centered care but to sustain the use of biologicals in a health-economic perspective.

One of the greatest criticisms of biologic therapy for CRSwNP is cost, particularly in a setting of ever-increasing health care costs. A recent review noted the average cost per year is greater than $30,000.
 

Real-life study verifies effectiveness

“As the authors pointed out, this is a real-life, prospective observational cohort with a decently large size, evaluating the therapeutic efficacy of add-on dupilumab,” said Seong H. Cho, MD, of the University of South Florida, Tampa, in an interview.

“Dupilumab is the first FDA-approved biologic to treat severe chronic rhinosinusitis with nasal polyps based on two phase 3 clinical trials,” said Dr. Cho, who was not involved with the study. “It has been more than 2 years since dupilumab was approved for severe CRSwNP by the FDA and EMA. This real-life, prospective, observational study with a decent size verified the efficacy of dupilumab as an add-on treatment when used with a proper indication such as EPOS2020 indication criteria.

“I am not surprised by the efficacy of dupilumab on severe CRSwNP, based on my clinical experience. My clinical observation is similar to the results of this study. This study verifies that dupilumab is highly efficacious in treating refractory and severe CRSwNP in a real-life setting by improving all subjective and objective clinical outcomes such as SNOT-22, NPS, and smell test score,” he said. The study also confirms that a stepwise, interdose interval prolongation from every 2-4 weeks for CRSwNP patients with good response should be a consideration for clinical practice, he added. 

The cost-effectiveness of dupilumab is the main barrier to more consistent use, Dr. Cho said. “There is no evidence that dupilumab can change the course of the disease, and we don’t know how long patients need to be on this drug. Therefore, nasal polyps need to be refractory and severe enough to use dupilumab and other biologics,” he explained.

Consequently, proper indication criteria, such as the EPOS2020 indication criteria for biologics, should be established before initiating dupilumab, Dr. Cho noted.

“Generally, endoscopic sinus surgery would be preferred in sinus-surgery naive CRSwNP patients, unless surgery is contraindicated or refused by patients because of cost-effectiveness rather than the superior efficacy,” he said. “If surgery fails, then dupilumab can be considered. In addition, proper evaluation of nasal polyp severity would be important.”

“One should establish an objective NPS by endoscopic exam before initiation of dupilumab. This baseline score would be an important marker to assess the efficacy of dupilumab in the course of treatment.”

Monitoring of the NPS together with the patient’s symptom improvement would be essential to implementing a stepwise, interdose interval prolongation to reduce the cost, he emphasized. 

“The most crucial additional research is establishing suitable biomarkers for the response of dupilumab and other biologics,” said Dr. Cho. “Overall, the performance of dupilumab seems to be good. But there are patients unresponsive to dupilumab, even more to other recently FDA-approved biologics for CRSwNP.”

Blood eosinophils and exhaled nitric oxide can be a good biomarker for type 2 asthma, Dr. Cho added. “Still, there is no evidence that these biomarkers are decent for CRSwNP, even though CRSwNP is mostly considered as type 2 disease. Therefore, it would be essential to find promising biomarkers for severe CRSwNP.”

Dr. Van der Lans disclosed serving as a consultant for GlaxoSmithKline, and several coauthors disclosed relationships with companies including Sanofi and Novartis. The patient registry from which the study population was drawn is cofunded by Sanofi and Novartis. Dr. Cho has disclosed no relevant financial relationships.

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

Sepsis is an alarmingly common cause behind ICU admissions in patients with multiple sclerosis (MS), a retrospective, population-based cohort study indicates.

Furthermore, it contributes to a disproportionately high percentage of the short-term mortality risk among patients with MS admitted to the ICU, findings also show. Short-term mortality risk was defined in the study as a combination of in-hospital death or discharge to hospice.

“We found that the risk of short-term mortality in critically ill patients with MS is four times higher among those with sepsis ... so sepsis appears to be comparatively more lethal among patients with MS than in the general population,” Lavi Oud, MD, professor of medicine, Texas Tech University HSC at the Permian Basin, Odessa, said in an email.

“[Although] the specific mechanisms underlying the markedly higher risk of sepsis among patients with MS compared to the general population remain to be fully elucidated ... it’s thought that the risk may stem from the dysfunction of the immune system in these patients related to MS itself and to the potentially adverse effect of the immunomodulating therapy we use in these patients,” he added.

The study was published online Jan. 11 in the Journal of Critical Care.
 

Sepsis rates

The Texas Inpatient Public Use Data File was used to identify adults with a diagnosis of MS admitted to the hospital between 2010 and 2017. Among the 19,837 patients with MS admitted to the ICU during the study interval, almost one-third (31.5%) had sepsis, investigators report. “The rate of sepsis among ICU admissions increased with age, ranging from 20.8% among those aged 18-44 to 39.4% among those aged 65 years or older,” investigators note.

The most common site of infection among MS patients admitted to the ICU were urinary in nature (65.2%), followed by respiratory (36.1%). A smaller proportion of infections (7.6%) involved the skin and soft tissues, researchers note. A full one-quarter of patients developed septic shock in response to their infection while the length of stay among patients with sepsis (mean of 10.9 days) was substantially longer than it was for those without sepsis (mean of 5.6 days), they observe.

At a mean total hospital cost of $121,797 for each ICU patient with sepsis, the cost of caring for each patient was nearly twofold higher than the mean total cost of taking care of ICU patients without sepsis (mean total cost, $65,179). On adjusted analysis, sepsis was associated with a 42.7% (95% confidence interval, 38.9-46.5; P < .0001) longer length of hospital stay and a 26.2% (95% CI, 23.1-29.1; P < .0001) higher total hospital cost compared with patients without sepsis, the authors point out.

Indeed, ICU admissions with sepsis accounted for 47.3% of all hospital days and for 46.1% of the aggregate hospital charges among all MS patients admitted to the ICU.

“The adjusted probability of short-term mortality was 13.4% (95% CI, 13.0-13.7) among ICU admissions with sepsis and 3.3% (95% CI, 3.2-3.4) among ICU admissions without sepsis,” the authors report.

This translated into a 44% higher risk of short-term mortality at an adjusted odds ratio of 1.44 (95% CI, 1.23-1.69; P < .0001) for those with sepsis, compared with those without, they add. Among all ICU admissions, sepsis was reported in over two-thirds of documented short-term mortality events. The risk of short-term mortality was also almost threefold higher among patients with sepsis who were age 65 years and older compared with patients aged 18-44. 

As Dr. Oud noted, there is no specific test for sepsis, and it can initially present in an atypical manner, especially in older, frailer, chronically ill patients as well as in patients with immune dysfunction. “Thus, considering sepsis as a possible cause of new deterioration in a patient’s condition is essential, along with the timely start of sepsis-related care,” Dr. Oud observed.

A limitation of the study was that the dataset did not include information on the type of MS a patient had, the duration of their illness, the treatment received, the level of disease activity, or the level of disability.

The study had no specific funding. The authors have disclosed no relevant financial relationships.

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

Sepsis is an alarmingly common cause behind ICU admissions in patients with multiple sclerosis (MS), a retrospective, population-based cohort study indicates.

Furthermore, it contributes to a disproportionately high percentage of the short-term mortality risk among patients with MS admitted to the ICU, findings also show. Short-term mortality risk was defined in the study as a combination of in-hospital death or discharge to hospice.

“We found that the risk of short-term mortality in critically ill patients with MS is four times higher among those with sepsis ... so sepsis appears to be comparatively more lethal among patients with MS than in the general population,” Lavi Oud, MD, professor of medicine, Texas Tech University HSC at the Permian Basin, Odessa, said in an email.

“[Although] the specific mechanisms underlying the markedly higher risk of sepsis among patients with MS compared to the general population remain to be fully elucidated ... it’s thought that the risk may stem from the dysfunction of the immune system in these patients related to MS itself and to the potentially adverse effect of the immunomodulating therapy we use in these patients,” he added.

The study was published online Jan. 11 in the Journal of Critical Care.
 

Sepsis rates

The Texas Inpatient Public Use Data File was used to identify adults with a diagnosis of MS admitted to the hospital between 2010 and 2017. Among the 19,837 patients with MS admitted to the ICU during the study interval, almost one-third (31.5%) had sepsis, investigators report. “The rate of sepsis among ICU admissions increased with age, ranging from 20.8% among those aged 18-44 to 39.4% among those aged 65 years or older,” investigators note.

The most common site of infection among MS patients admitted to the ICU were urinary in nature (65.2%), followed by respiratory (36.1%). A smaller proportion of infections (7.6%) involved the skin and soft tissues, researchers note. A full one-quarter of patients developed septic shock in response to their infection while the length of stay among patients with sepsis (mean of 10.9 days) was substantially longer than it was for those without sepsis (mean of 5.6 days), they observe.

At a mean total hospital cost of $121,797 for each ICU patient with sepsis, the cost of caring for each patient was nearly twofold higher than the mean total cost of taking care of ICU patients without sepsis (mean total cost, $65,179). On adjusted analysis, sepsis was associated with a 42.7% (95% confidence interval, 38.9-46.5; P < .0001) longer length of hospital stay and a 26.2% (95% CI, 23.1-29.1; P < .0001) higher total hospital cost compared with patients without sepsis, the authors point out.

Indeed, ICU admissions with sepsis accounted for 47.3% of all hospital days and for 46.1% of the aggregate hospital charges among all MS patients admitted to the ICU.

“The adjusted probability of short-term mortality was 13.4% (95% CI, 13.0-13.7) among ICU admissions with sepsis and 3.3% (95% CI, 3.2-3.4) among ICU admissions without sepsis,” the authors report.

This translated into a 44% higher risk of short-term mortality at an adjusted odds ratio of 1.44 (95% CI, 1.23-1.69; P < .0001) for those with sepsis, compared with those without, they add. Among all ICU admissions, sepsis was reported in over two-thirds of documented short-term mortality events. The risk of short-term mortality was also almost threefold higher among patients with sepsis who were age 65 years and older compared with patients aged 18-44. 

As Dr. Oud noted, there is no specific test for sepsis, and it can initially present in an atypical manner, especially in older, frailer, chronically ill patients as well as in patients with immune dysfunction. “Thus, considering sepsis as a possible cause of new deterioration in a patient’s condition is essential, along with the timely start of sepsis-related care,” Dr. Oud observed.

A limitation of the study was that the dataset did not include information on the type of MS a patient had, the duration of their illness, the treatment received, the level of disease activity, or the level of disability.

The study had no specific funding. The authors have disclosed no relevant financial relationships.

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

Sepsis is an alarmingly common cause behind ICU admissions in patients with multiple sclerosis (MS), a retrospective, population-based cohort study indicates.

Furthermore, it contributes to a disproportionately high percentage of the short-term mortality risk among patients with MS admitted to the ICU, findings also show. Short-term mortality risk was defined in the study as a combination of in-hospital death or discharge to hospice.

“We found that the risk of short-term mortality in critically ill patients with MS is four times higher among those with sepsis ... so sepsis appears to be comparatively more lethal among patients with MS than in the general population,” Lavi Oud, MD, professor of medicine, Texas Tech University HSC at the Permian Basin, Odessa, said in an email.

“[Although] the specific mechanisms underlying the markedly higher risk of sepsis among patients with MS compared to the general population remain to be fully elucidated ... it’s thought that the risk may stem from the dysfunction of the immune system in these patients related to MS itself and to the potentially adverse effect of the immunomodulating therapy we use in these patients,” he added.

The study was published online Jan. 11 in the Journal of Critical Care.
 

Sepsis rates

The Texas Inpatient Public Use Data File was used to identify adults with a diagnosis of MS admitted to the hospital between 2010 and 2017. Among the 19,837 patients with MS admitted to the ICU during the study interval, almost one-third (31.5%) had sepsis, investigators report. “The rate of sepsis among ICU admissions increased with age, ranging from 20.8% among those aged 18-44 to 39.4% among those aged 65 years or older,” investigators note.

The most common site of infection among MS patients admitted to the ICU were urinary in nature (65.2%), followed by respiratory (36.1%). A smaller proportion of infections (7.6%) involved the skin and soft tissues, researchers note. A full one-quarter of patients developed septic shock in response to their infection while the length of stay among patients with sepsis (mean of 10.9 days) was substantially longer than it was for those without sepsis (mean of 5.6 days), they observe.

At a mean total hospital cost of $121,797 for each ICU patient with sepsis, the cost of caring for each patient was nearly twofold higher than the mean total cost of taking care of ICU patients without sepsis (mean total cost, $65,179). On adjusted analysis, sepsis was associated with a 42.7% (95% confidence interval, 38.9-46.5; P < .0001) longer length of hospital stay and a 26.2% (95% CI, 23.1-29.1; P < .0001) higher total hospital cost compared with patients without sepsis, the authors point out.

Indeed, ICU admissions with sepsis accounted for 47.3% of all hospital days and for 46.1% of the aggregate hospital charges among all MS patients admitted to the ICU.

“The adjusted probability of short-term mortality was 13.4% (95% CI, 13.0-13.7) among ICU admissions with sepsis and 3.3% (95% CI, 3.2-3.4) among ICU admissions without sepsis,” the authors report.

This translated into a 44% higher risk of short-term mortality at an adjusted odds ratio of 1.44 (95% CI, 1.23-1.69; P < .0001) for those with sepsis, compared with those without, they add. Among all ICU admissions, sepsis was reported in over two-thirds of documented short-term mortality events. The risk of short-term mortality was also almost threefold higher among patients with sepsis who were age 65 years and older compared with patients aged 18-44. 

As Dr. Oud noted, there is no specific test for sepsis, and it can initially present in an atypical manner, especially in older, frailer, chronically ill patients as well as in patients with immune dysfunction. “Thus, considering sepsis as a possible cause of new deterioration in a patient’s condition is essential, along with the timely start of sepsis-related care,” Dr. Oud observed.

A limitation of the study was that the dataset did not include information on the type of MS a patient had, the duration of their illness, the treatment received, the level of disease activity, or the level of disability.

The study had no specific funding. The authors have disclosed no relevant financial relationships.

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

Use of e-cigarettes was not more effective than other methods at helping cigarette smokers quit, authors of new research found.

From 2013 to 2017, e-cigarette sales in the United States nearly doubled, driven by a rapid uptake of use by adolescents, wrote Riufeng Chen, MD, of the University of California, San Diego, and colleagues, in their paper published in Tobacco Control. However, the subsequent effect of increased e-cigarette use on smoking cessation have not been examined, they said.

In their study, Dr. Chen and colleagues analyzed data from 3,578 previous-year smokers with a recent quit attempt and 1,323 recent former smokers who were part of the PATH cohort in 2017. The participants reported using e-cigarettes or other products to quit cigarette smoking. The primary outcomes were at least 12 months of cigarette abstinence, and tobacco abstinence in 2019. In 2017, 32.8% of established smokers reported trying to quit. Of these, 12.6% used e-cigarettes to help them quit. Cigarette abstinence for at least 12 months for these individuals was 9.9%, which was lower than for those who used either nicotine replacement therapy or a pharmaceutical aid only (15.2%), and about half of the 18.6% abstinence in those who used no products to help them quit.

“In our study, e-cigarettes resulted in seven fewer successful quitters than those who used pharmaceutical aids,” emphasized corresponding author, John P. Pierce, PhD, of the University of California, San Diego.

Among smokers attempting to quit, the adjusted risk difference for cigarette abstinence for a least 12 months with e-cigarettes vs. pharmaceutical aids was –7.3%, and –7.7% for e-cigarettes vs. other smoking cessation methods.

*“Among recent former smokers who had switched to daily use of e-cigarettes in 2017, 43.2% had successfully quit cigarette smoking by 2019, which was similar to those who used e-cigarettes on a nondaily basis (34.6%) or to those who switched to another tobacco product, whether daily (43.6%) or nondaily (44.7%),” the researchers wrote.

The rapid growth in e-cigarette use between 2014 and 2017 has been attributed in part to aggressive marketing of high-nicotine e-cigarettes, they said. “The high-nicotine JUUL e-cigarette has been noted as the closest match to cigarettes in both nicotine delivery and user satisfaction, which should make it one of the best candidates as a product to which smokers could switch in order to maintain their nicotine habit,” they said in their discussion of the findings.

More research needed

The researchers acknowledged the need to review more recent data.

“When we looked ahead to 2019, recent former smokers had started using high-nicotine e-cigarettes. The effectiveness of high-nicotine e-cigarettes at preventing relapse will require another follow-up PATH survey,” they said.

Among recent former smokers, 2.2% reported switching to a high-nicotine e-cigarette. Although individuals who switched to e-cigarettes showed a higher rate of relapse to cigarettes than those who did not switch to other tobacco or e-cigarette products, this difference was not significant.

The study findings were limited by several factors including the observational design and inability to control for all potential confounding factors, the researchers noted. However, the results were strengthened by the use of a large and representative study population, and the inclusion of biological samples to validate self-reported smoking, they said.
 

Several findings surprised study author

Dr. Pierce said he was surprised by several aspects of the study findings.

“First of all, contrary to what we expected, there was a 25% decline in using e-cigarettes to quit, compared to the previous year (not the 40% increase that was expected from the increase in e-cigarette sales) and almost no smokers were using high-nicotine JUUL products to help them quit,” he said. “In this study, e-cigarettes were much less helpful (7 less successful quitters per 100) than pharmaceutical cessation aids in helping people quit,” he added.

“The fact that the proportion of smokers using e-cigarettes for cessation dropped from 17% to 12% was unexpected, and it suggests that the belief that they are a cessation aid is declining,” he said.

The implication for clinical practice is that e-cigarettes are not a useful tool for smoking cessation, Dr. Pierce said. “We are not finding any evidence in this very large nationally representative study that smokers who switch to getting their nicotine from e-cigarettes are less likely to relapse back to cigarette smoking,” he said.

“We don’t know about the high-nicotine versions,” he added. 
 

New review advises against e-cigarettes for cessation

A recent review article published in JAMA supported the use of pharmacotherapy and behavioral support for smokers wanting to quit. In the review, Nancy A. Rigotti, MD, of Massachusetts General Hospital, Boston, and colleagues summarized the evidence for managing tobacco smoking in clinical practice.

“The health risk from cigarette smoking is primarily due to chemicals produced by the burning of tobacco and not to nicotine,” they noted. However, the physical dependence on nicotine makes quitting a challenge, but it is one worth pursuing, the authors said.

The authors of this review identified 30 reviews, 12 randomized clinical trials, and 7 recent guidelines and evidence reviews. Their key message: Pharmacotherapy and behavioral support are effective when used alone, but even more effective when combined. Pharmacotherapy helps reduce the symptoms of nicotine withdrawal, while behavioral intervention tackles the challenge of changing learned behaviors associated with smoking, the researchers said.

Although combining medications, such as varenicline and nicotine replacement therapy or bupropion might improve successful quit rates, these combinations have not been well studied, they noted.

With regard to e-cigarettes, the researchers cited a 2021 Cochrane review of 16,759 individuals who used e-cigarettes for smoking cessation, which found no evidence of harm, but insufficient evidence to asses the balance of risks vs. benefits.

In addition to the lack of randomized trials, “the FDA regulates e-cigarettes as tobacco products, not as medical products and has not evaluated any e-cigarette for medical use as a cessation aid,” the authors of the new review noted.

The review was limited by several factors, including the lack of quality assessment for the selected studies and the exclusion of pharmacotherapy not licensed in the United States.

Commenting on the JAMA paper, Dr. Pierce said, “This review looks like a number of Cochrane Reports that have been published recently. Of course, it only considers randomized trials and not population evidence.”

“If public health had limited itself to this form of evidence, then we still would not know that smoking caused cancer,” he noted. “Randomized trials are very important for testing new drugs; they use selected populations and provide considerable support that is not available in the real world. Sometimes they do not generalize to the population.”
 

Findings may guide patient conversations

The Tobacco Control study was important, because few studies on e-cigarettes have been conducted, said Linda Girgis, MD, a family physician in private practice in South River, N.J., in an interview.

“As clinicians, we do not have a lot of data available in order to make clinical decisions that are evidence based. Also, getting patients to quit smoking is often very difficult, and having more tools available is a great benefit; however, we need to have the evidence that these tools are effective,” she said.

Dr. Girgis also said she was not surprised by the findings.

“Patients still have the same concerns from e-cigarettes regarding nicotine exposure, but just to a lesser degree; and we still don’t know the long-term effects of e-cigarette use, she said. Based on these studies, recommending e-cigarettes for smokers looking to quit may not be the best method, she noted.

“While it may seem reasonable that exposing lungs to lower doses of nicotine will reduce harm, we need to see actual evidence of this. Also, we also need to study the additives that are frequently used in e-cigs, such as artificial flavorings, to see what harms they may pose, she emphasized.

With regard to the JAMA review, Dr. Girgis said she agreed with the recommendations for pharmacotherapy and behavior therapy as first-line treatments for smoking cessation. “There is evidence regarding the efficacy and safety of these methods, and they have been used for decades,” she said.

Dr. Girgis added that there is a role for e-cigarettes in smoking cessation strategies as a method of harm reduction, but pointed out the problem of many people thinking these products are safe and not understanding the hazards they pose.

“They think they can replace smoking with e-cigarettes and be safe from the health risks associated with smoking. I think if the plan were to switch to e-cigarettes for a short period and then quit, there would be a role,” Dr. Girgis said. “However, replacing one risk for another may reduce harm, but doesn’t eliminate it.”

“To continue to use e-cigarettes indefinitely should not be the goal,” she added.

The Tobacco Control study was funded by the National Institutes of Health and the Tobacco-Related Disease Research Program of the University of California. The researchers had no financial conflicts to disclose.

The JAMA study was funded in part by a grant from the National Institute for Health Research, via Cochrane Infrastructure funds to the Cochrane Tobacco Addiction Group. Lead author Dr. Rigotti disclosed funding from the National Heart, Lung, and Blood Institute and Achieve Life Sciences and personal fees from UpToDate and Achieve Life Sciences. Dr. Girgis had no financial conflicts to disclose.

*This article was updated on 2/28/2022.

Use of e-cigarettes was not more effective than other methods at helping cigarette smokers quit, authors of new research found.

From 2013 to 2017, e-cigarette sales in the United States nearly doubled, driven by a rapid uptake of use by adolescents, wrote Riufeng Chen, MD, of the University of California, San Diego, and colleagues, in their paper published in Tobacco Control. However, the subsequent effect of increased e-cigarette use on smoking cessation have not been examined, they said.

In their study, Dr. Chen and colleagues analyzed data from 3,578 previous-year smokers with a recent quit attempt and 1,323 recent former smokers who were part of the PATH cohort in 2017. The participants reported using e-cigarettes or other products to quit cigarette smoking. The primary outcomes were at least 12 months of cigarette abstinence, and tobacco abstinence in 2019. In 2017, 32.8% of established smokers reported trying to quit. Of these, 12.6% used e-cigarettes to help them quit. Cigarette abstinence for at least 12 months for these individuals was 9.9%, which was lower than for those who used either nicotine replacement therapy or a pharmaceutical aid only (15.2%), and about half of the 18.6% abstinence in those who used no products to help them quit.

“In our study, e-cigarettes resulted in seven fewer successful quitters than those who used pharmaceutical aids,” emphasized corresponding author, John P. Pierce, PhD, of the University of California, San Diego.

Among smokers attempting to quit, the adjusted risk difference for cigarette abstinence for a least 12 months with e-cigarettes vs. pharmaceutical aids was –7.3%, and –7.7% for e-cigarettes vs. other smoking cessation methods.

*“Among recent former smokers who had switched to daily use of e-cigarettes in 2017, 43.2% had successfully quit cigarette smoking by 2019, which was similar to those who used e-cigarettes on a nondaily basis (34.6%) or to those who switched to another tobacco product, whether daily (43.6%) or nondaily (44.7%),” the researchers wrote.

The rapid growth in e-cigarette use between 2014 and 2017 has been attributed in part to aggressive marketing of high-nicotine e-cigarettes, they said. “The high-nicotine JUUL e-cigarette has been noted as the closest match to cigarettes in both nicotine delivery and user satisfaction, which should make it one of the best candidates as a product to which smokers could switch in order to maintain their nicotine habit,” they said in their discussion of the findings.

More research needed

The researchers acknowledged the need to review more recent data.

“When we looked ahead to 2019, recent former smokers had started using high-nicotine e-cigarettes. The effectiveness of high-nicotine e-cigarettes at preventing relapse will require another follow-up PATH survey,” they said.

Among recent former smokers, 2.2% reported switching to a high-nicotine e-cigarette. Although individuals who switched to e-cigarettes showed a higher rate of relapse to cigarettes than those who did not switch to other tobacco or e-cigarette products, this difference was not significant.

The study findings were limited by several factors including the observational design and inability to control for all potential confounding factors, the researchers noted. However, the results were strengthened by the use of a large and representative study population, and the inclusion of biological samples to validate self-reported smoking, they said.
 

Several findings surprised study author

Dr. Pierce said he was surprised by several aspects of the study findings.

“First of all, contrary to what we expected, there was a 25% decline in using e-cigarettes to quit, compared to the previous year (not the 40% increase that was expected from the increase in e-cigarette sales) and almost no smokers were using high-nicotine JUUL products to help them quit,” he said. “In this study, e-cigarettes were much less helpful (7 less successful quitters per 100) than pharmaceutical cessation aids in helping people quit,” he added.

“The fact that the proportion of smokers using e-cigarettes for cessation dropped from 17% to 12% was unexpected, and it suggests that the belief that they are a cessation aid is declining,” he said.

The implication for clinical practice is that e-cigarettes are not a useful tool for smoking cessation, Dr. Pierce said. “We are not finding any evidence in this very large nationally representative study that smokers who switch to getting their nicotine from e-cigarettes are less likely to relapse back to cigarette smoking,” he said.

“We don’t know about the high-nicotine versions,” he added. 
 

New review advises against e-cigarettes for cessation

A recent review article published in JAMA supported the use of pharmacotherapy and behavioral support for smokers wanting to quit. In the review, Nancy A. Rigotti, MD, of Massachusetts General Hospital, Boston, and colleagues summarized the evidence for managing tobacco smoking in clinical practice.

“The health risk from cigarette smoking is primarily due to chemicals produced by the burning of tobacco and not to nicotine,” they noted. However, the physical dependence on nicotine makes quitting a challenge, but it is one worth pursuing, the authors said.

The authors of this review identified 30 reviews, 12 randomized clinical trials, and 7 recent guidelines and evidence reviews. Their key message: Pharmacotherapy and behavioral support are effective when used alone, but even more effective when combined. Pharmacotherapy helps reduce the symptoms of nicotine withdrawal, while behavioral intervention tackles the challenge of changing learned behaviors associated with smoking, the researchers said.

Although combining medications, such as varenicline and nicotine replacement therapy or bupropion might improve successful quit rates, these combinations have not been well studied, they noted.

With regard to e-cigarettes, the researchers cited a 2021 Cochrane review of 16,759 individuals who used e-cigarettes for smoking cessation, which found no evidence of harm, but insufficient evidence to asses the balance of risks vs. benefits.

In addition to the lack of randomized trials, “the FDA regulates e-cigarettes as tobacco products, not as medical products and has not evaluated any e-cigarette for medical use as a cessation aid,” the authors of the new review noted.

The review was limited by several factors, including the lack of quality assessment for the selected studies and the exclusion of pharmacotherapy not licensed in the United States.

Commenting on the JAMA paper, Dr. Pierce said, “This review looks like a number of Cochrane Reports that have been published recently. Of course, it only considers randomized trials and not population evidence.”

“If public health had limited itself to this form of evidence, then we still would not know that smoking caused cancer,” he noted. “Randomized trials are very important for testing new drugs; they use selected populations and provide considerable support that is not available in the real world. Sometimes they do not generalize to the population.”
 

Findings may guide patient conversations

The Tobacco Control study was important, because few studies on e-cigarettes have been conducted, said Linda Girgis, MD, a family physician in private practice in South River, N.J., in an interview.

“As clinicians, we do not have a lot of data available in order to make clinical decisions that are evidence based. Also, getting patients to quit smoking is often very difficult, and having more tools available is a great benefit; however, we need to have the evidence that these tools are effective,” she said.

Dr. Girgis also said she was not surprised by the findings.

“Patients still have the same concerns from e-cigarettes regarding nicotine exposure, but just to a lesser degree; and we still don’t know the long-term effects of e-cigarette use, she said. Based on these studies, recommending e-cigarettes for smokers looking to quit may not be the best method, she noted.

“While it may seem reasonable that exposing lungs to lower doses of nicotine will reduce harm, we need to see actual evidence of this. Also, we also need to study the additives that are frequently used in e-cigs, such as artificial flavorings, to see what harms they may pose, she emphasized.

With regard to the JAMA review, Dr. Girgis said she agreed with the recommendations for pharmacotherapy and behavior therapy as first-line treatments for smoking cessation. “There is evidence regarding the efficacy and safety of these methods, and they have been used for decades,” she said.

Dr. Girgis added that there is a role for e-cigarettes in smoking cessation strategies as a method of harm reduction, but pointed out the problem of many people thinking these products are safe and not understanding the hazards they pose.

“They think they can replace smoking with e-cigarettes and be safe from the health risks associated with smoking. I think if the plan were to switch to e-cigarettes for a short period and then quit, there would be a role,” Dr. Girgis said. “However, replacing one risk for another may reduce harm, but doesn’t eliminate it.”

“To continue to use e-cigarettes indefinitely should not be the goal,” she added.

The Tobacco Control study was funded by the National Institutes of Health and the Tobacco-Related Disease Research Program of the University of California. The researchers had no financial conflicts to disclose.

The JAMA study was funded in part by a grant from the National Institute for Health Research, via Cochrane Infrastructure funds to the Cochrane Tobacco Addiction Group. Lead author Dr. Rigotti disclosed funding from the National Heart, Lung, and Blood Institute and Achieve Life Sciences and personal fees from UpToDate and Achieve Life Sciences. Dr. Girgis had no financial conflicts to disclose.

*This article was updated on 2/28/2022.

Use of e-cigarettes was not more effective than other methods at helping cigarette smokers quit, authors of new research found.

From 2013 to 2017, e-cigarette sales in the United States nearly doubled, driven by a rapid uptake of use by adolescents, wrote Riufeng Chen, MD, of the University of California, San Diego, and colleagues, in their paper published in Tobacco Control. However, the subsequent effect of increased e-cigarette use on smoking cessation have not been examined, they said.

In their study, Dr. Chen and colleagues analyzed data from 3,578 previous-year smokers with a recent quit attempt and 1,323 recent former smokers who were part of the PATH cohort in 2017. The participants reported using e-cigarettes or other products to quit cigarette smoking. The primary outcomes were at least 12 months of cigarette abstinence, and tobacco abstinence in 2019. In 2017, 32.8% of established smokers reported trying to quit. Of these, 12.6% used e-cigarettes to help them quit. Cigarette abstinence for at least 12 months for these individuals was 9.9%, which was lower than for those who used either nicotine replacement therapy or a pharmaceutical aid only (15.2%), and about half of the 18.6% abstinence in those who used no products to help them quit.

“In our study, e-cigarettes resulted in seven fewer successful quitters than those who used pharmaceutical aids,” emphasized corresponding author, John P. Pierce, PhD, of the University of California, San Diego.

Among smokers attempting to quit, the adjusted risk difference for cigarette abstinence for a least 12 months with e-cigarettes vs. pharmaceutical aids was –7.3%, and –7.7% for e-cigarettes vs. other smoking cessation methods.

*“Among recent former smokers who had switched to daily use of e-cigarettes in 2017, 43.2% had successfully quit cigarette smoking by 2019, which was similar to those who used e-cigarettes on a nondaily basis (34.6%) or to those who switched to another tobacco product, whether daily (43.6%) or nondaily (44.7%),” the researchers wrote.

The rapid growth in e-cigarette use between 2014 and 2017 has been attributed in part to aggressive marketing of high-nicotine e-cigarettes, they said. “The high-nicotine JUUL e-cigarette has been noted as the closest match to cigarettes in both nicotine delivery and user satisfaction, which should make it one of the best candidates as a product to which smokers could switch in order to maintain their nicotine habit,” they said in their discussion of the findings.

More research needed

The researchers acknowledged the need to review more recent data.

“When we looked ahead to 2019, recent former smokers had started using high-nicotine e-cigarettes. The effectiveness of high-nicotine e-cigarettes at preventing relapse will require another follow-up PATH survey,” they said.

Among recent former smokers, 2.2% reported switching to a high-nicotine e-cigarette. Although individuals who switched to e-cigarettes showed a higher rate of relapse to cigarettes than those who did not switch to other tobacco or e-cigarette products, this difference was not significant.

The study findings were limited by several factors including the observational design and inability to control for all potential confounding factors, the researchers noted. However, the results were strengthened by the use of a large and representative study population, and the inclusion of biological samples to validate self-reported smoking, they said.
 

Several findings surprised study author

Dr. Pierce said he was surprised by several aspects of the study findings.

“First of all, contrary to what we expected, there was a 25% decline in using e-cigarettes to quit, compared to the previous year (not the 40% increase that was expected from the increase in e-cigarette sales) and almost no smokers were using high-nicotine JUUL products to help them quit,” he said. “In this study, e-cigarettes were much less helpful (7 less successful quitters per 100) than pharmaceutical cessation aids in helping people quit,” he added.

“The fact that the proportion of smokers using e-cigarettes for cessation dropped from 17% to 12% was unexpected, and it suggests that the belief that they are a cessation aid is declining,” he said.

The implication for clinical practice is that e-cigarettes are not a useful tool for smoking cessation, Dr. Pierce said. “We are not finding any evidence in this very large nationally representative study that smokers who switch to getting their nicotine from e-cigarettes are less likely to relapse back to cigarette smoking,” he said.

“We don’t know about the high-nicotine versions,” he added. 
 

New review advises against e-cigarettes for cessation

A recent review article published in JAMA supported the use of pharmacotherapy and behavioral support for smokers wanting to quit. In the review, Nancy A. Rigotti, MD, of Massachusetts General Hospital, Boston, and colleagues summarized the evidence for managing tobacco smoking in clinical practice.

“The health risk from cigarette smoking is primarily due to chemicals produced by the burning of tobacco and not to nicotine,” they noted. However, the physical dependence on nicotine makes quitting a challenge, but it is one worth pursuing, the authors said.

The authors of this review identified 30 reviews, 12 randomized clinical trials, and 7 recent guidelines and evidence reviews. Their key message: Pharmacotherapy and behavioral support are effective when used alone, but even more effective when combined. Pharmacotherapy helps reduce the symptoms of nicotine withdrawal, while behavioral intervention tackles the challenge of changing learned behaviors associated with smoking, the researchers said.

Although combining medications, such as varenicline and nicotine replacement therapy or bupropion might improve successful quit rates, these combinations have not been well studied, they noted.

With regard to e-cigarettes, the researchers cited a 2021 Cochrane review of 16,759 individuals who used e-cigarettes for smoking cessation, which found no evidence of harm, but insufficient evidence to asses the balance of risks vs. benefits.

In addition to the lack of randomized trials, “the FDA regulates e-cigarettes as tobacco products, not as medical products and has not evaluated any e-cigarette for medical use as a cessation aid,” the authors of the new review noted.

The review was limited by several factors, including the lack of quality assessment for the selected studies and the exclusion of pharmacotherapy not licensed in the United States.

Commenting on the JAMA paper, Dr. Pierce said, “This review looks like a number of Cochrane Reports that have been published recently. Of course, it only considers randomized trials and not population evidence.”

“If public health had limited itself to this form of evidence, then we still would not know that smoking caused cancer,” he noted. “Randomized trials are very important for testing new drugs; they use selected populations and provide considerable support that is not available in the real world. Sometimes they do not generalize to the population.”
 

Findings may guide patient conversations

The Tobacco Control study was important, because few studies on e-cigarettes have been conducted, said Linda Girgis, MD, a family physician in private practice in South River, N.J., in an interview.

“As clinicians, we do not have a lot of data available in order to make clinical decisions that are evidence based. Also, getting patients to quit smoking is often very difficult, and having more tools available is a great benefit; however, we need to have the evidence that these tools are effective,” she said.

Dr. Girgis also said she was not surprised by the findings.

“Patients still have the same concerns from e-cigarettes regarding nicotine exposure, but just to a lesser degree; and we still don’t know the long-term effects of e-cigarette use, she said. Based on these studies, recommending e-cigarettes for smokers looking to quit may not be the best method, she noted.

“While it may seem reasonable that exposing lungs to lower doses of nicotine will reduce harm, we need to see actual evidence of this. Also, we also need to study the additives that are frequently used in e-cigs, such as artificial flavorings, to see what harms they may pose, she emphasized.

With regard to the JAMA review, Dr. Girgis said she agreed with the recommendations for pharmacotherapy and behavior therapy as first-line treatments for smoking cessation. “There is evidence regarding the efficacy and safety of these methods, and they have been used for decades,” she said.

Dr. Girgis added that there is a role for e-cigarettes in smoking cessation strategies as a method of harm reduction, but pointed out the problem of many people thinking these products are safe and not understanding the hazards they pose.

“They think they can replace smoking with e-cigarettes and be safe from the health risks associated with smoking. I think if the plan were to switch to e-cigarettes for a short period and then quit, there would be a role,” Dr. Girgis said. “However, replacing one risk for another may reduce harm, but doesn’t eliminate it.”

“To continue to use e-cigarettes indefinitely should not be the goal,” she added.

The Tobacco Control study was funded by the National Institutes of Health and the Tobacco-Related Disease Research Program of the University of California. The researchers had no financial conflicts to disclose.

The JAMA study was funded in part by a grant from the National Institute for Health Research, via Cochrane Infrastructure funds to the Cochrane Tobacco Addiction Group. Lead author Dr. Rigotti disclosed funding from the National Heart, Lung, and Blood Institute and Achieve Life Sciences and personal fees from UpToDate and Achieve Life Sciences. Dr. Girgis had no financial conflicts to disclose.

*This article was updated on 2/28/2022.

Nearly one-third of adults over age 65 developed one or more new medical conditions in the weeks following a COVID-19 infection, according to new research.

The findings of the observational study, which were published in the BMJ, show the risk of a new condition being triggered by COVID is more than twice as high in seniors, compared with younger patients. Plus, the researchers observed an even higher risk among those who were hospitalized, with nearly half (46%) of patients having developed new conditions after the acute COVID-19 infection period.

Respiratory failure with shortness of breath was the most common postacute sequela, but a wide range of heart, kidney, lung, liver, cognitive, mental health, and other conditions were diagnosed at least 3 weeks after initial infection and persisted beyond 30 days.

This is one of the first studies to specifically describe the incidence and severity of new conditions triggered by COVID-19 infection in a general sample of older adults, said study author Ken Cohen MD, FACP, executive director of translational research at Optum Labs and national senior medical director at Optum Care.

“Much of what has been published on the postacute sequelae of COVID-19 has been predominantly from a younger population, and many of the patients had been hospitalized,” Dr. Cohen noted. “This was the first study to focus on a large population of seniors, most of whom did not require hospitalization.”

Dr. Cohen and colleagues reviewed the health insurance records of more than 133,000 Medicare beneficiaries aged 65 or older who were diagnosed with COVID-19 before April 2020. They also matched individuals by age, race, sex, hospitalization status, and other factors to comparison groups without COVID-19 (one from 2020 and one from 2019), and to a group diagnosed with other lower respiratory tract viral infections before the pandemic.
 

Risk of developing new conditions was higher in hospitalized

After acute COVID-19 infection, 32% of seniors sought medical care for at least one new medical condition in 2020, compared with 21% of uninfected people in the same year.

The most commonly observed conditions included:

• Respiratory failure (7.55% higher risk).
• Fatigue (5.66% higher risk).
• High blood pressure (4.43% higher risk).
• Memory problems (2.63% higher risk).
• Kidney injury (2.59% higher risk).
• Mental health diagnoses (2.5% higher risk).
• Blood-clotting disorders (1.47 % higher risk).
• Heart rhythm disorders (2.9% higher risk).

The risk of developing new conditions was even higher among those 23,486 who were hospitalized in 2020. Those individuals showed a 23.6% higher risk for developing at least one new condition, compared with uninfected seniors in the same year. Also, patients older than 75 had a higher risk for neurological disorders, including dementia, encephalopathy, and memory problems. The researchers also found that respiratory failure and kidney injury were significantly more likely to affect men and Black patients.

When those who had COVID were compared with the group with other lower respiratory viral infections before the pandemic, only the risks of respiratory failure (2.39% higher), dementia (0.71% higher), and fatigue (0.18% higher) were higher.

Primary care providers can learn from these data to better evaluate and manage their geriatric patients with COVID-19 infection, said Amit Shah, MD, a geriatrician with the Mayo Clinic in Phoenix, in an interview.

“We must assess older patients who have had COVID-19 for more than just improvement from the respiratory symptoms of COVID-19 in post-COVID follow-up visits,” he said. “Older individuals with frailty have vulnerability to subsequent complications from severe illnesses and it is common to see post-illness diagnoses, such as new diagnosis of delirium; dementia; or renal, respiratory, or cardiac issues that is precipitated by the original illness. This study confirms that this is likely the case with COVID-19 as well.

“Primary care physicians should be vigilant for these complications, including attention to the rehabilitation needs of older patients with longer-term postviral fatigue from COVID-19,” Dr. Shah added.
 

Data predates ‘Omicron wave’

It remains uncertain whether sequelae will differ with the Omicron variant, but the findings remain applicable, Dr. Cohen said.

“We know that illness from the Omicron variant is on average less severe in those that have been vaccinated. However, throughout the Omicron wave, individuals who have not been vaccinated continue to have significant rates of serious illness and hospitalization,” he said.

“Our findings showed that serious illness with hospitalization was associated with a higher rate of sequelae. It can therefore be inferred that the rates of sequelae seen in our study would continue to occur in unvaccinated individuals who contract Omicron, but might occur less frequently in vaccinated individuals who contract Omicron and have less severe illness.”

Dr. Cohen serves as a consultant for Pfizer. Dr. Shah has disclosed no relevant financial relationships.

Nearly one-third of adults over age 65 developed one or more new medical conditions in the weeks following a COVID-19 infection, according to new research.

The findings of the observational study, which were published in the BMJ, show the risk of a new condition being triggered by COVID is more than twice as high in seniors, compared with younger patients. Plus, the researchers observed an even higher risk among those who were hospitalized, with nearly half (46%) of patients having developed new conditions after the acute COVID-19 infection period.

Respiratory failure with shortness of breath was the most common postacute sequela, but a wide range of heart, kidney, lung, liver, cognitive, mental health, and other conditions were diagnosed at least 3 weeks after initial infection and persisted beyond 30 days.

This is one of the first studies to specifically describe the incidence and severity of new conditions triggered by COVID-19 infection in a general sample of older adults, said study author Ken Cohen MD, FACP, executive director of translational research at Optum Labs and national senior medical director at Optum Care.

“Much of what has been published on the postacute sequelae of COVID-19 has been predominantly from a younger population, and many of the patients had been hospitalized,” Dr. Cohen noted. “This was the first study to focus on a large population of seniors, most of whom did not require hospitalization.”

Dr. Cohen and colleagues reviewed the health insurance records of more than 133,000 Medicare beneficiaries aged 65 or older who were diagnosed with COVID-19 before April 2020. They also matched individuals by age, race, sex, hospitalization status, and other factors to comparison groups without COVID-19 (one from 2020 and one from 2019), and to a group diagnosed with other lower respiratory tract viral infections before the pandemic.
 

Risk of developing new conditions was higher in hospitalized

After acute COVID-19 infection, 32% of seniors sought medical care for at least one new medical condition in 2020, compared with 21% of uninfected people in the same year.

The most commonly observed conditions included:

• Respiratory failure (7.55% higher risk).
• Fatigue (5.66% higher risk).
• High blood pressure (4.43% higher risk).
• Memory problems (2.63% higher risk).
• Kidney injury (2.59% higher risk).
• Mental health diagnoses (2.5% higher risk).
• Blood-clotting disorders (1.47 % higher risk).
• Heart rhythm disorders (2.9% higher risk).

The risk of developing new conditions was even higher among those 23,486 who were hospitalized in 2020. Those individuals showed a 23.6% higher risk for developing at least one new condition, compared with uninfected seniors in the same year. Also, patients older than 75 had a higher risk for neurological disorders, including dementia, encephalopathy, and memory problems. The researchers also found that respiratory failure and kidney injury were significantly more likely to affect men and Black patients.

When those who had COVID were compared with the group with other lower respiratory viral infections before the pandemic, only the risks of respiratory failure (2.39% higher), dementia (0.71% higher), and fatigue (0.18% higher) were higher.

Primary care providers can learn from these data to better evaluate and manage their geriatric patients with COVID-19 infection, said Amit Shah, MD, a geriatrician with the Mayo Clinic in Phoenix, in an interview.

“We must assess older patients who have had COVID-19 for more than just improvement from the respiratory symptoms of COVID-19 in post-COVID follow-up visits,” he said. “Older individuals with frailty have vulnerability to subsequent complications from severe illnesses and it is common to see post-illness diagnoses, such as new diagnosis of delirium; dementia; or renal, respiratory, or cardiac issues that is precipitated by the original illness. This study confirms that this is likely the case with COVID-19 as well.

“Primary care physicians should be vigilant for these complications, including attention to the rehabilitation needs of older patients with longer-term postviral fatigue from COVID-19,” Dr. Shah added.
 

Data predates ‘Omicron wave’

It remains uncertain whether sequelae will differ with the Omicron variant, but the findings remain applicable, Dr. Cohen said.

“We know that illness from the Omicron variant is on average less severe in those that have been vaccinated. However, throughout the Omicron wave, individuals who have not been vaccinated continue to have significant rates of serious illness and hospitalization,” he said.

“Our findings showed that serious illness with hospitalization was associated with a higher rate of sequelae. It can therefore be inferred that the rates of sequelae seen in our study would continue to occur in unvaccinated individuals who contract Omicron, but might occur less frequently in vaccinated individuals who contract Omicron and have less severe illness.”

Dr. Cohen serves as a consultant for Pfizer. Dr. Shah has disclosed no relevant financial relationships.

Nearly one-third of adults over age 65 developed one or more new medical conditions in the weeks following a COVID-19 infection, according to new research.

The findings of the observational study, which were published in the BMJ, show the risk of a new condition being triggered by COVID is more than twice as high in seniors, compared with younger patients. Plus, the researchers observed an even higher risk among those who were hospitalized, with nearly half (46%) of patients having developed new conditions after the acute COVID-19 infection period.

Respiratory failure with shortness of breath was the most common postacute sequela, but a wide range of heart, kidney, lung, liver, cognitive, mental health, and other conditions were diagnosed at least 3 weeks after initial infection and persisted beyond 30 days.

This is one of the first studies to specifically describe the incidence and severity of new conditions triggered by COVID-19 infection in a general sample of older adults, said study author Ken Cohen MD, FACP, executive director of translational research at Optum Labs and national senior medical director at Optum Care.

“Much of what has been published on the postacute sequelae of COVID-19 has been predominantly from a younger population, and many of the patients had been hospitalized,” Dr. Cohen noted. “This was the first study to focus on a large population of seniors, most of whom did not require hospitalization.”

Dr. Cohen and colleagues reviewed the health insurance records of more than 133,000 Medicare beneficiaries aged 65 or older who were diagnosed with COVID-19 before April 2020. They also matched individuals by age, race, sex, hospitalization status, and other factors to comparison groups without COVID-19 (one from 2020 and one from 2019), and to a group diagnosed with other lower respiratory tract viral infections before the pandemic.
 

Risk of developing new conditions was higher in hospitalized

After acute COVID-19 infection, 32% of seniors sought medical care for at least one new medical condition in 2020, compared with 21% of uninfected people in the same year.

The most commonly observed conditions included:

• Respiratory failure (7.55% higher risk).
• Fatigue (5.66% higher risk).
• High blood pressure (4.43% higher risk).
• Memory problems (2.63% higher risk).
• Kidney injury (2.59% higher risk).
• Mental health diagnoses (2.5% higher risk).
• Blood-clotting disorders (1.47 % higher risk).
• Heart rhythm disorders (2.9% higher risk).

The risk of developing new conditions was even higher among those 23,486 who were hospitalized in 2020. Those individuals showed a 23.6% higher risk for developing at least one new condition, compared with uninfected seniors in the same year. Also, patients older than 75 had a higher risk for neurological disorders, including dementia, encephalopathy, and memory problems. The researchers also found that respiratory failure and kidney injury were significantly more likely to affect men and Black patients.

When those who had COVID were compared with the group with other lower respiratory viral infections before the pandemic, only the risks of respiratory failure (2.39% higher), dementia (0.71% higher), and fatigue (0.18% higher) were higher.

Primary care providers can learn from these data to better evaluate and manage their geriatric patients with COVID-19 infection, said Amit Shah, MD, a geriatrician with the Mayo Clinic in Phoenix, in an interview.

“We must assess older patients who have had COVID-19 for more than just improvement from the respiratory symptoms of COVID-19 in post-COVID follow-up visits,” he said. “Older individuals with frailty have vulnerability to subsequent complications from severe illnesses and it is common to see post-illness diagnoses, such as new diagnosis of delirium; dementia; or renal, respiratory, or cardiac issues that is precipitated by the original illness. This study confirms that this is likely the case with COVID-19 as well.

“Primary care physicians should be vigilant for these complications, including attention to the rehabilitation needs of older patients with longer-term postviral fatigue from COVID-19,” Dr. Shah added.
 

Data predates ‘Omicron wave’

It remains uncertain whether sequelae will differ with the Omicron variant, but the findings remain applicable, Dr. Cohen said.

“We know that illness from the Omicron variant is on average less severe in those that have been vaccinated. However, throughout the Omicron wave, individuals who have not been vaccinated continue to have significant rates of serious illness and hospitalization,” he said.

“Our findings showed that serious illness with hospitalization was associated with a higher rate of sequelae. It can therefore be inferred that the rates of sequelae seen in our study would continue to occur in unvaccinated individuals who contract Omicron, but might occur less frequently in vaccinated individuals who contract Omicron and have less severe illness.”

Dr. Cohen serves as a consultant for Pfizer. Dr. Shah has disclosed no relevant financial relationships.

Adolescents and young adults who use e-cigarettes reported vaping cannabis, according to selected data from the national Population Assessment of Tobacco and Health (PATH) study.

Ruoyan Sun, PhD, an assistant professor at the University of Alabama at Birmingham, and colleagues examined results of PATH’s wave5 survey conducted from December 2018 to November 2019. PATH is a National Institutes of Health–Food and Drug Administration collaboration begun in 2013.

Their analysis, published online Feb. 7, 2022, in JAMA Pediatrics, evaluated the frequency of cannabis vaping across several age groups: 164 respondents ages 12-14; 919 participants ages 15-17; and 3,038 participants ages 18-24. Respondents included for analysis reported electronic nicotine product consumption in the past 30 days. In response to the question “When you have used an electronic product, how often were you using it to smoke marijuana, marijuana concentrates, marijuana waxes, THC, or hash oils?” 35.0% (95% confidence interval, 29.3%-41.2%) of current e-smokers aged 12-14 years said they had done so, as did 51.3% (95% CI, 47.7%-54.9%) of those aged 15-17 years and 54.6% (95% CI, 52.5%-56.7%) of young adults aged 18-24.

The prevalence of those who reported vaping cannabis every time they vaped was 3.1% (95% CI, 1.3%-6.9%) of youths aged 12-14 years, 6.7% (95% CI, 5.3%-8.6%) of youths aged 15-17 years, and 10.3% (95% CI, 9.0%-11.6%) of young adults aged 18-24.

Among children ages 12-14, 65% said they never vaped cannabis, while 48.7% and 45.4%, respectively, in the two older groups said they did.

“This is a very important finding and it mirrors what some of us have already seen in practice,” said pediatric pulmonologist S. Christy Sadreameli, MD, MHS, an assistant professor of pediatrics at John Hopkins University, Baltimore. “It is important for pediatricians to realize that dual use of cannabis and nicotine vaping, and exclusive use of cannabis vaping, are not uncommon. It informs how we ask questions and how we counsel our patients.” Dr. Sadreameli was not involved in the PATH study.

Overall, the survey participants were 56% male, with 24% of respondents identifying as Hispanic, 8% as non-Hispanic Black, 58% as non-Hispanic White, and 10% as of other race/ethnicity. The weighted proportion of current e-cigarette use was 3.0% (95% CI, 2.6%-3.4%) in youths ages 12-14 years, 14.4% (95% CI, 13.5%-15.3%) in those 15-17 years, and 26.2% (95% CI, 25.3%-27.1%) in young adults.

Other recent national surveys such as the National Institute on Drug Abuses’s Monitoring the Future are reporting a growing prevalence of youth cannabis vaping, Dr. Sun said. For example, the prevalence of cannabis vaping in the past 12-month period among grade 12 students grew from 9.5% in 2017 to 22.1% in 2020. Vaping cannabis was more prevalent among Hispanic teens than other ethnicities.

Vaping devices such as e-cigarettes, vaping pens, e-cigars, and e-hookahs can be used to inhale multiple substances, including nicotine, cannabis, and opium, Dr. Sun noted in an interview. “So in addition to asking about the behavior of vaping itself, pediatricians could pay more attention to what is being vaped in these devices.”

According to Dr. Sadreameli, vaping more than one substance at a time could potentially work synergistically to cause more harm, compared with one product alone. “The other aspect to consider is that vaping multiple types of products may increase the chance of harm from other components of the mixture,” she said. For instance, a lot of the e-cigarette or vaping use-associated lung injury (EVALI) cases have been linked to vitamin E acetate, which was found in certain cannabis formulations. “Anecdotally, most EVALI patients I’ve met seemed to report use of multiple products, including cannabis-containing and nicotine-containing products.”

Dr. Sadreameli added that some cannabis vapers will have other issues. “For example, there is a severe vomiting syndrome I’ve seen, which is induced by cannabis and improved by cessation from cannabis,” she said. “It is important for pediatricians to ask the right questions of their patients in order to better understand what they may be experiencing, provide counseling, and to help them.”

A related issue is cessation, she said. “For those working to achieve cessation from nicotine-based products, sometimes nicotine replacement therapies are helpful. However, cessation from cannabis-containing products is going to look different.”

Although the study did not yield information on the prevalence simultaneous nicotine/cannabis vaping, the authors suggested that some vapers may be combining substances. Previous studies may have modestly overestimated the prevalence of nicotine vaping given their finding that some current e-cigarette users reported vaping cannabis every time they vaped and may be vaping cannabis exclusively. “However, if some current users vaped nicotine and cannabis simultaneously, then overestimation of nicotine vaping would be smaller,” they wrote.

Future surveys on this area should contain detailed questions on nicotine and cannabis vaping, including the substance being vaped and the frequency and intensity of use, Dr. Sun said. “In addition, these surveys could examine some other substances that are being vaped, such as opium and cocaine.”

The PATH study is supported by the NIH, National Institute on Drug Abuse, Department of Health & Human Services, and the FDA’s Center for Tobacco Products. The authors and Dr. Sadreameli had no competing interests to disclose.

Adolescents and young adults who use e-cigarettes reported vaping cannabis, according to selected data from the national Population Assessment of Tobacco and Health (PATH) study.

Ruoyan Sun, PhD, an assistant professor at the University of Alabama at Birmingham, and colleagues examined results of PATH’s wave5 survey conducted from December 2018 to November 2019. PATH is a National Institutes of Health–Food and Drug Administration collaboration begun in 2013.

Their analysis, published online Feb. 7, 2022, in JAMA Pediatrics, evaluated the frequency of cannabis vaping across several age groups: 164 respondents ages 12-14; 919 participants ages 15-17; and 3,038 participants ages 18-24. Respondents included for analysis reported electronic nicotine product consumption in the past 30 days. In response to the question “When you have used an electronic product, how often were you using it to smoke marijuana, marijuana concentrates, marijuana waxes, THC, or hash oils?” 35.0% (95% confidence interval, 29.3%-41.2%) of current e-smokers aged 12-14 years said they had done so, as did 51.3% (95% CI, 47.7%-54.9%) of those aged 15-17 years and 54.6% (95% CI, 52.5%-56.7%) of young adults aged 18-24.

The prevalence of those who reported vaping cannabis every time they vaped was 3.1% (95% CI, 1.3%-6.9%) of youths aged 12-14 years, 6.7% (95% CI, 5.3%-8.6%) of youths aged 15-17 years, and 10.3% (95% CI, 9.0%-11.6%) of young adults aged 18-24.

Among children ages 12-14, 65% said they never vaped cannabis, while 48.7% and 45.4%, respectively, in the two older groups said they did.

“This is a very important finding and it mirrors what some of us have already seen in practice,” said pediatric pulmonologist S. Christy Sadreameli, MD, MHS, an assistant professor of pediatrics at John Hopkins University, Baltimore. “It is important for pediatricians to realize that dual use of cannabis and nicotine vaping, and exclusive use of cannabis vaping, are not uncommon. It informs how we ask questions and how we counsel our patients.” Dr. Sadreameli was not involved in the PATH study.

Overall, the survey participants were 56% male, with 24% of respondents identifying as Hispanic, 8% as non-Hispanic Black, 58% as non-Hispanic White, and 10% as of other race/ethnicity. The weighted proportion of current e-cigarette use was 3.0% (95% CI, 2.6%-3.4%) in youths ages 12-14 years, 14.4% (95% CI, 13.5%-15.3%) in those 15-17 years, and 26.2% (95% CI, 25.3%-27.1%) in young adults.

Other recent national surveys such as the National Institute on Drug Abuses’s Monitoring the Future are reporting a growing prevalence of youth cannabis vaping, Dr. Sun said. For example, the prevalence of cannabis vaping in the past 12-month period among grade 12 students grew from 9.5% in 2017 to 22.1% in 2020. Vaping cannabis was more prevalent among Hispanic teens than other ethnicities.

Vaping devices such as e-cigarettes, vaping pens, e-cigars, and e-hookahs can be used to inhale multiple substances, including nicotine, cannabis, and opium, Dr. Sun noted in an interview. “So in addition to asking about the behavior of vaping itself, pediatricians could pay more attention to what is being vaped in these devices.”

According to Dr. Sadreameli, vaping more than one substance at a time could potentially work synergistically to cause more harm, compared with one product alone. “The other aspect to consider is that vaping multiple types of products may increase the chance of harm from other components of the mixture,” she said. For instance, a lot of the e-cigarette or vaping use-associated lung injury (EVALI) cases have been linked to vitamin E acetate, which was found in certain cannabis formulations. “Anecdotally, most EVALI patients I’ve met seemed to report use of multiple products, including cannabis-containing and nicotine-containing products.”

Dr. Sadreameli added that some cannabis vapers will have other issues. “For example, there is a severe vomiting syndrome I’ve seen, which is induced by cannabis and improved by cessation from cannabis,” she said. “It is important for pediatricians to ask the right questions of their patients in order to better understand what they may be experiencing, provide counseling, and to help them.”

A related issue is cessation, she said. “For those working to achieve cessation from nicotine-based products, sometimes nicotine replacement therapies are helpful. However, cessation from cannabis-containing products is going to look different.”

Although the study did not yield information on the prevalence simultaneous nicotine/cannabis vaping, the authors suggested that some vapers may be combining substances. Previous studies may have modestly overestimated the prevalence of nicotine vaping given their finding that some current e-cigarette users reported vaping cannabis every time they vaped and may be vaping cannabis exclusively. “However, if some current users vaped nicotine and cannabis simultaneously, then overestimation of nicotine vaping would be smaller,” they wrote.

Future surveys on this area should contain detailed questions on nicotine and cannabis vaping, including the substance being vaped and the frequency and intensity of use, Dr. Sun said. “In addition, these surveys could examine some other substances that are being vaped, such as opium and cocaine.”

The PATH study is supported by the NIH, National Institute on Drug Abuse, Department of Health & Human Services, and the FDA’s Center for Tobacco Products. The authors and Dr. Sadreameli had no competing interests to disclose.

Adolescents and young adults who use e-cigarettes reported vaping cannabis, according to selected data from the national Population Assessment of Tobacco and Health (PATH) study.

Ruoyan Sun, PhD, an assistant professor at the University of Alabama at Birmingham, and colleagues examined results of PATH’s wave5 survey conducted from December 2018 to November 2019. PATH is a National Institutes of Health–Food and Drug Administration collaboration begun in 2013.

Their analysis, published online Feb. 7, 2022, in JAMA Pediatrics, evaluated the frequency of cannabis vaping across several age groups: 164 respondents ages 12-14; 919 participants ages 15-17; and 3,038 participants ages 18-24. Respondents included for analysis reported electronic nicotine product consumption in the past 30 days. In response to the question “When you have used an electronic product, how often were you using it to smoke marijuana, marijuana concentrates, marijuana waxes, THC, or hash oils?” 35.0% (95% confidence interval, 29.3%-41.2%) of current e-smokers aged 12-14 years said they had done so, as did 51.3% (95% CI, 47.7%-54.9%) of those aged 15-17 years and 54.6% (95% CI, 52.5%-56.7%) of young adults aged 18-24.

The prevalence of those who reported vaping cannabis every time they vaped was 3.1% (95% CI, 1.3%-6.9%) of youths aged 12-14 years, 6.7% (95% CI, 5.3%-8.6%) of youths aged 15-17 years, and 10.3% (95% CI, 9.0%-11.6%) of young adults aged 18-24.

Among children ages 12-14, 65% said they never vaped cannabis, while 48.7% and 45.4%, respectively, in the two older groups said they did.

“This is a very important finding and it mirrors what some of us have already seen in practice,” said pediatric pulmonologist S. Christy Sadreameli, MD, MHS, an assistant professor of pediatrics at John Hopkins University, Baltimore. “It is important for pediatricians to realize that dual use of cannabis and nicotine vaping, and exclusive use of cannabis vaping, are not uncommon. It informs how we ask questions and how we counsel our patients.” Dr. Sadreameli was not involved in the PATH study.

Overall, the survey participants were 56% male, with 24% of respondents identifying as Hispanic, 8% as non-Hispanic Black, 58% as non-Hispanic White, and 10% as of other race/ethnicity. The weighted proportion of current e-cigarette use was 3.0% (95% CI, 2.6%-3.4%) in youths ages 12-14 years, 14.4% (95% CI, 13.5%-15.3%) in those 15-17 years, and 26.2% (95% CI, 25.3%-27.1%) in young adults.

Other recent national surveys such as the National Institute on Drug Abuses’s Monitoring the Future are reporting a growing prevalence of youth cannabis vaping, Dr. Sun said. For example, the prevalence of cannabis vaping in the past 12-month period among grade 12 students grew from 9.5% in 2017 to 22.1% in 2020. Vaping cannabis was more prevalent among Hispanic teens than other ethnicities.

Vaping devices such as e-cigarettes, vaping pens, e-cigars, and e-hookahs can be used to inhale multiple substances, including nicotine, cannabis, and opium, Dr. Sun noted in an interview. “So in addition to asking about the behavior of vaping itself, pediatricians could pay more attention to what is being vaped in these devices.”

According to Dr. Sadreameli, vaping more than one substance at a time could potentially work synergistically to cause more harm, compared with one product alone. “The other aspect to consider is that vaping multiple types of products may increase the chance of harm from other components of the mixture,” she said. For instance, a lot of the e-cigarette or vaping use-associated lung injury (EVALI) cases have been linked to vitamin E acetate, which was found in certain cannabis formulations. “Anecdotally, most EVALI patients I’ve met seemed to report use of multiple products, including cannabis-containing and nicotine-containing products.”

Dr. Sadreameli added that some cannabis vapers will have other issues. “For example, there is a severe vomiting syndrome I’ve seen, which is induced by cannabis and improved by cessation from cannabis,” she said. “It is important for pediatricians to ask the right questions of their patients in order to better understand what they may be experiencing, provide counseling, and to help them.”

A related issue is cessation, she said. “For those working to achieve cessation from nicotine-based products, sometimes nicotine replacement therapies are helpful. However, cessation from cannabis-containing products is going to look different.”

Although the study did not yield information on the prevalence simultaneous nicotine/cannabis vaping, the authors suggested that some vapers may be combining substances. Previous studies may have modestly overestimated the prevalence of nicotine vaping given their finding that some current e-cigarette users reported vaping cannabis every time they vaped and may be vaping cannabis exclusively. “However, if some current users vaped nicotine and cannabis simultaneously, then overestimation of nicotine vaping would be smaller,” they wrote.

Future surveys on this area should contain detailed questions on nicotine and cannabis vaping, including the substance being vaped and the frequency and intensity of use, Dr. Sun said. “In addition, these surveys could examine some other substances that are being vaped, such as opium and cocaine.”

The PATH study is supported by the NIH, National Institute on Drug Abuse, Department of Health & Human Services, and the FDA’s Center for Tobacco Products. The authors and Dr. Sadreameli had no competing interests to disclose.

In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.

In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.

Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical 2014&amp;quot;. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.

Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.

In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.

“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
 

Genetic disorder

CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.

Emw/Wikimedia Commons/CC BY-SA 3.0

The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.

The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.

CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
 

Diagnosis

In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.

Treatment

There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.

CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).

Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.

“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.

In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV₁), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.

Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.

Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.

“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.

In addition, the need for lung and heart transplantation has sharply declined.

“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.

Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.


 

Burden of care

CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.

In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.

“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”

“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.

“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.

The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
 

‘A great problem to have’

One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.

With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.

“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.

Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”

He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
 

Cost and access

All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.

One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.

“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.

Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.

As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.

In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.

“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.

That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”

The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.

Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”

Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.

In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.

In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.

Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical 2014&amp;quot;. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.

Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.

In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.

“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
 

Genetic disorder

CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.

Emw/Wikimedia Commons/CC BY-SA 3.0

The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.

The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.

CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
 

Diagnosis

In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.

Treatment

There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.

CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).

Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.

“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.

In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV₁), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.

Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.

Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.

“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.

In addition, the need for lung and heart transplantation has sharply declined.

“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.

Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.


 

Burden of care

CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.

In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.

“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”

“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.

“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.

The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
 

‘A great problem to have’

One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.

With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.

“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.

Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”

He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
 

Cost and access

All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.

One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.

“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.

Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.

As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.

In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.

“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.

That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”

The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.

Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”

Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.

In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.

In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.

Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical 2014&amp;quot;. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.

Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.

In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.

“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
 

Genetic disorder

CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.

Emw/Wikimedia Commons/CC BY-SA 3.0

The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.

The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.

CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
 

Diagnosis

In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.

Treatment

There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.

CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).

Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.

“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.

In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV₁), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.

Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.

Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.

“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.

In addition, the need for lung and heart transplantation has sharply declined.

“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.

Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.


 

Burden of care

CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.

In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.

“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”

“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.

“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.

The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
 

‘A great problem to have’

One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.

With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.

“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.

Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”

He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
 

Cost and access

All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.

One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.

“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.

Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.

As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.

In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.

“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.

That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”

The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.

Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”

Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Right now, more than 106,600 people in the United States are on the national transplant waiting list, each hoping to hear soon that a lung, kidney, heart, or other vital organ has been found for them. It’s the promise not just of a new organ, but a new life.

Well before they are placed on that list, transplant candidates, as they’re known, are evaluated with a battery of tests and exams to be sure they are infection free, their other organs are healthy, and that all their vaccinations are up to date.

Now, COVID vaccinations – and some people’s resistance to them – have turned what used to be routine preparation controversial.

In January, a 31-year-old Boston father of two declined to get the COVID-19 vaccine, and Brigham and Women’s Hospital officials removed him from the heart transplant waiting list. And in North Carolina, a 38-year-old man in need of a kidney transplant said he, too, was denied the organ when he declined to get the vaccination.

Those are just two of the most recent cases. The decisions by the transplant centers to remove the candidates from the waiting list have set off a national debate among ethicists, family members, doctors, patients, and others.

On social media and in conversation, the question persists: Is removing them from the list unfair and cruel, or simply business as usual to keep the patient as healthy as possible and the transplant as successful as possible?

Two recent tweets sum up the debate.

“The people responsible for this should be charged with attempted homicide,” one Twitter user said, while another suggested that the more accurate way to headline the news about a transplant candidate refusing the COVID-19 vaccine would be: “Patient voluntarily forfeits donor organ.”

Doctors and ethics experts, as well as other patients on the waiting list, say it’s simply good medicine to require the COVID vaccine, along with a host of other pretransplant requirements.
 

Transplant protocols

“Transplant medicine has always been a strong promoter of vaccination,” said Silas Prescod Norman, MD, a clinical associate professor of nephrology and internal medicine at the University of Michigan, Ann Arbor. He is a kidney specialist who works in the university’s transplant clinic.

Requiring the COVID vaccine is in line with requirements to get numerous other vaccines, he said.“Promoting the COVID vaccine among our transplant candidates and recipients is just an extension of our usual practice.

“In transplantation, first and foremost is patient safety,” Dr. Norman said. “And we know that solid organ transplant patients are at substantially higher risk of contracting COVID than nontransplant patients.”

After the transplant, they are placed on immunosuppressant drugs, that weaken the immune system while also decreasing the body’s ability to reject the new organ.

“We know now, because there is good data about the vaccine to show that people who are on transplant medications are less likely to make detectable antibodies after vaccination,” said Dr. Norman, who’s also a medical adviser for the American Kidney Fund, a nonprofit that provides kidney health information and financial assistance for dialysis.

And this is not a surprise because of the immunosuppressive effects, he said. “So it only makes sense to get people vaccinated before transplantation.”

Researchers compared the cases of more than 17,000 people who had received organ transplants and were hospitalized from April to November 2020, either for COVID (1,682 of them) or other health issues. Those who had COVID were more likely to have complications and to die in the hospital than those who did not have it.
 

Vaccination guidelines, policies

Federal COVID-19 treatment guidelines from the National Institutes of Health state that transplant patients on immunosuppressant drugs used after the procedure should be considered at a higher risk of getting severe COVID if infected.

In a joint statement from the American Society of Transplant Surgeons, the American Society of Transplantation, and the International Society for Heart and Lung Transplantation, the organizations say they “strongly recommend that all eligible children and adult transplant candidates and recipients be vaccinated with a COVID-19 vaccine [and booster] that is approved or authorized in their jurisdiction. Whenever possible, vaccination should occur prior to transplantation.” Ideally, it should be completed at least 2 weeks before the transplant.

The organizations also “support the development of institutional policies regarding pretransplant vaccination. We believe that this is in the best interest of the transplant candidate, optimizing their chances of getting through the perioperative and posttransplant periods without severe COVID-19 disease, especially at times of greater infection prevalence.”

Officials at Brigham and Women’s Hospital, where the 31-year-old father was removed from the list, issued a statement that reads, in part: “Our Mass General Brigham health care system requires several [Centers for Disease Control and Prevention]-recommended vaccines, including the COVID-19 vaccine, and lifestyle behaviors for transplant candidates to create both the best chance for a successful operation and to optimize the patient’s survival after transplantation, given that their immune system is drastically suppressed. Patients are not active on the wait list without this.”
 

Ethics amid organ shortage

“Organs are scarce,” said Arthur L. Caplan, PhD, director of the division of medical ethics at New York University Langone Medical Center. That makes the goal of choosing the very best candidates for success even more crucial.

“You try to maximize the chance the organ will work,” he said. Pretransplant vaccination is one way.

The shortage is most severe for kidney transplants. In 2020, according to federal statistics, more than 91,000 kidney transplants were needed, but fewer than 23,000 were received. During 2021, 41,354 transplants were done, an increase of nearly 6% over the previous year. The total includes kidneys, hearts, lungs, and other organs, with kidneys accounting for more than 24,000 of the total.

Even with the rise in transplant numbers, supply does not meet demand. According to federal statistics, 17 people in the United States die each day waiting for an organ transplant. Every 9 minutes, someone is added to the waiting list.

“This isn’t and it shouldn’t be a fight about the COVID vaccine,” Dr. Caplan said. “This isn’t an issue about punishing non-COVID vaccinators. It’s deciding who is going to get a scarce organ.”

“A lot of people [opposed to removing the nonvaccinated from the list] think: ‘Oh, they are just killing those people who won’t take a COVID vaccine.’ That’s not what is going on.”

The transplant candidate must be in the best possible shape overall, Dr. Caplan and doctors agreed. Someone who is smoking, drinking heavily, or abusing drugs isn’t going to the top of the list either. And for other procedures, such as bariatric surgery or knee surgery, some patients are told first to lose weight before a surgeon will operate.

The worry about side effects from the vaccine, which some patients have cited as a concern, is misplaced, Dr. Caplan said. What transplant candidates who refuse the COVID vaccine may not be thinking about is that they are facing a serious operation and will be on numerous anti-rejection drugs, with side effects, after the surgery.

“So to be worried about the side effects of a COVID vaccine is irrational,” he said.
 

Transplants: The process

The patients who were recently removed from the transplant list could seek care and a transplant at an alternate center, said Anne Paschke, a spokesperson for the United Network for Organ Sharing, a nonprofit group that is under contract with the federal government and operates the national Organ Procurement and Transplantation Network (OPTN).

“Transplant hospitals decide which patients to add to the wait list based on their own criteria and medical judgment to create the best chance for a positive transplant outcome,” she said. That’s done with the understanding that patients will help with their medical care.

So, if one program won’t accept a patient, another may. But, if a patient turned down at one center due to refusing to get the COVID vaccine tries another center, the requirements at that hospital may be the same, she said.

OPTN maintains a list of transplant centers. As of Jan. 28, there were 251 transplant centers, according to UNOS, which manages the waiting list, matches donors and recipients, and strives for equity, among other duties.
 

Pretransplant refusers not typical

“The cases we are seeing are outliers,” Dr. Caplan said of the handful of known candidates who have refused the vaccine. Most ask their doctor exactly what they need to do to live and follow those instructions.

Dr. Norman agreed. Most of the kidney patients he cares for who are hoping for a transplant have been on dialysis, “which they do not like. They are doing whatever they can to make sure they don’t go back on dialysis. As a group, they tend to be very adherent, very safety conscious because they understand their risk and they understand the gift they have received [or will receive] through transplantation. They want to do everything they can to respect and protect that gift.”

Not surprisingly, some on the transplant list who are vaccinated have strong opinions about those who refuse to get the vaccine. Dana J. Ufkes, 61, a Seattle realtor, has been on the kidney transplant list – this time – since 2003, hoping for her third transplant. When asked if potential recipients should be removed from the list if they refuse the COVID vaccine, her answer was immediate: “Absolutely.”

At age 17, Ms. Ufkes got a serious kidney infection that went undiagnosed and untreated. Her kidney health worsened, and she needed a transplant. She got her first one in 1986, then again in 1992.

“They last longer than they used to,” she said. But not forever. (According to the American Kidney Fund, transplants from a living kidney donor last about 15-20 years; from a deceased donor, 10-15.)

The decision to decline the vaccine is, of course, each person’s choice, Ms. Ufkes said. But “if they don’t want to be vaccinated [and still want to be on the list], I think that’s BS.”

Citing the lack of organs, “it’s not like they are handing these out like jellybeans.”

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

Right now, more than 106,600 people in the United States are on the national transplant waiting list, each hoping to hear soon that a lung, kidney, heart, or other vital organ has been found for them. It’s the promise not just of a new organ, but a new life.

Well before they are placed on that list, transplant candidates, as they’re known, are evaluated with a battery of tests and exams to be sure they are infection free, their other organs are healthy, and that all their vaccinations are up to date.

Now, COVID vaccinations – and some people’s resistance to them – have turned what used to be routine preparation controversial.

In January, a 31-year-old Boston father of two declined to get the COVID-19 vaccine, and Brigham and Women’s Hospital officials removed him from the heart transplant waiting list. And in North Carolina, a 38-year-old man in need of a kidney transplant said he, too, was denied the organ when he declined to get the vaccination.

Those are just two of the most recent cases. The decisions by the transplant centers to remove the candidates from the waiting list have set off a national debate among ethicists, family members, doctors, patients, and others.

On social media and in conversation, the question persists: Is removing them from the list unfair and cruel, or simply business as usual to keep the patient as healthy as possible and the transplant as successful as possible?

Two recent tweets sum up the debate.

“The people responsible for this should be charged with attempted homicide,” one Twitter user said, while another suggested that the more accurate way to headline the news about a transplant candidate refusing the COVID-19 vaccine would be: “Patient voluntarily forfeits donor organ.”

Doctors and ethics experts, as well as other patients on the waiting list, say it’s simply good medicine to require the COVID vaccine, along with a host of other pretransplant requirements.
 

Transplant protocols

“Transplant medicine has always been a strong promoter of vaccination,” said Silas Prescod Norman, MD, a clinical associate professor of nephrology and internal medicine at the University of Michigan, Ann Arbor. He is a kidney specialist who works in the university’s transplant clinic.

Requiring the COVID vaccine is in line with requirements to get numerous other vaccines, he said.“Promoting the COVID vaccine among our transplant candidates and recipients is just an extension of our usual practice.

“In transplantation, first and foremost is patient safety,” Dr. Norman said. “And we know that solid organ transplant patients are at substantially higher risk of contracting COVID than nontransplant patients.”

After the transplant, they are placed on immunosuppressant drugs, that weaken the immune system while also decreasing the body’s ability to reject the new organ.

“We know now, because there is good data about the vaccine to show that people who are on transplant medications are less likely to make detectable antibodies after vaccination,” said Dr. Norman, who’s also a medical adviser for the American Kidney Fund, a nonprofit that provides kidney health information and financial assistance for dialysis.

And this is not a surprise because of the immunosuppressive effects, he said. “So it only makes sense to get people vaccinated before transplantation.”

Researchers compared the cases of more than 17,000 people who had received organ transplants and were hospitalized from April to November 2020, either for COVID (1,682 of them) or other health issues. Those who had COVID were more likely to have complications and to die in the hospital than those who did not have it.
 

Vaccination guidelines, policies

Federal COVID-19 treatment guidelines from the National Institutes of Health state that transplant patients on immunosuppressant drugs used after the procedure should be considered at a higher risk of getting severe COVID if infected.

In a joint statement from the American Society of Transplant Surgeons, the American Society of Transplantation, and the International Society for Heart and Lung Transplantation, the organizations say they “strongly recommend that all eligible children and adult transplant candidates and recipients be vaccinated with a COVID-19 vaccine [and booster] that is approved or authorized in their jurisdiction. Whenever possible, vaccination should occur prior to transplantation.” Ideally, it should be completed at least 2 weeks before the transplant.

The organizations also “support the development of institutional policies regarding pretransplant vaccination. We believe that this is in the best interest of the transplant candidate, optimizing their chances of getting through the perioperative and posttransplant periods without severe COVID-19 disease, especially at times of greater infection prevalence.”

Officials at Brigham and Women’s Hospital, where the 31-year-old father was removed from the list, issued a statement that reads, in part: “Our Mass General Brigham health care system requires several [Centers for Disease Control and Prevention]-recommended vaccines, including the COVID-19 vaccine, and lifestyle behaviors for transplant candidates to create both the best chance for a successful operation and to optimize the patient’s survival after transplantation, given that their immune system is drastically suppressed. Patients are not active on the wait list without this.”
 

Ethics amid organ shortage

“Organs are scarce,” said Arthur L. Caplan, PhD, director of the division of medical ethics at New York University Langone Medical Center. That makes the goal of choosing the very best candidates for success even more crucial.

“You try to maximize the chance the organ will work,” he said. Pretransplant vaccination is one way.

The shortage is most severe for kidney transplants. In 2020, according to federal statistics, more than 91,000 kidney transplants were needed, but fewer than 23,000 were received. During 2021, 41,354 transplants were done, an increase of nearly 6% over the previous year. The total includes kidneys, hearts, lungs, and other organs, with kidneys accounting for more than 24,000 of the total.

Even with the rise in transplant numbers, supply does not meet demand. According to federal statistics, 17 people in the United States die each day waiting for an organ transplant. Every 9 minutes, someone is added to the waiting list.

“This isn’t and it shouldn’t be a fight about the COVID vaccine,” Dr. Caplan said. “This isn’t an issue about punishing non-COVID vaccinators. It’s deciding who is going to get a scarce organ.”

“A lot of people [opposed to removing the nonvaccinated from the list] think: ‘Oh, they are just killing those people who won’t take a COVID vaccine.’ That’s not what is going on.”

The transplant candidate must be in the best possible shape overall, Dr. Caplan and doctors agreed. Someone who is smoking, drinking heavily, or abusing drugs isn’t going to the top of the list either. And for other procedures, such as bariatric surgery or knee surgery, some patients are told first to lose weight before a surgeon will operate.

The worry about side effects from the vaccine, which some patients have cited as a concern, is misplaced, Dr. Caplan said. What transplant candidates who refuse the COVID vaccine may not be thinking about is that they are facing a serious operation and will be on numerous anti-rejection drugs, with side effects, after the surgery.

“So to be worried about the side effects of a COVID vaccine is irrational,” he said.
 

Transplants: The process

The patients who were recently removed from the transplant list could seek care and a transplant at an alternate center, said Anne Paschke, a spokesperson for the United Network for Organ Sharing, a nonprofit group that is under contract with the federal government and operates the national Organ Procurement and Transplantation Network (OPTN).

“Transplant hospitals decide which patients to add to the wait list based on their own criteria and medical judgment to create the best chance for a positive transplant outcome,” she said. That’s done with the understanding that patients will help with their medical care.

So, if one program won’t accept a patient, another may. But, if a patient turned down at one center due to refusing to get the COVID vaccine tries another center, the requirements at that hospital may be the same, she said.

OPTN maintains a list of transplant centers. As of Jan. 28, there were 251 transplant centers, according to UNOS, which manages the waiting list, matches donors and recipients, and strives for equity, among other duties.
 

Pretransplant refusers not typical

“The cases we are seeing are outliers,” Dr. Caplan said of the handful of known candidates who have refused the vaccine. Most ask their doctor exactly what they need to do to live and follow those instructions.

Dr. Norman agreed. Most of the kidney patients he cares for who are hoping for a transplant have been on dialysis, “which they do not like. They are doing whatever they can to make sure they don’t go back on dialysis. As a group, they tend to be very adherent, very safety conscious because they understand their risk and they understand the gift they have received [or will receive] through transplantation. They want to do everything they can to respect and protect that gift.”

Not surprisingly, some on the transplant list who are vaccinated have strong opinions about those who refuse to get the vaccine. Dana J. Ufkes, 61, a Seattle realtor, has been on the kidney transplant list – this time – since 2003, hoping for her third transplant. When asked if potential recipients should be removed from the list if they refuse the COVID vaccine, her answer was immediate: “Absolutely.”

At age 17, Ms. Ufkes got a serious kidney infection that went undiagnosed and untreated. Her kidney health worsened, and she needed a transplant. She got her first one in 1986, then again in 1992.

“They last longer than they used to,” she said. But not forever. (According to the American Kidney Fund, transplants from a living kidney donor last about 15-20 years; from a deceased donor, 10-15.)

The decision to decline the vaccine is, of course, each person’s choice, Ms. Ufkes said. But “if they don’t want to be vaccinated [and still want to be on the list], I think that’s BS.”

Citing the lack of organs, “it’s not like they are handing these out like jellybeans.”

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

Right now, more than 106,600 people in the United States are on the national transplant waiting list, each hoping to hear soon that a lung, kidney, heart, or other vital organ has been found for them. It’s the promise not just of a new organ, but a new life.

Well before they are placed on that list, transplant candidates, as they’re known, are evaluated with a battery of tests and exams to be sure they are infection free, their other organs are healthy, and that all their vaccinations are up to date.

Now, COVID vaccinations – and some people’s resistance to them – have turned what used to be routine preparation controversial.

In January, a 31-year-old Boston father of two declined to get the COVID-19 vaccine, and Brigham and Women’s Hospital officials removed him from the heart transplant waiting list. And in North Carolina, a 38-year-old man in need of a kidney transplant said he, too, was denied the organ when he declined to get the vaccination.

Those are just two of the most recent cases. The decisions by the transplant centers to remove the candidates from the waiting list have set off a national debate among ethicists, family members, doctors, patients, and others.

On social media and in conversation, the question persists: Is removing them from the list unfair and cruel, or simply business as usual to keep the patient as healthy as possible and the transplant as successful as possible?

Two recent tweets sum up the debate.

“The people responsible for this should be charged with attempted homicide,” one Twitter user said, while another suggested that the more accurate way to headline the news about a transplant candidate refusing the COVID-19 vaccine would be: “Patient voluntarily forfeits donor organ.”

Doctors and ethics experts, as well as other patients on the waiting list, say it’s simply good medicine to require the COVID vaccine, along with a host of other pretransplant requirements.
 

Transplant protocols

“Transplant medicine has always been a strong promoter of vaccination,” said Silas Prescod Norman, MD, a clinical associate professor of nephrology and internal medicine at the University of Michigan, Ann Arbor. He is a kidney specialist who works in the university’s transplant clinic.

Requiring the COVID vaccine is in line with requirements to get numerous other vaccines, he said.“Promoting the COVID vaccine among our transplant candidates and recipients is just an extension of our usual practice.

“In transplantation, first and foremost is patient safety,” Dr. Norman said. “And we know that solid organ transplant patients are at substantially higher risk of contracting COVID than nontransplant patients.”

After the transplant, they are placed on immunosuppressant drugs, that weaken the immune system while also decreasing the body’s ability to reject the new organ.

“We know now, because there is good data about the vaccine to show that people who are on transplant medications are less likely to make detectable antibodies after vaccination,” said Dr. Norman, who’s also a medical adviser for the American Kidney Fund, a nonprofit that provides kidney health information and financial assistance for dialysis.

And this is not a surprise because of the immunosuppressive effects, he said. “So it only makes sense to get people vaccinated before transplantation.”

Researchers compared the cases of more than 17,000 people who had received organ transplants and were hospitalized from April to November 2020, either for COVID (1,682 of them) or other health issues. Those who had COVID were more likely to have complications and to die in the hospital than those who did not have it.
 

Vaccination guidelines, policies

Federal COVID-19 treatment guidelines from the National Institutes of Health state that transplant patients on immunosuppressant drugs used after the procedure should be considered at a higher risk of getting severe COVID if infected.

In a joint statement from the American Society of Transplant Surgeons, the American Society of Transplantation, and the International Society for Heart and Lung Transplantation, the organizations say they “strongly recommend that all eligible children and adult transplant candidates and recipients be vaccinated with a COVID-19 vaccine [and booster] that is approved or authorized in their jurisdiction. Whenever possible, vaccination should occur prior to transplantation.” Ideally, it should be completed at least 2 weeks before the transplant.

The organizations also “support the development of institutional policies regarding pretransplant vaccination. We believe that this is in the best interest of the transplant candidate, optimizing their chances of getting through the perioperative and posttransplant periods without severe COVID-19 disease, especially at times of greater infection prevalence.”

Officials at Brigham and Women’s Hospital, where the 31-year-old father was removed from the list, issued a statement that reads, in part: “Our Mass General Brigham health care system requires several [Centers for Disease Control and Prevention]-recommended vaccines, including the COVID-19 vaccine, and lifestyle behaviors for transplant candidates to create both the best chance for a successful operation and to optimize the patient’s survival after transplantation, given that their immune system is drastically suppressed. Patients are not active on the wait list without this.”
 

Ethics amid organ shortage

“Organs are scarce,” said Arthur L. Caplan, PhD, director of the division of medical ethics at New York University Langone Medical Center. That makes the goal of choosing the very best candidates for success even more crucial.

“You try to maximize the chance the organ will work,” he said. Pretransplant vaccination is one way.

The shortage is most severe for kidney transplants. In 2020, according to federal statistics, more than 91,000 kidney transplants were needed, but fewer than 23,000 were received. During 2021, 41,354 transplants were done, an increase of nearly 6% over the previous year. The total includes kidneys, hearts, lungs, and other organs, with kidneys accounting for more than 24,000 of the total.

Even with the rise in transplant numbers, supply does not meet demand. According to federal statistics, 17 people in the United States die each day waiting for an organ transplant. Every 9 minutes, someone is added to the waiting list.

“This isn’t and it shouldn’t be a fight about the COVID vaccine,” Dr. Caplan said. “This isn’t an issue about punishing non-COVID vaccinators. It’s deciding who is going to get a scarce organ.”

“A lot of people [opposed to removing the nonvaccinated from the list] think: ‘Oh, they are just killing those people who won’t take a COVID vaccine.’ That’s not what is going on.”

The transplant candidate must be in the best possible shape overall, Dr. Caplan and doctors agreed. Someone who is smoking, drinking heavily, or abusing drugs isn’t going to the top of the list either. And for other procedures, such as bariatric surgery or knee surgery, some patients are told first to lose weight before a surgeon will operate.

The worry about side effects from the vaccine, which some patients have cited as a concern, is misplaced, Dr. Caplan said. What transplant candidates who refuse the COVID vaccine may not be thinking about is that they are facing a serious operation and will be on numerous anti-rejection drugs, with side effects, after the surgery.

“So to be worried about the side effects of a COVID vaccine is irrational,” he said.
 

Transplants: The process

The patients who were recently removed from the transplant list could seek care and a transplant at an alternate center, said Anne Paschke, a spokesperson for the United Network for Organ Sharing, a nonprofit group that is under contract with the federal government and operates the national Organ Procurement and Transplantation Network (OPTN).

“Transplant hospitals decide which patients to add to the wait list based on their own criteria and medical judgment to create the best chance for a positive transplant outcome,” she said. That’s done with the understanding that patients will help with their medical care.

So, if one program won’t accept a patient, another may. But, if a patient turned down at one center due to refusing to get the COVID vaccine tries another center, the requirements at that hospital may be the same, she said.

OPTN maintains a list of transplant centers. As of Jan. 28, there were 251 transplant centers, according to UNOS, which manages the waiting list, matches donors and recipients, and strives for equity, among other duties.
 

Pretransplant refusers not typical

“The cases we are seeing are outliers,” Dr. Caplan said of the handful of known candidates who have refused the vaccine. Most ask their doctor exactly what they need to do to live and follow those instructions.

Dr. Norman agreed. Most of the kidney patients he cares for who are hoping for a transplant have been on dialysis, “which they do not like. They are doing whatever they can to make sure they don’t go back on dialysis. As a group, they tend to be very adherent, very safety conscious because they understand their risk and they understand the gift they have received [or will receive] through transplantation. They want to do everything they can to respect and protect that gift.”

Not surprisingly, some on the transplant list who are vaccinated have strong opinions about those who refuse to get the vaccine. Dana J. Ufkes, 61, a Seattle realtor, has been on the kidney transplant list – this time – since 2003, hoping for her third transplant. When asked if potential recipients should be removed from the list if they refuse the COVID vaccine, her answer was immediate: “Absolutely.”

At age 17, Ms. Ufkes got a serious kidney infection that went undiagnosed and untreated. Her kidney health worsened, and she needed a transplant. She got her first one in 1986, then again in 1992.

“They last longer than they used to,” she said. But not forever. (According to the American Kidney Fund, transplants from a living kidney donor last about 15-20 years; from a deceased donor, 10-15.)

The decision to decline the vaccine is, of course, each person’s choice, Ms. Ufkes said. But “if they don’t want to be vaccinated [and still want to be on the list], I think that’s BS.”

Citing the lack of organs, “it’s not like they are handing these out like jellybeans.”

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

Hospitalized intensive care patients with respiratory syncytial virus were significantly more likely to be immunocompromised and to have chronic respiratory conditions than those with influenza infections, but in-hospital mortality rates were similar, based on data from 618 adults.

Respiratory syncytial virus is common in adults, but characteristics of RSV patients requiring ICU care have not been explored, despite routine testing for RSV in critically ill patients in many institutions, Julien Coussement, PhD, of Université Libre de Bruxelles, Brussels, and colleagues wrote.

“Influenza is another respiratory virus routinely tested for in ICU patients with respiratory symptoms because of its well-known morbidity and mortality, but there are no data specifically comparing RSV and influenza infections in adult ICU patients,” they noted.

In a retrospective, multicenter study published in the journal CHEST, the researchers analyzed data from 309 adult ICU patients with RSV infection and 309 with influenza infection between November 2011 and April 2018 from 17 sites in France and Belgium. Each RSV patient was matched to a flu patient according to institution and date of diagnosis.

The primary objective was a comparison of in-hospital mortality between the groups, defined as death from any cause during an index hospital stay in acute care. Secondary objectives were comparisons of the clinical and biological characteristics of patients with RSV versus flu.

Overall, in-hospital mortality was not significantly different between the RSV and influenza groups (23.9% vs. 25.6%, P = .63).

However, patients with RSV infection were significantly more likely than those with flu to have an underlying chronic respiratory condition (60.2% vs. 40.1%, P < .001) and to be immunocompromised (35% vs. 26.2%, P = .02). Very few of the patients overall (39 patients, 6.3%) were considered young and healthy prior to hospitalization; and significantly fewer of these were in the RSV group than in the influenza group (9 patients and 30 patients, respectively).

Airway obstruction at the time of diagnosis was significantly more common in the RSV patients than in influenza patients (49.5% vs. 39.5%, P = .01), but influenza patients were significantly more likely to have acute respiratory distress syndrome at the time of diagnosis (21.7% vs. 14.6%, P = .02). Rates of coinfections were similar between the groups, and approximately 60% of coinfected patients received at least 72 hours of therapeutic antibiotics. Overall length of hospital stay, ICU stay, and duration of mechanical ventilation were similar between the groups.

The results show that severe RSV occurs mainly in older patients with comorbidities, and these results reflect data from previous studies, the researchers wrote in their discussion. In addition, “patients with influenza infection were significantly more likely to have fever, myalgia, increased CPK level, thrombocytopenia and transaminitis at diagnosis than were those with RSV infection. Whether these differences may be used to guide patient management remains to be determined.”

The study findings were limited by several factors including the retrospective design, and testing for respiratory viruses on symptomatic patients only, rather than all ICU patients, the researchers noted. Other limitations include the inability to show a causal link between viral infections and patient outcomes and the heterogenous management of patients among different centers.

However, the results were strengthened by the large sample size and multivariate analysis, and support the need for interventions to prevent and treat severe RSV, they concluded.

The study received no outside funding. Lead author Dr. Coussement disclosed serving on advisory board for Sanofi.

Hospitalized intensive care patients with respiratory syncytial virus were significantly more likely to be immunocompromised and to have chronic respiratory conditions than those with influenza infections, but in-hospital mortality rates were similar, based on data from 618 adults.

Respiratory syncytial virus is common in adults, but characteristics of RSV patients requiring ICU care have not been explored, despite routine testing for RSV in critically ill patients in many institutions, Julien Coussement, PhD, of Université Libre de Bruxelles, Brussels, and colleagues wrote.

“Influenza is another respiratory virus routinely tested for in ICU patients with respiratory symptoms because of its well-known morbidity and mortality, but there are no data specifically comparing RSV and influenza infections in adult ICU patients,” they noted.

In a retrospective, multicenter study published in the journal CHEST, the researchers analyzed data from 309 adult ICU patients with RSV infection and 309 with influenza infection between November 2011 and April 2018 from 17 sites in France and Belgium. Each RSV patient was matched to a flu patient according to institution and date of diagnosis.

The primary objective was a comparison of in-hospital mortality between the groups, defined as death from any cause during an index hospital stay in acute care. Secondary objectives were comparisons of the clinical and biological characteristics of patients with RSV versus flu.

Overall, in-hospital mortality was not significantly different between the RSV and influenza groups (23.9% vs. 25.6%, P = .63).

However, patients with RSV infection were significantly more likely than those with flu to have an underlying chronic respiratory condition (60.2% vs. 40.1%, P < .001) and to be immunocompromised (35% vs. 26.2%, P = .02). Very few of the patients overall (39 patients, 6.3%) were considered young and healthy prior to hospitalization; and significantly fewer of these were in the RSV group than in the influenza group (9 patients and 30 patients, respectively).

Airway obstruction at the time of diagnosis was significantly more common in the RSV patients than in influenza patients (49.5% vs. 39.5%, P = .01), but influenza patients were significantly more likely to have acute respiratory distress syndrome at the time of diagnosis (21.7% vs. 14.6%, P = .02). Rates of coinfections were similar between the groups, and approximately 60% of coinfected patients received at least 72 hours of therapeutic antibiotics. Overall length of hospital stay, ICU stay, and duration of mechanical ventilation were similar between the groups.

The results show that severe RSV occurs mainly in older patients with comorbidities, and these results reflect data from previous studies, the researchers wrote in their discussion. In addition, “patients with influenza infection were significantly more likely to have fever, myalgia, increased CPK level, thrombocytopenia and transaminitis at diagnosis than were those with RSV infection. Whether these differences may be used to guide patient management remains to be determined.”

The study findings were limited by several factors including the retrospective design, and testing for respiratory viruses on symptomatic patients only, rather than all ICU patients, the researchers noted. Other limitations include the inability to show a causal link between viral infections and patient outcomes and the heterogenous management of patients among different centers.

However, the results were strengthened by the large sample size and multivariate analysis, and support the need for interventions to prevent and treat severe RSV, they concluded.

The study received no outside funding. Lead author Dr. Coussement disclosed serving on advisory board for Sanofi.

Hospitalized intensive care patients with respiratory syncytial virus were significantly more likely to be immunocompromised and to have chronic respiratory conditions than those with influenza infections, but in-hospital mortality rates were similar, based on data from 618 adults.

Respiratory syncytial virus is common in adults, but characteristics of RSV patients requiring ICU care have not been explored, despite routine testing for RSV in critically ill patients in many institutions, Julien Coussement, PhD, of Université Libre de Bruxelles, Brussels, and colleagues wrote.

“Influenza is another respiratory virus routinely tested for in ICU patients with respiratory symptoms because of its well-known morbidity and mortality, but there are no data specifically comparing RSV and influenza infections in adult ICU patients,” they noted.

In a retrospective, multicenter study published in the journal CHEST, the researchers analyzed data from 309 adult ICU patients with RSV infection and 309 with influenza infection between November 2011 and April 2018 from 17 sites in France and Belgium. Each RSV patient was matched to a flu patient according to institution and date of diagnosis.

The primary objective was a comparison of in-hospital mortality between the groups, defined as death from any cause during an index hospital stay in acute care. Secondary objectives were comparisons of the clinical and biological characteristics of patients with RSV versus flu.

Overall, in-hospital mortality was not significantly different between the RSV and influenza groups (23.9% vs. 25.6%, P = .63).

However, patients with RSV infection were significantly more likely than those with flu to have an underlying chronic respiratory condition (60.2% vs. 40.1%, P < .001) and to be immunocompromised (35% vs. 26.2%, P = .02). Very few of the patients overall (39 patients, 6.3%) were considered young and healthy prior to hospitalization; and significantly fewer of these were in the RSV group than in the influenza group (9 patients and 30 patients, respectively).

Airway obstruction at the time of diagnosis was significantly more common in the RSV patients than in influenza patients (49.5% vs. 39.5%, P = .01), but influenza patients were significantly more likely to have acute respiratory distress syndrome at the time of diagnosis (21.7% vs. 14.6%, P = .02). Rates of coinfections were similar between the groups, and approximately 60% of coinfected patients received at least 72 hours of therapeutic antibiotics. Overall length of hospital stay, ICU stay, and duration of mechanical ventilation were similar between the groups.

The results show that severe RSV occurs mainly in older patients with comorbidities, and these results reflect data from previous studies, the researchers wrote in their discussion. In addition, “patients with influenza infection were significantly more likely to have fever, myalgia, increased CPK level, thrombocytopenia and transaminitis at diagnosis than were those with RSV infection. Whether these differences may be used to guide patient management remains to be determined.”

The study findings were limited by several factors including the retrospective design, and testing for respiratory viruses on symptomatic patients only, rather than all ICU patients, the researchers noted. Other limitations include the inability to show a causal link between viral infections and patient outcomes and the heterogenous management of patients among different centers.

However, the results were strengthened by the large sample size and multivariate analysis, and support the need for interventions to prevent and treat severe RSV, they concluded.

The study received no outside funding. Lead author Dr. Coussement disclosed serving on advisory board for Sanofi.