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Use of 6-minute walk distance as a clinical trial outcome in interstitial lung disease
Diffuse Lung & Transplant Network
Pulmonary Physiology & Rehabilitation Section
Pulmonary arterial hypertension (PH) and more recently interstitial lung disease (ILD) trials use the 6-minute walk test (6MWT) as a primary outcome due to its ability to conveniently capture a patient’s functional capacity and quality of life. However, interpreting the 6MWT in complex and diverse diseases, such as ILD, presents significant challenges.
A recent article (Harari, et al. Eur Respir Rev. 2022 Aug 23;31(165):220087. doi: 10.1183/16000617.0087-2022) advocates for further research to determine the optimal use of the 6MWT as a clinical endpoint in ILD trials. A decline in 6MWT can represent progression of ILD; ILD-related PH; or musculoskeletal, hematologic, or cardiac etiologies related to the underlying cause of ILD.
To enhance sensitivity, the authors endorse the inclusion of additional parameters in the analysis, possibly as a composite outcome. This would involve integrating the oxygen desaturation profile, dyspnea scores, and heart rate recovery with changes in the 6MWT-distance. They propose this composite measure could serve as a primary endpoint when the study intervention’s impact on clinical performance – either improvement or stabilization of ILD or ILD-related PH – is clearly defined. The prognostic significance of these additional parameters in patients with ILD, however, requires further investigation.
Inter-test reliability requires a standardized 6MWT, as previously proposed for this population (Lancaster, et al. Contemporary Clin Trials. 2021;Nov 25,2020). The standardized test protocol that includes continuous pulse oximetry and heart rate measurement, oxygen titration, and end of test guidelines, will reduce variability and boost reproducibility.
In light of recent advancements in the affordability, convenience, and portability of oxygen consumption (VO2) gas analyzers, we believe that incorporating V
Ruchicka Sangani, MD, Section Fellow-in-Training
Saqib Baig, MD, Section Member-at-Large
Diffuse Lung & Transplant Network
Pulmonary Physiology & Rehabilitation Section
Pulmonary arterial hypertension (PH) and more recently interstitial lung disease (ILD) trials use the 6-minute walk test (6MWT) as a primary outcome due to its ability to conveniently capture a patient’s functional capacity and quality of life. However, interpreting the 6MWT in complex and diverse diseases, such as ILD, presents significant challenges.
A recent article (Harari, et al. Eur Respir Rev. 2022 Aug 23;31(165):220087. doi: 10.1183/16000617.0087-2022) advocates for further research to determine the optimal use of the 6MWT as a clinical endpoint in ILD trials. A decline in 6MWT can represent progression of ILD; ILD-related PH; or musculoskeletal, hematologic, or cardiac etiologies related to the underlying cause of ILD.
To enhance sensitivity, the authors endorse the inclusion of additional parameters in the analysis, possibly as a composite outcome. This would involve integrating the oxygen desaturation profile, dyspnea scores, and heart rate recovery with changes in the 6MWT-distance. They propose this composite measure could serve as a primary endpoint when the study intervention’s impact on clinical performance – either improvement or stabilization of ILD or ILD-related PH – is clearly defined. The prognostic significance of these additional parameters in patients with ILD, however, requires further investigation.
Inter-test reliability requires a standardized 6MWT, as previously proposed for this population (Lancaster, et al. Contemporary Clin Trials. 2021;Nov 25,2020). The standardized test protocol that includes continuous pulse oximetry and heart rate measurement, oxygen titration, and end of test guidelines, will reduce variability and boost reproducibility.
In light of recent advancements in the affordability, convenience, and portability of oxygen consumption (VO2) gas analyzers, we believe that incorporating V
Ruchicka Sangani, MD, Section Fellow-in-Training
Saqib Baig, MD, Section Member-at-Large
Diffuse Lung & Transplant Network
Pulmonary Physiology & Rehabilitation Section
Pulmonary arterial hypertension (PH) and more recently interstitial lung disease (ILD) trials use the 6-minute walk test (6MWT) as a primary outcome due to its ability to conveniently capture a patient’s functional capacity and quality of life. However, interpreting the 6MWT in complex and diverse diseases, such as ILD, presents significant challenges.
A recent article (Harari, et al. Eur Respir Rev. 2022 Aug 23;31(165):220087. doi: 10.1183/16000617.0087-2022) advocates for further research to determine the optimal use of the 6MWT as a clinical endpoint in ILD trials. A decline in 6MWT can represent progression of ILD; ILD-related PH; or musculoskeletal, hematologic, or cardiac etiologies related to the underlying cause of ILD.
To enhance sensitivity, the authors endorse the inclusion of additional parameters in the analysis, possibly as a composite outcome. This would involve integrating the oxygen desaturation profile, dyspnea scores, and heart rate recovery with changes in the 6MWT-distance. They propose this composite measure could serve as a primary endpoint when the study intervention’s impact on clinical performance – either improvement or stabilization of ILD or ILD-related PH – is clearly defined. The prognostic significance of these additional parameters in patients with ILD, however, requires further investigation.
Inter-test reliability requires a standardized 6MWT, as previously proposed for this population (Lancaster, et al. Contemporary Clin Trials. 2021;Nov 25,2020). The standardized test protocol that includes continuous pulse oximetry and heart rate measurement, oxygen titration, and end of test guidelines, will reduce variability and boost reproducibility.
In light of recent advancements in the affordability, convenience, and portability of oxygen consumption (VO2) gas analyzers, we believe that incorporating V
Ruchicka Sangani, MD, Section Fellow-in-Training
Saqib Baig, MD, Section Member-at-Large
Now we have MERCY
Critical Care Network
Sepsis/Shock Section
Beta-lactam antibiotics, including penicillin, carbapenems, and cephalosporins, exhibit time-dependent bacterial eradication. Prolonged infusions are thought to enhance the duration of effective bactericidal antibiotic exposure, decreasing the emergence of drug resistance due to reduced bacterial regrowth between doses – which may lead to cost savings by reducing drug acquisition costs and shortening hospital stays (Lodise TP Jr, et al. Clin Infect Dis. 2007;44[3]:357-63).
The best evidence for these benefits comes from observational studies and meta-analyses. The Defining Antibiotic Levels in Intensive Care Unit Patients (DALI) study emphasized the correlation between achieving target concentrations of beta-lactam antibiotics in critically ill patients and positive clinical outcomes for bloodstream infections but not for lung or intra-abdominal infections (Roberts JA, et al. Clin Infect Dis. 2014;58[8]:1072-83). A meta-analysis of 29 studies suggested that prolonged infusion of piperacillin-tazobactam was associated with a mortality benefit compared with intermittent infusions, but prolonged infusions of cephalosporins or carbapenems resulted in comparable outcomes without mortality benefit (Teo J, et al. Int J Antimicrob Agents. 2014;43[5]:403-11).
MERCY was a multinational, randomized controlled trial investigating the efficacy of continuous vs intermittent administration of meropenem in critically ill patients with sepsis. The primary outcome, a composite of mortality and emergence of resistant bacteria at day 28, showed no significant difference between continuous and intermittent administration (47% vs. 49%). Secondary outcomes and adverse events also did not display significant differences, suggesting that continuous meropenem did not improve outcomes compared with intermittent administration (Monti G, et al. JAMA. 2023;330[2]:141-51).
MERCY adds to the existing body of evidence suggesting that prolonged and intermittent infusion strategies for meropenem are at least equivalent in efficacy. Therefore, the strategy chosen can depend on other individualized factors.
The views expressed are those of the authors and do not reflect the official policy or position of the U.S. Navy, Department of Defense, or the US Government.
Meredith L. Olsen, MD, Section Member-at-Large
Casey Cable, MD, FCCP, Section Member-at-Large
Kathryn Pendleton, MD, FCCP, Section Vice-Chair
Critical Care Network
Sepsis/Shock Section
Beta-lactam antibiotics, including penicillin, carbapenems, and cephalosporins, exhibit time-dependent bacterial eradication. Prolonged infusions are thought to enhance the duration of effective bactericidal antibiotic exposure, decreasing the emergence of drug resistance due to reduced bacterial regrowth between doses – which may lead to cost savings by reducing drug acquisition costs and shortening hospital stays (Lodise TP Jr, et al. Clin Infect Dis. 2007;44[3]:357-63).
The best evidence for these benefits comes from observational studies and meta-analyses. The Defining Antibiotic Levels in Intensive Care Unit Patients (DALI) study emphasized the correlation between achieving target concentrations of beta-lactam antibiotics in critically ill patients and positive clinical outcomes for bloodstream infections but not for lung or intra-abdominal infections (Roberts JA, et al. Clin Infect Dis. 2014;58[8]:1072-83). A meta-analysis of 29 studies suggested that prolonged infusion of piperacillin-tazobactam was associated with a mortality benefit compared with intermittent infusions, but prolonged infusions of cephalosporins or carbapenems resulted in comparable outcomes without mortality benefit (Teo J, et al. Int J Antimicrob Agents. 2014;43[5]:403-11).
MERCY was a multinational, randomized controlled trial investigating the efficacy of continuous vs intermittent administration of meropenem in critically ill patients with sepsis. The primary outcome, a composite of mortality and emergence of resistant bacteria at day 28, showed no significant difference between continuous and intermittent administration (47% vs. 49%). Secondary outcomes and adverse events also did not display significant differences, suggesting that continuous meropenem did not improve outcomes compared with intermittent administration (Monti G, et al. JAMA. 2023;330[2]:141-51).
MERCY adds to the existing body of evidence suggesting that prolonged and intermittent infusion strategies for meropenem are at least equivalent in efficacy. Therefore, the strategy chosen can depend on other individualized factors.
The views expressed are those of the authors and do not reflect the official policy or position of the U.S. Navy, Department of Defense, or the US Government.
Meredith L. Olsen, MD, Section Member-at-Large
Casey Cable, MD, FCCP, Section Member-at-Large
Kathryn Pendleton, MD, FCCP, Section Vice-Chair
Critical Care Network
Sepsis/Shock Section
Beta-lactam antibiotics, including penicillin, carbapenems, and cephalosporins, exhibit time-dependent bacterial eradication. Prolonged infusions are thought to enhance the duration of effective bactericidal antibiotic exposure, decreasing the emergence of drug resistance due to reduced bacterial regrowth between doses – which may lead to cost savings by reducing drug acquisition costs and shortening hospital stays (Lodise TP Jr, et al. Clin Infect Dis. 2007;44[3]:357-63).
The best evidence for these benefits comes from observational studies and meta-analyses. The Defining Antibiotic Levels in Intensive Care Unit Patients (DALI) study emphasized the correlation between achieving target concentrations of beta-lactam antibiotics in critically ill patients and positive clinical outcomes for bloodstream infections but not for lung or intra-abdominal infections (Roberts JA, et al. Clin Infect Dis. 2014;58[8]:1072-83). A meta-analysis of 29 studies suggested that prolonged infusion of piperacillin-tazobactam was associated with a mortality benefit compared with intermittent infusions, but prolonged infusions of cephalosporins or carbapenems resulted in comparable outcomes without mortality benefit (Teo J, et al. Int J Antimicrob Agents. 2014;43[5]:403-11).
MERCY was a multinational, randomized controlled trial investigating the efficacy of continuous vs intermittent administration of meropenem in critically ill patients with sepsis. The primary outcome, a composite of mortality and emergence of resistant bacteria at day 28, showed no significant difference between continuous and intermittent administration (47% vs. 49%). Secondary outcomes and adverse events also did not display significant differences, suggesting that continuous meropenem did not improve outcomes compared with intermittent administration (Monti G, et al. JAMA. 2023;330[2]:141-51).
MERCY adds to the existing body of evidence suggesting that prolonged and intermittent infusion strategies for meropenem are at least equivalent in efficacy. Therefore, the strategy chosen can depend on other individualized factors.
The views expressed are those of the authors and do not reflect the official policy or position of the U.S. Navy, Department of Defense, or the US Government.
Meredith L. Olsen, MD, Section Member-at-Large
Casey Cable, MD, FCCP, Section Member-at-Large
Kathryn Pendleton, MD, FCCP, Section Vice-Chair
Home oxygen therapy: What does the data show?
Inhalers, nebulizers, antibiotics, and steroids – these are some of the most common tools in our pulmonary arsenal that we deploy on a daily basis. But, there is no treatment more fundamental to a pulmonary practitioner than oxygen. So how is it that something that naturally occurs and comprises 21% of ambient air has become so medicalized?
It is difficult (perhaps impossible) to find a pulmonologist or a hospitalist who has not included the phrase “obtain ambulatory saturation to qualify the patient for home oxygen” in at least one of their progress notes on a daily basis. Chronic obstructive pulmonary disease (COPD) is the most common reason for the prescription of long-term oxygen therapy (LTOT), a large industry tightly regulated by the Centers for Medicare & Medicaid Services (CMS).
The evidence for the use of LTOT in patients with COPD dates back to two seminal papers published in 1980 and 1981. The British Medical Research Council Working Party conducted the BMRC trial, in which 87 patients with a Pa
Another study published around the same time, the Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease (NOTT) trial (Ann Intern Med. 1980;93[3]:391-8) directly compared continuous 24-hour to nocturnal home oxygen therapy in patients with COPD and severe hypoxemia with a Pa
Afterward, it became universally accepted dogma that patients with COPD and severe hypoxemia stood to substantially benefit from LTOT. For years, it was the only therapy associated with a mortality reduction. The LOTT study (Albert RK, et al. N Engl J Med. 2016;375[17]:1617-27) included 768 patients with stable COPD and a resting or nocturnal Sp
The INOX (Lacasse Y, et al. N Engl J Med. 2020;383[12]:1129-38) trial, in which 243 patients with oxygen saturation less than 90% for at least 30% of the night were assigned to receive nocturnal vs sham oxygen, found similar results. There was no difference in the composite outcome of all-cause mortality and progression to 24-7 oxygen requirement (according to the criteria originally defined by NOTT). A 2022 systematic review and meta-analysis including six studies designed to assess the role of LTOT in patients with COPD and moderate desaturation, including LOTT and INOX, found no benefit to providing LTOT (Lacasse Y, et al. Lancet Respir Med. 2022;10[11]:1029-37).
Based on these studies, a resting Sp
COPD management has changed significantly in the 40 years since NOTT was published. In the early 1980s, standard of care included an inhaled beta-agonist and oral theophylline. We now prescribe a regimen of modern-day inhaler combinations, which can lead to a mortality benefit in the correct population. Additionally, rates of smoking are markedly lower now than they were in 1980. In the Minnesota Heart Survey, the prevalence of being an ever-smoking man or woman in 1980 compared with 2009 dropped from 71.6% and 54.7% to 44.2% and 39.6%, respectively (Filion KB, et al. Am J Public Health. 2012;102[4]:705-13). Treatment of common comorbid conditions has also dramatically improved.
A report containing all fee-for-service data published in 2021 by CMS reported oxygen therapy accounted for 9.8% of all DME costs covered by CMS and totaled approximately $800,000,000 (Centers for Medicare & Medicaid Services. FFS Data. 2021. This represents a significant financial burden to our health system and government.
Two of the eligible groups per CMS (those with isolated ambulatory or nocturnal hypoxemia) do not benefit from LTOT in RCTs. The other two groups are eligible based on trial data from a small number of patients who were studied more than 40 years ago. These facts raise serious questions about the cost-efficacy of LTOT.
So where does this leave us?
There are significant barriers to repeating large randomized oxygen trials. Due to broad inclusion criteria for LTOT by CMS, there are undoubtedly many people prescribed LTOT for whom there is minimal to no benefit. Patients often feel restricted in their mobility and may feel isolated being tethered to medical equipment. It is good practice to think about LTOT the same way we do any other therapy we provide - as a medicine with associated risks, benefits, and costs.
Despite its ubiquity, oxygen remains an important therapeutic tool. Still, choosing wisely means recognizing that not all patients who qualify for LTOT by CMS criteria will benefit.
Drs. Kreisel and Sonti are with the Division of Pulmonary, Critical Care, and Sleep Medicine, MedStar Georgetown University Hospital, Washington, DC.
Inhalers, nebulizers, antibiotics, and steroids – these are some of the most common tools in our pulmonary arsenal that we deploy on a daily basis. But, there is no treatment more fundamental to a pulmonary practitioner than oxygen. So how is it that something that naturally occurs and comprises 21% of ambient air has become so medicalized?
It is difficult (perhaps impossible) to find a pulmonologist or a hospitalist who has not included the phrase “obtain ambulatory saturation to qualify the patient for home oxygen” in at least one of their progress notes on a daily basis. Chronic obstructive pulmonary disease (COPD) is the most common reason for the prescription of long-term oxygen therapy (LTOT), a large industry tightly regulated by the Centers for Medicare & Medicaid Services (CMS).
The evidence for the use of LTOT in patients with COPD dates back to two seminal papers published in 1980 and 1981. The British Medical Research Council Working Party conducted the BMRC trial, in which 87 patients with a Pa
Another study published around the same time, the Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease (NOTT) trial (Ann Intern Med. 1980;93[3]:391-8) directly compared continuous 24-hour to nocturnal home oxygen therapy in patients with COPD and severe hypoxemia with a Pa
Afterward, it became universally accepted dogma that patients with COPD and severe hypoxemia stood to substantially benefit from LTOT. For years, it was the only therapy associated with a mortality reduction. The LOTT study (Albert RK, et al. N Engl J Med. 2016;375[17]:1617-27) included 768 patients with stable COPD and a resting or nocturnal Sp
The INOX (Lacasse Y, et al. N Engl J Med. 2020;383[12]:1129-38) trial, in which 243 patients with oxygen saturation less than 90% for at least 30% of the night were assigned to receive nocturnal vs sham oxygen, found similar results. There was no difference in the composite outcome of all-cause mortality and progression to 24-7 oxygen requirement (according to the criteria originally defined by NOTT). A 2022 systematic review and meta-analysis including six studies designed to assess the role of LTOT in patients with COPD and moderate desaturation, including LOTT and INOX, found no benefit to providing LTOT (Lacasse Y, et al. Lancet Respir Med. 2022;10[11]:1029-37).
Based on these studies, a resting Sp
COPD management has changed significantly in the 40 years since NOTT was published. In the early 1980s, standard of care included an inhaled beta-agonist and oral theophylline. We now prescribe a regimen of modern-day inhaler combinations, which can lead to a mortality benefit in the correct population. Additionally, rates of smoking are markedly lower now than they were in 1980. In the Minnesota Heart Survey, the prevalence of being an ever-smoking man or woman in 1980 compared with 2009 dropped from 71.6% and 54.7% to 44.2% and 39.6%, respectively (Filion KB, et al. Am J Public Health. 2012;102[4]:705-13). Treatment of common comorbid conditions has also dramatically improved.
A report containing all fee-for-service data published in 2021 by CMS reported oxygen therapy accounted for 9.8% of all DME costs covered by CMS and totaled approximately $800,000,000 (Centers for Medicare & Medicaid Services. FFS Data. 2021. This represents a significant financial burden to our health system and government.
Two of the eligible groups per CMS (those with isolated ambulatory or nocturnal hypoxemia) do not benefit from LTOT in RCTs. The other two groups are eligible based on trial data from a small number of patients who were studied more than 40 years ago. These facts raise serious questions about the cost-efficacy of LTOT.
So where does this leave us?
There are significant barriers to repeating large randomized oxygen trials. Due to broad inclusion criteria for LTOT by CMS, there are undoubtedly many people prescribed LTOT for whom there is minimal to no benefit. Patients often feel restricted in their mobility and may feel isolated being tethered to medical equipment. It is good practice to think about LTOT the same way we do any other therapy we provide - as a medicine with associated risks, benefits, and costs.
Despite its ubiquity, oxygen remains an important therapeutic tool. Still, choosing wisely means recognizing that not all patients who qualify for LTOT by CMS criteria will benefit.
Drs. Kreisel and Sonti are with the Division of Pulmonary, Critical Care, and Sleep Medicine, MedStar Georgetown University Hospital, Washington, DC.
Inhalers, nebulizers, antibiotics, and steroids – these are some of the most common tools in our pulmonary arsenal that we deploy on a daily basis. But, there is no treatment more fundamental to a pulmonary practitioner than oxygen. So how is it that something that naturally occurs and comprises 21% of ambient air has become so medicalized?
It is difficult (perhaps impossible) to find a pulmonologist or a hospitalist who has not included the phrase “obtain ambulatory saturation to qualify the patient for home oxygen” in at least one of their progress notes on a daily basis. Chronic obstructive pulmonary disease (COPD) is the most common reason for the prescription of long-term oxygen therapy (LTOT), a large industry tightly regulated by the Centers for Medicare & Medicaid Services (CMS).
The evidence for the use of LTOT in patients with COPD dates back to two seminal papers published in 1980 and 1981. The British Medical Research Council Working Party conducted the BMRC trial, in which 87 patients with a Pa
Another study published around the same time, the Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease (NOTT) trial (Ann Intern Med. 1980;93[3]:391-8) directly compared continuous 24-hour to nocturnal home oxygen therapy in patients with COPD and severe hypoxemia with a Pa
Afterward, it became universally accepted dogma that patients with COPD and severe hypoxemia stood to substantially benefit from LTOT. For years, it was the only therapy associated with a mortality reduction. The LOTT study (Albert RK, et al. N Engl J Med. 2016;375[17]:1617-27) included 768 patients with stable COPD and a resting or nocturnal Sp
The INOX (Lacasse Y, et al. N Engl J Med. 2020;383[12]:1129-38) trial, in which 243 patients with oxygen saturation less than 90% for at least 30% of the night were assigned to receive nocturnal vs sham oxygen, found similar results. There was no difference in the composite outcome of all-cause mortality and progression to 24-7 oxygen requirement (according to the criteria originally defined by NOTT). A 2022 systematic review and meta-analysis including six studies designed to assess the role of LTOT in patients with COPD and moderate desaturation, including LOTT and INOX, found no benefit to providing LTOT (Lacasse Y, et al. Lancet Respir Med. 2022;10[11]:1029-37).
Based on these studies, a resting Sp
COPD management has changed significantly in the 40 years since NOTT was published. In the early 1980s, standard of care included an inhaled beta-agonist and oral theophylline. We now prescribe a regimen of modern-day inhaler combinations, which can lead to a mortality benefit in the correct population. Additionally, rates of smoking are markedly lower now than they were in 1980. In the Minnesota Heart Survey, the prevalence of being an ever-smoking man or woman in 1980 compared with 2009 dropped from 71.6% and 54.7% to 44.2% and 39.6%, respectively (Filion KB, et al. Am J Public Health. 2012;102[4]:705-13). Treatment of common comorbid conditions has also dramatically improved.
A report containing all fee-for-service data published in 2021 by CMS reported oxygen therapy accounted for 9.8% of all DME costs covered by CMS and totaled approximately $800,000,000 (Centers for Medicare & Medicaid Services. FFS Data. 2021. This represents a significant financial burden to our health system and government.
Two of the eligible groups per CMS (those with isolated ambulatory or nocturnal hypoxemia) do not benefit from LTOT in RCTs. The other two groups are eligible based on trial data from a small number of patients who were studied more than 40 years ago. These facts raise serious questions about the cost-efficacy of LTOT.
So where does this leave us?
There are significant barriers to repeating large randomized oxygen trials. Due to broad inclusion criteria for LTOT by CMS, there are undoubtedly many people prescribed LTOT for whom there is minimal to no benefit. Patients often feel restricted in their mobility and may feel isolated being tethered to medical equipment. It is good practice to think about LTOT the same way we do any other therapy we provide - as a medicine with associated risks, benefits, and costs.
Despite its ubiquity, oxygen remains an important therapeutic tool. Still, choosing wisely means recognizing that not all patients who qualify for LTOT by CMS criteria will benefit.
Drs. Kreisel and Sonti are with the Division of Pulmonary, Critical Care, and Sleep Medicine, MedStar Georgetown University Hospital, Washington, DC.
Environmental and occupational risk factors for lung cancer
Thoracic Oncology And Chest Imaging Network
Lung Cancer Section
Lung cancer is the third most prevalent cancer in United States, with the highest mortality (Oliver, 2022)(Siegel et al, 2023). The factors contributing to its occurrence have become more complex due to increased industrialization and worsening environmental pollution. Air pollution is a well-established environmental risk factor for lung cancer (Lu et al. 2019). On average, a full-time worker spends around 90,000 hours at work over their lifetime. It is crucial to control environmental and occupational exposures to decrease the risk of developing lung cancer. Occupations like asbestos-related work, mining, and transportation are well-known to be at risk for lung cancer (Li et al. 2021). With worsening air pollution, occupations such as firefighters, outdoor delivery workers, and forest rangers are facing an increased risk as well. Many of these carcinogens independently increase lung cancer risk (Li et al. 2021). Smoking combined with these exposures, causes a synergistic effect on lung cancer incidence. They also have a cell subtype differential risk favoring squamous and small cell lung cancer (Christiani, 2020). It is essential for workers in these high-risk occupations to use proper PPE, have regular check-ups and screenings and follow occupational safety regulations and guidelines. As air pollution continues to worsen, individuals living in these areas should reduce outdoor activities during AQI alerts, and use air purifiers and masks. Public health efforts to decrease air pollution with cleaner transportation and energy production, and better local and national air quality regulations will decrease risk in the general population (Rice et al. 2021).
Amaraja Kanitkar, MD, MBBSGuest Author
References
Christiani DC. Occupational exposures and lung cancer. Am J Respir Crit Care Med. 2020;202(3):317-19.
Li N, et al. Association of 13 occupational carcinogens in patients with cancer, individually and collectively, 1990-2017. JAMA Netw Open. 2021;4(2):e2037530.
Lu T, et al. Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades. Cancer Manag Res. 2019;11:943-53.
Oliver AL. Lung cancer: Epidemiology and screening. Surg Clin North Am. 2022;102(3):335-44.
Rice MB, et al. Respiratory impacts of wildland fire smoke: Future challenges and policy opportunities an official American thoracic society workshop report. Ann Am Thorac Soc. 2021;18(6):921-30.
Siegel RL, et al. Cancer statistics: 2023. CA Cancer J Clin. 2023;73(1):17-48.
Thoracic Oncology And Chest Imaging Network
Lung Cancer Section
Lung cancer is the third most prevalent cancer in United States, with the highest mortality (Oliver, 2022)(Siegel et al, 2023). The factors contributing to its occurrence have become more complex due to increased industrialization and worsening environmental pollution. Air pollution is a well-established environmental risk factor for lung cancer (Lu et al. 2019). On average, a full-time worker spends around 90,000 hours at work over their lifetime. It is crucial to control environmental and occupational exposures to decrease the risk of developing lung cancer. Occupations like asbestos-related work, mining, and transportation are well-known to be at risk for lung cancer (Li et al. 2021). With worsening air pollution, occupations such as firefighters, outdoor delivery workers, and forest rangers are facing an increased risk as well. Many of these carcinogens independently increase lung cancer risk (Li et al. 2021). Smoking combined with these exposures, causes a synergistic effect on lung cancer incidence. They also have a cell subtype differential risk favoring squamous and small cell lung cancer (Christiani, 2020). It is essential for workers in these high-risk occupations to use proper PPE, have regular check-ups and screenings and follow occupational safety regulations and guidelines. As air pollution continues to worsen, individuals living in these areas should reduce outdoor activities during AQI alerts, and use air purifiers and masks. Public health efforts to decrease air pollution with cleaner transportation and energy production, and better local and national air quality regulations will decrease risk in the general population (Rice et al. 2021).
Amaraja Kanitkar, MD, MBBSGuest Author
References
Christiani DC. Occupational exposures and lung cancer. Am J Respir Crit Care Med. 2020;202(3):317-19.
Li N, et al. Association of 13 occupational carcinogens in patients with cancer, individually and collectively, 1990-2017. JAMA Netw Open. 2021;4(2):e2037530.
Lu T, et al. Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades. Cancer Manag Res. 2019;11:943-53.
Oliver AL. Lung cancer: Epidemiology and screening. Surg Clin North Am. 2022;102(3):335-44.
Rice MB, et al. Respiratory impacts of wildland fire smoke: Future challenges and policy opportunities an official American thoracic society workshop report. Ann Am Thorac Soc. 2021;18(6):921-30.
Siegel RL, et al. Cancer statistics: 2023. CA Cancer J Clin. 2023;73(1):17-48.
Thoracic Oncology And Chest Imaging Network
Lung Cancer Section
Lung cancer is the third most prevalent cancer in United States, with the highest mortality (Oliver, 2022)(Siegel et al, 2023). The factors contributing to its occurrence have become more complex due to increased industrialization and worsening environmental pollution. Air pollution is a well-established environmental risk factor for lung cancer (Lu et al. 2019). On average, a full-time worker spends around 90,000 hours at work over their lifetime. It is crucial to control environmental and occupational exposures to decrease the risk of developing lung cancer. Occupations like asbestos-related work, mining, and transportation are well-known to be at risk for lung cancer (Li et al. 2021). With worsening air pollution, occupations such as firefighters, outdoor delivery workers, and forest rangers are facing an increased risk as well. Many of these carcinogens independently increase lung cancer risk (Li et al. 2021). Smoking combined with these exposures, causes a synergistic effect on lung cancer incidence. They also have a cell subtype differential risk favoring squamous and small cell lung cancer (Christiani, 2020). It is essential for workers in these high-risk occupations to use proper PPE, have regular check-ups and screenings and follow occupational safety regulations and guidelines. As air pollution continues to worsen, individuals living in these areas should reduce outdoor activities during AQI alerts, and use air purifiers and masks. Public health efforts to decrease air pollution with cleaner transportation and energy production, and better local and national air quality regulations will decrease risk in the general population (Rice et al. 2021).
Amaraja Kanitkar, MD, MBBSGuest Author
References
Christiani DC. Occupational exposures and lung cancer. Am J Respir Crit Care Med. 2020;202(3):317-19.
Li N, et al. Association of 13 occupational carcinogens in patients with cancer, individually and collectively, 1990-2017. JAMA Netw Open. 2021;4(2):e2037530.
Lu T, et al. Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades. Cancer Manag Res. 2019;11:943-53.
Oliver AL. Lung cancer: Epidemiology and screening. Surg Clin North Am. 2022;102(3):335-44.
Rice MB, et al. Respiratory impacts of wildland fire smoke: Future challenges and policy opportunities an official American thoracic society workshop report. Ann Am Thorac Soc. 2021;18(6):921-30.
Siegel RL, et al. Cancer statistics: 2023. CA Cancer J Clin. 2023;73(1):17-48.
PalliPulm: Time to expand our arsenal
Critical Care Network
Palliative and End-of-Life Section
Symptoms at the end of life in patients with COPD are just as severe as in patients with advanced cancer (Solano JP, et al. J Pain Symptom Manage. 2006;31[1]:58-69). However, despite the high symptom burden, palliative care is less common in patients with COPD (Gore J, et al. Thorax. 2000;55[12]:1000-6).
Palliative care is associated with a number of benefits, including improved symptom burden, quality of life, and patient satisfaction (Vermylen JH, et al. Int J Chron Obstruct Pulmon Dis. 2015;10:1543-51). The majority of pulmonologists report that palliative care for patients with COPD is desirable, but about half of pulmonologists indicate that they do not use the palliative care guidelines and many were not even aware they existed (Duenk RG, et al. Int J Chron Obstruct Pulmon Dis. 2017;12:299-311). Patients with COPD often have unmet needs, and the majority of patients with COPD do not have access to palliative care at their end of life (Gore JM, et al). Unfortunately, the supply of palliative care specialists is too low to meet demand, especially in outpatient settings (Kamal AH, et al. Am J Med. 2017;130:113-4).
The ATS released a multisociety policy statement in 2022 that established a framework for early palliative care in the care in patients with respiratory illnesses (Sullivan DR, et al. Am J Respir Crit Care Med. 2022;206[6]:e44-e69). However, given the paucity of specialists and the aging population, the needs of patients and their loved ones cannot be met exclusively by palliative care specialists. Pulmonologists must expand their practice to include guideline-based palliative care in order to truly serve our patients to the best of our abilities. It is incumbent on training programs to train future pulmonologists with these palliative skills, and upon medical organizations to supply time and resources to ensure the pulmonologist is able to use these skills.
Gretchen Winter, MD
Section Member-at-Large
Critical Care Network
Palliative and End-of-Life Section
Symptoms at the end of life in patients with COPD are just as severe as in patients with advanced cancer (Solano JP, et al. J Pain Symptom Manage. 2006;31[1]:58-69). However, despite the high symptom burden, palliative care is less common in patients with COPD (Gore J, et al. Thorax. 2000;55[12]:1000-6).
Palliative care is associated with a number of benefits, including improved symptom burden, quality of life, and patient satisfaction (Vermylen JH, et al. Int J Chron Obstruct Pulmon Dis. 2015;10:1543-51). The majority of pulmonologists report that palliative care for patients with COPD is desirable, but about half of pulmonologists indicate that they do not use the palliative care guidelines and many were not even aware they existed (Duenk RG, et al. Int J Chron Obstruct Pulmon Dis. 2017;12:299-311). Patients with COPD often have unmet needs, and the majority of patients with COPD do not have access to palliative care at their end of life (Gore JM, et al). Unfortunately, the supply of palliative care specialists is too low to meet demand, especially in outpatient settings (Kamal AH, et al. Am J Med. 2017;130:113-4).
The ATS released a multisociety policy statement in 2022 that established a framework for early palliative care in the care in patients with respiratory illnesses (Sullivan DR, et al. Am J Respir Crit Care Med. 2022;206[6]:e44-e69). However, given the paucity of specialists and the aging population, the needs of patients and their loved ones cannot be met exclusively by palliative care specialists. Pulmonologists must expand their practice to include guideline-based palliative care in order to truly serve our patients to the best of our abilities. It is incumbent on training programs to train future pulmonologists with these palliative skills, and upon medical organizations to supply time and resources to ensure the pulmonologist is able to use these skills.
Gretchen Winter, MD
Section Member-at-Large
Critical Care Network
Palliative and End-of-Life Section
Symptoms at the end of life in patients with COPD are just as severe as in patients with advanced cancer (Solano JP, et al. J Pain Symptom Manage. 2006;31[1]:58-69). However, despite the high symptom burden, palliative care is less common in patients with COPD (Gore J, et al. Thorax. 2000;55[12]:1000-6).
Palliative care is associated with a number of benefits, including improved symptom burden, quality of life, and patient satisfaction (Vermylen JH, et al. Int J Chron Obstruct Pulmon Dis. 2015;10:1543-51). The majority of pulmonologists report that palliative care for patients with COPD is desirable, but about half of pulmonologists indicate that they do not use the palliative care guidelines and many were not even aware they existed (Duenk RG, et al. Int J Chron Obstruct Pulmon Dis. 2017;12:299-311). Patients with COPD often have unmet needs, and the majority of patients with COPD do not have access to palliative care at their end of life (Gore JM, et al). Unfortunately, the supply of palliative care specialists is too low to meet demand, especially in outpatient settings (Kamal AH, et al. Am J Med. 2017;130:113-4).
The ATS released a multisociety policy statement in 2022 that established a framework for early palliative care in the care in patients with respiratory illnesses (Sullivan DR, et al. Am J Respir Crit Care Med. 2022;206[6]:e44-e69). However, given the paucity of specialists and the aging population, the needs of patients and their loved ones cannot be met exclusively by palliative care specialists. Pulmonologists must expand their practice to include guideline-based palliative care in order to truly serve our patients to the best of our abilities. It is incumbent on training programs to train future pulmonologists with these palliative skills, and upon medical organizations to supply time and resources to ensure the pulmonologist is able to use these skills.
Gretchen Winter, MD
Section Member-at-Large
Hot or cold – impact on asthma and COPD
Airways Disorders Network
Asthma & COPD Section
Earlier works investigating effects of temperature and humidity changes on the airway in patients with asthma are insightful (Strauss, et al. 1978). Heat can irritate asthmatic airways that are already hyperreactive. Cold air can remove airway moisture. Similar mechanisms with warm/hot air can affect airway inflammation in COPD. In addition, poor air quality often occurs during extreme heat events and can affect patients with COPD.
Seasonal variation in COPD exacerbations was demonstrated by the TORCH study, where a two-fold increase in COPD exacerbations and hospitalizations was noted during the winter months in both northern and southern regions of the world. This trend was not observed in tropical countries with average annual temperatures of >18 °C (64 °F). Factors accounting for this variation may include greater risk of viral infections, increased host susceptibility, and more time spent indoors, along with impact of temperature variation on lung function (Jenkins, et al. 2012). This effect was accompanied by variation in the treatment choices with antibiotics alone or in combination with steroids. A trend towards combined antibiotics and steroids was noted during winters.
Ideal conditions for patients with COPD to minimize risk for exacerbation would be home humidity between 30% and 50% with indoor temperature of 21°C at least 9 hours per day in living areas (Osman, et al. 2008).
Outdoor activities during extreme temperatures should be avoided. Air conditioning and/or humidifiers can be helpful in modifying influences.
Maria Azhar, MD
Section Fellow-in-Training
Richard George Barbers, MD, FCCP
Section Chair
References
Jenkins CR, et al. Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. Eur Respir J. 2012;39(1):38-45.
Osman LM, et al. Home warmth and health status of COPD patients. Eur J Public Health. 2008;18(4):399-405.
Strauss RH, et al. Influence of heat and humidity on the airway obstruction induced by exercise in asthma. J Clin Invest. 1978;61(2):433-40.
Airways Disorders Network
Asthma & COPD Section
Earlier works investigating effects of temperature and humidity changes on the airway in patients with asthma are insightful (Strauss, et al. 1978). Heat can irritate asthmatic airways that are already hyperreactive. Cold air can remove airway moisture. Similar mechanisms with warm/hot air can affect airway inflammation in COPD. In addition, poor air quality often occurs during extreme heat events and can affect patients with COPD.
Seasonal variation in COPD exacerbations was demonstrated by the TORCH study, where a two-fold increase in COPD exacerbations and hospitalizations was noted during the winter months in both northern and southern regions of the world. This trend was not observed in tropical countries with average annual temperatures of >18 °C (64 °F). Factors accounting for this variation may include greater risk of viral infections, increased host susceptibility, and more time spent indoors, along with impact of temperature variation on lung function (Jenkins, et al. 2012). This effect was accompanied by variation in the treatment choices with antibiotics alone or in combination with steroids. A trend towards combined antibiotics and steroids was noted during winters.
Ideal conditions for patients with COPD to minimize risk for exacerbation would be home humidity between 30% and 50% with indoor temperature of 21°C at least 9 hours per day in living areas (Osman, et al. 2008).
Outdoor activities during extreme temperatures should be avoided. Air conditioning and/or humidifiers can be helpful in modifying influences.
Maria Azhar, MD
Section Fellow-in-Training
Richard George Barbers, MD, FCCP
Section Chair
References
Jenkins CR, et al. Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. Eur Respir J. 2012;39(1):38-45.
Osman LM, et al. Home warmth and health status of COPD patients. Eur J Public Health. 2008;18(4):399-405.
Strauss RH, et al. Influence of heat and humidity on the airway obstruction induced by exercise in asthma. J Clin Invest. 1978;61(2):433-40.
Airways Disorders Network
Asthma & COPD Section
Earlier works investigating effects of temperature and humidity changes on the airway in patients with asthma are insightful (Strauss, et al. 1978). Heat can irritate asthmatic airways that are already hyperreactive. Cold air can remove airway moisture. Similar mechanisms with warm/hot air can affect airway inflammation in COPD. In addition, poor air quality often occurs during extreme heat events and can affect patients with COPD.
Seasonal variation in COPD exacerbations was demonstrated by the TORCH study, where a two-fold increase in COPD exacerbations and hospitalizations was noted during the winter months in both northern and southern regions of the world. This trend was not observed in tropical countries with average annual temperatures of >18 °C (64 °F). Factors accounting for this variation may include greater risk of viral infections, increased host susceptibility, and more time spent indoors, along with impact of temperature variation on lung function (Jenkins, et al. 2012). This effect was accompanied by variation in the treatment choices with antibiotics alone or in combination with steroids. A trend towards combined antibiotics and steroids was noted during winters.
Ideal conditions for patients with COPD to minimize risk for exacerbation would be home humidity between 30% and 50% with indoor temperature of 21°C at least 9 hours per day in living areas (Osman, et al. 2008).
Outdoor activities during extreme temperatures should be avoided. Air conditioning and/or humidifiers can be helpful in modifying influences.
Maria Azhar, MD
Section Fellow-in-Training
Richard George Barbers, MD, FCCP
Section Chair
References
Jenkins CR, et al. Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. Eur Respir J. 2012;39(1):38-45.
Osman LM, et al. Home warmth and health status of COPD patients. Eur J Public Health. 2008;18(4):399-405.
Strauss RH, et al. Influence of heat and humidity on the airway obstruction induced by exercise in asthma. J Clin Invest. 1978;61(2):433-40.
Implementing a hypoglossal nerve stimulation program in your sleep practice
It is estimated that almost one billion people globally are affected by obstructive sleep apnea (OSA) (Benjafield A, et al. Lancet Respir Med. 2019;7[8]:687-98). Despite such high prevalence, the treatment options for OSA are somewhat limited. As per certain estimates, nearly 50% of CPAP users discontinue treatment by the fifth year (Schoch O, et al. Respiration. 2014;87[2]:121-8). Furthermore, alternative options such as mandibular advancement devices, positional therapy, weight loss, and maxillofacial or palate surgery, also have unique challenges and limitations.
First described in 2001, hypoglossal nerve stimulation (HGNS) is a relatively new and emerging technology for the treatment of OSA (Schwartz A, et al. Arch Otolaryngol Head Neck Surg. 2001 Oct;127[10]:1216-23). HGNS therapy was approved by the Food and Drug Administration in 2014 for the treatment of moderate to severe OSA. The therapy involves surgical implantation of the HGNS device, optimization of device settings, and evaluation for treatment response. A physician-led multidisciplinary Hypoglossal Nerve Stimulation Clinic involves collaboration from essential stakeholders, most importantly sleep medicine providers, clinic staff, sleep technologists, and ENT sleep surgeons. Goals of the multidisciplinary program are to ensure timely follow-up, optimization of device settings, and maximizing treatment efficacy. This review describes steps involved in developing a successful multidisciplinary HGNS program within a sleep medicine practice.
Patient selection and evaluation
There is growing interest in HGNS relative to conventional CPAP therapy, with many patients presenting to clinic to inquire about this therapy. However, not all patients are candidates for HGNS therapy. Prioritizing appropriate patient selection and education are key first steps. The initial assessments usually occur with a sleep medicine specialist. It begins with confirmation of the diagnosis of OSA in all patients and a concerted effort to troubleshoot and address any barriers to CPAP use before consideration of surgery. Patients who are unwilling to use or unable to tolerate CPAP therapy undergo further evaluation for HGNS therapy. It is important to ensure that patients are also screened for other sleep disorders, such as insomnia or restless leg syndrome, to rule out its contribution to daytime (or nighttime) symptoms.
Other salient inclusion criteria include an apnea-hypopnea index (AHI) between 15-100 events per hour (previously 65), at least 18 years of age, and a body mass index (BMI) less than 40 kg/m2 (previously 32). Qualifying patients undergo an updated polysomnography if a recent study is not available. If the polysomnography reveals central and mixed apneas comprising less than 25 percent of the total AHI, patients are referred to ENT Sleep Surgery, and drug-induced sleep endoscopy is offered to examine upper airway anatomy. When a complete concentric collapse of the soft palate is seen on drug-induced sleep endoscopy, surgery is contraindicated. Prior palate surgery or maxillomandibular advancement (MMA) are not contraindications to HGNS therapy.
The patients receive comprehensive information on the nature of the surgery, expected recovery course, and device activation timeline. Perhaps most importantly, the patients receive structured education on HGNS therapy and potential outcomes to set realistic expectations. In the STAR trial, patients experienced a reduction in the AHI of approximately 70% (Strollo P, et al. N Engl J Med. 2014;370[2]:139-49). It is important to note that a response to therapy was defined as a reduction in the AHI by at least 50% and a value less than 20 events/hour (Strollo P, et al. Sleep. 2015;38[10]:1593-8). Therefore, patients who are expecting complete resolution of snoring and/or OSA may not be ideal candidates for surgery. Furthermore, patients who continue to experience fatigue and sleepiness on CPAP despite control of OSA may not experience amelioration of these symptoms with HGNS therapy.
Surgery and device management
The surgery, performed under general anesthesia, lasts approximately 3 hours, and may be followed by an overnight hospital stay depending on patient’s comorbidities. The device implantation involves placement of an implantable pulse generator (IPG) in the chest wall and leads to the hypoglossal nerve. The IPG is similar to a pacemaker and functions to stimulate the ipsilateral hypoglossal nerve innervating the tongue during sleep. The most common postoperative complications noted in the STAR trial data include incision site pain and swelling as well as temporary tongue weakness or paresthesia. Postoperative restrictions are minimal and include no heavy lifting for one month after surgery.
One week postsurgery, patients return to the ENT Sleep Surgery Clinic for follow-up, at which time the incisions as well as tongue strength and sensation are evaluated. In a subsequent visit between 4 and 6 weeks postsurgery, patients are evaluated in a joint Sleep Medicine and ENT clinic. They undergo device education and activation of the IPG using a dedicated programmer obtained from the device manufacturer. Device comfort features such as start delay and pause time are also programmed. Furthermore, appropriate tongue movement, lead placement, and voltage range settings are assessed during the visit. The ENT surgery team reevaluates the incision sites and assesses for tongue function and sensation. Patients are instructed to increase the voltage incrementally every week as tolerated with the goal of using the device nightly for the entirety of sleep. If patients tolerate the therapy well during the 2- to 3-month follow-up, a sleep study is scheduled to evaluate treatment effectiveness at the peak tolerable voltage. For those struggling with the therapy, adjustments to electrode configurations should be considered for pulse width, and rate. Occasionally, patients may require awake endoscopy and/or an advanced HGNS titration while asleep to determine the most appropriate settings to optimally control sleep apnea.
Until recently, patients implanted with an early version of the HGNS were limited to magnetic resonance imaging (MRI) scans of the head, neck, and extremities only. However, patients with the latest model IPGs can now undergo full-body MRI scans. It is important to note that the MRI’s Tesla cannot exceed 1.5T, necessitating specific imaging centers. Other constraints include the inability to adjust device settings remotely, which could mean long travel for minor setting adjustments such as altering start delay or pause times. Furthermore, provider education on operating and managing the device can be time consuming and may also be a barrier to implementation in a clinic. Also challenging may be the availability of an ENT surgery, which plays a critical role in the implantation of the devices and follow-up.
Currently, Inspire Medical Systems is the only FDA-approved hypoglossal nerve stimulation device available in the United States, and globally, more than 45,000 patients have been implanted. However, the field of neurostimulation is rapidly growing. Companies like LivaNova have secured Investigational Device Exemption for their HGNS device. The Genio system by Nyxoah is evaluating the use of bilateral hypoglossal nerve stimulation in patients with OSA and complete concentric collapse of the palate. A multidisciplinary Hypoglossal Nerve Stimulation Clinic is an important component of a comprehensive sleep medicine clinic for patient care and medical education. In the appropriate patient, this emerging technology may provide improvement in OSA severity and symptoms.
Dr. Gill is Clinical Associate Professor, Division of Sleep Medicine, Stanford (Calif.) University.
It is estimated that almost one billion people globally are affected by obstructive sleep apnea (OSA) (Benjafield A, et al. Lancet Respir Med. 2019;7[8]:687-98). Despite such high prevalence, the treatment options for OSA are somewhat limited. As per certain estimates, nearly 50% of CPAP users discontinue treatment by the fifth year (Schoch O, et al. Respiration. 2014;87[2]:121-8). Furthermore, alternative options such as mandibular advancement devices, positional therapy, weight loss, and maxillofacial or palate surgery, also have unique challenges and limitations.
First described in 2001, hypoglossal nerve stimulation (HGNS) is a relatively new and emerging technology for the treatment of OSA (Schwartz A, et al. Arch Otolaryngol Head Neck Surg. 2001 Oct;127[10]:1216-23). HGNS therapy was approved by the Food and Drug Administration in 2014 for the treatment of moderate to severe OSA. The therapy involves surgical implantation of the HGNS device, optimization of device settings, and evaluation for treatment response. A physician-led multidisciplinary Hypoglossal Nerve Stimulation Clinic involves collaboration from essential stakeholders, most importantly sleep medicine providers, clinic staff, sleep technologists, and ENT sleep surgeons. Goals of the multidisciplinary program are to ensure timely follow-up, optimization of device settings, and maximizing treatment efficacy. This review describes steps involved in developing a successful multidisciplinary HGNS program within a sleep medicine practice.
Patient selection and evaluation
There is growing interest in HGNS relative to conventional CPAP therapy, with many patients presenting to clinic to inquire about this therapy. However, not all patients are candidates for HGNS therapy. Prioritizing appropriate patient selection and education are key first steps. The initial assessments usually occur with a sleep medicine specialist. It begins with confirmation of the diagnosis of OSA in all patients and a concerted effort to troubleshoot and address any barriers to CPAP use before consideration of surgery. Patients who are unwilling to use or unable to tolerate CPAP therapy undergo further evaluation for HGNS therapy. It is important to ensure that patients are also screened for other sleep disorders, such as insomnia or restless leg syndrome, to rule out its contribution to daytime (or nighttime) symptoms.
Other salient inclusion criteria include an apnea-hypopnea index (AHI) between 15-100 events per hour (previously 65), at least 18 years of age, and a body mass index (BMI) less than 40 kg/m2 (previously 32). Qualifying patients undergo an updated polysomnography if a recent study is not available. If the polysomnography reveals central and mixed apneas comprising less than 25 percent of the total AHI, patients are referred to ENT Sleep Surgery, and drug-induced sleep endoscopy is offered to examine upper airway anatomy. When a complete concentric collapse of the soft palate is seen on drug-induced sleep endoscopy, surgery is contraindicated. Prior palate surgery or maxillomandibular advancement (MMA) are not contraindications to HGNS therapy.
The patients receive comprehensive information on the nature of the surgery, expected recovery course, and device activation timeline. Perhaps most importantly, the patients receive structured education on HGNS therapy and potential outcomes to set realistic expectations. In the STAR trial, patients experienced a reduction in the AHI of approximately 70% (Strollo P, et al. N Engl J Med. 2014;370[2]:139-49). It is important to note that a response to therapy was defined as a reduction in the AHI by at least 50% and a value less than 20 events/hour (Strollo P, et al. Sleep. 2015;38[10]:1593-8). Therefore, patients who are expecting complete resolution of snoring and/or OSA may not be ideal candidates for surgery. Furthermore, patients who continue to experience fatigue and sleepiness on CPAP despite control of OSA may not experience amelioration of these symptoms with HGNS therapy.
Surgery and device management
The surgery, performed under general anesthesia, lasts approximately 3 hours, and may be followed by an overnight hospital stay depending on patient’s comorbidities. The device implantation involves placement of an implantable pulse generator (IPG) in the chest wall and leads to the hypoglossal nerve. The IPG is similar to a pacemaker and functions to stimulate the ipsilateral hypoglossal nerve innervating the tongue during sleep. The most common postoperative complications noted in the STAR trial data include incision site pain and swelling as well as temporary tongue weakness or paresthesia. Postoperative restrictions are minimal and include no heavy lifting for one month after surgery.
One week postsurgery, patients return to the ENT Sleep Surgery Clinic for follow-up, at which time the incisions as well as tongue strength and sensation are evaluated. In a subsequent visit between 4 and 6 weeks postsurgery, patients are evaluated in a joint Sleep Medicine and ENT clinic. They undergo device education and activation of the IPG using a dedicated programmer obtained from the device manufacturer. Device comfort features such as start delay and pause time are also programmed. Furthermore, appropriate tongue movement, lead placement, and voltage range settings are assessed during the visit. The ENT surgery team reevaluates the incision sites and assesses for tongue function and sensation. Patients are instructed to increase the voltage incrementally every week as tolerated with the goal of using the device nightly for the entirety of sleep. If patients tolerate the therapy well during the 2- to 3-month follow-up, a sleep study is scheduled to evaluate treatment effectiveness at the peak tolerable voltage. For those struggling with the therapy, adjustments to electrode configurations should be considered for pulse width, and rate. Occasionally, patients may require awake endoscopy and/or an advanced HGNS titration while asleep to determine the most appropriate settings to optimally control sleep apnea.
Until recently, patients implanted with an early version of the HGNS were limited to magnetic resonance imaging (MRI) scans of the head, neck, and extremities only. However, patients with the latest model IPGs can now undergo full-body MRI scans. It is important to note that the MRI’s Tesla cannot exceed 1.5T, necessitating specific imaging centers. Other constraints include the inability to adjust device settings remotely, which could mean long travel for minor setting adjustments such as altering start delay or pause times. Furthermore, provider education on operating and managing the device can be time consuming and may also be a barrier to implementation in a clinic. Also challenging may be the availability of an ENT surgery, which plays a critical role in the implantation of the devices and follow-up.
Currently, Inspire Medical Systems is the only FDA-approved hypoglossal nerve stimulation device available in the United States, and globally, more than 45,000 patients have been implanted. However, the field of neurostimulation is rapidly growing. Companies like LivaNova have secured Investigational Device Exemption for their HGNS device. The Genio system by Nyxoah is evaluating the use of bilateral hypoglossal nerve stimulation in patients with OSA and complete concentric collapse of the palate. A multidisciplinary Hypoglossal Nerve Stimulation Clinic is an important component of a comprehensive sleep medicine clinic for patient care and medical education. In the appropriate patient, this emerging technology may provide improvement in OSA severity and symptoms.
Dr. Gill is Clinical Associate Professor, Division of Sleep Medicine, Stanford (Calif.) University.
It is estimated that almost one billion people globally are affected by obstructive sleep apnea (OSA) (Benjafield A, et al. Lancet Respir Med. 2019;7[8]:687-98). Despite such high prevalence, the treatment options for OSA are somewhat limited. As per certain estimates, nearly 50% of CPAP users discontinue treatment by the fifth year (Schoch O, et al. Respiration. 2014;87[2]:121-8). Furthermore, alternative options such as mandibular advancement devices, positional therapy, weight loss, and maxillofacial or palate surgery, also have unique challenges and limitations.
First described in 2001, hypoglossal nerve stimulation (HGNS) is a relatively new and emerging technology for the treatment of OSA (Schwartz A, et al. Arch Otolaryngol Head Neck Surg. 2001 Oct;127[10]:1216-23). HGNS therapy was approved by the Food and Drug Administration in 2014 for the treatment of moderate to severe OSA. The therapy involves surgical implantation of the HGNS device, optimization of device settings, and evaluation for treatment response. A physician-led multidisciplinary Hypoglossal Nerve Stimulation Clinic involves collaboration from essential stakeholders, most importantly sleep medicine providers, clinic staff, sleep technologists, and ENT sleep surgeons. Goals of the multidisciplinary program are to ensure timely follow-up, optimization of device settings, and maximizing treatment efficacy. This review describes steps involved in developing a successful multidisciplinary HGNS program within a sleep medicine practice.
Patient selection and evaluation
There is growing interest in HGNS relative to conventional CPAP therapy, with many patients presenting to clinic to inquire about this therapy. However, not all patients are candidates for HGNS therapy. Prioritizing appropriate patient selection and education are key first steps. The initial assessments usually occur with a sleep medicine specialist. It begins with confirmation of the diagnosis of OSA in all patients and a concerted effort to troubleshoot and address any barriers to CPAP use before consideration of surgery. Patients who are unwilling to use or unable to tolerate CPAP therapy undergo further evaluation for HGNS therapy. It is important to ensure that patients are also screened for other sleep disorders, such as insomnia or restless leg syndrome, to rule out its contribution to daytime (or nighttime) symptoms.
Other salient inclusion criteria include an apnea-hypopnea index (AHI) between 15-100 events per hour (previously 65), at least 18 years of age, and a body mass index (BMI) less than 40 kg/m2 (previously 32). Qualifying patients undergo an updated polysomnography if a recent study is not available. If the polysomnography reveals central and mixed apneas comprising less than 25 percent of the total AHI, patients are referred to ENT Sleep Surgery, and drug-induced sleep endoscopy is offered to examine upper airway anatomy. When a complete concentric collapse of the soft palate is seen on drug-induced sleep endoscopy, surgery is contraindicated. Prior palate surgery or maxillomandibular advancement (MMA) are not contraindications to HGNS therapy.
The patients receive comprehensive information on the nature of the surgery, expected recovery course, and device activation timeline. Perhaps most importantly, the patients receive structured education on HGNS therapy and potential outcomes to set realistic expectations. In the STAR trial, patients experienced a reduction in the AHI of approximately 70% (Strollo P, et al. N Engl J Med. 2014;370[2]:139-49). It is important to note that a response to therapy was defined as a reduction in the AHI by at least 50% and a value less than 20 events/hour (Strollo P, et al. Sleep. 2015;38[10]:1593-8). Therefore, patients who are expecting complete resolution of snoring and/or OSA may not be ideal candidates for surgery. Furthermore, patients who continue to experience fatigue and sleepiness on CPAP despite control of OSA may not experience amelioration of these symptoms with HGNS therapy.
Surgery and device management
The surgery, performed under general anesthesia, lasts approximately 3 hours, and may be followed by an overnight hospital stay depending on patient’s comorbidities. The device implantation involves placement of an implantable pulse generator (IPG) in the chest wall and leads to the hypoglossal nerve. The IPG is similar to a pacemaker and functions to stimulate the ipsilateral hypoglossal nerve innervating the tongue during sleep. The most common postoperative complications noted in the STAR trial data include incision site pain and swelling as well as temporary tongue weakness or paresthesia. Postoperative restrictions are minimal and include no heavy lifting for one month after surgery.
One week postsurgery, patients return to the ENT Sleep Surgery Clinic for follow-up, at which time the incisions as well as tongue strength and sensation are evaluated. In a subsequent visit between 4 and 6 weeks postsurgery, patients are evaluated in a joint Sleep Medicine and ENT clinic. They undergo device education and activation of the IPG using a dedicated programmer obtained from the device manufacturer. Device comfort features such as start delay and pause time are also programmed. Furthermore, appropriate tongue movement, lead placement, and voltage range settings are assessed during the visit. The ENT surgery team reevaluates the incision sites and assesses for tongue function and sensation. Patients are instructed to increase the voltage incrementally every week as tolerated with the goal of using the device nightly for the entirety of sleep. If patients tolerate the therapy well during the 2- to 3-month follow-up, a sleep study is scheduled to evaluate treatment effectiveness at the peak tolerable voltage. For those struggling with the therapy, adjustments to electrode configurations should be considered for pulse width, and rate. Occasionally, patients may require awake endoscopy and/or an advanced HGNS titration while asleep to determine the most appropriate settings to optimally control sleep apnea.
Until recently, patients implanted with an early version of the HGNS were limited to magnetic resonance imaging (MRI) scans of the head, neck, and extremities only. However, patients with the latest model IPGs can now undergo full-body MRI scans. It is important to note that the MRI’s Tesla cannot exceed 1.5T, necessitating specific imaging centers. Other constraints include the inability to adjust device settings remotely, which could mean long travel for minor setting adjustments such as altering start delay or pause times. Furthermore, provider education on operating and managing the device can be time consuming and may also be a barrier to implementation in a clinic. Also challenging may be the availability of an ENT surgery, which plays a critical role in the implantation of the devices and follow-up.
Currently, Inspire Medical Systems is the only FDA-approved hypoglossal nerve stimulation device available in the United States, and globally, more than 45,000 patients have been implanted. However, the field of neurostimulation is rapidly growing. Companies like LivaNova have secured Investigational Device Exemption for their HGNS device. The Genio system by Nyxoah is evaluating the use of bilateral hypoglossal nerve stimulation in patients with OSA and complete concentric collapse of the palate. A multidisciplinary Hypoglossal Nerve Stimulation Clinic is an important component of a comprehensive sleep medicine clinic for patient care and medical education. In the appropriate patient, this emerging technology may provide improvement in OSA severity and symptoms.
Dr. Gill is Clinical Associate Professor, Division of Sleep Medicine, Stanford (Calif.) University.
Sepsis-induced cardiomyopathy: Is it time to establish a standard of care?
Pulmonary Vascular & Cardiovascular Network
Cardiovascular Medicine and Surgery Section
Sepsis and septic shock still carry high morbidity and mortality in ICU patients despite recent improvements in care. Sepsis-induced cardiomyopathy (SICM), which complicates greater than 10% of sepsis and septic shock cases, carries a worse prognosis and is often underrecognized. Unfortunately, no universal definition of SICM exists, making diagnosis and evaluation of novel therapeutic options difficult. Initially described in the 1980s, common fundamental features of SICM include an acute and reversible decline in LVEF with typical resolution in days to weeks; RV, LV, or BiV dysfunction; LV dilation; diminished response to fluid resuscitation or catecholamines; and absence of acute coronary syndrome (L’Heureux, Sternberg et al, 2020). A definition of SICM based solely on LVEF is incomplete due to its reliance on cardiac loading conditions. Diagnostic advances using pulse contour analysis and echocardiographic measure of longitudinal strain hold promise in better characterizing cardiac dysfunction in sepsis (Beesley et al, 2018). SICM should further be distinguished from stress-induced cardiomyopathy or Takotsubo cardiomyopathy, which can also complicate cases of sepsis and is characterized by regional wall motion abnormalities, classically LV apical ballooning with preserved contractility of the basal segments. A movement toward a standard definition of SICM would allow a more rigorous evaluation of risk factors and future directions for therapy, including a potential role for mechanical circulatory support in patients who fail to improve with inotropic support.
Looking for more information on sepsis? Visit CHEST’s Sepsis Topic Collection Page at chestnet.org/Topic-Collections/Sepsis for research, infographics, and more developed by the CHEST Sepsis Resources Steering Committee.
Tarun Kapoor, MD: Section Fellow-in-Training
Andrew Petrilli, MD
Pulmonary Vascular & Cardiovascular Network
Cardiovascular Medicine and Surgery Section
Sepsis and septic shock still carry high morbidity and mortality in ICU patients despite recent improvements in care. Sepsis-induced cardiomyopathy (SICM), which complicates greater than 10% of sepsis and septic shock cases, carries a worse prognosis and is often underrecognized. Unfortunately, no universal definition of SICM exists, making diagnosis and evaluation of novel therapeutic options difficult. Initially described in the 1980s, common fundamental features of SICM include an acute and reversible decline in LVEF with typical resolution in days to weeks; RV, LV, or BiV dysfunction; LV dilation; diminished response to fluid resuscitation or catecholamines; and absence of acute coronary syndrome (L’Heureux, Sternberg et al, 2020). A definition of SICM based solely on LVEF is incomplete due to its reliance on cardiac loading conditions. Diagnostic advances using pulse contour analysis and echocardiographic measure of longitudinal strain hold promise in better characterizing cardiac dysfunction in sepsis (Beesley et al, 2018). SICM should further be distinguished from stress-induced cardiomyopathy or Takotsubo cardiomyopathy, which can also complicate cases of sepsis and is characterized by regional wall motion abnormalities, classically LV apical ballooning with preserved contractility of the basal segments. A movement toward a standard definition of SICM would allow a more rigorous evaluation of risk factors and future directions for therapy, including a potential role for mechanical circulatory support in patients who fail to improve with inotropic support.
Looking for more information on sepsis? Visit CHEST’s Sepsis Topic Collection Page at chestnet.org/Topic-Collections/Sepsis for research, infographics, and more developed by the CHEST Sepsis Resources Steering Committee.
Tarun Kapoor, MD: Section Fellow-in-Training
Andrew Petrilli, MD
Pulmonary Vascular & Cardiovascular Network
Cardiovascular Medicine and Surgery Section
Sepsis and septic shock still carry high morbidity and mortality in ICU patients despite recent improvements in care. Sepsis-induced cardiomyopathy (SICM), which complicates greater than 10% of sepsis and septic shock cases, carries a worse prognosis and is often underrecognized. Unfortunately, no universal definition of SICM exists, making diagnosis and evaluation of novel therapeutic options difficult. Initially described in the 1980s, common fundamental features of SICM include an acute and reversible decline in LVEF with typical resolution in days to weeks; RV, LV, or BiV dysfunction; LV dilation; diminished response to fluid resuscitation or catecholamines; and absence of acute coronary syndrome (L’Heureux, Sternberg et al, 2020). A definition of SICM based solely on LVEF is incomplete due to its reliance on cardiac loading conditions. Diagnostic advances using pulse contour analysis and echocardiographic measure of longitudinal strain hold promise in better characterizing cardiac dysfunction in sepsis (Beesley et al, 2018). SICM should further be distinguished from stress-induced cardiomyopathy or Takotsubo cardiomyopathy, which can also complicate cases of sepsis and is characterized by regional wall motion abnormalities, classically LV apical ballooning with preserved contractility of the basal segments. A movement toward a standard definition of SICM would allow a more rigorous evaluation of risk factors and future directions for therapy, including a potential role for mechanical circulatory support in patients who fail to improve with inotropic support.
Looking for more information on sepsis? Visit CHEST’s Sepsis Topic Collection Page at chestnet.org/Topic-Collections/Sepsis for research, infographics, and more developed by the CHEST Sepsis Resources Steering Committee.
Tarun Kapoor, MD: Section Fellow-in-Training
Andrew Petrilli, MD
Celebrating the inaugural issues of CHEST’s new open access journals
After much anticipation, the inaugural issues of both CHEST®Critical Care and CHEST®Pulmonary officially launched in late June. – promoting transparency, inclusiveness, and collaboration in research – and offer authors more avenues to share their practice-changing research.
The first issue of CHEST Critical Care featured research into ICU mortality across prepandemic and pandemic cohorts in resource-limited settings in South Africa, an exploration into symptom trajectory in recipients of hematopoietic stem-cell transplantation, a narrative review of post-intensive care syndrome, and an investigation into early echocardiographic and ultrasonographic findings in critically ill patients with COVID-19.
In addition, an editorial from Hayley Gershengorn, MD, Editor in Chief of CHEST Critical Care, offers readers more insights into the need for a publication focused on the breadth of clinical topics in critical care and her goals for the new publication.
“I’m ecstatic for this launch. We are grateful to our authors for the trust they put in us and are excited to share their work with our critical care colleagues around the world,” Dr. Gershengorn said. “The editorial team and the American College of Chest Physicians staff have worked tirelessly on this journal, and it’s incredibly gratifying to see the first issue publish.”
Read the full issue and new research from the journal at www.chestcc.org.
In his own editorial featured in the inaugural issue of CHEST Pulmonary, Editor in Chief Matthew Miles, MD, MEd, FCCP, shares how the flagship journal’s proud heritage of sharing impactful clinical research – and the need to target areas of pulmonary and sleep medicine research not covered by other journals – inspired the creation of this new publication.
The issue also includes research into mobile health opportunities for asthma management, an exploration into telemedicine for patients with interstitial lung diseases, an in-depth review into the rare and often underdiagnosed disorder primary ciliary dyskinesia, research on the impact of the social vulnerability index on pulmonary embolism mortality, and an investigation into pneumothorax complications after percutaneous lung biopsy.
“I am deeply grateful to our authors, reviewers, editorial board, and staff who have contributed to the launch of our first issue,” Dr. Miles said. “The journal CHEST is known for excellence in clinically relevant research and patient management guidance. CHEST Pulmonary expands the CHEST portfolio with additional opportunity for researchers to share their work in an exclusively open access format to reach the broadest possible audience. I know our readers will enjoy learning from the research and reviews in issue one.”
Review the full issue and new articles from CHEST Pulmonary at www.chestpulmonary.org.
After much anticipation, the inaugural issues of both CHEST®Critical Care and CHEST®Pulmonary officially launched in late June. – promoting transparency, inclusiveness, and collaboration in research – and offer authors more avenues to share their practice-changing research.
The first issue of CHEST Critical Care featured research into ICU mortality across prepandemic and pandemic cohorts in resource-limited settings in South Africa, an exploration into symptom trajectory in recipients of hematopoietic stem-cell transplantation, a narrative review of post-intensive care syndrome, and an investigation into early echocardiographic and ultrasonographic findings in critically ill patients with COVID-19.
In addition, an editorial from Hayley Gershengorn, MD, Editor in Chief of CHEST Critical Care, offers readers more insights into the need for a publication focused on the breadth of clinical topics in critical care and her goals for the new publication.
“I’m ecstatic for this launch. We are grateful to our authors for the trust they put in us and are excited to share their work with our critical care colleagues around the world,” Dr. Gershengorn said. “The editorial team and the American College of Chest Physicians staff have worked tirelessly on this journal, and it’s incredibly gratifying to see the first issue publish.”
Read the full issue and new research from the journal at www.chestcc.org.
In his own editorial featured in the inaugural issue of CHEST Pulmonary, Editor in Chief Matthew Miles, MD, MEd, FCCP, shares how the flagship journal’s proud heritage of sharing impactful clinical research – and the need to target areas of pulmonary and sleep medicine research not covered by other journals – inspired the creation of this new publication.
The issue also includes research into mobile health opportunities for asthma management, an exploration into telemedicine for patients with interstitial lung diseases, an in-depth review into the rare and often underdiagnosed disorder primary ciliary dyskinesia, research on the impact of the social vulnerability index on pulmonary embolism mortality, and an investigation into pneumothorax complications after percutaneous lung biopsy.
“I am deeply grateful to our authors, reviewers, editorial board, and staff who have contributed to the launch of our first issue,” Dr. Miles said. “The journal CHEST is known for excellence in clinically relevant research and patient management guidance. CHEST Pulmonary expands the CHEST portfolio with additional opportunity for researchers to share their work in an exclusively open access format to reach the broadest possible audience. I know our readers will enjoy learning from the research and reviews in issue one.”
Review the full issue and new articles from CHEST Pulmonary at www.chestpulmonary.org.
After much anticipation, the inaugural issues of both CHEST®Critical Care and CHEST®Pulmonary officially launched in late June. – promoting transparency, inclusiveness, and collaboration in research – and offer authors more avenues to share their practice-changing research.
The first issue of CHEST Critical Care featured research into ICU mortality across prepandemic and pandemic cohorts in resource-limited settings in South Africa, an exploration into symptom trajectory in recipients of hematopoietic stem-cell transplantation, a narrative review of post-intensive care syndrome, and an investigation into early echocardiographic and ultrasonographic findings in critically ill patients with COVID-19.
In addition, an editorial from Hayley Gershengorn, MD, Editor in Chief of CHEST Critical Care, offers readers more insights into the need for a publication focused on the breadth of clinical topics in critical care and her goals for the new publication.
“I’m ecstatic for this launch. We are grateful to our authors for the trust they put in us and are excited to share their work with our critical care colleagues around the world,” Dr. Gershengorn said. “The editorial team and the American College of Chest Physicians staff have worked tirelessly on this journal, and it’s incredibly gratifying to see the first issue publish.”
Read the full issue and new research from the journal at www.chestcc.org.
In his own editorial featured in the inaugural issue of CHEST Pulmonary, Editor in Chief Matthew Miles, MD, MEd, FCCP, shares how the flagship journal’s proud heritage of sharing impactful clinical research – and the need to target areas of pulmonary and sleep medicine research not covered by other journals – inspired the creation of this new publication.
The issue also includes research into mobile health opportunities for asthma management, an exploration into telemedicine for patients with interstitial lung diseases, an in-depth review into the rare and often underdiagnosed disorder primary ciliary dyskinesia, research on the impact of the social vulnerability index on pulmonary embolism mortality, and an investigation into pneumothorax complications after percutaneous lung biopsy.
“I am deeply grateful to our authors, reviewers, editorial board, and staff who have contributed to the launch of our first issue,” Dr. Miles said. “The journal CHEST is known for excellence in clinically relevant research and patient management guidance. CHEST Pulmonary expands the CHEST portfolio with additional opportunity for researchers to share their work in an exclusively open access format to reach the broadest possible audience. I know our readers will enjoy learning from the research and reviews in issue one.”
Review the full issue and new articles from CHEST Pulmonary at www.chestpulmonary.org.
Which biologic therapy should I use in patients who have moderate to severe asthma with associated comorbidities?
Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.
As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.
Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
Atopic dermatitis
There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).
These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).
Chronic rhinosinusitis with nasal polyposis
The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.
Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.
Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.
Eosinophilic esophagitis
Recent reports demonstrated a large portion of adults with a
diagnosis of eosinophilic
esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump
inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,
EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of
people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led
to a significant improvement in dysphagia symptoms and
histology when compared with placebo.
Allergic bronchopulmonary aspergillosis
Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).
Bronchiectasis
Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV1, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.
Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.
As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.
Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
Atopic dermatitis
There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).
These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).
Chronic rhinosinusitis with nasal polyposis
The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.
Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.
Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.
Eosinophilic esophagitis
Recent reports demonstrated a large portion of adults with a
diagnosis of eosinophilic
esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump
inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,
EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of
people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led
to a significant improvement in dysphagia symptoms and
histology when compared with placebo.
Allergic bronchopulmonary aspergillosis
Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).
Bronchiectasis
Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV1, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.
Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.
As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.
Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
Atopic dermatitis
There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).
These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).
Chronic rhinosinusitis with nasal polyposis
The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.
Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.
Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.
Eosinophilic esophagitis
Recent reports demonstrated a large portion of adults with a
diagnosis of eosinophilic
esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump
inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,
EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of
people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led
to a significant improvement in dysphagia symptoms and
histology when compared with placebo.
Allergic bronchopulmonary aspergillosis
Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).
Bronchiectasis
Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV1, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.