Specialty Sections From CHEST® Physician

Airways Disorders Network

Asthma and COPD Section  

Remodeling of airways and destruction of parenchyma by immune and inflammatory mechanisms are the leading cause of lung function decline in patients with COPD. Type 2 inflammation has been recognized as an important phenotypic pathway in asthma. However, its role in COPD has been much less clear, which had been largely associated with innate immune response.¹

Activation of Interleukin (IL)-25, IL-33, thymic stromal lymphopoietin (TSLP) produces type 2 cytokines IL-4, IL-5, and IL-13, either by binding to ILC2 or by direct Th2 cells resulting in elevated eosinophils in sputum, lungs, and blood, as well as fractional exhaled nitric oxide.² The combined inflammation from this pathway underpins the pathological changes seen in airway mucosa, causing mucous hypersecretion and hyperresponsiveness.

Prior trials delineating the role of biologics, such as mepolizumab and benralizumab, showed variable results with possible benefit of add-on biologics on the annual COPD exacerbations among patients with eosinophilic phenotype of COPD.³

More recently, the BOREAS trial evaluated the role of dupilumab as an add-on therapy for patients with type 2 inflammation-driven COPD established using blood eosinophil count of at least 300/mL at initial screening.⁴ Dupilumab is a human monoclonal antibody that blocks combined IL-4 and IL-13 pathways with a broader effect on the type 2 inflammation. It included patients with moderate to severe exacerbations despite maximal triple inhaler therapy with blood eosinophilia. Patients with asthma were excluded. This 52-week trial showed reduction in annual moderate to severe COPD exacerbations, sustained lung function improvement as measured by prebronchodilator FEV₁, and improvement in patient-reported respiratory symptoms.⁴ Evaluation of sustainability of these results with therapy step-down approaches should be explored.

References

1. Scanlon & McKenzie, 2012.

2. Brusselle et al, 2013.

3. Pavord et al, 2017.

4. Bhatt et al, 2023.

Airways Disorders Network

Asthma and COPD Section  

Remodeling of airways and destruction of parenchyma by immune and inflammatory mechanisms are the leading cause of lung function decline in patients with COPD. Type 2 inflammation has been recognized as an important phenotypic pathway in asthma. However, its role in COPD has been much less clear, which had been largely associated with innate immune response.¹

Activation of Interleukin (IL)-25, IL-33, thymic stromal lymphopoietin (TSLP) produces type 2 cytokines IL-4, IL-5, and IL-13, either by binding to ILC2 or by direct Th2 cells resulting in elevated eosinophils in sputum, lungs, and blood, as well as fractional exhaled nitric oxide.² The combined inflammation from this pathway underpins the pathological changes seen in airway mucosa, causing mucous hypersecretion and hyperresponsiveness.

Prior trials delineating the role of biologics, such as mepolizumab and benralizumab, showed variable results with possible benefit of add-on biologics on the annual COPD exacerbations among patients with eosinophilic phenotype of COPD.³

More recently, the BOREAS trial evaluated the role of dupilumab as an add-on therapy for patients with type 2 inflammation-driven COPD established using blood eosinophil count of at least 300/mL at initial screening.⁴ Dupilumab is a human monoclonal antibody that blocks combined IL-4 and IL-13 pathways with a broader effect on the type 2 inflammation. It included patients with moderate to severe exacerbations despite maximal triple inhaler therapy with blood eosinophilia. Patients with asthma were excluded. This 52-week trial showed reduction in annual moderate to severe COPD exacerbations, sustained lung function improvement as measured by prebronchodilator FEV₁, and improvement in patient-reported respiratory symptoms.⁴ Evaluation of sustainability of these results with therapy step-down approaches should be explored.

References

1. Scanlon & McKenzie, 2012.

2. Brusselle et al, 2013.

3. Pavord et al, 2017.

4. Bhatt et al, 2023.

Airways Disorders Network

Asthma and COPD Section  

Remodeling of airways and destruction of parenchyma by immune and inflammatory mechanisms are the leading cause of lung function decline in patients with COPD. Type 2 inflammation has been recognized as an important phenotypic pathway in asthma. However, its role in COPD has been much less clear, which had been largely associated with innate immune response.¹

Activation of Interleukin (IL)-25, IL-33, thymic stromal lymphopoietin (TSLP) produces type 2 cytokines IL-4, IL-5, and IL-13, either by binding to ILC2 or by direct Th2 cells resulting in elevated eosinophils in sputum, lungs, and blood, as well as fractional exhaled nitric oxide.² The combined inflammation from this pathway underpins the pathological changes seen in airway mucosa, causing mucous hypersecretion and hyperresponsiveness.

Prior trials delineating the role of biologics, such as mepolizumab and benralizumab, showed variable results with possible benefit of add-on biologics on the annual COPD exacerbations among patients with eosinophilic phenotype of COPD.³

More recently, the BOREAS trial evaluated the role of dupilumab as an add-on therapy for patients with type 2 inflammation-driven COPD established using blood eosinophil count of at least 300/mL at initial screening.⁴ Dupilumab is a human monoclonal antibody that blocks combined IL-4 and IL-13 pathways with a broader effect on the type 2 inflammation. It included patients with moderate to severe exacerbations despite maximal triple inhaler therapy with blood eosinophilia. Patients with asthma were excluded. This 52-week trial showed reduction in annual moderate to severe COPD exacerbations, sustained lung function improvement as measured by prebronchodilator FEV₁, and improvement in patient-reported respiratory symptoms.⁴ Evaluation of sustainability of these results with therapy step-down approaches should be explored.

References

1. Scanlon & McKenzie, 2012.

2. Brusselle et al, 2013.

3. Pavord et al, 2017.

4. Bhatt et al, 2023.

Bedside-focused cardiac ultrasound assessment, or cardiac point-of-care ultrasound (POCUS), has become common in intensive care units throughout the US and the world. Many clinicians argue a POCUS cardiac assessment should be completed in most hypotensive patients and all cases of undifferentiated shock.

However, obtaining images adequate for decision making via standard transthoracic echo (TTE) is not possible in a significant number of patients; as high as 30% of critically ill patients, according to The American Society of Echocardiography (ASE) guidelines.¹ Factors common to critically ill patients, such as invasive mechanical ventilation, external dressings, and limited mobility, contribute to poor image acquisition.

CHEST

In almost all these cases, the factors limiting image acquisition can be eliminated by utilizing a transesophageal approach. In a recent study, researchers were able to demonstrate that adding transesophageal echocardiography (TEE) to TTE in critically ill patients yielded a new diagnosis or a change in management about 45% of the time.²

Using transesophageal ultrasound for a focused cardiac assessment in hemodynamically unstable patients is not new—and is often referred to as rescue TEE or resuscitative TEE. A broader term, transesophageal ultrasound, has also been used to include sonographic evaluation of the lungs in patients with poor acoustic windows. At my institution, we use the term critical care TEE to define TEE performed by a noncardiology-trained intensivist in an intubated critically ill patient.

Regardless of the term, the use of transesophageal ultrasound by the noncardiologist in the ICU appears to be a developing trend. As with other uses of POCUS, ultrasound machines continue to be able to “do more” at a lower price point. In 2024, several cart-based ultrasound machines are compatible with transesophageal probes and contain software packages capable of common cardiac measurements.

Despite this growing interest, intensivists are likely to encounter barriers to implementing critical care TEE. Our division recently implemented adding TEE to our practice. Our practice involves two separate systems: a Veterans Administration hospital and a university-based county hospital. Our division has integrated the use of TEE in the medical ICU at both institutions. Having navigated the process at both institutions, I can offer some guidance in navigating barriers.

The development of a critical care TEE program must start with a strong base in transthoracic cardiac POCUS, at least for the foreseeable future. Having a strong background in TTE gives learners a solid foundation in cardiac anatomy, cardiac function, and ultrasound properties. Obtaining testamur status or board certification in critical care echocardiography is not an absolute must but is a definite benefit. Having significant experience in TTE image acquisition and interpretation will flatten the learning curve for TEE. Interestingly, image acquisition in TEE is often easier than in TTE, so the paradigm of learning TTE before TEE may reverse in the years to come.

Two barriers often work together to create a vicious cycle that stops the development of a TEE program at its start. These barriers include the lack of training and lack of equipment, specifically a TEE probe. Those who do not understand the value of TEE may ask, “Why purchase equipment for a procedure that you do not yet know how to do?” The opposite question can also be asked, “Why get trained to do something you don’t have the equipment to perform?”

My best advice to break this cycle is to “dive in” to whichever barrier seems easier to overcome first. I started with obtaining knowledge and training. Obtaining training and education in a procedure that is historically not done in your specialty is challenging but is not impossible. It takes a combination of high levels of self-motivation and at least one colleague with the training to support you. I approached a cardiac anesthesiologist, whom I knew from the surgical ICU. Cardiologists can also be a resource, but working with cardiac anesthesiologists offers several advantages. TEEs done by cardiac anesthesiologists are similar to those done in ICU patients (ie, all patients are intubated and sedated). The procedures are also scheduled several days in advance, making it easier to integrate training into your daily work schedule. Lastly, the TEE probe remains in place for several hours, so repeating the probe manipulations again as a learner does not add additional risk to the patient. In my case, we somewhat arbitrarily agreed that I participate in 25 TEE exams. (CME courses, both online and in-person simulation, exist and greatly supplement self-study.)

Obtaining equipment is also a common barrier, though this has become less restrictive in the last several years. As previously mentioned, many cart-based ultrasound machines can accommodate a TEE probe. This changes the request from purchasing a new machine to “just a probe.” Despite the higher cost than most other probes, those in charge of purchasing are often more open to purchasing “a probe” than to purchasing an ultrasound machine.

Additionally, the purchasing decision regarding probes may fall to a different person than it does for an ultrasound machine. If available, POCUS image archiving into the medical record can help offset the cost of equipment, both by increasing revenue via billing and by demonstrating that equipment is being used. If initially declined, continue to ask and work to integrate the purchase into the next year’s budget. Inquire about the process of making a formal request and follow that process. This will often involve obtaining a quote or quotes from the ultrasound manufacturer(s).

Keep in mind that the probe will require a special storage cabinet specifically designed for TEE probes. It is prudent to include this in budget requests. If needed, the echocardiography lab can be a useful resource for additional information regarding the cabinet requirements. It is strongly recommended to discuss TEE probe models with sterile processing before any purchasing. If options are available, it is wise to choose a model the hospital already uses, as the cleaning protocol is well established. Our unit purchased a model that did not have an established protocol, which took nearly 6 months to develop. If probe options are limited, involving sterile processing early to start developing a protocol will help decrease delays.

Obtaining hospital privileges is also a common barrier, though this may not be as challenging as expected. Hospitals typically have well-outlined policies on obtaining privileges for established procedures. One of our hospital systems had four different options; the most straightforward required 20 hours of CME specific to TEE and 10 supervised cases by a proctor currently holding TEE privileges (see Table 1).

Dr. Proud is Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Pulmonary and Critical Care Medicine Program Director, UT Health San Antonio.

References:

1. Porter TR, Abdelmoneim S, Belcik FT, et al. Guidelines for the cardiac sonographer in the performance of contrast echocardiography: a focused update from the American Society of Echocardiography. J Am Soc Echocardiogr. 2024;27(8):797-810.

2. Si X, Ma J, Cao DY, et al. Transesophageal echocardiography instead or in addition to transthoracic echocardiography in evaluating haemodynamic problems in intubated critically ill patients. Ann Transl Med. 2020;8(12):785. 

3. Hahn RT, Abraham T, Adams MS, et al. Guidelines for performing a cmprehensive transesophageal echocardiographic examination: recommendations from the American Society of Echocardioraphy and the Society of Cardiovascular Anesthesiologists. J Am Soc Echocardiogr. 2013;26(9):921-964.

Bedside-focused cardiac ultrasound assessment, or cardiac point-of-care ultrasound (POCUS), has become common in intensive care units throughout the US and the world. Many clinicians argue a POCUS cardiac assessment should be completed in most hypotensive patients and all cases of undifferentiated shock.

However, obtaining images adequate for decision making via standard transthoracic echo (TTE) is not possible in a significant number of patients; as high as 30% of critically ill patients, according to The American Society of Echocardiography (ASE) guidelines.¹ Factors common to critically ill patients, such as invasive mechanical ventilation, external dressings, and limited mobility, contribute to poor image acquisition.

CHEST

In almost all these cases, the factors limiting image acquisition can be eliminated by utilizing a transesophageal approach. In a recent study, researchers were able to demonstrate that adding transesophageal echocardiography (TEE) to TTE in critically ill patients yielded a new diagnosis or a change in management about 45% of the time.²

Using transesophageal ultrasound for a focused cardiac assessment in hemodynamically unstable patients is not new—and is often referred to as rescue TEE or resuscitative TEE. A broader term, transesophageal ultrasound, has also been used to include sonographic evaluation of the lungs in patients with poor acoustic windows. At my institution, we use the term critical care TEE to define TEE performed by a noncardiology-trained intensivist in an intubated critically ill patient.

Regardless of the term, the use of transesophageal ultrasound by the noncardiologist in the ICU appears to be a developing trend. As with other uses of POCUS, ultrasound machines continue to be able to “do more” at a lower price point. In 2024, several cart-based ultrasound machines are compatible with transesophageal probes and contain software packages capable of common cardiac measurements.

Despite this growing interest, intensivists are likely to encounter barriers to implementing critical care TEE. Our division recently implemented adding TEE to our practice. Our practice involves two separate systems: a Veterans Administration hospital and a university-based county hospital. Our division has integrated the use of TEE in the medical ICU at both institutions. Having navigated the process at both institutions, I can offer some guidance in navigating barriers.

The development of a critical care TEE program must start with a strong base in transthoracic cardiac POCUS, at least for the foreseeable future. Having a strong background in TTE gives learners a solid foundation in cardiac anatomy, cardiac function, and ultrasound properties. Obtaining testamur status or board certification in critical care echocardiography is not an absolute must but is a definite benefit. Having significant experience in TTE image acquisition and interpretation will flatten the learning curve for TEE. Interestingly, image acquisition in TEE is often easier than in TTE, so the paradigm of learning TTE before TEE may reverse in the years to come.

Two barriers often work together to create a vicious cycle that stops the development of a TEE program at its start. These barriers include the lack of training and lack of equipment, specifically a TEE probe. Those who do not understand the value of TEE may ask, “Why purchase equipment for a procedure that you do not yet know how to do?” The opposite question can also be asked, “Why get trained to do something you don’t have the equipment to perform?”

My best advice to break this cycle is to “dive in” to whichever barrier seems easier to overcome first. I started with obtaining knowledge and training. Obtaining training and education in a procedure that is historically not done in your specialty is challenging but is not impossible. It takes a combination of high levels of self-motivation and at least one colleague with the training to support you. I approached a cardiac anesthesiologist, whom I knew from the surgical ICU. Cardiologists can also be a resource, but working with cardiac anesthesiologists offers several advantages. TEEs done by cardiac anesthesiologists are similar to those done in ICU patients (ie, all patients are intubated and sedated). The procedures are also scheduled several days in advance, making it easier to integrate training into your daily work schedule. Lastly, the TEE probe remains in place for several hours, so repeating the probe manipulations again as a learner does not add additional risk to the patient. In my case, we somewhat arbitrarily agreed that I participate in 25 TEE exams. (CME courses, both online and in-person simulation, exist and greatly supplement self-study.)

Obtaining equipment is also a common barrier, though this has become less restrictive in the last several years. As previously mentioned, many cart-based ultrasound machines can accommodate a TEE probe. This changes the request from purchasing a new machine to “just a probe.” Despite the higher cost than most other probes, those in charge of purchasing are often more open to purchasing “a probe” than to purchasing an ultrasound machine.

Additionally, the purchasing decision regarding probes may fall to a different person than it does for an ultrasound machine. If available, POCUS image archiving into the medical record can help offset the cost of equipment, both by increasing revenue via billing and by demonstrating that equipment is being used. If initially declined, continue to ask and work to integrate the purchase into the next year’s budget. Inquire about the process of making a formal request and follow that process. This will often involve obtaining a quote or quotes from the ultrasound manufacturer(s).

Keep in mind that the probe will require a special storage cabinet specifically designed for TEE probes. It is prudent to include this in budget requests. If needed, the echocardiography lab can be a useful resource for additional information regarding the cabinet requirements. It is strongly recommended to discuss TEE probe models with sterile processing before any purchasing. If options are available, it is wise to choose a model the hospital already uses, as the cleaning protocol is well established. Our unit purchased a model that did not have an established protocol, which took nearly 6 months to develop. If probe options are limited, involving sterile processing early to start developing a protocol will help decrease delays.

Obtaining hospital privileges is also a common barrier, though this may not be as challenging as expected. Hospitals typically have well-outlined policies on obtaining privileges for established procedures. One of our hospital systems had four different options; the most straightforward required 20 hours of CME specific to TEE and 10 supervised cases by a proctor currently holding TEE privileges (see Table 1).

Dr. Proud is Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Pulmonary and Critical Care Medicine Program Director, UT Health San Antonio.

References:

1. Porter TR, Abdelmoneim S, Belcik FT, et al. Guidelines for the cardiac sonographer in the performance of contrast echocardiography: a focused update from the American Society of Echocardiography. J Am Soc Echocardiogr. 2024;27(8):797-810.

2. Si X, Ma J, Cao DY, et al. Transesophageal echocardiography instead or in addition to transthoracic echocardiography in evaluating haemodynamic problems in intubated critically ill patients. Ann Transl Med. 2020;8(12):785. 

3. Hahn RT, Abraham T, Adams MS, et al. Guidelines for performing a cmprehensive transesophageal echocardiographic examination: recommendations from the American Society of Echocardioraphy and the Society of Cardiovascular Anesthesiologists. J Am Soc Echocardiogr. 2013;26(9):921-964.

Bedside-focused cardiac ultrasound assessment, or cardiac point-of-care ultrasound (POCUS), has become common in intensive care units throughout the US and the world. Many clinicians argue a POCUS cardiac assessment should be completed in most hypotensive patients and all cases of undifferentiated shock.

However, obtaining images adequate for decision making via standard transthoracic echo (TTE) is not possible in a significant number of patients; as high as 30% of critically ill patients, according to The American Society of Echocardiography (ASE) guidelines.¹ Factors common to critically ill patients, such as invasive mechanical ventilation, external dressings, and limited mobility, contribute to poor image acquisition.

CHEST

In almost all these cases, the factors limiting image acquisition can be eliminated by utilizing a transesophageal approach. In a recent study, researchers were able to demonstrate that adding transesophageal echocardiography (TEE) to TTE in critically ill patients yielded a new diagnosis or a change in management about 45% of the time.²

Using transesophageal ultrasound for a focused cardiac assessment in hemodynamically unstable patients is not new—and is often referred to as rescue TEE or resuscitative TEE. A broader term, transesophageal ultrasound, has also been used to include sonographic evaluation of the lungs in patients with poor acoustic windows. At my institution, we use the term critical care TEE to define TEE performed by a noncardiology-trained intensivist in an intubated critically ill patient.

Regardless of the term, the use of transesophageal ultrasound by the noncardiologist in the ICU appears to be a developing trend. As with other uses of POCUS, ultrasound machines continue to be able to “do more” at a lower price point. In 2024, several cart-based ultrasound machines are compatible with transesophageal probes and contain software packages capable of common cardiac measurements.

Despite this growing interest, intensivists are likely to encounter barriers to implementing critical care TEE. Our division recently implemented adding TEE to our practice. Our practice involves two separate systems: a Veterans Administration hospital and a university-based county hospital. Our division has integrated the use of TEE in the medical ICU at both institutions. Having navigated the process at both institutions, I can offer some guidance in navigating barriers.

The development of a critical care TEE program must start with a strong base in transthoracic cardiac POCUS, at least for the foreseeable future. Having a strong background in TTE gives learners a solid foundation in cardiac anatomy, cardiac function, and ultrasound properties. Obtaining testamur status or board certification in critical care echocardiography is not an absolute must but is a definite benefit. Having significant experience in TTE image acquisition and interpretation will flatten the learning curve for TEE. Interestingly, image acquisition in TEE is often easier than in TTE, so the paradigm of learning TTE before TEE may reverse in the years to come.

Two barriers often work together to create a vicious cycle that stops the development of a TEE program at its start. These barriers include the lack of training and lack of equipment, specifically a TEE probe. Those who do not understand the value of TEE may ask, “Why purchase equipment for a procedure that you do not yet know how to do?” The opposite question can also be asked, “Why get trained to do something you don’t have the equipment to perform?”

My best advice to break this cycle is to “dive in” to whichever barrier seems easier to overcome first. I started with obtaining knowledge and training. Obtaining training and education in a procedure that is historically not done in your specialty is challenging but is not impossible. It takes a combination of high levels of self-motivation and at least one colleague with the training to support you. I approached a cardiac anesthesiologist, whom I knew from the surgical ICU. Cardiologists can also be a resource, but working with cardiac anesthesiologists offers several advantages. TEEs done by cardiac anesthesiologists are similar to those done in ICU patients (ie, all patients are intubated and sedated). The procedures are also scheduled several days in advance, making it easier to integrate training into your daily work schedule. Lastly, the TEE probe remains in place for several hours, so repeating the probe manipulations again as a learner does not add additional risk to the patient. In my case, we somewhat arbitrarily agreed that I participate in 25 TEE exams. (CME courses, both online and in-person simulation, exist and greatly supplement self-study.)

Obtaining equipment is also a common barrier, though this has become less restrictive in the last several years. As previously mentioned, many cart-based ultrasound machines can accommodate a TEE probe. This changes the request from purchasing a new machine to “just a probe.” Despite the higher cost than most other probes, those in charge of purchasing are often more open to purchasing “a probe” than to purchasing an ultrasound machine.

Additionally, the purchasing decision regarding probes may fall to a different person than it does for an ultrasound machine. If available, POCUS image archiving into the medical record can help offset the cost of equipment, both by increasing revenue via billing and by demonstrating that equipment is being used. If initially declined, continue to ask and work to integrate the purchase into the next year’s budget. Inquire about the process of making a formal request and follow that process. This will often involve obtaining a quote or quotes from the ultrasound manufacturer(s).

Keep in mind that the probe will require a special storage cabinet specifically designed for TEE probes. It is prudent to include this in budget requests. If needed, the echocardiography lab can be a useful resource for additional information regarding the cabinet requirements. It is strongly recommended to discuss TEE probe models with sterile processing before any purchasing. If options are available, it is wise to choose a model the hospital already uses, as the cleaning protocol is well established. Our unit purchased a model that did not have an established protocol, which took nearly 6 months to develop. If probe options are limited, involving sterile processing early to start developing a protocol will help decrease delays.

Obtaining hospital privileges is also a common barrier, though this may not be as challenging as expected. Hospitals typically have well-outlined policies on obtaining privileges for established procedures. One of our hospital systems had four different options; the most straightforward required 20 hours of CME specific to TEE and 10 supervised cases by a proctor currently holding TEE privileges (see Table 1).

Dr. Proud is Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Pulmonary and Critical Care Medicine Program Director, UT Health San Antonio.

References:

1. Porter TR, Abdelmoneim S, Belcik FT, et al. Guidelines for the cardiac sonographer in the performance of contrast echocardiography: a focused update from the American Society of Echocardiography. J Am Soc Echocardiogr. 2024;27(8):797-810.

2. Si X, Ma J, Cao DY, et al. Transesophageal echocardiography instead or in addition to transthoracic echocardiography in evaluating haemodynamic problems in intubated critically ill patients. Ann Transl Med. 2020;8(12):785. 

3. Hahn RT, Abraham T, Adams MS, et al. Guidelines for performing a cmprehensive transesophageal echocardiographic examination: recommendations from the American Society of Echocardioraphy and the Society of Cardiovascular Anesthesiologists. J Am Soc Echocardiogr. 2013;26(9):921-964.

“Janice Turner” (name changed to protect confidentiality) is a 66-year-old woman with a 40-pack per year history of smoking. She quit smoking 1 year ago and presents to your office for a follow-up visit after discharge from the hospital 14 days ago. This was her second hospitalization for a COPD exacerbation in the past 12 months. She is very worried about having another COPD exacerbation and wants to know if there are additional medications she could try.

Over the past 2 weeks, her respiratory symptoms have improved and returned to her baseline. She has a daily cough with white phlegm on most days and dyspnea on exertion at one-half block on level ground. She reports using her medications as prescribed and is enrolled in a pulmonary rehabilitation program, which she attends twice per week. She uses 2 to 4 inhalations of albuterol each day.

CHEST

She is on the following regimen for her COPD, which is unchanged compared with what she has been prescribed for the past 12 months: 1) combination inhaled fluticasone furoate, umeclidinium, and vilanterol via the Ellipta^® device, one actuation once daily and 2) inhaled albuterol, two puffs as needed every 4 hours via metered dose inhaler. She demonstrates mastery of inhaler technique for both inhaled devices. Her vaccinations are current (pneumococcus, influenza, respiratory syncytial virus, and COVID-19).

On examination, she can complete sentences without respiratory difficulty, and her vital signs are normal. She has decreased breath sounds in all lung fields, with occasional rhonchi. Heart sounds are distant, but regular, at 92 beats per minute, and she has no peripheral edema. Arterial blood gas at rest on room air indicates a pH of 7.38, PaO₂ of 63 mm Hg, and PaCO₂ of 42 mm Hg. An electrocardiogram shows sinus rhythm and a QTc interval of 420 milliseconds.

Three months ago, when she was clinically stable, you obtained spirometry, a complete blood count with differential, and a chest radiograph to exclude alternate diagnoses for her ongoing respiratory symptoms. She had severe airflow limitation (post-bronchodilator FEV₁ = 40% predicted, FVC = 61% predicted, FEV₁/FVC = 65%). At the time, she also had peripheral eosinophilia (eosinophil count of 350 cells/μL) and hyperinflation without parenchymal infiltrates.

CHEST

In summary, Ms. Turner has severe smoking-associated COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3E and chronic bronchitis with two severe exacerbations in the past 12 months.¹ She is currently prescribed triple inhaled maintenance therapy with corticosteroids, long-acting β₂-agonist, and long-acting muscarinic antagonist. She has a normal QTc interval.

So what would you recommend to reduce Ms. Turner’s risk of future exacerbations?

In 2011, the US Food and Drug Administration (FDA) approved roflumilast 500 mcg by mouth per day, a selective phosphodiesterase 4 (PDE4) inhibitor, as maintenance therapy to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis.² The FDA approval was based on a review of the efficacy and safety of roflumilast in eight randomized, double-blind, controlled clinical trials in 9,394 adults with COPD.

Two subsequently completed randomized clinical trials in 2015 (REACT, 1,945 adults) and 2016 (RE2SPOND, 2,354 adults) also found that maintenance oral treatment escalation with roflumilast significantly reduced the risk of COPD exacerbations compared with placebo.² The most common adverse effects reported with long-term use of roflumilast are related to the gastrointestinal tract (diarrhea, nausea, decreased appetite), weight loss, and insomnia. Four weeks of roflumilast at 250 mcg per day prior to dose escalation to 500 mcg per day reduces the risk of treatment discontinuation and improves tolerability compared with initiating treatment with the maintenance dose.

In 2022, the FDA approved a generic version of roflumilast, providing an opportunity for patients to use roflumilast at a lower cost than was previously possible. Importantly, the FDA Prescribing Information includes a warning to avoid the use of roflumilast in patients being treated with strong cytochrome P450 enzyme inducers (eg, rifampin, phenytoin). The FDA Prescribing Information also recommends weighing the risks and benefits of roflumilast in patients with a history of depression or suicidal thoughts or behavior, or patients with unexplained or clinically significant weight loss.

In 2011 (the same year as the FDA approval of roflumilast), the National Institutes of Health/National Heart, Lung, and Blood Institute-funded COPD Clinical Research Network reported that maintenance treatment with azithromycin reduced the risk of COPD exacerbations compared with placebo in a randomized clinical trial of 1,142 adults with COPD (MACRO study).³ Subgroup analyses indicated that the reduction in the risk of COPD exacerbations with azithromycin was observed in participants with or without chronic bronchitis but not in participants who currently smoked.

Subsequently, two other smaller randomized clinical trials in 2014 (COLUMBUS, 92 participants) and in 2019 (BACE, 301 participants) also demonstrated a reduction in the risk of COPD exacerbations with maintenance azithromycin treatment compared with placebo. Azithromycin can prolong the QT interval and, in rare cases, cause cardiac arrythmias, especially when used with other medications that can prolong the QT interval. There are also concerns that maintenance azithromycin therapy could lead to decrements in hearing or promote the development of macrolide-resistant bacteria. Maintenance treatment with azithromycin to prevent COPD exacerbations is not an FDA-approved indication.⁴ The FDA approval for azithromycin is currently limited to treatment of patients with mild to moderate infections caused by susceptible bacteria, but it is often prescribed off-label as maintenance treatment for COPD.

On the basis of this body of evidence from clinical trials in COPD, the 2015 CHEST and Canadian Thoracic Society (CTS) guidelines,⁵ the 2017 European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines,⁶ and the 2024 GOLD Strategy Report all include recommendations for treatment escalation with maintenance roflumilast or azithromycin to reduce the risk of COPD exacerbations. For example, the 2024 GOLD Strategy Report recommends roflumilast in patients with severe COPD and chronic bronchitis who continue to have exacerbations despite inhaled maintenance treatment with combination long-acting β₂-agonist and long-acting muscarinic antagonist or with triple therapy with inhaled corticosteroids, long-acting β₂-agonist, and long-acting muscarinic antagonist. An alternative, 2024 GOLD-recommended strategy in this population is maintenance therapy with azithromycin, “preferentially in former smokers.” GOLD’s preference for using azithromycin in patients with smoking history is based on post-hoc (ie, not part of the original study design) subgroup analyses “suggesting lesser benefit in active smokers” in the MACRO study. Results of such analyses have not been reported in other studies.

There are no results from clinical trials that have directly compared the harms and benefits of initiating maintenance therapy with roflumilast or azithromycin in patients with COPD. The roflumilast or azithromycin to prevent COPD exacerbations (RELIANCE; NCT04069312) multicenter clinical trial is addressing this evidence gap.⁷ The RELIANCE study is funded by the Patient-Centered Outcomes Research Institute and co-led by the COPD Foundation, a not-for-profit organization founded by John W. Walsh, a patient advocate with α1-related COPD. Also, results of two recently completed phase 3 clinical trials with nebulized ensifentrine (ENHANCE-1 and ENHANCE-2), a novel inhibitor of PDE3 and PDE4, were recently published. ENHANCE-1 and ENHANCE-2 studies indicate that twice daily nebulized ensifentrine reduces the risk of COPD exacerbations in patients with moderate or severe COPD.⁸ Ensifentrine is under review by the FDA, and a decision about its use in the US is expected in the summer of 2024.

Until the results from the RELIANCE clinical trial and the decision by the FDA about ensifentrine are available, we recommended a discussion with Ms. Turner about whether to initiate treatment with maintenance roflumilast or azithromycin. Both can reduce the risk of exacerbations, and the relative benefits and risks of these two evidence-based options are not yet known. Unless Ms. Turner has specific preferences (eg, concerns about specific adverse effects or differences in out-of-pocket cost) in favor of one over the other, she could flip a coin to decide between initiating maintenance roflumilast or azithromycin.
 

Dr. Krishnan is Professor of Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy, and Professor of Public Health, Division of Epidemiology and Biostatistics, University of Illinois Chicago. Dr. Adrish is Associate Professor, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston.

References:

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report. https://goldcopd.org/2024-gold-report-2/

2. US Food and Drug Administration (Daliresp^®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf

3. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromucin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. PMID: 21864166. doi: 10.1056/NEJMoa1104623.

4. US Food and Drug Administration (Zithromyax^®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf

5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acure exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4)894-942. PMID: 25321320. doi: 10.1378/chest.14-1676.

6. Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265. PMID: 28889106. doi:10.1183/13993003.02265-2016.

7. Krishnan JA, Albert RK, Rennard SI; RELIANCE study. Waiting for actionable evidence: roflumilast or azithromycin? Chronic Obst Pulm Dis. 2022;9(1):1-3. PMID: 34783231. doi: 10.15326/jcopdf.2021.0272.

8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phospodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. PMID: 37364283.

“Janice Turner” (name changed to protect confidentiality) is a 66-year-old woman with a 40-pack per year history of smoking. She quit smoking 1 year ago and presents to your office for a follow-up visit after discharge from the hospital 14 days ago. This was her second hospitalization for a COPD exacerbation in the past 12 months. She is very worried about having another COPD exacerbation and wants to know if there are additional medications she could try.

Over the past 2 weeks, her respiratory symptoms have improved and returned to her baseline. She has a daily cough with white phlegm on most days and dyspnea on exertion at one-half block on level ground. She reports using her medications as prescribed and is enrolled in a pulmonary rehabilitation program, which she attends twice per week. She uses 2 to 4 inhalations of albuterol each day.

CHEST

She is on the following regimen for her COPD, which is unchanged compared with what she has been prescribed for the past 12 months: 1) combination inhaled fluticasone furoate, umeclidinium, and vilanterol via the Ellipta^® device, one actuation once daily and 2) inhaled albuterol, two puffs as needed every 4 hours via metered dose inhaler. She demonstrates mastery of inhaler technique for both inhaled devices. Her vaccinations are current (pneumococcus, influenza, respiratory syncytial virus, and COVID-19).

On examination, she can complete sentences without respiratory difficulty, and her vital signs are normal. She has decreased breath sounds in all lung fields, with occasional rhonchi. Heart sounds are distant, but regular, at 92 beats per minute, and she has no peripheral edema. Arterial blood gas at rest on room air indicates a pH of 7.38, PaO₂ of 63 mm Hg, and PaCO₂ of 42 mm Hg. An electrocardiogram shows sinus rhythm and a QTc interval of 420 milliseconds.

Three months ago, when she was clinically stable, you obtained spirometry, a complete blood count with differential, and a chest radiograph to exclude alternate diagnoses for her ongoing respiratory symptoms. She had severe airflow limitation (post-bronchodilator FEV₁ = 40% predicted, FVC = 61% predicted, FEV₁/FVC = 65%). At the time, she also had peripheral eosinophilia (eosinophil count of 350 cells/μL) and hyperinflation without parenchymal infiltrates.

CHEST

In summary, Ms. Turner has severe smoking-associated COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3E and chronic bronchitis with two severe exacerbations in the past 12 months.¹ She is currently prescribed triple inhaled maintenance therapy with corticosteroids, long-acting β₂-agonist, and long-acting muscarinic antagonist. She has a normal QTc interval.

So what would you recommend to reduce Ms. Turner’s risk of future exacerbations?

In 2011, the US Food and Drug Administration (FDA) approved roflumilast 500 mcg by mouth per day, a selective phosphodiesterase 4 (PDE4) inhibitor, as maintenance therapy to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis.² The FDA approval was based on a review of the efficacy and safety of roflumilast in eight randomized, double-blind, controlled clinical trials in 9,394 adults with COPD.

Two subsequently completed randomized clinical trials in 2015 (REACT, 1,945 adults) and 2016 (RE2SPOND, 2,354 adults) also found that maintenance oral treatment escalation with roflumilast significantly reduced the risk of COPD exacerbations compared with placebo.² The most common adverse effects reported with long-term use of roflumilast are related to the gastrointestinal tract (diarrhea, nausea, decreased appetite), weight loss, and insomnia. Four weeks of roflumilast at 250 mcg per day prior to dose escalation to 500 mcg per day reduces the risk of treatment discontinuation and improves tolerability compared with initiating treatment with the maintenance dose.

In 2022, the FDA approved a generic version of roflumilast, providing an opportunity for patients to use roflumilast at a lower cost than was previously possible. Importantly, the FDA Prescribing Information includes a warning to avoid the use of roflumilast in patients being treated with strong cytochrome P450 enzyme inducers (eg, rifampin, phenytoin). The FDA Prescribing Information also recommends weighing the risks and benefits of roflumilast in patients with a history of depression or suicidal thoughts or behavior, or patients with unexplained or clinically significant weight loss.

In 2011 (the same year as the FDA approval of roflumilast), the National Institutes of Health/National Heart, Lung, and Blood Institute-funded COPD Clinical Research Network reported that maintenance treatment with azithromycin reduced the risk of COPD exacerbations compared with placebo in a randomized clinical trial of 1,142 adults with COPD (MACRO study).³ Subgroup analyses indicated that the reduction in the risk of COPD exacerbations with azithromycin was observed in participants with or without chronic bronchitis but not in participants who currently smoked.

Subsequently, two other smaller randomized clinical trials in 2014 (COLUMBUS, 92 participants) and in 2019 (BACE, 301 participants) also demonstrated a reduction in the risk of COPD exacerbations with maintenance azithromycin treatment compared with placebo. Azithromycin can prolong the QT interval and, in rare cases, cause cardiac arrythmias, especially when used with other medications that can prolong the QT interval. There are also concerns that maintenance azithromycin therapy could lead to decrements in hearing or promote the development of macrolide-resistant bacteria. Maintenance treatment with azithromycin to prevent COPD exacerbations is not an FDA-approved indication.⁴ The FDA approval for azithromycin is currently limited to treatment of patients with mild to moderate infections caused by susceptible bacteria, but it is often prescribed off-label as maintenance treatment for COPD.

On the basis of this body of evidence from clinical trials in COPD, the 2015 CHEST and Canadian Thoracic Society (CTS) guidelines,⁵ the 2017 European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines,⁶ and the 2024 GOLD Strategy Report all include recommendations for treatment escalation with maintenance roflumilast or azithromycin to reduce the risk of COPD exacerbations. For example, the 2024 GOLD Strategy Report recommends roflumilast in patients with severe COPD and chronic bronchitis who continue to have exacerbations despite inhaled maintenance treatment with combination long-acting β₂-agonist and long-acting muscarinic antagonist or with triple therapy with inhaled corticosteroids, long-acting β₂-agonist, and long-acting muscarinic antagonist. An alternative, 2024 GOLD-recommended strategy in this population is maintenance therapy with azithromycin, “preferentially in former smokers.” GOLD’s preference for using azithromycin in patients with smoking history is based on post-hoc (ie, not part of the original study design) subgroup analyses “suggesting lesser benefit in active smokers” in the MACRO study. Results of such analyses have not been reported in other studies.

There are no results from clinical trials that have directly compared the harms and benefits of initiating maintenance therapy with roflumilast or azithromycin in patients with COPD. The roflumilast or azithromycin to prevent COPD exacerbations (RELIANCE; NCT04069312) multicenter clinical trial is addressing this evidence gap.⁷ The RELIANCE study is funded by the Patient-Centered Outcomes Research Institute and co-led by the COPD Foundation, a not-for-profit organization founded by John W. Walsh, a patient advocate with α1-related COPD. Also, results of two recently completed phase 3 clinical trials with nebulized ensifentrine (ENHANCE-1 and ENHANCE-2), a novel inhibitor of PDE3 and PDE4, were recently published. ENHANCE-1 and ENHANCE-2 studies indicate that twice daily nebulized ensifentrine reduces the risk of COPD exacerbations in patients with moderate or severe COPD.⁸ Ensifentrine is under review by the FDA, and a decision about its use in the US is expected in the summer of 2024.

Until the results from the RELIANCE clinical trial and the decision by the FDA about ensifentrine are available, we recommended a discussion with Ms. Turner about whether to initiate treatment with maintenance roflumilast or azithromycin. Both can reduce the risk of exacerbations, and the relative benefits and risks of these two evidence-based options are not yet known. Unless Ms. Turner has specific preferences (eg, concerns about specific adverse effects or differences in out-of-pocket cost) in favor of one over the other, she could flip a coin to decide between initiating maintenance roflumilast or azithromycin.
 

Dr. Krishnan is Professor of Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy, and Professor of Public Health, Division of Epidemiology and Biostatistics, University of Illinois Chicago. Dr. Adrish is Associate Professor, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston.

References:

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report. https://goldcopd.org/2024-gold-report-2/

2. US Food and Drug Administration (Daliresp^®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf

3. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromucin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. PMID: 21864166. doi: 10.1056/NEJMoa1104623.

4. US Food and Drug Administration (Zithromyax^®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf

5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acure exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4)894-942. PMID: 25321320. doi: 10.1378/chest.14-1676.

6. Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265. PMID: 28889106. doi:10.1183/13993003.02265-2016.

7. Krishnan JA, Albert RK, Rennard SI; RELIANCE study. Waiting for actionable evidence: roflumilast or azithromycin? Chronic Obst Pulm Dis. 2022;9(1):1-3. PMID: 34783231. doi: 10.15326/jcopdf.2021.0272.

8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phospodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. PMID: 37364283.

“Janice Turner” (name changed to protect confidentiality) is a 66-year-old woman with a 40-pack per year history of smoking. She quit smoking 1 year ago and presents to your office for a follow-up visit after discharge from the hospital 14 days ago. This was her second hospitalization for a COPD exacerbation in the past 12 months. She is very worried about having another COPD exacerbation and wants to know if there are additional medications she could try.

Over the past 2 weeks, her respiratory symptoms have improved and returned to her baseline. She has a daily cough with white phlegm on most days and dyspnea on exertion at one-half block on level ground. She reports using her medications as prescribed and is enrolled in a pulmonary rehabilitation program, which she attends twice per week. She uses 2 to 4 inhalations of albuterol each day.

CHEST

She is on the following regimen for her COPD, which is unchanged compared with what she has been prescribed for the past 12 months: 1) combination inhaled fluticasone furoate, umeclidinium, and vilanterol via the Ellipta^® device, one actuation once daily and 2) inhaled albuterol, two puffs as needed every 4 hours via metered dose inhaler. She demonstrates mastery of inhaler technique for both inhaled devices. Her vaccinations are current (pneumococcus, influenza, respiratory syncytial virus, and COVID-19).

On examination, she can complete sentences without respiratory difficulty, and her vital signs are normal. She has decreased breath sounds in all lung fields, with occasional rhonchi. Heart sounds are distant, but regular, at 92 beats per minute, and she has no peripheral edema. Arterial blood gas at rest on room air indicates a pH of 7.38, PaO₂ of 63 mm Hg, and PaCO₂ of 42 mm Hg. An electrocardiogram shows sinus rhythm and a QTc interval of 420 milliseconds.

Three months ago, when she was clinically stable, you obtained spirometry, a complete blood count with differential, and a chest radiograph to exclude alternate diagnoses for her ongoing respiratory symptoms. She had severe airflow limitation (post-bronchodilator FEV₁ = 40% predicted, FVC = 61% predicted, FEV₁/FVC = 65%). At the time, she also had peripheral eosinophilia (eosinophil count of 350 cells/μL) and hyperinflation without parenchymal infiltrates.

CHEST

In summary, Ms. Turner has severe smoking-associated COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3E and chronic bronchitis with two severe exacerbations in the past 12 months.¹ She is currently prescribed triple inhaled maintenance therapy with corticosteroids, long-acting β₂-agonist, and long-acting muscarinic antagonist. She has a normal QTc interval.

So what would you recommend to reduce Ms. Turner’s risk of future exacerbations?

In 2011, the US Food and Drug Administration (FDA) approved roflumilast 500 mcg by mouth per day, a selective phosphodiesterase 4 (PDE4) inhibitor, as maintenance therapy to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis.² The FDA approval was based on a review of the efficacy and safety of roflumilast in eight randomized, double-blind, controlled clinical trials in 9,394 adults with COPD.

Two subsequently completed randomized clinical trials in 2015 (REACT, 1,945 adults) and 2016 (RE2SPOND, 2,354 adults) also found that maintenance oral treatment escalation with roflumilast significantly reduced the risk of COPD exacerbations compared with placebo.² The most common adverse effects reported with long-term use of roflumilast are related to the gastrointestinal tract (diarrhea, nausea, decreased appetite), weight loss, and insomnia. Four weeks of roflumilast at 250 mcg per day prior to dose escalation to 500 mcg per day reduces the risk of treatment discontinuation and improves tolerability compared with initiating treatment with the maintenance dose.

In 2022, the FDA approved a generic version of roflumilast, providing an opportunity for patients to use roflumilast at a lower cost than was previously possible. Importantly, the FDA Prescribing Information includes a warning to avoid the use of roflumilast in patients being treated with strong cytochrome P450 enzyme inducers (eg, rifampin, phenytoin). The FDA Prescribing Information also recommends weighing the risks and benefits of roflumilast in patients with a history of depression or suicidal thoughts or behavior, or patients with unexplained or clinically significant weight loss.

In 2011 (the same year as the FDA approval of roflumilast), the National Institutes of Health/National Heart, Lung, and Blood Institute-funded COPD Clinical Research Network reported that maintenance treatment with azithromycin reduced the risk of COPD exacerbations compared with placebo in a randomized clinical trial of 1,142 adults with COPD (MACRO study).³ Subgroup analyses indicated that the reduction in the risk of COPD exacerbations with azithromycin was observed in participants with or without chronic bronchitis but not in participants who currently smoked.

Subsequently, two other smaller randomized clinical trials in 2014 (COLUMBUS, 92 participants) and in 2019 (BACE, 301 participants) also demonstrated a reduction in the risk of COPD exacerbations with maintenance azithromycin treatment compared with placebo. Azithromycin can prolong the QT interval and, in rare cases, cause cardiac arrythmias, especially when used with other medications that can prolong the QT interval. There are also concerns that maintenance azithromycin therapy could lead to decrements in hearing or promote the development of macrolide-resistant bacteria. Maintenance treatment with azithromycin to prevent COPD exacerbations is not an FDA-approved indication.⁴ The FDA approval for azithromycin is currently limited to treatment of patients with mild to moderate infections caused by susceptible bacteria, but it is often prescribed off-label as maintenance treatment for COPD.

On the basis of this body of evidence from clinical trials in COPD, the 2015 CHEST and Canadian Thoracic Society (CTS) guidelines,⁵ the 2017 European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines,⁶ and the 2024 GOLD Strategy Report all include recommendations for treatment escalation with maintenance roflumilast or azithromycin to reduce the risk of COPD exacerbations. For example, the 2024 GOLD Strategy Report recommends roflumilast in patients with severe COPD and chronic bronchitis who continue to have exacerbations despite inhaled maintenance treatment with combination long-acting β₂-agonist and long-acting muscarinic antagonist or with triple therapy with inhaled corticosteroids, long-acting β₂-agonist, and long-acting muscarinic antagonist. An alternative, 2024 GOLD-recommended strategy in this population is maintenance therapy with azithromycin, “preferentially in former smokers.” GOLD’s preference for using azithromycin in patients with smoking history is based on post-hoc (ie, not part of the original study design) subgroup analyses “suggesting lesser benefit in active smokers” in the MACRO study. Results of such analyses have not been reported in other studies.

There are no results from clinical trials that have directly compared the harms and benefits of initiating maintenance therapy with roflumilast or azithromycin in patients with COPD. The roflumilast or azithromycin to prevent COPD exacerbations (RELIANCE; NCT04069312) multicenter clinical trial is addressing this evidence gap.⁷ The RELIANCE study is funded by the Patient-Centered Outcomes Research Institute and co-led by the COPD Foundation, a not-for-profit organization founded by John W. Walsh, a patient advocate with α1-related COPD. Also, results of two recently completed phase 3 clinical trials with nebulized ensifentrine (ENHANCE-1 and ENHANCE-2), a novel inhibitor of PDE3 and PDE4, were recently published. ENHANCE-1 and ENHANCE-2 studies indicate that twice daily nebulized ensifentrine reduces the risk of COPD exacerbations in patients with moderate or severe COPD.⁸ Ensifentrine is under review by the FDA, and a decision about its use in the US is expected in the summer of 2024.

Until the results from the RELIANCE clinical trial and the decision by the FDA about ensifentrine are available, we recommended a discussion with Ms. Turner about whether to initiate treatment with maintenance roflumilast or azithromycin. Both can reduce the risk of exacerbations, and the relative benefits and risks of these two evidence-based options are not yet known. Unless Ms. Turner has specific preferences (eg, concerns about specific adverse effects or differences in out-of-pocket cost) in favor of one over the other, she could flip a coin to decide between initiating maintenance roflumilast or azithromycin.
 

Dr. Krishnan is Professor of Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy, and Professor of Public Health, Division of Epidemiology and Biostatistics, University of Illinois Chicago. Dr. Adrish is Associate Professor, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston.

References:

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report. https://goldcopd.org/2024-gold-report-2/

2. US Food and Drug Administration (Daliresp^®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf

3. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromucin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. PMID: 21864166. doi: 10.1056/NEJMoa1104623.

4. US Food and Drug Administration (Zithromyax^®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf

5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acure exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4)894-942. PMID: 25321320. doi: 10.1378/chest.14-1676.

6. Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265. PMID: 28889106. doi:10.1183/13993003.02265-2016.

7. Krishnan JA, Albert RK, Rennard SI; RELIANCE study. Waiting for actionable evidence: roflumilast or azithromycin? Chronic Obst Pulm Dis. 2022;9(1):1-3. PMID: 34783231. doi: 10.15326/jcopdf.2021.0272.

8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phospodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. PMID: 37364283.

The American Academy of Sleep Medicine recently published its position statement reaffirming its support of utilizing permanent Standard Time (ST) as opposed to Daylight Saving Time (DST).¹ DST usually occurs on the second Sunday in March when we “spring forward” by advancing the clock by 1 hour. The analogous “fall back” on the first Sunday in November refers to reversion back to the original ST, which is more synchronous with the sun’s natural pattern of rise and fall.

The earliest argument for DST practice dates back to the 1700s when Benjamin Franklin wrote a satirical piece in the Journal of Paris suggesting that advancing the clock to rise earlier in the summer would lead to economization in candle usage and save significant resources for Parisians. The modern version of this assertion infers that increased daylight in the evening will lead to increased consumer activity and work productivity with consequent economic benefits. Interestingly, the adoption of DST has demonstrated the opposite—a reduction in work productivity and economic losses.² Another often-cited claim is that increased daylight in the evening could lead to fewer motor vehicle accidents. However, the reality is that DST is associated with more frequent car accidents in the morning.

The greatest drawback of DST is that, initially, it leads to sleep deprivation and chronically drives asynchronization between the circadian clock and the social clock. Humans synchronize their internal clock based on several factors, including light, temperature, feeding, and social habits. However, light is the strongest exogenous factor that regulates the internal clock. Light inhibits secretion of melatonin, an endogenous hormone that promotes sleep onset. While there is some individual variation in circadian patterns, exposure to bright light in the morning leads to increased physical, mental, and goal-directed activity.

Conversely, darkness or reduced light exposure in the evening hours promotes decreased activity and sleep onset via melatonin release. DST disrupts this natural process by promoting increased light exposure in the evening. This desynchronizes solar light from our internal clocks, causing a relative phase delay. Acutely, patients experience a form of imposed social jet lag. They lose an hour of sleep due to diminished sleep opportunity, as work and social obligations are typically not altered to allow for a later awakening. With recurrent delays, this lends to a pattern of chronic sleep deprivation which has significant health consequences.

Losing an hour of sleep opportunity as the clock advances in spring has dire consequences. The transition to DST is associated with increased cardiovascular events, including myocardial infarction, stroke, and admissions for acute atrial fibrillation.^{3 4 5} A large body of work has shown that acute reduction of sleep is associated with higher sympathetic tone, compromised immunity, and increased inflammation. Further, cognitive consequences can ensue in the form of altered situational awareness, increased risky behavior, and worse reaction time—which manifest as increased motor vehicle accidents, injuries, and fatalities.⁶ Emergency room visits and bounce-back admissions, medical errors and injuries, and missed appointments increase following the switch to DST.⁷ Psychiatric outcomes, including deaths due to suicide and overdose, are worse with the spring transition.⁸

Is the problem with DST merely limited to springtime, when we lose an hour of sleep? Not quite. During the “fall back” period, despite theoretically gaining an hour of sleep opportunity, people exhibit evidence of sleep disruption, psychiatric issues, traffic accidents, and inflammatory bowel disease exacerbations. These consequences likely stem from a discordance between circadian and social time, which leads to an earlier awakening based on circadian physiology as opposed to the clock time.

The acute impact of changing our sleep patterns during transitions in clock time may be appreciated more readily, but the damage is much more insidious. Chronic exposure to light in the late evening creates a state of enhanced arousal when the body should be winding down. The chronic incongruency between clock and solar time leads to dyssynchrony in our usual functions, such as food intake, social and physical activity, and basal temperature. Consequently, there is an impetus to fall asleep later. This leads to an accumulation of sleep debt and its associated negative consequences in the general, already chronically sleep-deprived population. This is especially impactful to adolescents and young adults who tend to have a delay in their sleep and wake patterns and, yet, are socially bound to early morning awakenings for school or work.

The scientific evidence behind the health risk and benefit profile of DST and ST is incontrovertible and in favor of ST. The hallmark of appropriate sleep habits involves consistency and appropriate duration. Changing timing forward or backward increases the likelihood of an alteration of the baseline established sleep and circadian consistency.

Unfortunately, despite multiple polls demonstrating the populace’s dislike of DST, repeat attempts to codify DST and negate ST persist. The latest initiative, the Sunshine Protection Act, which promised permanent DST, was passed by the US Senate but was thankfully foiled by Congress in 2022. The act of setting a time is not one that should be taken lightly or in isolation because there are significant, long-lasting health, safety, and socioeconomic consequences of this decision. Practically, this entails a concerted effort from all major economies since consistency is essential for trade and geopolitical relations. China, Japan, and India don’t practice DST. The European Parliament voted successfully to abolish DST in the European Union in 2019 with a plan to implement ST in 2021. Implementation has yet to be successful due to interruptions from the COVID-19 pandemic as well as the current economic and political climate in Europe. Political or theoretical political victories should not supersede the health and safety of an elected official’s constituents. As a medical community, we should continue to use our collective voice to encourage our representatives to vote in ways that positively affect our patients’ health outcomes.

References:

1. Rishi MA, et al. JCSM. 2024;20(1):121.

2. Gibson M, et al. Rev Econ Stat. 2018;100(5):783.

3. Jansky I, et al. N Engl J Med. 2008;359(18):1966.

4. Sipilia J, et al. Sleep Med. 2016;27-28:20.

5. Chudow JJ, et al. Sleep Med. 2020;69:155.

6. Fritz J, et al. Curr Biol. 2020;30(4):729.

7. Ferrazzi E, et al. J Biol Rhythms. 2018;33(5):555-564.

8. Berk M, et al. Sleep Biol Rhythms. 2008;6(1):22.

The American Academy of Sleep Medicine recently published its position statement reaffirming its support of utilizing permanent Standard Time (ST) as opposed to Daylight Saving Time (DST).¹ DST usually occurs on the second Sunday in March when we “spring forward” by advancing the clock by 1 hour. The analogous “fall back” on the first Sunday in November refers to reversion back to the original ST, which is more synchronous with the sun’s natural pattern of rise and fall.

The earliest argument for DST practice dates back to the 1700s when Benjamin Franklin wrote a satirical piece in the Journal of Paris suggesting that advancing the clock to rise earlier in the summer would lead to economization in candle usage and save significant resources for Parisians. The modern version of this assertion infers that increased daylight in the evening will lead to increased consumer activity and work productivity with consequent economic benefits. Interestingly, the adoption of DST has demonstrated the opposite—a reduction in work productivity and economic losses.² Another often-cited claim is that increased daylight in the evening could lead to fewer motor vehicle accidents. However, the reality is that DST is associated with more frequent car accidents in the morning.

The greatest drawback of DST is that, initially, it leads to sleep deprivation and chronically drives asynchronization between the circadian clock and the social clock. Humans synchronize their internal clock based on several factors, including light, temperature, feeding, and social habits. However, light is the strongest exogenous factor that regulates the internal clock. Light inhibits secretion of melatonin, an endogenous hormone that promotes sleep onset. While there is some individual variation in circadian patterns, exposure to bright light in the morning leads to increased physical, mental, and goal-directed activity.

Conversely, darkness or reduced light exposure in the evening hours promotes decreased activity and sleep onset via melatonin release. DST disrupts this natural process by promoting increased light exposure in the evening. This desynchronizes solar light from our internal clocks, causing a relative phase delay. Acutely, patients experience a form of imposed social jet lag. They lose an hour of sleep due to diminished sleep opportunity, as work and social obligations are typically not altered to allow for a later awakening. With recurrent delays, this lends to a pattern of chronic sleep deprivation which has significant health consequences.

Losing an hour of sleep opportunity as the clock advances in spring has dire consequences. The transition to DST is associated with increased cardiovascular events, including myocardial infarction, stroke, and admissions for acute atrial fibrillation.^{3 4 5} A large body of work has shown that acute reduction of sleep is associated with higher sympathetic tone, compromised immunity, and increased inflammation. Further, cognitive consequences can ensue in the form of altered situational awareness, increased risky behavior, and worse reaction time—which manifest as increased motor vehicle accidents, injuries, and fatalities.⁶ Emergency room visits and bounce-back admissions, medical errors and injuries, and missed appointments increase following the switch to DST.⁷ Psychiatric outcomes, including deaths due to suicide and overdose, are worse with the spring transition.⁸

Is the problem with DST merely limited to springtime, when we lose an hour of sleep? Not quite. During the “fall back” period, despite theoretically gaining an hour of sleep opportunity, people exhibit evidence of sleep disruption, psychiatric issues, traffic accidents, and inflammatory bowel disease exacerbations. These consequences likely stem from a discordance between circadian and social time, which leads to an earlier awakening based on circadian physiology as opposed to the clock time.

The acute impact of changing our sleep patterns during transitions in clock time may be appreciated more readily, but the damage is much more insidious. Chronic exposure to light in the late evening creates a state of enhanced arousal when the body should be winding down. The chronic incongruency between clock and solar time leads to dyssynchrony in our usual functions, such as food intake, social and physical activity, and basal temperature. Consequently, there is an impetus to fall asleep later. This leads to an accumulation of sleep debt and its associated negative consequences in the general, already chronically sleep-deprived population. This is especially impactful to adolescents and young adults who tend to have a delay in their sleep and wake patterns and, yet, are socially bound to early morning awakenings for school or work.

The scientific evidence behind the health risk and benefit profile of DST and ST is incontrovertible and in favor of ST. The hallmark of appropriate sleep habits involves consistency and appropriate duration. Changing timing forward or backward increases the likelihood of an alteration of the baseline established sleep and circadian consistency.

Unfortunately, despite multiple polls demonstrating the populace’s dislike of DST, repeat attempts to codify DST and negate ST persist. The latest initiative, the Sunshine Protection Act, which promised permanent DST, was passed by the US Senate but was thankfully foiled by Congress in 2022. The act of setting a time is not one that should be taken lightly or in isolation because there are significant, long-lasting health, safety, and socioeconomic consequences of this decision. Practically, this entails a concerted effort from all major economies since consistency is essential for trade and geopolitical relations. China, Japan, and India don’t practice DST. The European Parliament voted successfully to abolish DST in the European Union in 2019 with a plan to implement ST in 2021. Implementation has yet to be successful due to interruptions from the COVID-19 pandemic as well as the current economic and political climate in Europe. Political or theoretical political victories should not supersede the health and safety of an elected official’s constituents. As a medical community, we should continue to use our collective voice to encourage our representatives to vote in ways that positively affect our patients’ health outcomes.

References:

1. Rishi MA, et al. JCSM. 2024;20(1):121.

2. Gibson M, et al. Rev Econ Stat. 2018;100(5):783.

3. Jansky I, et al. N Engl J Med. 2008;359(18):1966.

4. Sipilia J, et al. Sleep Med. 2016;27-28:20.

5. Chudow JJ, et al. Sleep Med. 2020;69:155.

6. Fritz J, et al. Curr Biol. 2020;30(4):729.

7. Ferrazzi E, et al. J Biol Rhythms. 2018;33(5):555-564.

8. Berk M, et al. Sleep Biol Rhythms. 2008;6(1):22.

The American Academy of Sleep Medicine recently published its position statement reaffirming its support of utilizing permanent Standard Time (ST) as opposed to Daylight Saving Time (DST).¹ DST usually occurs on the second Sunday in March when we “spring forward” by advancing the clock by 1 hour. The analogous “fall back” on the first Sunday in November refers to reversion back to the original ST, which is more synchronous with the sun’s natural pattern of rise and fall.

The earliest argument for DST practice dates back to the 1700s when Benjamin Franklin wrote a satirical piece in the Journal of Paris suggesting that advancing the clock to rise earlier in the summer would lead to economization in candle usage and save significant resources for Parisians. The modern version of this assertion infers that increased daylight in the evening will lead to increased consumer activity and work productivity with consequent economic benefits. Interestingly, the adoption of DST has demonstrated the opposite—a reduction in work productivity and economic losses.² Another often-cited claim is that increased daylight in the evening could lead to fewer motor vehicle accidents. However, the reality is that DST is associated with more frequent car accidents in the morning.

The greatest drawback of DST is that, initially, it leads to sleep deprivation and chronically drives asynchronization between the circadian clock and the social clock. Humans synchronize their internal clock based on several factors, including light, temperature, feeding, and social habits. However, light is the strongest exogenous factor that regulates the internal clock. Light inhibits secretion of melatonin, an endogenous hormone that promotes sleep onset. While there is some individual variation in circadian patterns, exposure to bright light in the morning leads to increased physical, mental, and goal-directed activity.

Conversely, darkness or reduced light exposure in the evening hours promotes decreased activity and sleep onset via melatonin release. DST disrupts this natural process by promoting increased light exposure in the evening. This desynchronizes solar light from our internal clocks, causing a relative phase delay. Acutely, patients experience a form of imposed social jet lag. They lose an hour of sleep due to diminished sleep opportunity, as work and social obligations are typically not altered to allow for a later awakening. With recurrent delays, this lends to a pattern of chronic sleep deprivation which has significant health consequences.

Losing an hour of sleep opportunity as the clock advances in spring has dire consequences. The transition to DST is associated with increased cardiovascular events, including myocardial infarction, stroke, and admissions for acute atrial fibrillation.^{3 4 5} A large body of work has shown that acute reduction of sleep is associated with higher sympathetic tone, compromised immunity, and increased inflammation. Further, cognitive consequences can ensue in the form of altered situational awareness, increased risky behavior, and worse reaction time—which manifest as increased motor vehicle accidents, injuries, and fatalities.⁶ Emergency room visits and bounce-back admissions, medical errors and injuries, and missed appointments increase following the switch to DST.⁷ Psychiatric outcomes, including deaths due to suicide and overdose, are worse with the spring transition.⁸

Is the problem with DST merely limited to springtime, when we lose an hour of sleep? Not quite. During the “fall back” period, despite theoretically gaining an hour of sleep opportunity, people exhibit evidence of sleep disruption, psychiatric issues, traffic accidents, and inflammatory bowel disease exacerbations. These consequences likely stem from a discordance between circadian and social time, which leads to an earlier awakening based on circadian physiology as opposed to the clock time.

The acute impact of changing our sleep patterns during transitions in clock time may be appreciated more readily, but the damage is much more insidious. Chronic exposure to light in the late evening creates a state of enhanced arousal when the body should be winding down. The chronic incongruency between clock and solar time leads to dyssynchrony in our usual functions, such as food intake, social and physical activity, and basal temperature. Consequently, there is an impetus to fall asleep later. This leads to an accumulation of sleep debt and its associated negative consequences in the general, already chronically sleep-deprived population. This is especially impactful to adolescents and young adults who tend to have a delay in their sleep and wake patterns and, yet, are socially bound to early morning awakenings for school or work.

The scientific evidence behind the health risk and benefit profile of DST and ST is incontrovertible and in favor of ST. The hallmark of appropriate sleep habits involves consistency and appropriate duration. Changing timing forward or backward increases the likelihood of an alteration of the baseline established sleep and circadian consistency.

Unfortunately, despite multiple polls demonstrating the populace’s dislike of DST, repeat attempts to codify DST and negate ST persist. The latest initiative, the Sunshine Protection Act, which promised permanent DST, was passed by the US Senate but was thankfully foiled by Congress in 2022. The act of setting a time is not one that should be taken lightly or in isolation because there are significant, long-lasting health, safety, and socioeconomic consequences of this decision. Practically, this entails a concerted effort from all major economies since consistency is essential for trade and geopolitical relations. China, Japan, and India don’t practice DST. The European Parliament voted successfully to abolish DST in the European Union in 2019 with a plan to implement ST in 2021. Implementation has yet to be successful due to interruptions from the COVID-19 pandemic as well as the current economic and political climate in Europe. Political or theoretical political victories should not supersede the health and safety of an elected official’s constituents. As a medical community, we should continue to use our collective voice to encourage our representatives to vote in ways that positively affect our patients’ health outcomes.

References:

1. Rishi MA, et al. JCSM. 2024;20(1):121.

2. Gibson M, et al. Rev Econ Stat. 2018;100(5):783.

3. Jansky I, et al. N Engl J Med. 2008;359(18):1966.

4. Sipilia J, et al. Sleep Med. 2016;27-28:20.

5. Chudow JJ, et al. Sleep Med. 2020;69:155.

6. Fritz J, et al. Curr Biol. 2020;30(4):729.

7. Ferrazzi E, et al. J Biol Rhythms. 2018;33(5):555-564.

8. Berk M, et al. Sleep Biol Rhythms. 2008;6(1):22.

Now is the time for pulmonary clinicians to become comfortable counseling patients about and treating obesity. By 2030, half of the US population will have obesity, a quarter of which will be severe (Ward et al. NEJM. 2019;2440-2450).

Many pulmonary diseases, including asthma, COPD, and interstitial pulmonary fibrosis (IPF) are linked to and made worse by obesity with increased exacerbations, patient-reported decreased quality of life, and resistance to therapy (Ray et al. Am Rev Respir Dis. 1983;501-6). Asthma is even recognized as an obesity-related comorbid condition by both the American Society Metabolic and Bariatric Surgery (ASMBS) and the American Association of Clinical Endocrinologists (AACE) when considering indications for early or more aggressive treatment of obesity (Eisenberg et al. Obesity Surg. 2023;3-14) (Garvey et al. Endocr Pract. 2016;1-203).

Obesity has multiple negative effects on pulmonary function due to the physical forces of extra weight on the lungs and inflammation related to adipose tissue (see Figure 1) (Zerah et al. Chest. 1993;1470-6).

CHEST

Obesity-related respiratory changes include reduced lung compliance, functional residual capacity (FRC), and expiratory reserve volume (ERV). These changes lead to peripheral atelectasis and V/Q mismatch and increased metabolic demands placed on the respiratory system (Parameswaran et al. Can Respir J. 2006;203-10). The increased weight supported by the thoracic cage alters the equilibrium between the chest wall and lung tissue decreasing FRC and ERV. This reduces lung compliance and increases stiffness by promoting areas of atelectasis and increased alveolar surface tension (Dixon et al. Expert Rev Respir Med. 2018;755-67).

CHEST

Another biomechanical cost of obesity on respiratory function is the increased consumption of oxygen to sustain ventilation at rest (Koenig SM, Am J Med Sci. 2001;249-79). This can lead to early respiratory muscle fatigue when respiratory rate and tidal volume increase with activity. Patients with obesity are more likely to develop obstructive sleep apnea and obesity hypoventilation syndrome. The resulting alveolar hypoxemia is thought to contribute to the increase in pulmonary hypertension observed in patients with obesity (Shah et al. Breathe. 2023;19[1]). In addition to the biomechanical consequences of obesity, increased adipose tissue can lead to chronic, systemic inflammation that can exacerbate or unmask underlying respiratory disease. Increased leptin and downregulation of adiponectin have been shown to increase systemic cytokine production (Ray et al. Am Rev Respir Dis. 1983;501-6). This inflammatory process contributes to increased airway resistance and an altered response to corticosteroids (inhaled or systemic) in obese patients treated for bronchial hyperresponsiveness. This perhaps reflects the Th2-low phenotype seen in patients with obesity and metabolic syndrome-related asthma (Shah et al. Breathe. 2023;19[1]) (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812).

CHEST

Multiple studies have demonstrated weight loss through lifestyle changes, medical therapy, and obesity surgery result benefits pulmonary disease (Forno et al. PloS One. 2019;14[4]) (Ardila-Gatas et al. Surg Endosc. 2019;1952-8). Benefits include decreased exacerbation frequency, improved functional testing, and improved patient-reported quality of life. Pulmonary clinicians should be empowered to address obesity as a comorbid condition and treat with appropriate referrals for obesity surgery and initiation of medications when indicated.
 

GLP-1 receptor agonists

In the past year, glucagon-like peptide receptor agonists (GLP-1RAs) have garnered attention in the medical literature and popular news outlets. GLP-1RAs, including semaglutide, liraglutide, and tirzepatide, are currently FDA approved for the treatment of obesity in patients with a body mass index (BMI) greater than or equal to 30 or a BMI greater than or equal to 27 in the setting of an obesity-related comorbidity, including asthma.

This class of medications acts by increasing the physiologic insulin response to a glucose load, delaying gastric emptying, and reducing production of glucagon. In a phase III study, semaglutide resulted in greater than 15% weight reduction from baseline (Wadden et al. JAMA. 2021;1403-13). In clinical trials, these medications have not only resulted in significant, sustained weight loss but also improved lipid profiles, decreased A1c, and reduced major cardiovascular events (Lincoff et al. N Engl J Med. 2023;389[23]:2221-32) (Verma et al. Circulation. 2018;138[25]:2884-94).
 

GLP-1RAs and lung disease

GLP-1RAs are associated with ranges of weight loss that lead to symptom improvement. Beyond the anticipated benefits for pulmonary health, there is interest in whether GLP-1RAs may improve specific lung diseases. GLP-1 receptors are found throughout the body (eg, gastrointestinal tract, kidneys, and heart) with the largest proportion located in the lungs (Wu AY and Peebles RS. Expert Rev Clin Immunol. 2021;1053-7). In addition to their known effect on insulin response, GLP-1RAs are hypothesized to reduce proinflammatory cytokine signaling and alter surfactant production potentially improving both airway resistance and lung compliance (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812). Animal models suggest an antifibrotic effect with delay in the endothelial-mesenchymal transition. If further substantiated, this could impact both acute and chronic lung injury.

Early clinical studies of GLP-1RAs in patients with respiratory diseases have demonstrated improved symptoms and pulmonary function (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812). Even modest weight loss (2.5 kg in a year) with GLP-1RAs leads to improved symptoms and a reduction in asthma exacerbations. Other asthma literature shows GLP-1RAs improve symptoms and reduce exacerbations independent of changes in weight, supporting the hypothesis that the benefit of GLP-1RAs may be more than biomechanical improvement from weight loss alone (Foer et al. Am J Respir Crit Care Med. 2021;831-40).

GLP-1RAs reduce the proinflammatory cytokine signaling in both TH2-high and TH2-low asthma phenotypes and alter surfactant production, airway resistance, and perhaps even pulmonary vascular resistance (Altintas Dogan et al. Int J Chron Obstruct Pulmon Dis. 2022,405-14). GATA-3 is an ongoing clinical trial examining whether GLP-1RAs reduce airway inflammation via direct effects on of the respiratory tract (NCT05254314).

Drugs developed to treat one condition are often found to impact others during validation studies or postmarketing observation. Some examples are aspirin, sildenafil, minoxidil, hydroxychloroquine, and SGLT-2 inhibitors. Will GLP-1RAs be the latest medication to affect a broad array of physiologic process and end up improving not just metabolic but also lung health?

Now is the time for pulmonary clinicians to become comfortable counseling patients about and treating obesity. By 2030, half of the US population will have obesity, a quarter of which will be severe (Ward et al. NEJM. 2019;2440-2450).

Many pulmonary diseases, including asthma, COPD, and interstitial pulmonary fibrosis (IPF) are linked to and made worse by obesity with increased exacerbations, patient-reported decreased quality of life, and resistance to therapy (Ray et al. Am Rev Respir Dis. 1983;501-6). Asthma is even recognized as an obesity-related comorbid condition by both the American Society Metabolic and Bariatric Surgery (ASMBS) and the American Association of Clinical Endocrinologists (AACE) when considering indications for early or more aggressive treatment of obesity (Eisenberg et al. Obesity Surg. 2023;3-14) (Garvey et al. Endocr Pract. 2016;1-203).

Obesity has multiple negative effects on pulmonary function due to the physical forces of extra weight on the lungs and inflammation related to adipose tissue (see Figure 1) (Zerah et al. Chest. 1993;1470-6).

CHEST

Obesity-related respiratory changes include reduced lung compliance, functional residual capacity (FRC), and expiratory reserve volume (ERV). These changes lead to peripheral atelectasis and V/Q mismatch and increased metabolic demands placed on the respiratory system (Parameswaran et al. Can Respir J. 2006;203-10). The increased weight supported by the thoracic cage alters the equilibrium between the chest wall and lung tissue decreasing FRC and ERV. This reduces lung compliance and increases stiffness by promoting areas of atelectasis and increased alveolar surface tension (Dixon et al. Expert Rev Respir Med. 2018;755-67).

CHEST

Another biomechanical cost of obesity on respiratory function is the increased consumption of oxygen to sustain ventilation at rest (Koenig SM, Am J Med Sci. 2001;249-79). This can lead to early respiratory muscle fatigue when respiratory rate and tidal volume increase with activity. Patients with obesity are more likely to develop obstructive sleep apnea and obesity hypoventilation syndrome. The resulting alveolar hypoxemia is thought to contribute to the increase in pulmonary hypertension observed in patients with obesity (Shah et al. Breathe. 2023;19[1]). In addition to the biomechanical consequences of obesity, increased adipose tissue can lead to chronic, systemic inflammation that can exacerbate or unmask underlying respiratory disease. Increased leptin and downregulation of adiponectin have been shown to increase systemic cytokine production (Ray et al. Am Rev Respir Dis. 1983;501-6). This inflammatory process contributes to increased airway resistance and an altered response to corticosteroids (inhaled or systemic) in obese patients treated for bronchial hyperresponsiveness. This perhaps reflects the Th2-low phenotype seen in patients with obesity and metabolic syndrome-related asthma (Shah et al. Breathe. 2023;19[1]) (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812).

CHEST

Multiple studies have demonstrated weight loss through lifestyle changes, medical therapy, and obesity surgery result benefits pulmonary disease (Forno et al. PloS One. 2019;14[4]) (Ardila-Gatas et al. Surg Endosc. 2019;1952-8). Benefits include decreased exacerbation frequency, improved functional testing, and improved patient-reported quality of life. Pulmonary clinicians should be empowered to address obesity as a comorbid condition and treat with appropriate referrals for obesity surgery and initiation of medications when indicated.
 

GLP-1 receptor agonists

In the past year, glucagon-like peptide receptor agonists (GLP-1RAs) have garnered attention in the medical literature and popular news outlets. GLP-1RAs, including semaglutide, liraglutide, and tirzepatide, are currently FDA approved for the treatment of obesity in patients with a body mass index (BMI) greater than or equal to 30 or a BMI greater than or equal to 27 in the setting of an obesity-related comorbidity, including asthma.

This class of medications acts by increasing the physiologic insulin response to a glucose load, delaying gastric emptying, and reducing production of glucagon. In a phase III study, semaglutide resulted in greater than 15% weight reduction from baseline (Wadden et al. JAMA. 2021;1403-13). In clinical trials, these medications have not only resulted in significant, sustained weight loss but also improved lipid profiles, decreased A1c, and reduced major cardiovascular events (Lincoff et al. N Engl J Med. 2023;389[23]:2221-32) (Verma et al. Circulation. 2018;138[25]:2884-94).
 

GLP-1RAs and lung disease

GLP-1RAs are associated with ranges of weight loss that lead to symptom improvement. Beyond the anticipated benefits for pulmonary health, there is interest in whether GLP-1RAs may improve specific lung diseases. GLP-1 receptors are found throughout the body (eg, gastrointestinal tract, kidneys, and heart) with the largest proportion located in the lungs (Wu AY and Peebles RS. Expert Rev Clin Immunol. 2021;1053-7). In addition to their known effect on insulin response, GLP-1RAs are hypothesized to reduce proinflammatory cytokine signaling and alter surfactant production potentially improving both airway resistance and lung compliance (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812). Animal models suggest an antifibrotic effect with delay in the endothelial-mesenchymal transition. If further substantiated, this could impact both acute and chronic lung injury.

Early clinical studies of GLP-1RAs in patients with respiratory diseases have demonstrated improved symptoms and pulmonary function (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812). Even modest weight loss (2.5 kg in a year) with GLP-1RAs leads to improved symptoms and a reduction in asthma exacerbations. Other asthma literature shows GLP-1RAs improve symptoms and reduce exacerbations independent of changes in weight, supporting the hypothesis that the benefit of GLP-1RAs may be more than biomechanical improvement from weight loss alone (Foer et al. Am J Respir Crit Care Med. 2021;831-40).

GLP-1RAs reduce the proinflammatory cytokine signaling in both TH2-high and TH2-low asthma phenotypes and alter surfactant production, airway resistance, and perhaps even pulmonary vascular resistance (Altintas Dogan et al. Int J Chron Obstruct Pulmon Dis. 2022,405-14). GATA-3 is an ongoing clinical trial examining whether GLP-1RAs reduce airway inflammation via direct effects on of the respiratory tract (NCT05254314).

Drugs developed to treat one condition are often found to impact others during validation studies or postmarketing observation. Some examples are aspirin, sildenafil, minoxidil, hydroxychloroquine, and SGLT-2 inhibitors. Will GLP-1RAs be the latest medication to affect a broad array of physiologic process and end up improving not just metabolic but also lung health?

Now is the time for pulmonary clinicians to become comfortable counseling patients about and treating obesity. By 2030, half of the US population will have obesity, a quarter of which will be severe (Ward et al. NEJM. 2019;2440-2450).

Many pulmonary diseases, including asthma, COPD, and interstitial pulmonary fibrosis (IPF) are linked to and made worse by obesity with increased exacerbations, patient-reported decreased quality of life, and resistance to therapy (Ray et al. Am Rev Respir Dis. 1983;501-6). Asthma is even recognized as an obesity-related comorbid condition by both the American Society Metabolic and Bariatric Surgery (ASMBS) and the American Association of Clinical Endocrinologists (AACE) when considering indications for early or more aggressive treatment of obesity (Eisenberg et al. Obesity Surg. 2023;3-14) (Garvey et al. Endocr Pract. 2016;1-203).

Obesity has multiple negative effects on pulmonary function due to the physical forces of extra weight on the lungs and inflammation related to adipose tissue (see Figure 1) (Zerah et al. Chest. 1993;1470-6).

CHEST

Obesity-related respiratory changes include reduced lung compliance, functional residual capacity (FRC), and expiratory reserve volume (ERV). These changes lead to peripheral atelectasis and V/Q mismatch and increased metabolic demands placed on the respiratory system (Parameswaran et al. Can Respir J. 2006;203-10). The increased weight supported by the thoracic cage alters the equilibrium between the chest wall and lung tissue decreasing FRC and ERV. This reduces lung compliance and increases stiffness by promoting areas of atelectasis and increased alveolar surface tension (Dixon et al. Expert Rev Respir Med. 2018;755-67).

CHEST

Another biomechanical cost of obesity on respiratory function is the increased consumption of oxygen to sustain ventilation at rest (Koenig SM, Am J Med Sci. 2001;249-79). This can lead to early respiratory muscle fatigue when respiratory rate and tidal volume increase with activity. Patients with obesity are more likely to develop obstructive sleep apnea and obesity hypoventilation syndrome. The resulting alveolar hypoxemia is thought to contribute to the increase in pulmonary hypertension observed in patients with obesity (Shah et al. Breathe. 2023;19[1]). In addition to the biomechanical consequences of obesity, increased adipose tissue can lead to chronic, systemic inflammation that can exacerbate or unmask underlying respiratory disease. Increased leptin and downregulation of adiponectin have been shown to increase systemic cytokine production (Ray et al. Am Rev Respir Dis. 1983;501-6). This inflammatory process contributes to increased airway resistance and an altered response to corticosteroids (inhaled or systemic) in obese patients treated for bronchial hyperresponsiveness. This perhaps reflects the Th2-low phenotype seen in patients with obesity and metabolic syndrome-related asthma (Shah et al. Breathe. 2023;19[1]) (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812).

CHEST

Multiple studies have demonstrated weight loss through lifestyle changes, medical therapy, and obesity surgery result benefits pulmonary disease (Forno et al. PloS One. 2019;14[4]) (Ardila-Gatas et al. Surg Endosc. 2019;1952-8). Benefits include decreased exacerbation frequency, improved functional testing, and improved patient-reported quality of life. Pulmonary clinicians should be empowered to address obesity as a comorbid condition and treat with appropriate referrals for obesity surgery and initiation of medications when indicated.
 

GLP-1 receptor agonists

In the past year, glucagon-like peptide receptor agonists (GLP-1RAs) have garnered attention in the medical literature and popular news outlets. GLP-1RAs, including semaglutide, liraglutide, and tirzepatide, are currently FDA approved for the treatment of obesity in patients with a body mass index (BMI) greater than or equal to 30 or a BMI greater than or equal to 27 in the setting of an obesity-related comorbidity, including asthma.

This class of medications acts by increasing the physiologic insulin response to a glucose load, delaying gastric emptying, and reducing production of glucagon. In a phase III study, semaglutide resulted in greater than 15% weight reduction from baseline (Wadden et al. JAMA. 2021;1403-13). In clinical trials, these medications have not only resulted in significant, sustained weight loss but also improved lipid profiles, decreased A1c, and reduced major cardiovascular events (Lincoff et al. N Engl J Med. 2023;389[23]:2221-32) (Verma et al. Circulation. 2018;138[25]:2884-94).
 

GLP-1RAs and lung disease

GLP-1RAs are associated with ranges of weight loss that lead to symptom improvement. Beyond the anticipated benefits for pulmonary health, there is interest in whether GLP-1RAs may improve specific lung diseases. GLP-1 receptors are found throughout the body (eg, gastrointestinal tract, kidneys, and heart) with the largest proportion located in the lungs (Wu AY and Peebles RS. Expert Rev Clin Immunol. 2021;1053-7). In addition to their known effect on insulin response, GLP-1RAs are hypothesized to reduce proinflammatory cytokine signaling and alter surfactant production potentially improving both airway resistance and lung compliance (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812). Animal models suggest an antifibrotic effect with delay in the endothelial-mesenchymal transition. If further substantiated, this could impact both acute and chronic lung injury.

Early clinical studies of GLP-1RAs in patients with respiratory diseases have demonstrated improved symptoms and pulmonary function (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812). Even modest weight loss (2.5 kg in a year) with GLP-1RAs leads to improved symptoms and a reduction in asthma exacerbations. Other asthma literature shows GLP-1RAs improve symptoms and reduce exacerbations independent of changes in weight, supporting the hypothesis that the benefit of GLP-1RAs may be more than biomechanical improvement from weight loss alone (Foer et al. Am J Respir Crit Care Med. 2021;831-40).

GLP-1RAs reduce the proinflammatory cytokine signaling in both TH2-high and TH2-low asthma phenotypes and alter surfactant production, airway resistance, and perhaps even pulmonary vascular resistance (Altintas Dogan et al. Int J Chron Obstruct Pulmon Dis. 2022,405-14). GATA-3 is an ongoing clinical trial examining whether GLP-1RAs reduce airway inflammation via direct effects on of the respiratory tract (NCT05254314).

Drugs developed to treat one condition are often found to impact others during validation studies or postmarketing observation. Some examples are aspirin, sildenafil, minoxidil, hydroxychloroquine, and SGLT-2 inhibitors. Will GLP-1RAs be the latest medication to affect a broad array of physiologic process and end up improving not just metabolic but also lung health?

THORACIC ONCOLOGY AND CHEST PROCEDURES NETWORK

Interventional Procedures Section

During the last decade, the explosion of technological advancements in the field of interventional pulmonary (IP) has afforded patients the opportunity to undergo novel, minimally invasive diagnostic and therapeutic procedures. However, these unprecedented technological advances have often been introduced without the support of high-quality research on safety and efficacy, and without evaluating their impact on meaningful patient outcomes. Encouraging and participating in high-quality IP research should remain a top priority for those practicing in the field.

CHEST

Structured research networks, such as the UK Pleural Society and more recently the Interventional Pulmonary Outcome Group, have facilitated the transition of IP research from observational case series and single-center experiences to multicenter, randomized controlled trials to generate level I evidence and inform patient care (Laskawiec-Szkonter M, et al. Br J Hosp Med (Lond). 2019 Apr 2;80[4]:186-7) (Maldonado F, et al. J Bronchology Interv Pulmonol. 2019 Jul;26(3):150-2). In the bronchoscopy space, important investigator-initiated clinical trial results anticipated in 2024 include VERITAS (NCT04250194), FROSTBITE2 (NCT05751278), and RELIANT (NCT05705544), among others. These research efforts complement industry-sponsored clinical trials (such as RheSolve, NCT04677465) and aim to emulate the extraordinary track record achieved in the field of pleural disease that has led to recently updated evidence-based guidelines for the management of challenging diseases like malignant pleural effusions, pleural space infections, and pneumothorax (Davies HE, et a l. JAMA. 2012 Jun 13;307[22]:2383-9, Mishra EK, et al. Am J Respir Crit Care Med. 2018 Feb 15;197[4]:502-8) (Rahman NM, et al. N Engl J Med. 2011 Aug 11;365[6]:518-26) (Hallifax RJ, et al. Lancet. 2020 Jul 4;396[10243]:39-49).

Ultimately, the rapidly evolving technological advancements in interventional pulmonology must be supported by research based on high-quality clinical trials, which will be contingent on appropriate trial funding requiring partnership with industry and federal funding agencies. Only through such collaboration can researchers design robust clinical trials based on complex methodology, which will advance patient care and lead to improved patient outcomes.

– Jennifer D. Duke, MD

Section Fellow-in-Training

– Fabien Maldonado, MD, MSc, FCCP

Section Member

THORACIC ONCOLOGY AND CHEST PROCEDURES NETWORK

Interventional Procedures Section

During the last decade, the explosion of technological advancements in the field of interventional pulmonary (IP) has afforded patients the opportunity to undergo novel, minimally invasive diagnostic and therapeutic procedures. However, these unprecedented technological advances have often been introduced without the support of high-quality research on safety and efficacy, and without evaluating their impact on meaningful patient outcomes. Encouraging and participating in high-quality IP research should remain a top priority for those practicing in the field.

CHEST

Structured research networks, such as the UK Pleural Society and more recently the Interventional Pulmonary Outcome Group, have facilitated the transition of IP research from observational case series and single-center experiences to multicenter, randomized controlled trials to generate level I evidence and inform patient care (Laskawiec-Szkonter M, et al. Br J Hosp Med (Lond). 2019 Apr 2;80[4]:186-7) (Maldonado F, et al. J Bronchology Interv Pulmonol. 2019 Jul;26(3):150-2). In the bronchoscopy space, important investigator-initiated clinical trial results anticipated in 2024 include VERITAS (NCT04250194), FROSTBITE2 (NCT05751278), and RELIANT (NCT05705544), among others. These research efforts complement industry-sponsored clinical trials (such as RheSolve, NCT04677465) and aim to emulate the extraordinary track record achieved in the field of pleural disease that has led to recently updated evidence-based guidelines for the management of challenging diseases like malignant pleural effusions, pleural space infections, and pneumothorax (Davies HE, et a l. JAMA. 2012 Jun 13;307[22]:2383-9, Mishra EK, et al. Am J Respir Crit Care Med. 2018 Feb 15;197[4]:502-8) (Rahman NM, et al. N Engl J Med. 2011 Aug 11;365[6]:518-26) (Hallifax RJ, et al. Lancet. 2020 Jul 4;396[10243]:39-49).

Ultimately, the rapidly evolving technological advancements in interventional pulmonology must be supported by research based on high-quality clinical trials, which will be contingent on appropriate trial funding requiring partnership with industry and federal funding agencies. Only through such collaboration can researchers design robust clinical trials based on complex methodology, which will advance patient care and lead to improved patient outcomes.

– Jennifer D. Duke, MD

Section Fellow-in-Training

– Fabien Maldonado, MD, MSc, FCCP

Section Member

THORACIC ONCOLOGY AND CHEST PROCEDURES NETWORK

Interventional Procedures Section

During the last decade, the explosion of technological advancements in the field of interventional pulmonary (IP) has afforded patients the opportunity to undergo novel, minimally invasive diagnostic and therapeutic procedures. However, these unprecedented technological advances have often been introduced without the support of high-quality research on safety and efficacy, and without evaluating their impact on meaningful patient outcomes. Encouraging and participating in high-quality IP research should remain a top priority for those practicing in the field.

CHEST

Structured research networks, such as the UK Pleural Society and more recently the Interventional Pulmonary Outcome Group, have facilitated the transition of IP research from observational case series and single-center experiences to multicenter, randomized controlled trials to generate level I evidence and inform patient care (Laskawiec-Szkonter M, et al. Br J Hosp Med (Lond). 2019 Apr 2;80[4]:186-7) (Maldonado F, et al. J Bronchology Interv Pulmonol. 2019 Jul;26(3):150-2). In the bronchoscopy space, important investigator-initiated clinical trial results anticipated in 2024 include VERITAS (NCT04250194), FROSTBITE2 (NCT05751278), and RELIANT (NCT05705544), among others. These research efforts complement industry-sponsored clinical trials (such as RheSolve, NCT04677465) and aim to emulate the extraordinary track record achieved in the field of pleural disease that has led to recently updated evidence-based guidelines for the management of challenging diseases like malignant pleural effusions, pleural space infections, and pneumothorax (Davies HE, et a l. JAMA. 2012 Jun 13;307[22]:2383-9, Mishra EK, et al. Am J Respir Crit Care Med. 2018 Feb 15;197[4]:502-8) (Rahman NM, et al. N Engl J Med. 2011 Aug 11;365[6]:518-26) (Hallifax RJ, et al. Lancet. 2020 Jul 4;396[10243]:39-49).

Ultimately, the rapidly evolving technological advancements in interventional pulmonology must be supported by research based on high-quality clinical trials, which will be contingent on appropriate trial funding requiring partnership with industry and federal funding agencies. Only through such collaboration can researchers design robust clinical trials based on complex methodology, which will advance patient care and lead to improved patient outcomes.

– Jennifer D. Duke, MD

Section Fellow-in-Training

– Fabien Maldonado, MD, MSc, FCCP

Section Member

DIFFUSE LUNG DISEASE AND LUNG TRANSPLANT NETWORK

Interstitial Lung Disease Section

Interstitial lung diseases (ILD) are a heterogeneous group of fibro-inflammatory disorders that can be progressive despite available therapies. The cornerstones of pharmacologic therapy include immunosuppression and antifibrotics.

CHEST

Data on the use of rituximab, a B-lymphocyte-depleting monoclonal antibody, often utilized as rescue therapy in progressive and severe ILD, was limited until recently. The RECITAL trial reported the first randomized controlled trial investigating rituximab in severe or progressive autoimmune ILD. Though rituximab was not superior to cyclophosphamide, both agents improved forced vital capacity (FVC) at 24 weeks and respiratory-related quality of life. Rituximab was associated with less adverse events and lower corticosteroid exposure (Maher et al. Lancet Respir Med. 2023;11:45-54). In the DESIRES trial, patients with systemic sclerosis-associated ILD treated with rituximab had preservation of FVC at 24 and 48 weeks compared to placebo (Ebata et al. Lancet Rheumatol. 2021;3:e489-97; Lancet Rheumatol. 2022;4:e546-55). The EVER-ILD investigators compared mycophenolate mofetil (MMF) alone vs addition of rituximab in patients with autoimmune and idiopathic nonspecific interstitial pneumonia (NSIP). Combination therapy was superior to MMF alone in improving FVC and progression-free survival. Combination regimen was well tolerated though nonserious viral and bacterial infections were more frequent (Mankikian et al. Eur Respir J. 2023;61[6]:2202071).

These findings, primarily in autoimmune ILD, are promising and provide clinicians with evidence for utilizing rituximab in patients with severe and progressive ILD. Nonetheless, they highlight the need for additional research and standardized guidance regarding the target population who stands to most benefit from rituximab.
 

–Tessy K. Paul, MD

Section Member-at-Large

–Tejaswini Kulkarni, MD, MBBS, FCCP

Section Chair

DIFFUSE LUNG DISEASE AND LUNG TRANSPLANT NETWORK

Interstitial Lung Disease Section

Interstitial lung diseases (ILD) are a heterogeneous group of fibro-inflammatory disorders that can be progressive despite available therapies. The cornerstones of pharmacologic therapy include immunosuppression and antifibrotics.

CHEST

Data on the use of rituximab, a B-lymphocyte-depleting monoclonal antibody, often utilized as rescue therapy in progressive and severe ILD, was limited until recently. The RECITAL trial reported the first randomized controlled trial investigating rituximab in severe or progressive autoimmune ILD. Though rituximab was not superior to cyclophosphamide, both agents improved forced vital capacity (FVC) at 24 weeks and respiratory-related quality of life. Rituximab was associated with less adverse events and lower corticosteroid exposure (Maher et al. Lancet Respir Med. 2023;11:45-54). In the DESIRES trial, patients with systemic sclerosis-associated ILD treated with rituximab had preservation of FVC at 24 and 48 weeks compared to placebo (Ebata et al. Lancet Rheumatol. 2021;3:e489-97; Lancet Rheumatol. 2022;4:e546-55). The EVER-ILD investigators compared mycophenolate mofetil (MMF) alone vs addition of rituximab in patients with autoimmune and idiopathic nonspecific interstitial pneumonia (NSIP). Combination therapy was superior to MMF alone in improving FVC and progression-free survival. Combination regimen was well tolerated though nonserious viral and bacterial infections were more frequent (Mankikian et al. Eur Respir J. 2023;61[6]:2202071).

These findings, primarily in autoimmune ILD, are promising and provide clinicians with evidence for utilizing rituximab in patients with severe and progressive ILD. Nonetheless, they highlight the need for additional research and standardized guidance regarding the target population who stands to most benefit from rituximab.
 

–Tessy K. Paul, MD

Section Member-at-Large

–Tejaswini Kulkarni, MD, MBBS, FCCP

Section Chair

DIFFUSE LUNG DISEASE AND LUNG TRANSPLANT NETWORK

Interstitial Lung Disease Section

Interstitial lung diseases (ILD) are a heterogeneous group of fibro-inflammatory disorders that can be progressive despite available therapies. The cornerstones of pharmacologic therapy include immunosuppression and antifibrotics.

CHEST

Data on the use of rituximab, a B-lymphocyte-depleting monoclonal antibody, often utilized as rescue therapy in progressive and severe ILD, was limited until recently. The RECITAL trial reported the first randomized controlled trial investigating rituximab in severe or progressive autoimmune ILD. Though rituximab was not superior to cyclophosphamide, both agents improved forced vital capacity (FVC) at 24 weeks and respiratory-related quality of life. Rituximab was associated with less adverse events and lower corticosteroid exposure (Maher et al. Lancet Respir Med. 2023;11:45-54). In the DESIRES trial, patients with systemic sclerosis-associated ILD treated with rituximab had preservation of FVC at 24 and 48 weeks compared to placebo (Ebata et al. Lancet Rheumatol. 2021;3:e489-97; Lancet Rheumatol. 2022;4:e546-55). The EVER-ILD investigators compared mycophenolate mofetil (MMF) alone vs addition of rituximab in patients with autoimmune and idiopathic nonspecific interstitial pneumonia (NSIP). Combination therapy was superior to MMF alone in improving FVC and progression-free survival. Combination regimen was well tolerated though nonserious viral and bacterial infections were more frequent (Mankikian et al. Eur Respir J. 2023;61[6]:2202071).

These findings, primarily in autoimmune ILD, are promising and provide clinicians with evidence for utilizing rituximab in patients with severe and progressive ILD. Nonetheless, they highlight the need for additional research and standardized guidance regarding the target population who stands to most benefit from rituximab.
 

–Tessy K. Paul, MD

Section Member-at-Large

–Tejaswini Kulkarni, MD, MBBS, FCCP

Section Chair

APP Intersection

Postgraduate training for advanced practice providers (APPs) has existed in one form or another since the genesis of the allied professions. They are typically referred to as residencies, fellowships, postgraduate programs, and transition-to-practice.

The desire and necessity for these programs has increased in the past decade with workforce changes; namely the increasing number of nurse practitioners (NPs) graduating with fewer years of experience at the bedside compared with previous eras, a similar decrease in patient contact hours for graduating PAs, the transition of physician colleagues from employers to employees and the subsequent change in priorities in training new graduate APPs, and resident work hour restrictions necessitating more APPs to staff inpatient units and work in various specialties.

CHEST

The goal of these programs is to provide postgraduate training to physician assistants/associates (PAs) and NPs across myriad medical specialties to both newly graduated APPs and those looking to transition specialties. Current programs exist in family medicine, emergency medicine, urgent care, critical care medicine, pulmonary medicine, oncology, surgery, and various surgical subspecialties, to name a few. Program length is highly variable, though most programs advertise as lasting around 12 months, with varying ratios of clinical and didactic education. Postgraduate APP programs are largely advertise as salaried, benefitted positions, though usually at a rate below that of a so-called “direct hire” due to the protected learning time associated with the postgraduate training year.

CHEST

Accreditation for these programs is still disjointed, although unifying efforts have been made as of late, and is currently available through the Advanced Practice Provider Fellowship Accreditation, Association of Postgraduate Physician Assistant Programs, ARC-PA, the Accreditation Commission for Education in Nursing, and the Consortium for Advanced Practice Providers. Other organizations, such as the Association of Post Graduate APRN Programs, host regular conferences to discuss the formulation of postgraduate APP education curricula and program development.

While accreditation offers guidance for fledgling programs, many utilize the standards published by the American College of Graduate Medical Education to ensure that appropriate clinical milestones are being met and that a common language among APPs and physicians who are involved in the evaluation of the postgraduate APP trainee is being used. Programs also seek to utilize other well-established curricula and certification programs published by various national and international organizations. A key distinction from physician postgraduate training is that there is currently no fiscal or legislative support for postgraduate APP programs; these issues have been cited as reasons for the limited scope and number of programs.

When starting APP Fellowship programs, it is important to consider why this would be beneficial to a specific division and health care organization. Usually, fellowship programs develop out of a need to train and retain APPs. It is no secret that turnover and retention of skilled APPs is a nationwide problem associated with significant costs to organizations. The ability to retain fellowship-trained APPs will result in cost savings due to the reduction in onboarding time and orientation costs, as these APP fellows finish their programs ready to be fully productive team members.

Additional considerations for the development of an APP fellowship include improving access to care and increasing the quality of the care provided. Fellowship programs encourage a smoother transition to practice by offering more support through education, closer evaluation, and frequent feedback, which improves competence and confidence of these providers. A supported APP is more likely to practice to the fullest extent of their license and have improved personal and professional satisfaction, leading to employee retention and better patient care.

When developing a budget for these types of programs, it is important to include the full-time equivalent (FTE) for the fellow, benefits, onboarding/licensure, simulations, and fellowship faculty costs.

Faculty compensation varies by institution but can include salary support, FTE reduction, and nonclinical appointments. Tracking metrics such as fellow billing, length of stay, and access to care during the fellowship year are helpful to highlight the benefit of these programs to the organization.

Initiating a program like those described may seem like a Herculean feat, but motivated individuals have been able to accomplish similar goals in both adequately and poorly resourced areas. For those aspiring to start a postgraduate APP program at their instruction, these authors suggest the following approach.

First, identify your institution’s need for such a program. Next, define your curriculum, evaluation process, and expectations. Then, create buy-in from stakeholders, including administrative and clinical personnel. Finally, focus on recruitment. Seeking accreditation may be challenging for new programs, but identifying the accreditation standard you plan to pursue early will pay dividends when the time comes for the program to apply. Those starting down this path should realistically expect an 18- to 24-month period between their first efforts and the start of the first class.

“APP Intersection” is a new quarterly column focusing on areas of interest for the entire chest medicine health care team.

APP Intersection

Postgraduate training for advanced practice providers (APPs) has existed in one form or another since the genesis of the allied professions. They are typically referred to as residencies, fellowships, postgraduate programs, and transition-to-practice.

The desire and necessity for these programs has increased in the past decade with workforce changes; namely the increasing number of nurse practitioners (NPs) graduating with fewer years of experience at the bedside compared with previous eras, a similar decrease in patient contact hours for graduating PAs, the transition of physician colleagues from employers to employees and the subsequent change in priorities in training new graduate APPs, and resident work hour restrictions necessitating more APPs to staff inpatient units and work in various specialties.

CHEST

The goal of these programs is to provide postgraduate training to physician assistants/associates (PAs) and NPs across myriad medical specialties to both newly graduated APPs and those looking to transition specialties. Current programs exist in family medicine, emergency medicine, urgent care, critical care medicine, pulmonary medicine, oncology, surgery, and various surgical subspecialties, to name a few. Program length is highly variable, though most programs advertise as lasting around 12 months, with varying ratios of clinical and didactic education. Postgraduate APP programs are largely advertise as salaried, benefitted positions, though usually at a rate below that of a so-called “direct hire” due to the protected learning time associated with the postgraduate training year.

CHEST

Accreditation for these programs is still disjointed, although unifying efforts have been made as of late, and is currently available through the Advanced Practice Provider Fellowship Accreditation, Association of Postgraduate Physician Assistant Programs, ARC-PA, the Accreditation Commission for Education in Nursing, and the Consortium for Advanced Practice Providers. Other organizations, such as the Association of Post Graduate APRN Programs, host regular conferences to discuss the formulation of postgraduate APP education curricula and program development.

While accreditation offers guidance for fledgling programs, many utilize the standards published by the American College of Graduate Medical Education to ensure that appropriate clinical milestones are being met and that a common language among APPs and physicians who are involved in the evaluation of the postgraduate APP trainee is being used. Programs also seek to utilize other well-established curricula and certification programs published by various national and international organizations. A key distinction from physician postgraduate training is that there is currently no fiscal or legislative support for postgraduate APP programs; these issues have been cited as reasons for the limited scope and number of programs.

When starting APP Fellowship programs, it is important to consider why this would be beneficial to a specific division and health care organization. Usually, fellowship programs develop out of a need to train and retain APPs. It is no secret that turnover and retention of skilled APPs is a nationwide problem associated with significant costs to organizations. The ability to retain fellowship-trained APPs will result in cost savings due to the reduction in onboarding time and orientation costs, as these APP fellows finish their programs ready to be fully productive team members.

Additional considerations for the development of an APP fellowship include improving access to care and increasing the quality of the care provided. Fellowship programs encourage a smoother transition to practice by offering more support through education, closer evaluation, and frequent feedback, which improves competence and confidence of these providers. A supported APP is more likely to practice to the fullest extent of their license and have improved personal and professional satisfaction, leading to employee retention and better patient care.

When developing a budget for these types of programs, it is important to include the full-time equivalent (FTE) for the fellow, benefits, onboarding/licensure, simulations, and fellowship faculty costs.

Faculty compensation varies by institution but can include salary support, FTE reduction, and nonclinical appointments. Tracking metrics such as fellow billing, length of stay, and access to care during the fellowship year are helpful to highlight the benefit of these programs to the organization.

Initiating a program like those described may seem like a Herculean feat, but motivated individuals have been able to accomplish similar goals in both adequately and poorly resourced areas. For those aspiring to start a postgraduate APP program at their instruction, these authors suggest the following approach.

First, identify your institution’s need for such a program. Next, define your curriculum, evaluation process, and expectations. Then, create buy-in from stakeholders, including administrative and clinical personnel. Finally, focus on recruitment. Seeking accreditation may be challenging for new programs, but identifying the accreditation standard you plan to pursue early will pay dividends when the time comes for the program to apply. Those starting down this path should realistically expect an 18- to 24-month period between their first efforts and the start of the first class.

“APP Intersection” is a new quarterly column focusing on areas of interest for the entire chest medicine health care team.

APP Intersection

Postgraduate training for advanced practice providers (APPs) has existed in one form or another since the genesis of the allied professions. They are typically referred to as residencies, fellowships, postgraduate programs, and transition-to-practice.

The desire and necessity for these programs has increased in the past decade with workforce changes; namely the increasing number of nurse practitioners (NPs) graduating with fewer years of experience at the bedside compared with previous eras, a similar decrease in patient contact hours for graduating PAs, the transition of physician colleagues from employers to employees and the subsequent change in priorities in training new graduate APPs, and resident work hour restrictions necessitating more APPs to staff inpatient units and work in various specialties.

CHEST

The goal of these programs is to provide postgraduate training to physician assistants/associates (PAs) and NPs across myriad medical specialties to both newly graduated APPs and those looking to transition specialties. Current programs exist in family medicine, emergency medicine, urgent care, critical care medicine, pulmonary medicine, oncology, surgery, and various surgical subspecialties, to name a few. Program length is highly variable, though most programs advertise as lasting around 12 months, with varying ratios of clinical and didactic education. Postgraduate APP programs are largely advertise as salaried, benefitted positions, though usually at a rate below that of a so-called “direct hire” due to the protected learning time associated with the postgraduate training year.

CHEST

Accreditation for these programs is still disjointed, although unifying efforts have been made as of late, and is currently available through the Advanced Practice Provider Fellowship Accreditation, Association of Postgraduate Physician Assistant Programs, ARC-PA, the Accreditation Commission for Education in Nursing, and the Consortium for Advanced Practice Providers. Other organizations, such as the Association of Post Graduate APRN Programs, host regular conferences to discuss the formulation of postgraduate APP education curricula and program development.

While accreditation offers guidance for fledgling programs, many utilize the standards published by the American College of Graduate Medical Education to ensure that appropriate clinical milestones are being met and that a common language among APPs and physicians who are involved in the evaluation of the postgraduate APP trainee is being used. Programs also seek to utilize other well-established curricula and certification programs published by various national and international organizations. A key distinction from physician postgraduate training is that there is currently no fiscal or legislative support for postgraduate APP programs; these issues have been cited as reasons for the limited scope and number of programs.

When starting APP Fellowship programs, it is important to consider why this would be beneficial to a specific division and health care organization. Usually, fellowship programs develop out of a need to train and retain APPs. It is no secret that turnover and retention of skilled APPs is a nationwide problem associated with significant costs to organizations. The ability to retain fellowship-trained APPs will result in cost savings due to the reduction in onboarding time and orientation costs, as these APP fellows finish their programs ready to be fully productive team members.

Additional considerations for the development of an APP fellowship include improving access to care and increasing the quality of the care provided. Fellowship programs encourage a smoother transition to practice by offering more support through education, closer evaluation, and frequent feedback, which improves competence and confidence of these providers. A supported APP is more likely to practice to the fullest extent of their license and have improved personal and professional satisfaction, leading to employee retention and better patient care.

When developing a budget for these types of programs, it is important to include the full-time equivalent (FTE) for the fellow, benefits, onboarding/licensure, simulations, and fellowship faculty costs.

Faculty compensation varies by institution but can include salary support, FTE reduction, and nonclinical appointments. Tracking metrics such as fellow billing, length of stay, and access to care during the fellowship year are helpful to highlight the benefit of these programs to the organization.

Initiating a program like those described may seem like a Herculean feat, but motivated individuals have been able to accomplish similar goals in both adequately and poorly resourced areas. For those aspiring to start a postgraduate APP program at their instruction, these authors suggest the following approach.

First, identify your institution’s need for such a program. Next, define your curriculum, evaluation process, and expectations. Then, create buy-in from stakeholders, including administrative and clinical personnel. Finally, focus on recruitment. Seeking accreditation may be challenging for new programs, but identifying the accreditation standard you plan to pursue early will pay dividends when the time comes for the program to apply. Those starting down this path should realistically expect an 18- to 24-month period between their first efforts and the start of the first class.

“APP Intersection” is a new quarterly column focusing on areas of interest for the entire chest medicine health care team.

The practice of initiating early and adequate nutrition in critically ill patients is a cornerstone of ICU management. Adequate nutrition combats the dangerous catabolic state that accompanies critical illness. A few of the benefits of this practice are a decrease in disease severity with resultant lessened hospital and ICU lengths of stay, reduced infection rates, and a decrease in hospital mortality. Enteral nutrition (EN) is the route of nutritional support most associated with safe and effective provision of enhanced immunologic function and the ability to preserve the patient’s lean body mass while avoiding metabolic and infectious complications.

The practice of initiating early and adequate nutrition in critically ill patients is a cornerstone of ICU management. Adequate nutrition combats the dangerous catabolic state that accompanies critical illness. A few of the benefits of this practice are a decrease in disease severity with resultant lessened hospital and ICU lengths of stay, reduced infection rates, and a decrease in hospital mortality. Enteral nutrition (EN) is the route of nutritional support most associated with safe and effective provision of enhanced immunologic function and the ability to preserve the patient’s lean body mass while avoiding metabolic and infectious complications.

The practice of initiating early and adequate nutrition in critically ill patients is a cornerstone of ICU management. Adequate nutrition combats the dangerous catabolic state that accompanies critical illness. A few of the benefits of this practice are a decrease in disease severity with resultant lessened hospital and ICU lengths of stay, reduced infection rates, and a decrease in hospital mortality. Enteral nutrition (EN) is the route of nutritional support most associated with safe and effective provision of enhanced immunologic function and the ability to preserve the patient’s lean body mass while avoiding metabolic and infectious complications.

Pulmonary physicians and particularly interventional bronchoscopists have been receiving denials when CPT^® codes 31628 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial lung biopsy(s), single lobe and 31629 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial needle aspiration biopsy(s), trachea, main stem and/or lobar bronchus(i) are billed during the same procedure.

While the difference between a transbronchial forceps biopsy and transbronchial needle biopsy are obvious to bronchoscopists, there has been confusion with payers. This could have been partly on the basis of a CPT Assistant article from March 2021 describing the use of both codes that stated, “Note that performing two types of lung biopsy (forceps and needle aspiration) on the same lesion would be considered unusual and documentation of medical necessity should clearly describe why both types of biopsy were clinically necessary.” This may have been interpreted by coders and/or payers to mean that the two codes should be billed together rarely or not at all. It is also possible that computer-based coding programs (eg, Optum/Encoder Pro, etc) are responsible for these inappropriate denials. There are, however, no NCCI edits that disallow this nor was this the intent of the CPT codes when they were developed.

The previous statement from the CPT Assistant article was clarified in the following sentences, “For example, if needle aspiration were performed and immediate screening of the sample were insufficient for diagnosis, a forceps biopsy would be appropriate and reported separately. On the other hand, if a physician performed a needle aspiration out of concern that the lesion was vascular and found that it was not and proceeded with a forceps biopsy, then the needle aspiration would be integral to the forceps biopsy and not separately reported.” Importantly, with the increasing use of navigational bronchoscopy and robotic bronchoscopy, these codes will be used together more frequently, appropriately, and correctly, especially on distal lesions.

Remember, these codes are used for procedures in a single lobe. If multiple lobes are sampled then CPT codes 31632 and 31633 would be added to 31628 and 31629, respectively. If one is receiving denials for these procedures, coders and payers should be notified of these errors, and denials should be appealed.

Q&A

Question: My practice is wondering if we can use the newer codes for online digital E/M services? We know they are time-based, but we are confused about when they cannot be used. Can you please help? For example, I had an established COPD patient send a message through the electronic health record’s patient portal reporting new symptoms of headache, cough, and sputum production. They asked me to review the chest x-ray that was done two days prior when they went to urgent care. The patient is asking for an assessment and management plan. We message back and forth over the next day for a total of 13 minutes. Three days later, the patient developed more symptoms and then scheduled an office visit. How would I bill for this? 99212-99215 (Established Office E/M) or 99422 (Online digital E/M 11-20 minutes?

Answer: Online Digital E/M services (99421, 99422, 99423) are to be used for established patients, only. They are time-based codes and cumulative up to seven days. They are to be reported for asynchronous communication via HIPAA-compliance secure platforms, such as through the electronic health record portal, portal email, etc. They may not be reported if an E/M occurs within seven days before or after, though the time may be incorporated into the subsequent E/M. These codes are not to be used for communication of test results, scheduling of appointments, or other communication that does not include E/M. In your example, you would report the appropriate Office/ Outpatient Established CPT code (99212-99215).


99421 – Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 5-10 minutes

99422 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 11-20 minutes

99423 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 21 or more minutes


Question: Is Cardiopulmonary Resuscitation in the Intensive Care Unit considered to be part of Critical Care services? (99291- 99292)? There appears to be confusion in our billing department on this issue.

Answer: 92959 Cardiopulmonary resuscitation is not bundled into 99291-99292. Consider it as a procedure. To code for this service in addition to Critical Care, the time for the CPR must be separate from the time for Critical Care (99291-99292). A separate procedure note must also be documented. There is no minimum time for this service, and a 25 modifier must be included, as well. 92950 reimburses at 4.00 wRVUs and may be reported two times per calendar day.

Originally published in the September 2023 issue of the American Thoracic Society’s ATS Coding & Billing Quarterly. Republished with permission from the American Thoracic Society.

Pulmonary physicians and particularly interventional bronchoscopists have been receiving denials when CPT^® codes 31628 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial lung biopsy(s), single lobe and 31629 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial needle aspiration biopsy(s), trachea, main stem and/or lobar bronchus(i) are billed during the same procedure.

While the difference between a transbronchial forceps biopsy and transbronchial needle biopsy are obvious to bronchoscopists, there has been confusion with payers. This could have been partly on the basis of a CPT Assistant article from March 2021 describing the use of both codes that stated, “Note that performing two types of lung biopsy (forceps and needle aspiration) on the same lesion would be considered unusual and documentation of medical necessity should clearly describe why both types of biopsy were clinically necessary.” This may have been interpreted by coders and/or payers to mean that the two codes should be billed together rarely or not at all. It is also possible that computer-based coding programs (eg, Optum/Encoder Pro, etc) are responsible for these inappropriate denials. There are, however, no NCCI edits that disallow this nor was this the intent of the CPT codes when they were developed.

The previous statement from the CPT Assistant article was clarified in the following sentences, “For example, if needle aspiration were performed and immediate screening of the sample were insufficient for diagnosis, a forceps biopsy would be appropriate and reported separately. On the other hand, if a physician performed a needle aspiration out of concern that the lesion was vascular and found that it was not and proceeded with a forceps biopsy, then the needle aspiration would be integral to the forceps biopsy and not separately reported.” Importantly, with the increasing use of navigational bronchoscopy and robotic bronchoscopy, these codes will be used together more frequently, appropriately, and correctly, especially on distal lesions.

Remember, these codes are used for procedures in a single lobe. If multiple lobes are sampled then CPT codes 31632 and 31633 would be added to 31628 and 31629, respectively. If one is receiving denials for these procedures, coders and payers should be notified of these errors, and denials should be appealed.

Q&A

Question: My practice is wondering if we can use the newer codes for online digital E/M services? We know they are time-based, but we are confused about when they cannot be used. Can you please help? For example, I had an established COPD patient send a message through the electronic health record’s patient portal reporting new symptoms of headache, cough, and sputum production. They asked me to review the chest x-ray that was done two days prior when they went to urgent care. The patient is asking for an assessment and management plan. We message back and forth over the next day for a total of 13 minutes. Three days later, the patient developed more symptoms and then scheduled an office visit. How would I bill for this? 99212-99215 (Established Office E/M) or 99422 (Online digital E/M 11-20 minutes?

Answer: Online Digital E/M services (99421, 99422, 99423) are to be used for established patients, only. They are time-based codes and cumulative up to seven days. They are to be reported for asynchronous communication via HIPAA-compliance secure platforms, such as through the electronic health record portal, portal email, etc. They may not be reported if an E/M occurs within seven days before or after, though the time may be incorporated into the subsequent E/M. These codes are not to be used for communication of test results, scheduling of appointments, or other communication that does not include E/M. In your example, you would report the appropriate Office/ Outpatient Established CPT code (99212-99215).


99421 – Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 5-10 minutes

99422 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 11-20 minutes

99423 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 21 or more minutes


Question: Is Cardiopulmonary Resuscitation in the Intensive Care Unit considered to be part of Critical Care services? (99291- 99292)? There appears to be confusion in our billing department on this issue.

Answer: 92959 Cardiopulmonary resuscitation is not bundled into 99291-99292. Consider it as a procedure. To code for this service in addition to Critical Care, the time for the CPR must be separate from the time for Critical Care (99291-99292). A separate procedure note must also be documented. There is no minimum time for this service, and a 25 modifier must be included, as well. 92950 reimburses at 4.00 wRVUs and may be reported two times per calendar day.

Originally published in the September 2023 issue of the American Thoracic Society’s ATS Coding & Billing Quarterly. Republished with permission from the American Thoracic Society.

Pulmonary physicians and particularly interventional bronchoscopists have been receiving denials when CPT^® codes 31628 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial lung biopsy(s), single lobe and 31629 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial needle aspiration biopsy(s), trachea, main stem and/or lobar bronchus(i) are billed during the same procedure.

While the difference between a transbronchial forceps biopsy and transbronchial needle biopsy are obvious to bronchoscopists, there has been confusion with payers. This could have been partly on the basis of a CPT Assistant article from March 2021 describing the use of both codes that stated, “Note that performing two types of lung biopsy (forceps and needle aspiration) on the same lesion would be considered unusual and documentation of medical necessity should clearly describe why both types of biopsy were clinically necessary.” This may have been interpreted by coders and/or payers to mean that the two codes should be billed together rarely or not at all. It is also possible that computer-based coding programs (eg, Optum/Encoder Pro, etc) are responsible for these inappropriate denials. There are, however, no NCCI edits that disallow this nor was this the intent of the CPT codes when they were developed.

The previous statement from the CPT Assistant article was clarified in the following sentences, “For example, if needle aspiration were performed and immediate screening of the sample were insufficient for diagnosis, a forceps biopsy would be appropriate and reported separately. On the other hand, if a physician performed a needle aspiration out of concern that the lesion was vascular and found that it was not and proceeded with a forceps biopsy, then the needle aspiration would be integral to the forceps biopsy and not separately reported.” Importantly, with the increasing use of navigational bronchoscopy and robotic bronchoscopy, these codes will be used together more frequently, appropriately, and correctly, especially on distal lesions.

Remember, these codes are used for procedures in a single lobe. If multiple lobes are sampled then CPT codes 31632 and 31633 would be added to 31628 and 31629, respectively. If one is receiving denials for these procedures, coders and payers should be notified of these errors, and denials should be appealed.

Q&A

Question: My practice is wondering if we can use the newer codes for online digital E/M services? We know they are time-based, but we are confused about when they cannot be used. Can you please help? For example, I had an established COPD patient send a message through the electronic health record’s patient portal reporting new symptoms of headache, cough, and sputum production. They asked me to review the chest x-ray that was done two days prior when they went to urgent care. The patient is asking for an assessment and management plan. We message back and forth over the next day for a total of 13 minutes. Three days later, the patient developed more symptoms and then scheduled an office visit. How would I bill for this? 99212-99215 (Established Office E/M) or 99422 (Online digital E/M 11-20 minutes?

Answer: Online Digital E/M services (99421, 99422, 99423) are to be used for established patients, only. They are time-based codes and cumulative up to seven days. They are to be reported for asynchronous communication via HIPAA-compliance secure platforms, such as through the electronic health record portal, portal email, etc. They may not be reported if an E/M occurs within seven days before or after, though the time may be incorporated into the subsequent E/M. These codes are not to be used for communication of test results, scheduling of appointments, or other communication that does not include E/M. In your example, you would report the appropriate Office/ Outpatient Established CPT code (99212-99215).


99421 – Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 5-10 minutes

99422 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 11-20 minutes

99423 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 21 or more minutes


Question: Is Cardiopulmonary Resuscitation in the Intensive Care Unit considered to be part of Critical Care services? (99291- 99292)? There appears to be confusion in our billing department on this issue.

Answer: 92959 Cardiopulmonary resuscitation is not bundled into 99291-99292. Consider it as a procedure. To code for this service in addition to Critical Care, the time for the CPR must be separate from the time for Critical Care (99291-99292). A separate procedure note must also be documented. There is no minimum time for this service, and a 25 modifier must be included, as well. 92950 reimburses at 4.00 wRVUs and may be reported two times per calendar day.

Originally published in the September 2023 issue of the American Thoracic Society’s ATS Coding & Billing Quarterly. Republished with permission from the American Thoracic Society.