Pulmonary Perspectives®

Ghionni_Nicholas_E_BALT_web.jpg

Evidence-based medicine (EBM) stems from making the best patient-centered decision from the highest-quality data available that comports with our understanding of pathophysiology. In some situations, clinicians are forced to draw conclusions from data that are imperfect and apply it to patients who are complex and dynamic. For most pathologies, available data provides some direction. There is, however, one pathophysiologic state that remains understudied, precarious, and common.

The Centers for Disease Control and Prevention (CDC) estimates that about 7.7% of the United States population has asthma. There were about 1 million ED visits in 2020, with asthma listed as the primary diagnosis, and only 94,000 required hospitalization.¹ There are many tools we employ that have greatly decreased inpatient admissions for asthma. The uptake of inhaled corticosteroids (ICS) has significantly reduced asthma-related morbidity and mortality and reduced exacerbations that require admission to a hospital. This treatment strategy is supported by the Global Initiative for Asthma (GINA) and National Asthma Education and Prevention Program (NAEPP) guidelines.^2,3 While we should celebrate the impact that EBM and ICS have had on asthma outcomes, we continue to struggle to control severe asthma.

Bronchodilator therapy in the hospital is ubiquitous. House staff and hospitalists click the bronchodilator order set early and often. However, the optimal frequency, dose, and duration of inhaled bronchodilator therapy for acute asthma exacerbation are unknown. Do frequency, dose, and duration change with exacerbation severity? Nothing gets ED, inpatient, or ICU physicians more jittery than the phrase “exacerbation of asthma on BiPap” or “intubated for asthma.” With its enormous clinical impact and notoriously difficult hospital and ICU course, the lack of evidence we have for managing these patients outside of the initial 24- to 48-hour visit is concerning. Neither NAEPP nor GINA provide management recommendations for the patient with severe asthma exacerbation that necessitates admission.

Albuterol is a commonly used medication for asthma and chronic obstructive airway disease. It is rapid acting and effective—few medications give patients (or clinicians) such instant satisfaction. As an internal medicine resident and pulmonary fellow, I ordered it countless times without ever looking at the dose. Sometimes, patients would come up from the emergency department after receiving a “continuous dose.” I would often wonder exactly what that meant. After some investigation, I found that in my hospital at the time, one dose of albuterol was 2.5 mg in 2 mL, and a continuous nebulization was four doses for a total of 10 mg.

Shrestha et al. found that high-dose albuterol (7.5 mg) administered continuously was superior to 2.5 mg albuterol delivered three times over 1.5 hours. There were demonstrable improvements in FEV₁ and no ICU admissions.⁴ This study is one of many that compared intermittent to continuous and high-dose vs low-dose albuterol in the emergency department. Most are small and occur over the first 24 hours of presentation to the hospital. They often use short-term changes in spirometry as their primary outcome measure. Being a pulmonary and critical care doctor, I see patients who require advanced rescue maneuvers such as noninvasive positive pressure ventilation (NIPPV) or other pharmacologic adjuncts, for which the current evidence is limited.

Because studies of inhaled bronchodilators in acute asthma exacerbation use spirometry as their primary outcome, those with more severe disease and higher acuity are excluded. Patients on NIPPV can’t perform spirometry. There is essentially no literature to guide treatment for a patient with asthma in the adult ICU. In pediatric intensive care units, there are some data to support either continuous or intermittent inhaled bronchodilator that extends beyond the initial ED visit up to about 60 hours.⁵ Much of the pediatric data revolve about the amount of albuterol given, which can be as high as 75 mg/hr though is typically closer to 10-20 mg/hr.⁶ This rate is continued until respiratory improvement occurs.

With poor evidence to guide us and no specific direction from major guidelines, how should providers manage severe asthma exacerbation? The amount of drug deposited in the lung varies by the device used to deliver it. For nebulization, only about 10% of the nebulized amount reaches the lungs for effect; this is a smaller amount compared with all other devices one could use, such as MDI or DPI.⁷ Once a patient with asthma reaches the emergency department, that person is usually placed on some form of nebulizer treatment. But based on local hospital protocols, the amount and duration can vary widely. Sometimes, in patients with severe exacerbation, there is trepidation to continuing albuterol therapy due to ongoing tachycardia. This seems reasonable given increased albuterol administration could beget an ongoing cycle of dyspnea and anxiety. It could also lead to choosing therapies that are less evidence based.

In closing, this seemingly mundane topic takes on new meaning when a patient is in severe exacerbation. Fortunately, providers are not often faced with the decision to wade into the evidence-free territory of severe asthma exacerbation that is unresponsive to first-line treatments. This narrative should serve as a general alert that this pathophysiologic state is understudied. When encountered, thoughtful consideration of pathology, physiology, and pharmacology is required to reverse it.

References

1. Centers for Disease Control and Prevention. (2023, May 10). Most recent national asthma data. Centers for Disease Control and Prevention. https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm

2. Global Initiative for Asthma - GINA. (2023, August 15). 2023 GINA Main Report - Global Initiative for Asthma - GINA. https://ginasthma.org/2023-gina-main-report/

3. Kiley J, Mensah GA, Boyce CA, et al (A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group). 2020 Focused updates to the: Asthma Management Guidelines. US Department of Health and Human Services, NIH, NHLBI 2020.

4. Shrestha M, Bidadi K, Gourlay S, Hayes J. Continuous vs intermittent albuterol, at high and low doses, in the treatment of severe acute asthma in adults. Chest. 1996 Jul;110(1):42-7. doi: 10.1378/chest.110.1.42. PMID: 8681661.

5. Kulalert P, Phinyo P, Patumanond J, Smathakanee C, Chuenjit W, Nanthapisal S. Continuous versus intermittent short-acting β2-agonists nebulization as first-line therapy in hospitalized children with severe asthma exacerbation: a propensity score matching analysis. Asthma Res Pract. 2020 Jul 2;6:6. doi: 10.1186/s40733-020-00059-5. PMID: 32632352; PMCID: PMC7329360.

6. Phumeetham S, Bahk TJ, Abd-Allah S, Mathur M. Effect of high-dose continuous albuterol nebulization on clinical variables in children with status asthmaticus. Pediatr Crit Care Med. 2015 Feb;16(2):e41-6. doi: 10.1097/PCC.0000000000000314. PMID: 25560428.

7. Gardenhire DS, Burnett D, Strickland S, Myers, TR. A guide to aerosol delivery devices for respiratory therapists. American Association for Respiratory Care, Dallas, Texas 2017.

Ghionni_Nicholas_E_BALT_web.jpg

Evidence-based medicine (EBM) stems from making the best patient-centered decision from the highest-quality data available that comports with our understanding of pathophysiology. In some situations, clinicians are forced to draw conclusions from data that are imperfect and apply it to patients who are complex and dynamic. For most pathologies, available data provides some direction. There is, however, one pathophysiologic state that remains understudied, precarious, and common.

The Centers for Disease Control and Prevention (CDC) estimates that about 7.7% of the United States population has asthma. There were about 1 million ED visits in 2020, with asthma listed as the primary diagnosis, and only 94,000 required hospitalization.¹ There are many tools we employ that have greatly decreased inpatient admissions for asthma. The uptake of inhaled corticosteroids (ICS) has significantly reduced asthma-related morbidity and mortality and reduced exacerbations that require admission to a hospital. This treatment strategy is supported by the Global Initiative for Asthma (GINA) and National Asthma Education and Prevention Program (NAEPP) guidelines.^2,3 While we should celebrate the impact that EBM and ICS have had on asthma outcomes, we continue to struggle to control severe asthma.

Bronchodilator therapy in the hospital is ubiquitous. House staff and hospitalists click the bronchodilator order set early and often. However, the optimal frequency, dose, and duration of inhaled bronchodilator therapy for acute asthma exacerbation are unknown. Do frequency, dose, and duration change with exacerbation severity? Nothing gets ED, inpatient, or ICU physicians more jittery than the phrase “exacerbation of asthma on BiPap” or “intubated for asthma.” With its enormous clinical impact and notoriously difficult hospital and ICU course, the lack of evidence we have for managing these patients outside of the initial 24- to 48-hour visit is concerning. Neither NAEPP nor GINA provide management recommendations for the patient with severe asthma exacerbation that necessitates admission.

Albuterol is a commonly used medication for asthma and chronic obstructive airway disease. It is rapid acting and effective—few medications give patients (or clinicians) such instant satisfaction. As an internal medicine resident and pulmonary fellow, I ordered it countless times without ever looking at the dose. Sometimes, patients would come up from the emergency department after receiving a “continuous dose.” I would often wonder exactly what that meant. After some investigation, I found that in my hospital at the time, one dose of albuterol was 2.5 mg in 2 mL, and a continuous nebulization was four doses for a total of 10 mg.

Shrestha et al. found that high-dose albuterol (7.5 mg) administered continuously was superior to 2.5 mg albuterol delivered three times over 1.5 hours. There were demonstrable improvements in FEV₁ and no ICU admissions.⁴ This study is one of many that compared intermittent to continuous and high-dose vs low-dose albuterol in the emergency department. Most are small and occur over the first 24 hours of presentation to the hospital. They often use short-term changes in spirometry as their primary outcome measure. Being a pulmonary and critical care doctor, I see patients who require advanced rescue maneuvers such as noninvasive positive pressure ventilation (NIPPV) or other pharmacologic adjuncts, for which the current evidence is limited.

Because studies of inhaled bronchodilators in acute asthma exacerbation use spirometry as their primary outcome, those with more severe disease and higher acuity are excluded. Patients on NIPPV can’t perform spirometry. There is essentially no literature to guide treatment for a patient with asthma in the adult ICU. In pediatric intensive care units, there are some data to support either continuous or intermittent inhaled bronchodilator that extends beyond the initial ED visit up to about 60 hours.⁵ Much of the pediatric data revolve about the amount of albuterol given, which can be as high as 75 mg/hr though is typically closer to 10-20 mg/hr.⁶ This rate is continued until respiratory improvement occurs.

With poor evidence to guide us and no specific direction from major guidelines, how should providers manage severe asthma exacerbation? The amount of drug deposited in the lung varies by the device used to deliver it. For nebulization, only about 10% of the nebulized amount reaches the lungs for effect; this is a smaller amount compared with all other devices one could use, such as MDI or DPI.⁷ Once a patient with asthma reaches the emergency department, that person is usually placed on some form of nebulizer treatment. But based on local hospital protocols, the amount and duration can vary widely. Sometimes, in patients with severe exacerbation, there is trepidation to continuing albuterol therapy due to ongoing tachycardia. This seems reasonable given increased albuterol administration could beget an ongoing cycle of dyspnea and anxiety. It could also lead to choosing therapies that are less evidence based.

In closing, this seemingly mundane topic takes on new meaning when a patient is in severe exacerbation. Fortunately, providers are not often faced with the decision to wade into the evidence-free territory of severe asthma exacerbation that is unresponsive to first-line treatments. This narrative should serve as a general alert that this pathophysiologic state is understudied. When encountered, thoughtful consideration of pathology, physiology, and pharmacology is required to reverse it.

References

1. Centers for Disease Control and Prevention. (2023, May 10). Most recent national asthma data. Centers for Disease Control and Prevention. https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm

2. Global Initiative for Asthma - GINA. (2023, August 15). 2023 GINA Main Report - Global Initiative for Asthma - GINA. https://ginasthma.org/2023-gina-main-report/

3. Kiley J, Mensah GA, Boyce CA, et al (A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group). 2020 Focused updates to the: Asthma Management Guidelines. US Department of Health and Human Services, NIH, NHLBI 2020.

4. Shrestha M, Bidadi K, Gourlay S, Hayes J. Continuous vs intermittent albuterol, at high and low doses, in the treatment of severe acute asthma in adults. Chest. 1996 Jul;110(1):42-7. doi: 10.1378/chest.110.1.42. PMID: 8681661.

5. Kulalert P, Phinyo P, Patumanond J, Smathakanee C, Chuenjit W, Nanthapisal S. Continuous versus intermittent short-acting β2-agonists nebulization as first-line therapy in hospitalized children with severe asthma exacerbation: a propensity score matching analysis. Asthma Res Pract. 2020 Jul 2;6:6. doi: 10.1186/s40733-020-00059-5. PMID: 32632352; PMCID: PMC7329360.

6. Phumeetham S, Bahk TJ, Abd-Allah S, Mathur M. Effect of high-dose continuous albuterol nebulization on clinical variables in children with status asthmaticus. Pediatr Crit Care Med. 2015 Feb;16(2):e41-6. doi: 10.1097/PCC.0000000000000314. PMID: 25560428.

7. Gardenhire DS, Burnett D, Strickland S, Myers, TR. A guide to aerosol delivery devices for respiratory therapists. American Association for Respiratory Care, Dallas, Texas 2017.

Ghionni_Nicholas_E_BALT_web.jpg

Evidence-based medicine (EBM) stems from making the best patient-centered decision from the highest-quality data available that comports with our understanding of pathophysiology. In some situations, clinicians are forced to draw conclusions from data that are imperfect and apply it to patients who are complex and dynamic. For most pathologies, available data provides some direction. There is, however, one pathophysiologic state that remains understudied, precarious, and common.

The Centers for Disease Control and Prevention (CDC) estimates that about 7.7% of the United States population has asthma. There were about 1 million ED visits in 2020, with asthma listed as the primary diagnosis, and only 94,000 required hospitalization.¹ There are many tools we employ that have greatly decreased inpatient admissions for asthma. The uptake of inhaled corticosteroids (ICS) has significantly reduced asthma-related morbidity and mortality and reduced exacerbations that require admission to a hospital. This treatment strategy is supported by the Global Initiative for Asthma (GINA) and National Asthma Education and Prevention Program (NAEPP) guidelines.^2,3 While we should celebrate the impact that EBM and ICS have had on asthma outcomes, we continue to struggle to control severe asthma.

Bronchodilator therapy in the hospital is ubiquitous. House staff and hospitalists click the bronchodilator order set early and often. However, the optimal frequency, dose, and duration of inhaled bronchodilator therapy for acute asthma exacerbation are unknown. Do frequency, dose, and duration change with exacerbation severity? Nothing gets ED, inpatient, or ICU physicians more jittery than the phrase “exacerbation of asthma on BiPap” or “intubated for asthma.” With its enormous clinical impact and notoriously difficult hospital and ICU course, the lack of evidence we have for managing these patients outside of the initial 24- to 48-hour visit is concerning. Neither NAEPP nor GINA provide management recommendations for the patient with severe asthma exacerbation that necessitates admission.

Albuterol is a commonly used medication for asthma and chronic obstructive airway disease. It is rapid acting and effective—few medications give patients (or clinicians) such instant satisfaction. As an internal medicine resident and pulmonary fellow, I ordered it countless times without ever looking at the dose. Sometimes, patients would come up from the emergency department after receiving a “continuous dose.” I would often wonder exactly what that meant. After some investigation, I found that in my hospital at the time, one dose of albuterol was 2.5 mg in 2 mL, and a continuous nebulization was four doses for a total of 10 mg.

Shrestha et al. found that high-dose albuterol (7.5 mg) administered continuously was superior to 2.5 mg albuterol delivered three times over 1.5 hours. There were demonstrable improvements in FEV₁ and no ICU admissions.⁴ This study is one of many that compared intermittent to continuous and high-dose vs low-dose albuterol in the emergency department. Most are small and occur over the first 24 hours of presentation to the hospital. They often use short-term changes in spirometry as their primary outcome measure. Being a pulmonary and critical care doctor, I see patients who require advanced rescue maneuvers such as noninvasive positive pressure ventilation (NIPPV) or other pharmacologic adjuncts, for which the current evidence is limited.

Because studies of inhaled bronchodilators in acute asthma exacerbation use spirometry as their primary outcome, those with more severe disease and higher acuity are excluded. Patients on NIPPV can’t perform spirometry. There is essentially no literature to guide treatment for a patient with asthma in the adult ICU. In pediatric intensive care units, there are some data to support either continuous or intermittent inhaled bronchodilator that extends beyond the initial ED visit up to about 60 hours.⁵ Much of the pediatric data revolve about the amount of albuterol given, which can be as high as 75 mg/hr though is typically closer to 10-20 mg/hr.⁶ This rate is continued until respiratory improvement occurs.

With poor evidence to guide us and no specific direction from major guidelines, how should providers manage severe asthma exacerbation? The amount of drug deposited in the lung varies by the device used to deliver it. For nebulization, only about 10% of the nebulized amount reaches the lungs for effect; this is a smaller amount compared with all other devices one could use, such as MDI or DPI.⁷ Once a patient with asthma reaches the emergency department, that person is usually placed on some form of nebulizer treatment. But based on local hospital protocols, the amount and duration can vary widely. Sometimes, in patients with severe exacerbation, there is trepidation to continuing albuterol therapy due to ongoing tachycardia. This seems reasonable given increased albuterol administration could beget an ongoing cycle of dyspnea and anxiety. It could also lead to choosing therapies that are less evidence based.

In closing, this seemingly mundane topic takes on new meaning when a patient is in severe exacerbation. Fortunately, providers are not often faced with the decision to wade into the evidence-free territory of severe asthma exacerbation that is unresponsive to first-line treatments. This narrative should serve as a general alert that this pathophysiologic state is understudied. When encountered, thoughtful consideration of pathology, physiology, and pharmacology is required to reverse it.

References

1. Centers for Disease Control and Prevention. (2023, May 10). Most recent national asthma data. Centers for Disease Control and Prevention. https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm

2. Global Initiative for Asthma - GINA. (2023, August 15). 2023 GINA Main Report - Global Initiative for Asthma - GINA. https://ginasthma.org/2023-gina-main-report/

3. Kiley J, Mensah GA, Boyce CA, et al (A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group). 2020 Focused updates to the: Asthma Management Guidelines. US Department of Health and Human Services, NIH, NHLBI 2020.

4. Shrestha M, Bidadi K, Gourlay S, Hayes J. Continuous vs intermittent albuterol, at high and low doses, in the treatment of severe acute asthma in adults. Chest. 1996 Jul;110(1):42-7. doi: 10.1378/chest.110.1.42. PMID: 8681661.

5. Kulalert P, Phinyo P, Patumanond J, Smathakanee C, Chuenjit W, Nanthapisal S. Continuous versus intermittent short-acting β2-agonists nebulization as first-line therapy in hospitalized children with severe asthma exacerbation: a propensity score matching analysis. Asthma Res Pract. 2020 Jul 2;6:6. doi: 10.1186/s40733-020-00059-5. PMID: 32632352; PMCID: PMC7329360.

6. Phumeetham S, Bahk TJ, Abd-Allah S, Mathur M. Effect of high-dose continuous albuterol nebulization on clinical variables in children with status asthmaticus. Pediatr Crit Care Med. 2015 Feb;16(2):e41-6. doi: 10.1097/PCC.0000000000000314. PMID: 25560428.

7. Gardenhire DS, Burnett D, Strickland S, Myers, TR. A guide to aerosol delivery devices for respiratory therapists. American Association for Respiratory Care, Dallas, Texas 2017.

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).

166561_obesity_chart_web.jpg

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).

Mespelt_Kiefer_BETHESDA_web.jpg

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).

Fabyan_Kimberly_BETHESDA_web.jpg

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).

166561_obesity_chart_web.jpg

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).

Mespelt_Kiefer_BETHESDA_web.jpg

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).

Fabyan_Kimberly_BETHESDA_web.jpg

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).

166561_obesity_chart_web.jpg

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).

Mespelt_Kiefer_BETHESDA_web.jpg

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).

Fabyan_Kimberly_BETHESDA_web.jpg

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?

Pulmonary rehabilitation (PR) is an invaluable program typically set in structured in-person environments for individuals living with chronic respiratory conditions. It offers a comprehensive approach to improving lung health and overall quality of life using a combination of tailored exercise routines, educational sessions, and emotional support. It empowers our patients to better manage their conditions, improve their fitness level, and regain a sense of control over their lives. However, the response to the COVID-19 pandemic increased the use of telemedicine as a method for providing health care (Shaver J. Prim Care. 2022;49[4]:517).

Many patients have welcomed the convenience offered by virtual care, and studies have demonstrated high levels of patient satisfaction (Polinski JM, et al. Gen Intern Med. 2016;31[3]:269). Geography also drives telehealth use. In urban areas in the United States, the median travel distance is 7.5 miles one way with a resulting travel time of 3 to 25 minutes. In rural areas, the estimated travel distance is three times as long. Distance and travel time have been recognized as major barriers to attending PR (Keating A, et al. Chron Respir Dis. 2011;8[2]:89).

Access to PR is also hindered by lack of program availability. As of 2019, there were only 831 pulmonary rehab centers in the United States serving roughly 24 million patients with COPD. Only 561 of these centers are certified by the American Association of Cardiovascular and Pulmonary Rehabilitation, leaving only one certified center for every 43,000 patients with COPD (Chan L, et al. J Rural Health. 2006;22[2]:140). As such, virtual PR is one option for augmenting availability and accessibility.

While virtual PR programs offer numerous advantages, including accessibility and convenience, there are inherent risks and challenges. There is also concern that they are inferior to in-person PR. They offer less supervision by trained health care professionals and no immediate access to medical assistance. Combined with the absence of real-time monitoring of vitals or symptoms, there may be a higher risk of adverse events despite the incorporation of safety measures. Furthermore, the lack of accountability forces an increased reliance on self-motivation, which may hinder progress (Spruit MA, et al. Am J Respir Crit Care Med. 2013;188[8]:e13).

Although the digital divide is narrowing rapidly, reliable access to technology, combined with poor internet connections or computer literacy, will prevent adoption by some patients. Even in well-resourced areas, technical issues can disrupt continuity. Finally, virtual PR lacks the intangible benefits from in-person group sessions. Social interactions in this already isolated subset of patients are lost in virtual PR, and the cultivation of motivation and support to seek a common goal goes unrealized.

While these concerns are appreciated, PR is currently highly underutilized and essentially unavailable to most pulmonary patients. As such, further study is needed to shape the future design of quality virtual PR programs. In the March 2023 issue of the journal CHEST, Huynh and colleagues published an observational cohort study comparing virtual with traditional PR programs (Huynh VC, et al. Chest. 2023; Mar;163[3]:529). Of the 554 participants in the study, 171 were enrolled in virtual and 383 to in-person PR. Attendance and drop-out rates did not differ, CAT scores significantly improved in both programs, and there were no adverse events during virtual PR. Participants in the virtual group received a TheraBand and were required to have a sturdy chair, three large step-lengths of empty space surrounding their chair, and access to internet/Zoom. They had one-on-one Zoom meetings but relied mostly on staff-made or online videos. These results replicate past investigations that have demonstrated low adverse event rates, positive overall patient satisfaction, and noninferiority in patient-centered outcomes with PR. The total volume of data remains limited though (Cox NS, et al. Cochrane Database Syst Rev. 2021;Issue 1;Art No: CD013040).

PR is an essential resource for the management of chronic lung diseases. Given existing barriers and the growing number of eligible patients, we must embrace alternative delivery strategies, all the while ensuring that a quality and useful product is deployed (Rochester CL, et al. Am J Respir Crit Care Med. 2015;192[11]:1373). Additional study is needed to standardize and validate the implementation of virtual PR. Ultimately, virtual and alternative methods of care delivery may help optimize outcomes for our patients where more traditional methods fall short.
 

The views and opinions of authors expressed herein do not necessarily reflect those of the Department of Veterans Affairs or the U.S. government. Dr. Cagle and Dr. Gartman are with the Warren Alpert Medical School of Brown University and Providence VA Medical Center, Division of Pulmonary, Critical Care, and Sleep Medicine. Providence, R.I.

Pulmonary rehabilitation (PR) is an invaluable program typically set in structured in-person environments for individuals living with chronic respiratory conditions. It offers a comprehensive approach to improving lung health and overall quality of life using a combination of tailored exercise routines, educational sessions, and emotional support. It empowers our patients to better manage their conditions, improve their fitness level, and regain a sense of control over their lives. However, the response to the COVID-19 pandemic increased the use of telemedicine as a method for providing health care (Shaver J. Prim Care. 2022;49[4]:517).

Many patients have welcomed the convenience offered by virtual care, and studies have demonstrated high levels of patient satisfaction (Polinski JM, et al. Gen Intern Med. 2016;31[3]:269). Geography also drives telehealth use. In urban areas in the United States, the median travel distance is 7.5 miles one way with a resulting travel time of 3 to 25 minutes. In rural areas, the estimated travel distance is three times as long. Distance and travel time have been recognized as major barriers to attending PR (Keating A, et al. Chron Respir Dis. 2011;8[2]:89).

Access to PR is also hindered by lack of program availability. As of 2019, there were only 831 pulmonary rehab centers in the United States serving roughly 24 million patients with COPD. Only 561 of these centers are certified by the American Association of Cardiovascular and Pulmonary Rehabilitation, leaving only one certified center for every 43,000 patients with COPD (Chan L, et al. J Rural Health. 2006;22[2]:140). As such, virtual PR is one option for augmenting availability and accessibility.

While virtual PR programs offer numerous advantages, including accessibility and convenience, there are inherent risks and challenges. There is also concern that they are inferior to in-person PR. They offer less supervision by trained health care professionals and no immediate access to medical assistance. Combined with the absence of real-time monitoring of vitals or symptoms, there may be a higher risk of adverse events despite the incorporation of safety measures. Furthermore, the lack of accountability forces an increased reliance on self-motivation, which may hinder progress (Spruit MA, et al. Am J Respir Crit Care Med. 2013;188[8]:e13).

Although the digital divide is narrowing rapidly, reliable access to technology, combined with poor internet connections or computer literacy, will prevent adoption by some patients. Even in well-resourced areas, technical issues can disrupt continuity. Finally, virtual PR lacks the intangible benefits from in-person group sessions. Social interactions in this already isolated subset of patients are lost in virtual PR, and the cultivation of motivation and support to seek a common goal goes unrealized.

While these concerns are appreciated, PR is currently highly underutilized and essentially unavailable to most pulmonary patients. As such, further study is needed to shape the future design of quality virtual PR programs. In the March 2023 issue of the journal CHEST, Huynh and colleagues published an observational cohort study comparing virtual with traditional PR programs (Huynh VC, et al. Chest. 2023; Mar;163[3]:529). Of the 554 participants in the study, 171 were enrolled in virtual and 383 to in-person PR. Attendance and drop-out rates did not differ, CAT scores significantly improved in both programs, and there were no adverse events during virtual PR. Participants in the virtual group received a TheraBand and were required to have a sturdy chair, three large step-lengths of empty space surrounding their chair, and access to internet/Zoom. They had one-on-one Zoom meetings but relied mostly on staff-made or online videos. These results replicate past investigations that have demonstrated low adverse event rates, positive overall patient satisfaction, and noninferiority in patient-centered outcomes with PR. The total volume of data remains limited though (Cox NS, et al. Cochrane Database Syst Rev. 2021;Issue 1;Art No: CD013040).

PR is an essential resource for the management of chronic lung diseases. Given existing barriers and the growing number of eligible patients, we must embrace alternative delivery strategies, all the while ensuring that a quality and useful product is deployed (Rochester CL, et al. Am J Respir Crit Care Med. 2015;192[11]:1373). Additional study is needed to standardize and validate the implementation of virtual PR. Ultimately, virtual and alternative methods of care delivery may help optimize outcomes for our patients where more traditional methods fall short.
 

The views and opinions of authors expressed herein do not necessarily reflect those of the Department of Veterans Affairs or the U.S. government. Dr. Cagle and Dr. Gartman are with the Warren Alpert Medical School of Brown University and Providence VA Medical Center, Division of Pulmonary, Critical Care, and Sleep Medicine. Providence, R.I.

Pulmonary rehabilitation (PR) is an invaluable program typically set in structured in-person environments for individuals living with chronic respiratory conditions. It offers a comprehensive approach to improving lung health and overall quality of life using a combination of tailored exercise routines, educational sessions, and emotional support. It empowers our patients to better manage their conditions, improve their fitness level, and regain a sense of control over their lives. However, the response to the COVID-19 pandemic increased the use of telemedicine as a method for providing health care (Shaver J. Prim Care. 2022;49[4]:517).

Many patients have welcomed the convenience offered by virtual care, and studies have demonstrated high levels of patient satisfaction (Polinski JM, et al. Gen Intern Med. 2016;31[3]:269). Geography also drives telehealth use. In urban areas in the United States, the median travel distance is 7.5 miles one way with a resulting travel time of 3 to 25 minutes. In rural areas, the estimated travel distance is three times as long. Distance and travel time have been recognized as major barriers to attending PR (Keating A, et al. Chron Respir Dis. 2011;8[2]:89).

Access to PR is also hindered by lack of program availability. As of 2019, there were only 831 pulmonary rehab centers in the United States serving roughly 24 million patients with COPD. Only 561 of these centers are certified by the American Association of Cardiovascular and Pulmonary Rehabilitation, leaving only one certified center for every 43,000 patients with COPD (Chan L, et al. J Rural Health. 2006;22[2]:140). As such, virtual PR is one option for augmenting availability and accessibility.

While virtual PR programs offer numerous advantages, including accessibility and convenience, there are inherent risks and challenges. There is also concern that they are inferior to in-person PR. They offer less supervision by trained health care professionals and no immediate access to medical assistance. Combined with the absence of real-time monitoring of vitals or symptoms, there may be a higher risk of adverse events despite the incorporation of safety measures. Furthermore, the lack of accountability forces an increased reliance on self-motivation, which may hinder progress (Spruit MA, et al. Am J Respir Crit Care Med. 2013;188[8]:e13).

Although the digital divide is narrowing rapidly, reliable access to technology, combined with poor internet connections or computer literacy, will prevent adoption by some patients. Even in well-resourced areas, technical issues can disrupt continuity. Finally, virtual PR lacks the intangible benefits from in-person group sessions. Social interactions in this already isolated subset of patients are lost in virtual PR, and the cultivation of motivation and support to seek a common goal goes unrealized.

While these concerns are appreciated, PR is currently highly underutilized and essentially unavailable to most pulmonary patients. As such, further study is needed to shape the future design of quality virtual PR programs. In the March 2023 issue of the journal CHEST, Huynh and colleagues published an observational cohort study comparing virtual with traditional PR programs (Huynh VC, et al. Chest. 2023; Mar;163[3]:529). Of the 554 participants in the study, 171 were enrolled in virtual and 383 to in-person PR. Attendance and drop-out rates did not differ, CAT scores significantly improved in both programs, and there were no adverse events during virtual PR. Participants in the virtual group received a TheraBand and were required to have a sturdy chair, three large step-lengths of empty space surrounding their chair, and access to internet/Zoom. They had one-on-one Zoom meetings but relied mostly on staff-made or online videos. These results replicate past investigations that have demonstrated low adverse event rates, positive overall patient satisfaction, and noninferiority in patient-centered outcomes with PR. The total volume of data remains limited though (Cox NS, et al. Cochrane Database Syst Rev. 2021;Issue 1;Art No: CD013040).

PR is an essential resource for the management of chronic lung diseases. Given existing barriers and the growing number of eligible patients, we must embrace alternative delivery strategies, all the while ensuring that a quality and useful product is deployed (Rochester CL, et al. Am J Respir Crit Care Med. 2015;192[11]:1373). Additional study is needed to standardize and validate the implementation of virtual PR. Ultimately, virtual and alternative methods of care delivery may help optimize outcomes for our patients where more traditional methods fall short.
 

The views and opinions of authors expressed herein do not necessarily reflect those of the Department of Veterans Affairs or the U.S. government. Dr. Cagle and Dr. Gartman are with the Warren Alpert Medical School of Brown University and Providence VA Medical Center, Division of Pulmonary, Critical Care, and Sleep Medicine. Providence, R.I.

Inhalers, nebulizers, antibiotics, and steroids – these are some of the most common tools in our pulmonary arsenal that we deploy on a daily basis. But, there is no treatment more fundamental to a pulmonary practitioner than oxygen. So how is it that something that naturally occurs and comprises 21% of ambient air has become so medicalized?

It is difficult (perhaps impossible) to find a pulmonologist or a hospitalist who has not included the phrase “obtain ambulatory saturation to qualify the patient for home oxygen” in at least one of their progress notes on a daily basis. Chronic obstructive pulmonary disease (COPD) is the most common reason for the prescription of long-term oxygen therapy (LTOT), a large industry tightly regulated by the Centers for Medicare & Medicaid Services (CMS).

The evidence for the use of LTOT in patients with COPD dates back to two seminal papers published in 1980 and 1981. The British Medical Research Council Working Party conducted the BMRC trial, in which 87 patients with a Pao2 of 40 mm Hg to 60 mm Hg, CO2 retention, and a history of congestive heart failure were randomized to treatment with 15 hours per day of home oxygen therapy, starting at 2 L and titrating to Pao2 of 60 mm Hg vs. standard therapy without oxygen (Lancet. 1981;1[8222]:681-6). There was an impressive 22% mortality benefit at 3 years.

Another study published around the same time, the Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease (NOTT) trial (Ann Intern Med. 1980;93[3]:391-8) directly compared continuous 24-hour to nocturnal home oxygen therapy in patients with COPD and severe hypoxemia with a Pao2 less than 55 mm Hg. Again, there was an impressive mortality benefit in favor of continuous home oxygen with a 9% and 18% mortality difference at 1 and 2 years of enrollment, respectively.

Afterward, it became universally accepted dogma that patients with COPD and severe hypoxemia stood to substantially benefit from LTOT. For years, it was the only therapy associated with a mortality reduction. The LOTT study (Albert RK, et al. N Engl J Med. 2016;375[17]:1617-27) included 768 patients with stable COPD and a resting or nocturnal Spo2 of 89% to93%, as well as patients with moderate exercise-induced desaturation (Spo2 of greater than or equal to 80% and less than 90% for greater than or equal to 10 seconds during the 6-minute walk test). Half of these patients received oxygen for 24 hours per day, during sleep, or during exercise (depending on when desaturation would occur) and half received no oxygen. There was no difference in time to death or first hospitalization or in rates of hospitalization or exacerbation. There was also no difference between groups in quality of life, lung function, or distance walked in 6 minutes.

The INOX (Lacasse Y, et al. N Engl J Med. 2020;383[12]:1129-38) trial, in which 243 patients with oxygen saturation less than 90% for at least 30% of the night were assigned to receive nocturnal vs sham oxygen, found similar results. There was no difference in the composite outcome of all-cause mortality and progression to 24-7 oxygen requirement (according to the criteria originally defined by NOTT). A 2022 systematic review and meta-analysis including six studies designed to assess the role of LTOT in patients with COPD and moderate desaturation, including LOTT and INOX, found no benefit to providing LTOT (Lacasse Y, et al. Lancet Respir Med. 2022;10[11]:1029-37).

Based on these studies, a resting Spo2 of 88% seems to be the threshold below which LTOT improves outcomes. CMS lists four classes of patients eligible for LTOT: (1) Patients with Pao2 < 55 mm Hg or pulse oximetry less than or equal to 88% at rest or (2) during sleep or (3) during exercise, and (4) patients with Pao2 > 55 mm Hg but less than or equal to 59 mm Hg or pulse oximetry of 89% who have lower extremity edema, evidence of pulmonary hypertension, or erythrocythemia (Centers for Medicare & Medicaid Services. Medicare Coverage Database. 2021;100-103:240.2. These criteria reflect the inclusion criteria of the BMRC trial and NOTT.

COPD management has changed significantly in the 40 years since NOTT was published. In the early 1980s, standard of care included an inhaled beta-agonist and oral theophylline. We now prescribe a regimen of modern-day inhaler combinations, which can lead to a mortality benefit in the correct population. Additionally, rates of smoking are markedly lower now than they were in 1980. In the Minnesota Heart Survey, the prevalence of being an ever-smoking man or woman in 1980 compared with 2009 dropped from 71.6% and 54.7% to 44.2% and 39.6%, respectively (Filion KB, et al. Am J Public Health. 2012;102[4]:705-13). Treatment of common comorbid conditions has also dramatically improved.

A report containing all fee-for-service data published in 2021 by CMS reported oxygen therapy accounted for 9.8% of all DME costs covered by CMS and totaled approximately $800,000,000 (Centers for Medicare & Medicaid Services. FFS Data. 2021. This represents a significant financial burden to our health system and government.

Two of the eligible groups per CMS (those with isolated ambulatory or nocturnal hypoxemia) do not benefit from LTOT in RCTs. The other two groups are eligible based on trial data from a small number of patients who were studied more than 40 years ago. These facts raise serious questions about the cost-efficacy of LTOT.

So where does this leave us?

There are significant barriers to repeating large randomized oxygen trials. Due to broad inclusion criteria for LTOT by CMS, there are undoubtedly many people prescribed LTOT for whom there is minimal to no benefit. Patients often feel restricted in their mobility and may feel isolated being tethered to medical equipment. It is good practice to think about LTOT the same way we do any other therapy we provide - as a medicine with associated risks, benefits, and costs.

Despite its ubiquity, oxygen remains an important therapeutic tool. Still, choosing wisely means recognizing that not all patients who qualify for LTOT by CMS criteria will benefit.

Drs. Kreisel and Sonti are with the Division of Pulmonary, Critical Care, and Sleep Medicine, MedStar Georgetown University Hospital, Washington, DC.

Inhalers, nebulizers, antibiotics, and steroids – these are some of the most common tools in our pulmonary arsenal that we deploy on a daily basis. But, there is no treatment more fundamental to a pulmonary practitioner than oxygen. So how is it that something that naturally occurs and comprises 21% of ambient air has become so medicalized?

It is difficult (perhaps impossible) to find a pulmonologist or a hospitalist who has not included the phrase “obtain ambulatory saturation to qualify the patient for home oxygen” in at least one of their progress notes on a daily basis. Chronic obstructive pulmonary disease (COPD) is the most common reason for the prescription of long-term oxygen therapy (LTOT), a large industry tightly regulated by the Centers for Medicare & Medicaid Services (CMS).

The evidence for the use of LTOT in patients with COPD dates back to two seminal papers published in 1980 and 1981. The British Medical Research Council Working Party conducted the BMRC trial, in which 87 patients with a Pao2 of 40 mm Hg to 60 mm Hg, CO2 retention, and a history of congestive heart failure were randomized to treatment with 15 hours per day of home oxygen therapy, starting at 2 L and titrating to Pao2 of 60 mm Hg vs. standard therapy without oxygen (Lancet. 1981;1[8222]:681-6). There was an impressive 22% mortality benefit at 3 years.

Another study published around the same time, the Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease (NOTT) trial (Ann Intern Med. 1980;93[3]:391-8) directly compared continuous 24-hour to nocturnal home oxygen therapy in patients with COPD and severe hypoxemia with a Pao2 less than 55 mm Hg. Again, there was an impressive mortality benefit in favor of continuous home oxygen with a 9% and 18% mortality difference at 1 and 2 years of enrollment, respectively.

Afterward, it became universally accepted dogma that patients with COPD and severe hypoxemia stood to substantially benefit from LTOT. For years, it was the only therapy associated with a mortality reduction. The LOTT study (Albert RK, et al. N Engl J Med. 2016;375[17]:1617-27) included 768 patients with stable COPD and a resting or nocturnal Spo2 of 89% to93%, as well as patients with moderate exercise-induced desaturation (Spo2 of greater than or equal to 80% and less than 90% for greater than or equal to 10 seconds during the 6-minute walk test). Half of these patients received oxygen for 24 hours per day, during sleep, or during exercise (depending on when desaturation would occur) and half received no oxygen. There was no difference in time to death or first hospitalization or in rates of hospitalization or exacerbation. There was also no difference between groups in quality of life, lung function, or distance walked in 6 minutes.

The INOX (Lacasse Y, et al. N Engl J Med. 2020;383[12]:1129-38) trial, in which 243 patients with oxygen saturation less than 90% for at least 30% of the night were assigned to receive nocturnal vs sham oxygen, found similar results. There was no difference in the composite outcome of all-cause mortality and progression to 24-7 oxygen requirement (according to the criteria originally defined by NOTT). A 2022 systematic review and meta-analysis including six studies designed to assess the role of LTOT in patients with COPD and moderate desaturation, including LOTT and INOX, found no benefit to providing LTOT (Lacasse Y, et al. Lancet Respir Med. 2022;10[11]:1029-37).

Based on these studies, a resting Spo2 of 88% seems to be the threshold below which LTOT improves outcomes. CMS lists four classes of patients eligible for LTOT: (1) Patients with Pao2 < 55 mm Hg or pulse oximetry less than or equal to 88% at rest or (2) during sleep or (3) during exercise, and (4) patients with Pao2 > 55 mm Hg but less than or equal to 59 mm Hg or pulse oximetry of 89% who have lower extremity edema, evidence of pulmonary hypertension, or erythrocythemia (Centers for Medicare & Medicaid Services. Medicare Coverage Database. 2021;100-103:240.2. These criteria reflect the inclusion criteria of the BMRC trial and NOTT.

COPD management has changed significantly in the 40 years since NOTT was published. In the early 1980s, standard of care included an inhaled beta-agonist and oral theophylline. We now prescribe a regimen of modern-day inhaler combinations, which can lead to a mortality benefit in the correct population. Additionally, rates of smoking are markedly lower now than they were in 1980. In the Minnesota Heart Survey, the prevalence of being an ever-smoking man or woman in 1980 compared with 2009 dropped from 71.6% and 54.7% to 44.2% and 39.6%, respectively (Filion KB, et al. Am J Public Health. 2012;102[4]:705-13). Treatment of common comorbid conditions has also dramatically improved.

A report containing all fee-for-service data published in 2021 by CMS reported oxygen therapy accounted for 9.8% of all DME costs covered by CMS and totaled approximately $800,000,000 (Centers for Medicare & Medicaid Services. FFS Data. 2021. This represents a significant financial burden to our health system and government.

Two of the eligible groups per CMS (those with isolated ambulatory or nocturnal hypoxemia) do not benefit from LTOT in RCTs. The other two groups are eligible based on trial data from a small number of patients who were studied more than 40 years ago. These facts raise serious questions about the cost-efficacy of LTOT.

So where does this leave us?

There are significant barriers to repeating large randomized oxygen trials. Due to broad inclusion criteria for LTOT by CMS, there are undoubtedly many people prescribed LTOT for whom there is minimal to no benefit. Patients often feel restricted in their mobility and may feel isolated being tethered to medical equipment. It is good practice to think about LTOT the same way we do any other therapy we provide - as a medicine with associated risks, benefits, and costs.

Despite its ubiquity, oxygen remains an important therapeutic tool. Still, choosing wisely means recognizing that not all patients who qualify for LTOT by CMS criteria will benefit.

Drs. Kreisel and Sonti are with the Division of Pulmonary, Critical Care, and Sleep Medicine, MedStar Georgetown University Hospital, Washington, DC.

Inhalers, nebulizers, antibiotics, and steroids – these are some of the most common tools in our pulmonary arsenal that we deploy on a daily basis. But, there is no treatment more fundamental to a pulmonary practitioner than oxygen. So how is it that something that naturally occurs and comprises 21% of ambient air has become so medicalized?

It is difficult (perhaps impossible) to find a pulmonologist or a hospitalist who has not included the phrase “obtain ambulatory saturation to qualify the patient for home oxygen” in at least one of their progress notes on a daily basis. Chronic obstructive pulmonary disease (COPD) is the most common reason for the prescription of long-term oxygen therapy (LTOT), a large industry tightly regulated by the Centers for Medicare & Medicaid Services (CMS).

The evidence for the use of LTOT in patients with COPD dates back to two seminal papers published in 1980 and 1981. The British Medical Research Council Working Party conducted the BMRC trial, in which 87 patients with a Pao2 of 40 mm Hg to 60 mm Hg, CO2 retention, and a history of congestive heart failure were randomized to treatment with 15 hours per day of home oxygen therapy, starting at 2 L and titrating to Pao2 of 60 mm Hg vs. standard therapy without oxygen (Lancet. 1981;1[8222]:681-6). There was an impressive 22% mortality benefit at 3 years.

Another study published around the same time, the Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease (NOTT) trial (Ann Intern Med. 1980;93[3]:391-8) directly compared continuous 24-hour to nocturnal home oxygen therapy in patients with COPD and severe hypoxemia with a Pao2 less than 55 mm Hg. Again, there was an impressive mortality benefit in favor of continuous home oxygen with a 9% and 18% mortality difference at 1 and 2 years of enrollment, respectively.

Afterward, it became universally accepted dogma that patients with COPD and severe hypoxemia stood to substantially benefit from LTOT. For years, it was the only therapy associated with a mortality reduction. The LOTT study (Albert RK, et al. N Engl J Med. 2016;375[17]:1617-27) included 768 patients with stable COPD and a resting or nocturnal Spo2 of 89% to93%, as well as patients with moderate exercise-induced desaturation (Spo2 of greater than or equal to 80% and less than 90% for greater than or equal to 10 seconds during the 6-minute walk test). Half of these patients received oxygen for 24 hours per day, during sleep, or during exercise (depending on when desaturation would occur) and half received no oxygen. There was no difference in time to death or first hospitalization or in rates of hospitalization or exacerbation. There was also no difference between groups in quality of life, lung function, or distance walked in 6 minutes.

The INOX (Lacasse Y, et al. N Engl J Med. 2020;383[12]:1129-38) trial, in which 243 patients with oxygen saturation less than 90% for at least 30% of the night were assigned to receive nocturnal vs sham oxygen, found similar results. There was no difference in the composite outcome of all-cause mortality and progression to 24-7 oxygen requirement (according to the criteria originally defined by NOTT). A 2022 systematic review and meta-analysis including six studies designed to assess the role of LTOT in patients with COPD and moderate desaturation, including LOTT and INOX, found no benefit to providing LTOT (Lacasse Y, et al. Lancet Respir Med. 2022;10[11]:1029-37).

Based on these studies, a resting Spo2 of 88% seems to be the threshold below which LTOT improves outcomes. CMS lists four classes of patients eligible for LTOT: (1) Patients with Pao2 < 55 mm Hg or pulse oximetry less than or equal to 88% at rest or (2) during sleep or (3) during exercise, and (4) patients with Pao2 > 55 mm Hg but less than or equal to 59 mm Hg or pulse oximetry of 89% who have lower extremity edema, evidence of pulmonary hypertension, or erythrocythemia (Centers for Medicare & Medicaid Services. Medicare Coverage Database. 2021;100-103:240.2. These criteria reflect the inclusion criteria of the BMRC trial and NOTT.

COPD management has changed significantly in the 40 years since NOTT was published. In the early 1980s, standard of care included an inhaled beta-agonist and oral theophylline. We now prescribe a regimen of modern-day inhaler combinations, which can lead to a mortality benefit in the correct population. Additionally, rates of smoking are markedly lower now than they were in 1980. In the Minnesota Heart Survey, the prevalence of being an ever-smoking man or woman in 1980 compared with 2009 dropped from 71.6% and 54.7% to 44.2% and 39.6%, respectively (Filion KB, et al. Am J Public Health. 2012;102[4]:705-13). Treatment of common comorbid conditions has also dramatically improved.

A report containing all fee-for-service data published in 2021 by CMS reported oxygen therapy accounted for 9.8% of all DME costs covered by CMS and totaled approximately $800,000,000 (Centers for Medicare & Medicaid Services. FFS Data. 2021. This represents a significant financial burden to our health system and government.

Two of the eligible groups per CMS (those with isolated ambulatory or nocturnal hypoxemia) do not benefit from LTOT in RCTs. The other two groups are eligible based on trial data from a small number of patients who were studied more than 40 years ago. These facts raise serious questions about the cost-efficacy of LTOT.

So where does this leave us?

There are significant barriers to repeating large randomized oxygen trials. Due to broad inclusion criteria for LTOT by CMS, there are undoubtedly many people prescribed LTOT for whom there is minimal to no benefit. Patients often feel restricted in their mobility and may feel isolated being tethered to medical equipment. It is good practice to think about LTOT the same way we do any other therapy we provide - as a medicine with associated risks, benefits, and costs.

Despite its ubiquity, oxygen remains an important therapeutic tool. Still, choosing wisely means recognizing that not all patients who qualify for LTOT by CMS criteria will benefit.

Drs. Kreisel and Sonti are with the Division of Pulmonary, Critical Care, and Sleep Medicine, MedStar Georgetown University Hospital, Washington, DC.

Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.

As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. In the past decade, research to help providers decide which biologic therapy to use for defined cases has increased. It is now customary to call such treatment “tailored therapy” because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.

Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
 

Atopic dermatitis

There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).

Hossri_Sami_TEXAS_web.jpg

These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).

Chronic rhinosinusitis with nasal polyposis

The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.

Ivashchuk_Halyna_TEXAS_web.jpg

Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.

Eosinophilic esophagitis

Recent reports demonstrated a large portion of adults with a

diagnosis of eosinophilic

esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump

inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,

EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of

people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led

to a significant improvement in dysphagia symptoms and

histology when compared with placebo.

Allergic bronchopulmonary aspergillosis

Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).

Bronchiectasis

Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV₁, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.

Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.

As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. In the past decade, research to help providers decide which biologic therapy to use for defined cases has increased. It is now customary to call such treatment “tailored therapy” because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.

Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
 

Atopic dermatitis

There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).

Hossri_Sami_TEXAS_web.jpg

These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).

Chronic rhinosinusitis with nasal polyposis

The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.

Ivashchuk_Halyna_TEXAS_web.jpg

Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.

Eosinophilic esophagitis

Recent reports demonstrated a large portion of adults with a

diagnosis of eosinophilic

esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump

inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,

EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of

people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led

to a significant improvement in dysphagia symptoms and

histology when compared with placebo.

Allergic bronchopulmonary aspergillosis

Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).

Bronchiectasis

Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV₁, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.

Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.

As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. In the past decade, research to help providers decide which biologic therapy to use for defined cases has increased. It is now customary to call such treatment “tailored therapy” because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.

Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
 

Atopic dermatitis

There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).

Hossri_Sami_TEXAS_web.jpg

These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).

Chronic rhinosinusitis with nasal polyposis

The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.

Ivashchuk_Halyna_TEXAS_web.jpg

Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.

Eosinophilic esophagitis

Recent reports demonstrated a large portion of adults with a

diagnosis of eosinophilic

esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump

inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,

EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of

people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led

to a significant improvement in dysphagia symptoms and

histology when compared with placebo.

Allergic bronchopulmonary aspergillosis

Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).

Bronchiectasis

Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV₁, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.

Unexplained dyspnea is a common complaint among patients seen in pulmonary clinics, and can be difficult to define, quantify, and determine the etiology. The ATS official statement defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (Am J Respir Crit Care Med. 2012; 185:435). A myriad of diseases can cause dyspnea, including cardiac, pulmonary, neuromuscular, psychological, and hematologic disorders; obesity, deconditioning, and the normal aging process may also contribute to dyspnea. Adding further diagnostic confusion, multiple causes may exist in a given patient.

Finding the cause or causes of dyspnea can be difficult and may require extensive testing, time, and cost. Initially, a history and physical exam are performed with more focused testing undertaken depending on most likely causes. For most patients, initial evaluation includes a CBC, TSH, pulmonary function tests, chest radiograph, and, often, a transthoracic echocardiogram. If these tests are unrevealing, or if clinical suspicion is high, more costly, invasive, and time-consuming tests are obtained. These may include bronchoprovocation testing, cardiac stress tests, chest CT scan, and, if warranted, right- and/or left-sided heart catheterization. Ideally, these tests are utilized appropriately based on the patient’s clinical presentation and the results of initial evaluation. In addition to high cost, invasive testing risks injury.

Cardiopulmonary exercise testing (CPET) has been called the “gold standard” test for evaluation of unexplained dyspnea (Palange P, et al. Eur Respir J. 2007;29:185).

Symptom-limited CPET measures multiple physiological variables during stress, potentially identifying the cause of dyspnea that is not evident by measurements made at rest. CPET may also differentiate the limiting factor in patients with multiple diseases that each could be contributing to dyspnea. CPET provides an objective measurement of cardiorespiratory fitness and may provide prognostic information. CPET typically consists of a symptom-limited maximal incremental exercise test using either a treadmill or cycle ergometer. The primary measurements include oxygen uptake (Vo₂), carbon dioxide output (Vco₂), minute ventilation (VE), ECG, blood pressure, oxygen saturation (Spo₂) and, depending on the indication, arterial blood gases at rest and peak exercise. An invasive CPET includes the above measurements and the addition of a pulmonary artery catheter and radial artery catheter allowing the assessment of ventricular filling pressures, pulmonary arterial pressures, cardiac output, and measures of oxygen transport. Invasive CPET is less commonly performed in clinical practice due to cost, high resource utilization, and greater risk of complications.

What is the evidence that CPET is the gold standard for evaluating dyspnea? Limited evidence supports this claim. Martinez and colleagues (Chest. 1994;105[1]:168) evaluated 50 patients presenting with unexplained dyspnea with normal CBC, thyroid studies, chest radiograph, and spirometry with no-invasive CPET. CPET was used to make an initial diagnosis, and this was compared with a definitive diagnosis based on additional testing guided by CPET findings and response to targeted therapy. Most patients (68%) eventually received a diagnossis of normal, deconditioned, hyperactive airway disease, or a psychogenic cause of dyspnea. The important findings from this study include: (1) CPET was able to identify cardiac or pulmonary disease, if present; (2) A normal CPET excluded significant cardiac or pulmonary disease in most patients suggesting that a normal CPET is useful in limiting subsequent testing; (3) In some patients, CPET wasn’t able to accurately differentiate cardiac disease from deconditioning as both exhibited an abnormal CPET pattern including low peak Vo₂, low Vo₂ at anaerobic threshold, decreased O₂ pulse, and often low peak heart rate. In more than 75% of patients, the CPET, and focused testing based on CPET findings, confidently identified the cause of dyspnea not explained by routine testing.

There is evidence that invasive CPET may provide diagnostic information when the cause of dyspnea is not identified using noninvasive testing. Huang and colleagues (Eur J Prev Cardiol. 2017;24[11]:1190) investigated the use of invasive CPET in 530 patients who had undergone extensive evaluation for dyspnea, including noninvasive CPET in 30% of patients, and the diagnosis remained unclear. The cause of dyspnea was determinedin all patients and included: exercise-induced pulmonary arterial hypertension (17%), heart failure with preserved ejection fraction (18%), dysautonomia or preload failure (21%), oxidative myopathy (25%), primary hyperventilation (8%), and various other conditions (11%). Most patients had been undergoing work up for unexplained dyspnea for a median of 511 days before evaluation in the dyspnea clinic. Huang et al’s study demonstrates some of the limitations of noninvasive CPET, including distinguishing cardiac limitation from dysautonomia or preload failure, deconditioning, oxidative myopathies, and mild pulmonary vascular disease. This study didn’t answer how many patients having noninvasive CPET would need an invasive study to get their diagnosis.

A limitation of both the Martinez et al and Huang et al studies is that they were conducted at subspecialty dyspnea clinics located in large referral centers and may not be representative of patients seen in general pulmonary clinics for the evaluation of dyspnea. This may result in over-representation of less common diseases, such as oxidative myopathies and dysautonomia or preload failure. Even with this limitation, these two studies showed that CPETs have the potential to expedite diagnoses and treatment in patients with unexplained dyspnea.

More investigation is needed to understand the clinical utility, and potential cost savings, of CPET for patients referred to general pulmonary clinics with unexplained dyspnea. We retrospectively reviewed 89 patients who underwent CPET for unexplained dyspnea from 2017 to 2019 at Intermountain Medical Center (Cook CP. Eur Respir J. 2022; 60: Suppl. 66, 1939). Nearly 50% of the patients undergoing CPET were diagnosed with obesity, deconditioning, or normal. In patients under the age of 60 years, 64% were diagnosed with obesity, deconditioning, or a normal study. Conversely, 70% of patients over the age of 60 years had an abnormal cardiac or pulmonary limitation.

We also evaluated whether CPET affected diagnostic testing patterns in the 6 months following testing. We determined that potentially inappropriate testing was performed in only 13% of patients after obtaining a CPET diagnosis. These data suggest that CPET results affect ordering provider behavior. Also, in younger patients, in whom initial evaluation is unrevealing of cardiopulmonary disease, a CPET could be performed early in the evaluation process. This may result in decreased health care cost and time to diagnosis. At our institution, CPET is less expensive than a transthoracic echocardiogram.

So, is CPET worthy of its status as the gold standard for determining the etiology of unexplained dysp-nea? The answer for noninvasive CPET is a definite “maybe.” There is evidence that some CPET patterns support a specific diagnosis. However, referring providers may be disappointed by CPET reports that do not provide a definitive cause for a patient’s dyspnea. An abnormal cardiac limitation may be caused by systolic or diastolic dysfunction, myocardial ischemia, preload failure or dysautonomia, deconditioning, and oxidative myopathy. Even in these situations, a specific CPET pattern may limit the differential diagnosis and facilitate a more focused and cost-effective evaluation. A normal CPET provides reassurance that significant disease is not causing the patient’s dyspnea and prevent further unnecessary and costly evaluation.

Unexplained dyspnea is a common complaint among patients seen in pulmonary clinics, and can be difficult to define, quantify, and determine the etiology. The ATS official statement defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (Am J Respir Crit Care Med. 2012; 185:435). A myriad of diseases can cause dyspnea, including cardiac, pulmonary, neuromuscular, psychological, and hematologic disorders; obesity, deconditioning, and the normal aging process may also contribute to dyspnea. Adding further diagnostic confusion, multiple causes may exist in a given patient.

Finding the cause or causes of dyspnea can be difficult and may require extensive testing, time, and cost. Initially, a history and physical exam are performed with more focused testing undertaken depending on most likely causes. For most patients, initial evaluation includes a CBC, TSH, pulmonary function tests, chest radiograph, and, often, a transthoracic echocardiogram. If these tests are unrevealing, or if clinical suspicion is high, more costly, invasive, and time-consuming tests are obtained. These may include bronchoprovocation testing, cardiac stress tests, chest CT scan, and, if warranted, right- and/or left-sided heart catheterization. Ideally, these tests are utilized appropriately based on the patient’s clinical presentation and the results of initial evaluation. In addition to high cost, invasive testing risks injury.

Cardiopulmonary exercise testing (CPET) has been called the “gold standard” test for evaluation of unexplained dyspnea (Palange P, et al. Eur Respir J. 2007;29:185).

Symptom-limited CPET measures multiple physiological variables during stress, potentially identifying the cause of dyspnea that is not evident by measurements made at rest. CPET may also differentiate the limiting factor in patients with multiple diseases that each could be contributing to dyspnea. CPET provides an objective measurement of cardiorespiratory fitness and may provide prognostic information. CPET typically consists of a symptom-limited maximal incremental exercise test using either a treadmill or cycle ergometer. The primary measurements include oxygen uptake (Vo₂), carbon dioxide output (Vco₂), minute ventilation (VE), ECG, blood pressure, oxygen saturation (Spo₂) and, depending on the indication, arterial blood gases at rest and peak exercise. An invasive CPET includes the above measurements and the addition of a pulmonary artery catheter and radial artery catheter allowing the assessment of ventricular filling pressures, pulmonary arterial pressures, cardiac output, and measures of oxygen transport. Invasive CPET is less commonly performed in clinical practice due to cost, high resource utilization, and greater risk of complications.

What is the evidence that CPET is the gold standard for evaluating dyspnea? Limited evidence supports this claim. Martinez and colleagues (Chest. 1994;105[1]:168) evaluated 50 patients presenting with unexplained dyspnea with normal CBC, thyroid studies, chest radiograph, and spirometry with no-invasive CPET. CPET was used to make an initial diagnosis, and this was compared with a definitive diagnosis based on additional testing guided by CPET findings and response to targeted therapy. Most patients (68%) eventually received a diagnossis of normal, deconditioned, hyperactive airway disease, or a psychogenic cause of dyspnea. The important findings from this study include: (1) CPET was able to identify cardiac or pulmonary disease, if present; (2) A normal CPET excluded significant cardiac or pulmonary disease in most patients suggesting that a normal CPET is useful in limiting subsequent testing; (3) In some patients, CPET wasn’t able to accurately differentiate cardiac disease from deconditioning as both exhibited an abnormal CPET pattern including low peak Vo₂, low Vo₂ at anaerobic threshold, decreased O₂ pulse, and often low peak heart rate. In more than 75% of patients, the CPET, and focused testing based on CPET findings, confidently identified the cause of dyspnea not explained by routine testing.

There is evidence that invasive CPET may provide diagnostic information when the cause of dyspnea is not identified using noninvasive testing. Huang and colleagues (Eur J Prev Cardiol. 2017;24[11]:1190) investigated the use of invasive CPET in 530 patients who had undergone extensive evaluation for dyspnea, including noninvasive CPET in 30% of patients, and the diagnosis remained unclear. The cause of dyspnea was determinedin all patients and included: exercise-induced pulmonary arterial hypertension (17%), heart failure with preserved ejection fraction (18%), dysautonomia or preload failure (21%), oxidative myopathy (25%), primary hyperventilation (8%), and various other conditions (11%). Most patients had been undergoing work up for unexplained dyspnea for a median of 511 days before evaluation in the dyspnea clinic. Huang et al’s study demonstrates some of the limitations of noninvasive CPET, including distinguishing cardiac limitation from dysautonomia or preload failure, deconditioning, oxidative myopathies, and mild pulmonary vascular disease. This study didn’t answer how many patients having noninvasive CPET would need an invasive study to get their diagnosis.

A limitation of both the Martinez et al and Huang et al studies is that they were conducted at subspecialty dyspnea clinics located in large referral centers and may not be representative of patients seen in general pulmonary clinics for the evaluation of dyspnea. This may result in over-representation of less common diseases, such as oxidative myopathies and dysautonomia or preload failure. Even with this limitation, these two studies showed that CPETs have the potential to expedite diagnoses and treatment in patients with unexplained dyspnea.

More investigation is needed to understand the clinical utility, and potential cost savings, of CPET for patients referred to general pulmonary clinics with unexplained dyspnea. We retrospectively reviewed 89 patients who underwent CPET for unexplained dyspnea from 2017 to 2019 at Intermountain Medical Center (Cook CP. Eur Respir J. 2022; 60: Suppl. 66, 1939). Nearly 50% of the patients undergoing CPET were diagnosed with obesity, deconditioning, or normal. In patients under the age of 60 years, 64% were diagnosed with obesity, deconditioning, or a normal study. Conversely, 70% of patients over the age of 60 years had an abnormal cardiac or pulmonary limitation.

We also evaluated whether CPET affected diagnostic testing patterns in the 6 months following testing. We determined that potentially inappropriate testing was performed in only 13% of patients after obtaining a CPET diagnosis. These data suggest that CPET results affect ordering provider behavior. Also, in younger patients, in whom initial evaluation is unrevealing of cardiopulmonary disease, a CPET could be performed early in the evaluation process. This may result in decreased health care cost and time to diagnosis. At our institution, CPET is less expensive than a transthoracic echocardiogram.

So, is CPET worthy of its status as the gold standard for determining the etiology of unexplained dysp-nea? The answer for noninvasive CPET is a definite “maybe.” There is evidence that some CPET patterns support a specific diagnosis. However, referring providers may be disappointed by CPET reports that do not provide a definitive cause for a patient’s dyspnea. An abnormal cardiac limitation may be caused by systolic or diastolic dysfunction, myocardial ischemia, preload failure or dysautonomia, deconditioning, and oxidative myopathy. Even in these situations, a specific CPET pattern may limit the differential diagnosis and facilitate a more focused and cost-effective evaluation. A normal CPET provides reassurance that significant disease is not causing the patient’s dyspnea and prevent further unnecessary and costly evaluation.

Unexplained dyspnea is a common complaint among patients seen in pulmonary clinics, and can be difficult to define, quantify, and determine the etiology. The ATS official statement defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (Am J Respir Crit Care Med. 2012; 185:435). A myriad of diseases can cause dyspnea, including cardiac, pulmonary, neuromuscular, psychological, and hematologic disorders; obesity, deconditioning, and the normal aging process may also contribute to dyspnea. Adding further diagnostic confusion, multiple causes may exist in a given patient.

Finding the cause or causes of dyspnea can be difficult and may require extensive testing, time, and cost. Initially, a history and physical exam are performed with more focused testing undertaken depending on most likely causes. For most patients, initial evaluation includes a CBC, TSH, pulmonary function tests, chest radiograph, and, often, a transthoracic echocardiogram. If these tests are unrevealing, or if clinical suspicion is high, more costly, invasive, and time-consuming tests are obtained. These may include bronchoprovocation testing, cardiac stress tests, chest CT scan, and, if warranted, right- and/or left-sided heart catheterization. Ideally, these tests are utilized appropriately based on the patient’s clinical presentation and the results of initial evaluation. In addition to high cost, invasive testing risks injury.

Cardiopulmonary exercise testing (CPET) has been called the “gold standard” test for evaluation of unexplained dyspnea (Palange P, et al. Eur Respir J. 2007;29:185).

Symptom-limited CPET measures multiple physiological variables during stress, potentially identifying the cause of dyspnea that is not evident by measurements made at rest. CPET may also differentiate the limiting factor in patients with multiple diseases that each could be contributing to dyspnea. CPET provides an objective measurement of cardiorespiratory fitness and may provide prognostic information. CPET typically consists of a symptom-limited maximal incremental exercise test using either a treadmill or cycle ergometer. The primary measurements include oxygen uptake (Vo₂), carbon dioxide output (Vco₂), minute ventilation (VE), ECG, blood pressure, oxygen saturation (Spo₂) and, depending on the indication, arterial blood gases at rest and peak exercise. An invasive CPET includes the above measurements and the addition of a pulmonary artery catheter and radial artery catheter allowing the assessment of ventricular filling pressures, pulmonary arterial pressures, cardiac output, and measures of oxygen transport. Invasive CPET is less commonly performed in clinical practice due to cost, high resource utilization, and greater risk of complications.

What is the evidence that CPET is the gold standard for evaluating dyspnea? Limited evidence supports this claim. Martinez and colleagues (Chest. 1994;105[1]:168) evaluated 50 patients presenting with unexplained dyspnea with normal CBC, thyroid studies, chest radiograph, and spirometry with no-invasive CPET. CPET was used to make an initial diagnosis, and this was compared with a definitive diagnosis based on additional testing guided by CPET findings and response to targeted therapy. Most patients (68%) eventually received a diagnossis of normal, deconditioned, hyperactive airway disease, or a psychogenic cause of dyspnea. The important findings from this study include: (1) CPET was able to identify cardiac or pulmonary disease, if present; (2) A normal CPET excluded significant cardiac or pulmonary disease in most patients suggesting that a normal CPET is useful in limiting subsequent testing; (3) In some patients, CPET wasn’t able to accurately differentiate cardiac disease from deconditioning as both exhibited an abnormal CPET pattern including low peak Vo₂, low Vo₂ at anaerobic threshold, decreased O₂ pulse, and often low peak heart rate. In more than 75% of patients, the CPET, and focused testing based on CPET findings, confidently identified the cause of dyspnea not explained by routine testing.

There is evidence that invasive CPET may provide diagnostic information when the cause of dyspnea is not identified using noninvasive testing. Huang and colleagues (Eur J Prev Cardiol. 2017;24[11]:1190) investigated the use of invasive CPET in 530 patients who had undergone extensive evaluation for dyspnea, including noninvasive CPET in 30% of patients, and the diagnosis remained unclear. The cause of dyspnea was determinedin all patients and included: exercise-induced pulmonary arterial hypertension (17%), heart failure with preserved ejection fraction (18%), dysautonomia or preload failure (21%), oxidative myopathy (25%), primary hyperventilation (8%), and various other conditions (11%). Most patients had been undergoing work up for unexplained dyspnea for a median of 511 days before evaluation in the dyspnea clinic. Huang et al’s study demonstrates some of the limitations of noninvasive CPET, including distinguishing cardiac limitation from dysautonomia or preload failure, deconditioning, oxidative myopathies, and mild pulmonary vascular disease. This study didn’t answer how many patients having noninvasive CPET would need an invasive study to get their diagnosis.

A limitation of both the Martinez et al and Huang et al studies is that they were conducted at subspecialty dyspnea clinics located in large referral centers and may not be representative of patients seen in general pulmonary clinics for the evaluation of dyspnea. This may result in over-representation of less common diseases, such as oxidative myopathies and dysautonomia or preload failure. Even with this limitation, these two studies showed that CPETs have the potential to expedite diagnoses and treatment in patients with unexplained dyspnea.

More investigation is needed to understand the clinical utility, and potential cost savings, of CPET for patients referred to general pulmonary clinics with unexplained dyspnea. We retrospectively reviewed 89 patients who underwent CPET for unexplained dyspnea from 2017 to 2019 at Intermountain Medical Center (Cook CP. Eur Respir J. 2022; 60: Suppl. 66, 1939). Nearly 50% of the patients undergoing CPET were diagnosed with obesity, deconditioning, or normal. In patients under the age of 60 years, 64% were diagnosed with obesity, deconditioning, or a normal study. Conversely, 70% of patients over the age of 60 years had an abnormal cardiac or pulmonary limitation.

We also evaluated whether CPET affected diagnostic testing patterns in the 6 months following testing. We determined that potentially inappropriate testing was performed in only 13% of patients after obtaining a CPET diagnosis. These data suggest that CPET results affect ordering provider behavior. Also, in younger patients, in whom initial evaluation is unrevealing of cardiopulmonary disease, a CPET could be performed early in the evaluation process. This may result in decreased health care cost and time to diagnosis. At our institution, CPET is less expensive than a transthoracic echocardiogram.

So, is CPET worthy of its status as the gold standard for determining the etiology of unexplained dysp-nea? The answer for noninvasive CPET is a definite “maybe.” There is evidence that some CPET patterns support a specific diagnosis. However, referring providers may be disappointed by CPET reports that do not provide a definitive cause for a patient’s dyspnea. An abnormal cardiac limitation may be caused by systolic or diastolic dysfunction, myocardial ischemia, preload failure or dysautonomia, deconditioning, and oxidative myopathy. Even in these situations, a specific CPET pattern may limit the differential diagnosis and facilitate a more focused and cost-effective evaluation. A normal CPET provides reassurance that significant disease is not causing the patient’s dyspnea and prevent further unnecessary and costly evaluation.

The threshold for abandoning supportive measures and initiating invasive mechanical ventilation (IMV) in patients with respiratory failure is unclear. Noninvasive respiratory support (RS) devices, such as high-flow nasal cannula (HFNC) and noninvasive positive-pressure ventilation (NIV), are tools used to support patients in distress prior to failure and the need for IMV. However, prolonged RS in patients who ultimately require IMV can be harmful.

As the COVID-19 pandemic evolved, ICUs around the world were overrun by patients with varying degrees of respiratory failure. With this novel pathogen came novel approaches to management. Here we will review data available prior to the pandemic and relate them to emerging evidence on prolonged RS in patients with COVID-19. We believe it is time to acknowledge that prolonged RS in patients who ultimately require IMV is likely deleterious. Increased awareness and care to avoid this situation (often meaning earlier intubation) should be implemented in clinical practice.

Wilson_Benjamin_T_DC_web.jpg

Excessive tidal volume delivered during IMV can lead to lung injury. Though this principle is widely accepted, the recognition that the same physiology holds in a spontaneously breathing patient receiving RS has been slow to take hold. In the presence of a high respiratory drive injury from overdistension and large transpulmonary pressure, swings can occur with or without IMV. An excellent review summarizing the existing evidence of this risk was published years before the COVID-19 pandemic (Brochard L, et al. AJRCCM. 2017;195[4]:438).

A number of pre-COVID-19 publications focused on examining this topic in clinical practice deserve specific mention. A study of respiratory mechanics in patients on NIV found it was nearly impossible to meet traditional targets for lung protective tidal volumes. Those patients who progressed to IMV had higher expired tidal volumes (Carteaux G, et al. Crit Care Med. 2016;44[2]:282). A large systematic review and metanalysis including more than 11,000 immunocompromised patients found delayed intubation led to increased mortality (Dumas G, et al. AJRCCM. 2021;204[2]:187). This study did not specifically implicate RS days and patient self-induced lung injury as factors driving the excess mortality; another smaller propensity-matched retrospective analysis of patients in the ICU supported with HFNC noted a 65% reduction in mortality among patients intubated after less than vs greater than 48 hours on HFNC who ultimately required IMV (Kang B, et al. Intensive Care Med. 2015;41[4]:623).

Despite this and other existing evidence regarding the hazards of prolonged RS prior to IMV, COVID-19’s burden on the health care system dramatically changed the way hypoxemic respiratory failure is managed in the ICU. Anecdotally, during the height of the pandemic, it was commonplace to encounter patients with severe COVID-19 supported with very high RS settings for days or often weeks. Occasionally, RS may have stabilized breathing mechanics. However, it was often our experience that among those patients supported with RS for extended periods prior to IMV lung compliance was poor, lung recovery did not occur, and prognosis was dismal. Various factors, including early reports of high mortality among patients with COVID-19 supported with IMV, resulted in reliance on RS as a means for delaying or avoiding IMV. Interestingly, a propensity-matched study of more than 2,700 patients found that prolonged RS was associated with significantly higher in-hospital mortality but despite this finding, the practice increased over the course of the pandemic (Riera J, et al. Eur Respir J. 2023;61[3]:2201426). Further, a prospective study comparing outcomes between patients intubated within 48 hours for COVID-19-related respiratory failure to those intubated later found a greater risk of in-hospital mortality and worse long-term outpatient lung function testing (in survivors) in the latter group.

Chandel_Abhimanyu_DC_web.jpg

It has previously been postulated that longer duration of IMV prior to the initiation of extracorporeal membrane oxygenation (ECMO) support in patients with hypoxemic respiratory failure may contribute to worse overall ECMO-related outcomes. This supposition is based on the principle that ECMO protects the lung by reducing ventilatory drive, tidal volume, and transpulmonary pressure swings. Several studies have documented an increase in mortality in patients supported with ECMO for COVID-19-related respiratory failure over the course of the pandemic. These investigators have noted that time to cannulation, but not IMV days (possibly reflecting duration of RS), correlates with worse ECMO outcomes (Ahmad Q, et al. ASAIO J. 2022;68[2]:171; Barbaro R, et al. Lancet. 2021;398[10307]:1230). We wonder if this reflects greater attention to low tidal volume ventilation during IMV but lack of awareness of or the inability to prevent injurious ventilation during prolonged RS. We view this as an important area for future research that may aid in patient selection in the ongoing effort to improve COVID-19-related ECMO outcomes.

The COVID-19 pandemic remains a significant burden on the health care system. Changes in care necessitated by the crisis produced innovations with the potential to rapidly improve outcomes. Notably though, it also has resulted in negative changes in response to a new pathogen that are hard to reconcile with physiologic principles. Evidence before and since the emergence of COVID-19 suggests prolonged RS prior to IMV is potentially harmful. It is critical for clinicians to recognize this principle and take steps to mitigate this problem in patients where a positive response to RS is not demonstrated in a timely manner.



Drs. Wilson and Chandel are with the Department of Pulmonary and Critical Care, Walter Reed National Military Medical Center, Washington, DC.

The threshold for abandoning supportive measures and initiating invasive mechanical ventilation (IMV) in patients with respiratory failure is unclear. Noninvasive respiratory support (RS) devices, such as high-flow nasal cannula (HFNC) and noninvasive positive-pressure ventilation (NIV), are tools used to support patients in distress prior to failure and the need for IMV. However, prolonged RS in patients who ultimately require IMV can be harmful.

As the COVID-19 pandemic evolved, ICUs around the world were overrun by patients with varying degrees of respiratory failure. With this novel pathogen came novel approaches to management. Here we will review data available prior to the pandemic and relate them to emerging evidence on prolonged RS in patients with COVID-19. We believe it is time to acknowledge that prolonged RS in patients who ultimately require IMV is likely deleterious. Increased awareness and care to avoid this situation (often meaning earlier intubation) should be implemented in clinical practice.

Wilson_Benjamin_T_DC_web.jpg

Excessive tidal volume delivered during IMV can lead to lung injury. Though this principle is widely accepted, the recognition that the same physiology holds in a spontaneously breathing patient receiving RS has been slow to take hold. In the presence of a high respiratory drive injury from overdistension and large transpulmonary pressure, swings can occur with or without IMV. An excellent review summarizing the existing evidence of this risk was published years before the COVID-19 pandemic (Brochard L, et al. AJRCCM. 2017;195[4]:438).

A number of pre-COVID-19 publications focused on examining this topic in clinical practice deserve specific mention. A study of respiratory mechanics in patients on NIV found it was nearly impossible to meet traditional targets for lung protective tidal volumes. Those patients who progressed to IMV had higher expired tidal volumes (Carteaux G, et al. Crit Care Med. 2016;44[2]:282). A large systematic review and metanalysis including more than 11,000 immunocompromised patients found delayed intubation led to increased mortality (Dumas G, et al. AJRCCM. 2021;204[2]:187). This study did not specifically implicate RS days and patient self-induced lung injury as factors driving the excess mortality; another smaller propensity-matched retrospective analysis of patients in the ICU supported with HFNC noted a 65% reduction in mortality among patients intubated after less than vs greater than 48 hours on HFNC who ultimately required IMV (Kang B, et al. Intensive Care Med. 2015;41[4]:623).

Despite this and other existing evidence regarding the hazards of prolonged RS prior to IMV, COVID-19’s burden on the health care system dramatically changed the way hypoxemic respiratory failure is managed in the ICU. Anecdotally, during the height of the pandemic, it was commonplace to encounter patients with severe COVID-19 supported with very high RS settings for days or often weeks. Occasionally, RS may have stabilized breathing mechanics. However, it was often our experience that among those patients supported with RS for extended periods prior to IMV lung compliance was poor, lung recovery did not occur, and prognosis was dismal. Various factors, including early reports of high mortality among patients with COVID-19 supported with IMV, resulted in reliance on RS as a means for delaying or avoiding IMV. Interestingly, a propensity-matched study of more than 2,700 patients found that prolonged RS was associated with significantly higher in-hospital mortality but despite this finding, the practice increased over the course of the pandemic (Riera J, et al. Eur Respir J. 2023;61[3]:2201426). Further, a prospective study comparing outcomes between patients intubated within 48 hours for COVID-19-related respiratory failure to those intubated later found a greater risk of in-hospital mortality and worse long-term outpatient lung function testing (in survivors) in the latter group.

Chandel_Abhimanyu_DC_web.jpg

It has previously been postulated that longer duration of IMV prior to the initiation of extracorporeal membrane oxygenation (ECMO) support in patients with hypoxemic respiratory failure may contribute to worse overall ECMO-related outcomes. This supposition is based on the principle that ECMO protects the lung by reducing ventilatory drive, tidal volume, and transpulmonary pressure swings. Several studies have documented an increase in mortality in patients supported with ECMO for COVID-19-related respiratory failure over the course of the pandemic. These investigators have noted that time to cannulation, but not IMV days (possibly reflecting duration of RS), correlates with worse ECMO outcomes (Ahmad Q, et al. ASAIO J. 2022;68[2]:171; Barbaro R, et al. Lancet. 2021;398[10307]:1230). We wonder if this reflects greater attention to low tidal volume ventilation during IMV but lack of awareness of or the inability to prevent injurious ventilation during prolonged RS. We view this as an important area for future research that may aid in patient selection in the ongoing effort to improve COVID-19-related ECMO outcomes.

The COVID-19 pandemic remains a significant burden on the health care system. Changes in care necessitated by the crisis produced innovations with the potential to rapidly improve outcomes. Notably though, it also has resulted in negative changes in response to a new pathogen that are hard to reconcile with physiologic principles. Evidence before and since the emergence of COVID-19 suggests prolonged RS prior to IMV is potentially harmful. It is critical for clinicians to recognize this principle and take steps to mitigate this problem in patients where a positive response to RS is not demonstrated in a timely manner.



Drs. Wilson and Chandel are with the Department of Pulmonary and Critical Care, Walter Reed National Military Medical Center, Washington, DC.

The threshold for abandoning supportive measures and initiating invasive mechanical ventilation (IMV) in patients with respiratory failure is unclear. Noninvasive respiratory support (RS) devices, such as high-flow nasal cannula (HFNC) and noninvasive positive-pressure ventilation (NIV), are tools used to support patients in distress prior to failure and the need for IMV. However, prolonged RS in patients who ultimately require IMV can be harmful.

As the COVID-19 pandemic evolved, ICUs around the world were overrun by patients with varying degrees of respiratory failure. With this novel pathogen came novel approaches to management. Here we will review data available prior to the pandemic and relate them to emerging evidence on prolonged RS in patients with COVID-19. We believe it is time to acknowledge that prolonged RS in patients who ultimately require IMV is likely deleterious. Increased awareness and care to avoid this situation (often meaning earlier intubation) should be implemented in clinical practice.

Wilson_Benjamin_T_DC_web.jpg

Excessive tidal volume delivered during IMV can lead to lung injury. Though this principle is widely accepted, the recognition that the same physiology holds in a spontaneously breathing patient receiving RS has been slow to take hold. In the presence of a high respiratory drive injury from overdistension and large transpulmonary pressure, swings can occur with or without IMV. An excellent review summarizing the existing evidence of this risk was published years before the COVID-19 pandemic (Brochard L, et al. AJRCCM. 2017;195[4]:438).

A number of pre-COVID-19 publications focused on examining this topic in clinical practice deserve specific mention. A study of respiratory mechanics in patients on NIV found it was nearly impossible to meet traditional targets for lung protective tidal volumes. Those patients who progressed to IMV had higher expired tidal volumes (Carteaux G, et al. Crit Care Med. 2016;44[2]:282). A large systematic review and metanalysis including more than 11,000 immunocompromised patients found delayed intubation led to increased mortality (Dumas G, et al. AJRCCM. 2021;204[2]:187). This study did not specifically implicate RS days and patient self-induced lung injury as factors driving the excess mortality; another smaller propensity-matched retrospective analysis of patients in the ICU supported with HFNC noted a 65% reduction in mortality among patients intubated after less than vs greater than 48 hours on HFNC who ultimately required IMV (Kang B, et al. Intensive Care Med. 2015;41[4]:623).

Despite this and other existing evidence regarding the hazards of prolonged RS prior to IMV, COVID-19’s burden on the health care system dramatically changed the way hypoxemic respiratory failure is managed in the ICU. Anecdotally, during the height of the pandemic, it was commonplace to encounter patients with severe COVID-19 supported with very high RS settings for days or often weeks. Occasionally, RS may have stabilized breathing mechanics. However, it was often our experience that among those patients supported with RS for extended periods prior to IMV lung compliance was poor, lung recovery did not occur, and prognosis was dismal. Various factors, including early reports of high mortality among patients with COVID-19 supported with IMV, resulted in reliance on RS as a means for delaying or avoiding IMV. Interestingly, a propensity-matched study of more than 2,700 patients found that prolonged RS was associated with significantly higher in-hospital mortality but despite this finding, the practice increased over the course of the pandemic (Riera J, et al. Eur Respir J. 2023;61[3]:2201426). Further, a prospective study comparing outcomes between patients intubated within 48 hours for COVID-19-related respiratory failure to those intubated later found a greater risk of in-hospital mortality and worse long-term outpatient lung function testing (in survivors) in the latter group.

Chandel_Abhimanyu_DC_web.jpg

It has previously been postulated that longer duration of IMV prior to the initiation of extracorporeal membrane oxygenation (ECMO) support in patients with hypoxemic respiratory failure may contribute to worse overall ECMO-related outcomes. This supposition is based on the principle that ECMO protects the lung by reducing ventilatory drive, tidal volume, and transpulmonary pressure swings. Several studies have documented an increase in mortality in patients supported with ECMO for COVID-19-related respiratory failure over the course of the pandemic. These investigators have noted that time to cannulation, but not IMV days (possibly reflecting duration of RS), correlates with worse ECMO outcomes (Ahmad Q, et al. ASAIO J. 2022;68[2]:171; Barbaro R, et al. Lancet. 2021;398[10307]:1230). We wonder if this reflects greater attention to low tidal volume ventilation during IMV but lack of awareness of or the inability to prevent injurious ventilation during prolonged RS. We view this as an important area for future research that may aid in patient selection in the ongoing effort to improve COVID-19-related ECMO outcomes.

The COVID-19 pandemic remains a significant burden on the health care system. Changes in care necessitated by the crisis produced innovations with the potential to rapidly improve outcomes. Notably though, it also has resulted in negative changes in response to a new pathogen that are hard to reconcile with physiologic principles. Evidence before and since the emergence of COVID-19 suggests prolonged RS prior to IMV is potentially harmful. It is critical for clinicians to recognize this principle and take steps to mitigate this problem in patients where a positive response to RS is not demonstrated in a timely manner.



Drs. Wilson and Chandel are with the Department of Pulmonary and Critical Care, Walter Reed National Military Medical Center, Washington, DC.

The SARS-CoV-2 pandemic changed the way intensivists approach extracorporeal membrane oxygenation (ECMO). Patients with COVID-19 acute respiratory distress syndrome (ARDS) placed on ECMO have a high prevalence of right ventricular (RV) failure, which is associated with reduced survival (Maharaj V et al. ASAIO Journal. 2022;68[6]:772). In 2021, our institution supported 51 patients with COVID-19 ARDS with ECMO: 51% developed RV failure, defined as a clinical syndrome (reduced cardiac output) in the presence of RV dysfunction on transthoracic echocardiogram (TTE) (Marra A et al. Chest. 2022;161[2]:535). Total numbers for RV dysfunction and RV dilation on TTE were 78% and 91% respectively, so many of those with RV changes on TTE did not progress to clinical failure. In essence then, TTE signs of RV dysfunction are sensitive but not specific for clinical RV failure.

Rates for survival to decannulation were far lower when RV failure was present (27%) vs. absent (84%). Given these numbers, we felt a reduction in RV failure would be an important target for improving outcomes for patients with COVID-19 ARDS receiving ECMO. Existing studies on RV failure in patients with ARDS receiving ECMO are plagued by scant data, small sample sizes, differences in diagnostic criteria, and heterogenous treatment approaches. Despite these limitations, we felt the need to make changes in our approach to RV management.

Because outcomes once clinical RV-failure occurs are so poor, we focused on prevention. While we’re short on data and evidence-based medicine (EBM) here, we know a lot about the physiology of COVID19, the pulmonary vasculature, and the right side of the heart. There are multiple physiologic and disease-related pathways that converge to produce RV-failure in patients with COVID-19 ARDS on ECMO (Sato R et al. Crit Care. 2021;25:172). Ongoing relative hypoxemia, hypercapnia, acidemia, and microvascular thromboses/immunothromboses can all lead to increased pulmonary vascular resistance (PVR) and an increased workload for the RV (Zochios V et al. ASAIO Journal. 2022; 68[4]:456). ARDS management typically involves high positive end-expiratory pressure (PEEP), which can produce RV-PA uncoupling (Wanner P et al. J Clin Med. 2020;9:432).

We do know that ECMO relieves the stress on the right side of the heart by improving hypoxemia, hypercapnia, and acidemia while allowing for reduction in PEEP (Zochios V et al. ASAIO Journal. 2022; 68[4]:456). In addition to ECMO, proning and pulmonary vasodilators offload RV by further reducing pulmonary pressures (Sato R et al. Crit Care. 2021;25:172). Lastly, a right ventricular assist device (RVAD) can dissipate the work required by the RV and prevent decompensation. Collectively, these therapies can be considered preventive.

Knowing the RV parameters on RV are sensitive but not specific for outcomes though, when should some of these treatments be instituted? It’s clear that once RV failure has developed it’s probably too late, but it’s hard to find data to guide us on when to act. One institution used right ventricular assist devices (RVADs) at the time of ECMO initiation with protocolized care and achieved a survival to discharge rate of 73% (Mustafa AK et al. JAMA Surgery. 2020;155[10]:990). The publication generated enthusiasm for RVAD support with ECMO, but it’s possible the protocolized care drove the high survival rate, at least in part.

At our institution, we developed our own protocol for evaluation of the RV with proactive treatment based on specific targets. We performed daily, bedside TTE and assessed the RV fractional area of change (FAC) and outflow tract velocity time integral (VTI). These parameters provide a quantitative assessment of global RV function, and FAC is directly related to ability to wean from ECMO support (Maharaj V et al. ASAIO Journal. 2022;68[6]:772). We avoided using the tricuspid annular plain systolic excursion (TAPSE) due to its poor sensitivity (Marra AM et al. Chest. 2022;161[2]:535). Patients receiving ECMO with subjective, global mild to moderate RV dysfunction on TTE with worsening clinical data, an FAC of 20%-35%, and a VTI of 10-14 cm were treated with aggressive diuresis, pulmonary vasodilators, and inotropy for 48 hours. If there was no improvement or deterioration, an RVAD was placed. For patients with signs of severe RV dysfunction (FAC < 20% or VTI < 10 cm), we proceeded directly to RVAD. We’re currently collecting data and tracking outcomes.

While data exist on various interventions in RV failure due to COVID-19 ARDS with ECMO, our understanding of this disease is still in its infancy. The optimal timing of interventions to manage and prevent RV failure is not known. We would argue that those who wait for RV failure to occur before instituting protective or supportive therapies are missing the opportunity to impact outcomes. We currently do not have the evidence to support the specific protocol we’ve outlined here and instituted at our hospital. However, we do believe there’s enough literature and experience to support the concept that close monitoring of RV function is critical for patients with COVID19 ARDS receiving ECMO. Failure to anticipate worsening function on the way to failure means reacting to it rather than staving it off. By then, it’s too late.
 

Dr. Thomas is Maj, USAF, assistant professor, pulmonary/critical care; Dr. O’Neil is Maj, USAF, pediatric and ECMO intensivist, PICU medical director; and Dr. Villalobos is Capt, USAF, assistant professor, pulmonary/critical care, medical ICU director, Brooke Army Medical Center, San Antonio, Tex. The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. government.

The SARS-CoV-2 pandemic changed the way intensivists approach extracorporeal membrane oxygenation (ECMO). Patients with COVID-19 acute respiratory distress syndrome (ARDS) placed on ECMO have a high prevalence of right ventricular (RV) failure, which is associated with reduced survival (Maharaj V et al. ASAIO Journal. 2022;68[6]:772). In 2021, our institution supported 51 patients with COVID-19 ARDS with ECMO: 51% developed RV failure, defined as a clinical syndrome (reduced cardiac output) in the presence of RV dysfunction on transthoracic echocardiogram (TTE) (Marra A et al. Chest. 2022;161[2]:535). Total numbers for RV dysfunction and RV dilation on TTE were 78% and 91% respectively, so many of those with RV changes on TTE did not progress to clinical failure. In essence then, TTE signs of RV dysfunction are sensitive but not specific for clinical RV failure.

Rates for survival to decannulation were far lower when RV failure was present (27%) vs. absent (84%). Given these numbers, we felt a reduction in RV failure would be an important target for improving outcomes for patients with COVID-19 ARDS receiving ECMO. Existing studies on RV failure in patients with ARDS receiving ECMO are plagued by scant data, small sample sizes, differences in diagnostic criteria, and heterogenous treatment approaches. Despite these limitations, we felt the need to make changes in our approach to RV management.

Because outcomes once clinical RV-failure occurs are so poor, we focused on prevention. While we’re short on data and evidence-based medicine (EBM) here, we know a lot about the physiology of COVID19, the pulmonary vasculature, and the right side of the heart. There are multiple physiologic and disease-related pathways that converge to produce RV-failure in patients with COVID-19 ARDS on ECMO (Sato R et al. Crit Care. 2021;25:172). Ongoing relative hypoxemia, hypercapnia, acidemia, and microvascular thromboses/immunothromboses can all lead to increased pulmonary vascular resistance (PVR) and an increased workload for the RV (Zochios V et al. ASAIO Journal. 2022; 68[4]:456). ARDS management typically involves high positive end-expiratory pressure (PEEP), which can produce RV-PA uncoupling (Wanner P et al. J Clin Med. 2020;9:432).

We do know that ECMO relieves the stress on the right side of the heart by improving hypoxemia, hypercapnia, and acidemia while allowing for reduction in PEEP (Zochios V et al. ASAIO Journal. 2022; 68[4]:456). In addition to ECMO, proning and pulmonary vasodilators offload RV by further reducing pulmonary pressures (Sato R et al. Crit Care. 2021;25:172). Lastly, a right ventricular assist device (RVAD) can dissipate the work required by the RV and prevent decompensation. Collectively, these therapies can be considered preventive.

Knowing the RV parameters on RV are sensitive but not specific for outcomes though, when should some of these treatments be instituted? It’s clear that once RV failure has developed it’s probably too late, but it’s hard to find data to guide us on when to act. One institution used right ventricular assist devices (RVADs) at the time of ECMO initiation with protocolized care and achieved a survival to discharge rate of 73% (Mustafa AK et al. JAMA Surgery. 2020;155[10]:990). The publication generated enthusiasm for RVAD support with ECMO, but it’s possible the protocolized care drove the high survival rate, at least in part.

At our institution, we developed our own protocol for evaluation of the RV with proactive treatment based on specific targets. We performed daily, bedside TTE and assessed the RV fractional area of change (FAC) and outflow tract velocity time integral (VTI). These parameters provide a quantitative assessment of global RV function, and FAC is directly related to ability to wean from ECMO support (Maharaj V et al. ASAIO Journal. 2022;68[6]:772). We avoided using the tricuspid annular plain systolic excursion (TAPSE) due to its poor sensitivity (Marra AM et al. Chest. 2022;161[2]:535). Patients receiving ECMO with subjective, global mild to moderate RV dysfunction on TTE with worsening clinical data, an FAC of 20%-35%, and a VTI of 10-14 cm were treated with aggressive diuresis, pulmonary vasodilators, and inotropy for 48 hours. If there was no improvement or deterioration, an RVAD was placed. For patients with signs of severe RV dysfunction (FAC < 20% or VTI < 10 cm), we proceeded directly to RVAD. We’re currently collecting data and tracking outcomes.

While data exist on various interventions in RV failure due to COVID-19 ARDS with ECMO, our understanding of this disease is still in its infancy. The optimal timing of interventions to manage and prevent RV failure is not known. We would argue that those who wait for RV failure to occur before instituting protective or supportive therapies are missing the opportunity to impact outcomes. We currently do not have the evidence to support the specific protocol we’ve outlined here and instituted at our hospital. However, we do believe there’s enough literature and experience to support the concept that close monitoring of RV function is critical for patients with COVID19 ARDS receiving ECMO. Failure to anticipate worsening function on the way to failure means reacting to it rather than staving it off. By then, it’s too late.
 

Dr. Thomas is Maj, USAF, assistant professor, pulmonary/critical care; Dr. O’Neil is Maj, USAF, pediatric and ECMO intensivist, PICU medical director; and Dr. Villalobos is Capt, USAF, assistant professor, pulmonary/critical care, medical ICU director, Brooke Army Medical Center, San Antonio, Tex. The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. government.

The SARS-CoV-2 pandemic changed the way intensivists approach extracorporeal membrane oxygenation (ECMO). Patients with COVID-19 acute respiratory distress syndrome (ARDS) placed on ECMO have a high prevalence of right ventricular (RV) failure, which is associated with reduced survival (Maharaj V et al. ASAIO Journal. 2022;68[6]:772). In 2021, our institution supported 51 patients with COVID-19 ARDS with ECMO: 51% developed RV failure, defined as a clinical syndrome (reduced cardiac output) in the presence of RV dysfunction on transthoracic echocardiogram (TTE) (Marra A et al. Chest. 2022;161[2]:535). Total numbers for RV dysfunction and RV dilation on TTE were 78% and 91% respectively, so many of those with RV changes on TTE did not progress to clinical failure. In essence then, TTE signs of RV dysfunction are sensitive but not specific for clinical RV failure.

Rates for survival to decannulation were far lower when RV failure was present (27%) vs. absent (84%). Given these numbers, we felt a reduction in RV failure would be an important target for improving outcomes for patients with COVID-19 ARDS receiving ECMO. Existing studies on RV failure in patients with ARDS receiving ECMO are plagued by scant data, small sample sizes, differences in diagnostic criteria, and heterogenous treatment approaches. Despite these limitations, we felt the need to make changes in our approach to RV management.

Because outcomes once clinical RV-failure occurs are so poor, we focused on prevention. While we’re short on data and evidence-based medicine (EBM) here, we know a lot about the physiology of COVID19, the pulmonary vasculature, and the right side of the heart. There are multiple physiologic and disease-related pathways that converge to produce RV-failure in patients with COVID-19 ARDS on ECMO (Sato R et al. Crit Care. 2021;25:172). Ongoing relative hypoxemia, hypercapnia, acidemia, and microvascular thromboses/immunothromboses can all lead to increased pulmonary vascular resistance (PVR) and an increased workload for the RV (Zochios V et al. ASAIO Journal. 2022; 68[4]:456). ARDS management typically involves high positive end-expiratory pressure (PEEP), which can produce RV-PA uncoupling (Wanner P et al. J Clin Med. 2020;9:432).

We do know that ECMO relieves the stress on the right side of the heart by improving hypoxemia, hypercapnia, and acidemia while allowing for reduction in PEEP (Zochios V et al. ASAIO Journal. 2022; 68[4]:456). In addition to ECMO, proning and pulmonary vasodilators offload RV by further reducing pulmonary pressures (Sato R et al. Crit Care. 2021;25:172). Lastly, a right ventricular assist device (RVAD) can dissipate the work required by the RV and prevent decompensation. Collectively, these therapies can be considered preventive.

Knowing the RV parameters on RV are sensitive but not specific for outcomes though, when should some of these treatments be instituted? It’s clear that once RV failure has developed it’s probably too late, but it’s hard to find data to guide us on when to act. One institution used right ventricular assist devices (RVADs) at the time of ECMO initiation with protocolized care and achieved a survival to discharge rate of 73% (Mustafa AK et al. JAMA Surgery. 2020;155[10]:990). The publication generated enthusiasm for RVAD support with ECMO, but it’s possible the protocolized care drove the high survival rate, at least in part.

At our institution, we developed our own protocol for evaluation of the RV with proactive treatment based on specific targets. We performed daily, bedside TTE and assessed the RV fractional area of change (FAC) and outflow tract velocity time integral (VTI). These parameters provide a quantitative assessment of global RV function, and FAC is directly related to ability to wean from ECMO support (Maharaj V et al. ASAIO Journal. 2022;68[6]:772). We avoided using the tricuspid annular plain systolic excursion (TAPSE) due to its poor sensitivity (Marra AM et al. Chest. 2022;161[2]:535). Patients receiving ECMO with subjective, global mild to moderate RV dysfunction on TTE with worsening clinical data, an FAC of 20%-35%, and a VTI of 10-14 cm were treated with aggressive diuresis, pulmonary vasodilators, and inotropy for 48 hours. If there was no improvement or deterioration, an RVAD was placed. For patients with signs of severe RV dysfunction (FAC < 20% or VTI < 10 cm), we proceeded directly to RVAD. We’re currently collecting data and tracking outcomes.

While data exist on various interventions in RV failure due to COVID-19 ARDS with ECMO, our understanding of this disease is still in its infancy. The optimal timing of interventions to manage and prevent RV failure is not known. We would argue that those who wait for RV failure to occur before instituting protective or supportive therapies are missing the opportunity to impact outcomes. We currently do not have the evidence to support the specific protocol we’ve outlined here and instituted at our hospital. However, we do believe there’s enough literature and experience to support the concept that close monitoring of RV function is critical for patients with COVID19 ARDS receiving ECMO. Failure to anticipate worsening function on the way to failure means reacting to it rather than staving it off. By then, it’s too late.
 

Dr. Thomas is Maj, USAF, assistant professor, pulmonary/critical care; Dr. O’Neil is Maj, USAF, pediatric and ECMO intensivist, PICU medical director; and Dr. Villalobos is Capt, USAF, assistant professor, pulmonary/critical care, medical ICU director, Brooke Army Medical Center, San Antonio, Tex. The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. government.

The European Respiratory Society (ERS) and American Thoracic Society (ATS) just published an update to their guidelines on lung function interpretation (Stanojevic S, et al. Eur Respir J. 2022; 60: 2101499). As with any update, the document builds on past work and integrates new advances the field has seen since 2005.

The current iteration comes at a time when academics, clinicians, and epidemiologists are re-analyzing what we think we know about the complex ways race and ethnicity intersect with the practice of medicine. Several experts on lung function testing, many if not most of whom are authors on the ERS/ATS guideline, have written letters or published reviews commenting on the way accounting for race or ethnicity affects lung function interpretation.

Race/ethnicity and lung function was also the topic of an excellent session at the recent CHEST 2022 Annual Meeting in Nashville, Tennessee. Here, we’ll provide a brief review and direct the reader to relevant sources for a more detailed analysis.

Spirometry is an integral part of the diagnosis and management of a wide range of pulmonary conditions. Dr. Aaron Baugh from the University of California San Francisco (UCSF) lectured on the spirometer’s history at CHEST 2022 and detailed its interactions with race over the past 2 centuries. Other authors have chronicled this history, as well (Braun L, et al. Can J Respir Ther. 2015;51[4]:99-101). The short version is that since the British surgeon John Hutchinson created the first spirometer in 1846, race has been a part of the discussion of lung function interpretation.

In 2022, we know far more about the factors that determine lung function than we did in the 19th century. Age, height, and sex assigned at birth all explain a high percentage of the variability seen in FEV1 and FVC. When modeled, race also explains a portion of the variability, and the NHANES III investigators found its inclusion in regression equations, along with age, height, and sex, improved their precision. Case closed, right? Modern medicine is defined by phenotyping, precision, and individualized care, so why shouldn’t race be a part of lung function interpretation?

Well, it’s complicated. With the increasing recognition of health disparities across racial groups the way race is incorporated in medical practice is understandably being scrutinized. As clinicians and academics, we must analyze the root cause of differences in health outcomes between racial groups.

Publications on pulse oximetry (Gottlieb ER, et al. JAMA Intern Med. 2022; 182:849-858) and glomerular filtration rate (Williams WW, et al. N Engl J Med. 2021;385:1804-1806) have revealed some of the ways our use of instruments and equations may exacerbate or perpetuate current disparities. Even small differences in a measure like pulse oximetry could have a profound impact on clinical decisions at the individual and population levels.

The 2022 ERS/ATS lung function interpretation guidelines have abandoned the use of NHANES III as a reference set. They now recommend the equations developed by the Global Lung Initiative (GLI) for referencing to normal for spirometry, diffusion capacity, and lung volumes. For spirometry the GLI was able to integrate data from countries around the world. This allowed ethnicity to be included in their regression equations and, similar to NHANES III, they found ethnicity improved the precision of their equations. They also published an equation that did not account for country of origin that could be applied to individuals of any race/ethnicity (Quanjer PH, et al. Eur Respir J. 2014;43:505-512). This allowed for applying the GLI equations to external data sets with or without ethnicity included as a co-variate.

Given well-established discrepancies in spirometry, it should come as no surprise that applying the race/ethnicity-neutral GLI equations to non-White populations increases the percentage of patients with pulmonary defects (Moffett AT, et al. Am J Respir Crit Care Med. 2021; A1030). Other data suggest that elimination of race/ethnicity as a co-variate improves the association between percent predicted lung function and important outcomes like mortality (McCormack MC, et al. Am J Respir Crit Care Med. 2022;205:723-724). The first analysis implies that by adjusting for race/ethnicity we may be missing abnormalities, and the second suggests accuracy for outcomes is lost. So case closed, right? Let’s abandon race/ethnicity as a co- variate for our spirometry reference equations.

Perhaps, but a few caveats are in order. It’s important to note that doing so would result in a dramatic increase in abnormal findings in otherwise healthy and asymptomatic non-White individuals. This could negatively affect eligibility for employment and military service (Townsend MC, et al. Am J Respir Crit Care Med. 2022;789-790). We’ve also yet to fully explain the factors driving differences in lung function between races. If socioeconomic factors explained the entirety of the difference, it would be easier to argue for elimination of using race/ethnicity in our equations. Currently, the etiology is thought to be multifactorial and is yet to be fully explained (Braun L, et al. Eur Respir J. 2013;41:1362-1370).

The more we look for institutional racism, the more we will find it. As we realize that attaining health and wellness is more difficult for the disenfranchised, we need to ensure our current practices are part of the solution.

The ERS/ATS guidelines suggest eliminating fixed correction factors for race but do not require elimination of race/ethnicity as a co-variate in the equations selected for use. This seems very reasonable given what we know now. As pulmonary medicine academics and researchers, we need to continue to study the impact integrating race/ethnicity has on precision, accuracy, and clinical outcomes. As pulmonary medicine clinicians, we need to be aware of the reference equations being used in our lab, understand how inclusion of race/ethnicity affects findings, and act accordingly, depending on the clinical situation.
 

Dr. Ghionni is a Pulmonary/Critical Care Fellow, and Dr. Woods is Program Director – PCCM Fellowship and Associate Program Director – IM Residency, Medstar Washington Hospital Center; Dr. Woods is Associate Professor of Medicine, Georgetown University School of Medicine, Washington, DC.

The European Respiratory Society (ERS) and American Thoracic Society (ATS) just published an update to their guidelines on lung function interpretation (Stanojevic S, et al. Eur Respir J. 2022; 60: 2101499). As with any update, the document builds on past work and integrates new advances the field has seen since 2005.

The current iteration comes at a time when academics, clinicians, and epidemiologists are re-analyzing what we think we know about the complex ways race and ethnicity intersect with the practice of medicine. Several experts on lung function testing, many if not most of whom are authors on the ERS/ATS guideline, have written letters or published reviews commenting on the way accounting for race or ethnicity affects lung function interpretation.

Race/ethnicity and lung function was also the topic of an excellent session at the recent CHEST 2022 Annual Meeting in Nashville, Tennessee. Here, we’ll provide a brief review and direct the reader to relevant sources for a more detailed analysis.

Spirometry is an integral part of the diagnosis and management of a wide range of pulmonary conditions. Dr. Aaron Baugh from the University of California San Francisco (UCSF) lectured on the spirometer’s history at CHEST 2022 and detailed its interactions with race over the past 2 centuries. Other authors have chronicled this history, as well (Braun L, et al. Can J Respir Ther. 2015;51[4]:99-101). The short version is that since the British surgeon John Hutchinson created the first spirometer in 1846, race has been a part of the discussion of lung function interpretation.

In 2022, we know far more about the factors that determine lung function than we did in the 19th century. Age, height, and sex assigned at birth all explain a high percentage of the variability seen in FEV1 and FVC. When modeled, race also explains a portion of the variability, and the NHANES III investigators found its inclusion in regression equations, along with age, height, and sex, improved their precision. Case closed, right? Modern medicine is defined by phenotyping, precision, and individualized care, so why shouldn’t race be a part of lung function interpretation?

Well, it’s complicated. With the increasing recognition of health disparities across racial groups the way race is incorporated in medical practice is understandably being scrutinized. As clinicians and academics, we must analyze the root cause of differences in health outcomes between racial groups.

Publications on pulse oximetry (Gottlieb ER, et al. JAMA Intern Med. 2022; 182:849-858) and glomerular filtration rate (Williams WW, et al. N Engl J Med. 2021;385:1804-1806) have revealed some of the ways our use of instruments and equations may exacerbate or perpetuate current disparities. Even small differences in a measure like pulse oximetry could have a profound impact on clinical decisions at the individual and population levels.

The 2022 ERS/ATS lung function interpretation guidelines have abandoned the use of NHANES III as a reference set. They now recommend the equations developed by the Global Lung Initiative (GLI) for referencing to normal for spirometry, diffusion capacity, and lung volumes. For spirometry the GLI was able to integrate data from countries around the world. This allowed ethnicity to be included in their regression equations and, similar to NHANES III, they found ethnicity improved the precision of their equations. They also published an equation that did not account for country of origin that could be applied to individuals of any race/ethnicity (Quanjer PH, et al. Eur Respir J. 2014;43:505-512). This allowed for applying the GLI equations to external data sets with or without ethnicity included as a co-variate.

Given well-established discrepancies in spirometry, it should come as no surprise that applying the race/ethnicity-neutral GLI equations to non-White populations increases the percentage of patients with pulmonary defects (Moffett AT, et al. Am J Respir Crit Care Med. 2021; A1030). Other data suggest that elimination of race/ethnicity as a co-variate improves the association between percent predicted lung function and important outcomes like mortality (McCormack MC, et al. Am J Respir Crit Care Med. 2022;205:723-724). The first analysis implies that by adjusting for race/ethnicity we may be missing abnormalities, and the second suggests accuracy for outcomes is lost. So case closed, right? Let’s abandon race/ethnicity as a co- variate for our spirometry reference equations.

Perhaps, but a few caveats are in order. It’s important to note that doing so would result in a dramatic increase in abnormal findings in otherwise healthy and asymptomatic non-White individuals. This could negatively affect eligibility for employment and military service (Townsend MC, et al. Am J Respir Crit Care Med. 2022;789-790). We’ve also yet to fully explain the factors driving differences in lung function between races. If socioeconomic factors explained the entirety of the difference, it would be easier to argue for elimination of using race/ethnicity in our equations. Currently, the etiology is thought to be multifactorial and is yet to be fully explained (Braun L, et al. Eur Respir J. 2013;41:1362-1370).

The more we look for institutional racism, the more we will find it. As we realize that attaining health and wellness is more difficult for the disenfranchised, we need to ensure our current practices are part of the solution.

The ERS/ATS guidelines suggest eliminating fixed correction factors for race but do not require elimination of race/ethnicity as a co-variate in the equations selected for use. This seems very reasonable given what we know now. As pulmonary medicine academics and researchers, we need to continue to study the impact integrating race/ethnicity has on precision, accuracy, and clinical outcomes. As pulmonary medicine clinicians, we need to be aware of the reference equations being used in our lab, understand how inclusion of race/ethnicity affects findings, and act accordingly, depending on the clinical situation.
 

Dr. Ghionni is a Pulmonary/Critical Care Fellow, and Dr. Woods is Program Director – PCCM Fellowship and Associate Program Director – IM Residency, Medstar Washington Hospital Center; Dr. Woods is Associate Professor of Medicine, Georgetown University School of Medicine, Washington, DC.

The European Respiratory Society (ERS) and American Thoracic Society (ATS) just published an update to their guidelines on lung function interpretation (Stanojevic S, et al. Eur Respir J. 2022; 60: 2101499). As with any update, the document builds on past work and integrates new advances the field has seen since 2005.

The current iteration comes at a time when academics, clinicians, and epidemiologists are re-analyzing what we think we know about the complex ways race and ethnicity intersect with the practice of medicine. Several experts on lung function testing, many if not most of whom are authors on the ERS/ATS guideline, have written letters or published reviews commenting on the way accounting for race or ethnicity affects lung function interpretation.

Race/ethnicity and lung function was also the topic of an excellent session at the recent CHEST 2022 Annual Meeting in Nashville, Tennessee. Here, we’ll provide a brief review and direct the reader to relevant sources for a more detailed analysis.

Spirometry is an integral part of the diagnosis and management of a wide range of pulmonary conditions. Dr. Aaron Baugh from the University of California San Francisco (UCSF) lectured on the spirometer’s history at CHEST 2022 and detailed its interactions with race over the past 2 centuries. Other authors have chronicled this history, as well (Braun L, et al. Can J Respir Ther. 2015;51[4]:99-101). The short version is that since the British surgeon John Hutchinson created the first spirometer in 1846, race has been a part of the discussion of lung function interpretation.

In 2022, we know far more about the factors that determine lung function than we did in the 19th century. Age, height, and sex assigned at birth all explain a high percentage of the variability seen in FEV1 and FVC. When modeled, race also explains a portion of the variability, and the NHANES III investigators found its inclusion in regression equations, along with age, height, and sex, improved their precision. Case closed, right? Modern medicine is defined by phenotyping, precision, and individualized care, so why shouldn’t race be a part of lung function interpretation?

Well, it’s complicated. With the increasing recognition of health disparities across racial groups the way race is incorporated in medical practice is understandably being scrutinized. As clinicians and academics, we must analyze the root cause of differences in health outcomes between racial groups.

Publications on pulse oximetry (Gottlieb ER, et al. JAMA Intern Med. 2022; 182:849-858) and glomerular filtration rate (Williams WW, et al. N Engl J Med. 2021;385:1804-1806) have revealed some of the ways our use of instruments and equations may exacerbate or perpetuate current disparities. Even small differences in a measure like pulse oximetry could have a profound impact on clinical decisions at the individual and population levels.

The 2022 ERS/ATS lung function interpretation guidelines have abandoned the use of NHANES III as a reference set. They now recommend the equations developed by the Global Lung Initiative (GLI) for referencing to normal for spirometry, diffusion capacity, and lung volumes. For spirometry the GLI was able to integrate data from countries around the world. This allowed ethnicity to be included in their regression equations and, similar to NHANES III, they found ethnicity improved the precision of their equations. They also published an equation that did not account for country of origin that could be applied to individuals of any race/ethnicity (Quanjer PH, et al. Eur Respir J. 2014;43:505-512). This allowed for applying the GLI equations to external data sets with or without ethnicity included as a co-variate.

Given well-established discrepancies in spirometry, it should come as no surprise that applying the race/ethnicity-neutral GLI equations to non-White populations increases the percentage of patients with pulmonary defects (Moffett AT, et al. Am J Respir Crit Care Med. 2021; A1030). Other data suggest that elimination of race/ethnicity as a co-variate improves the association between percent predicted lung function and important outcomes like mortality (McCormack MC, et al. Am J Respir Crit Care Med. 2022;205:723-724). The first analysis implies that by adjusting for race/ethnicity we may be missing abnormalities, and the second suggests accuracy for outcomes is lost. So case closed, right? Let’s abandon race/ethnicity as a co- variate for our spirometry reference equations.

Perhaps, but a few caveats are in order. It’s important to note that doing so would result in a dramatic increase in abnormal findings in otherwise healthy and asymptomatic non-White individuals. This could negatively affect eligibility for employment and military service (Townsend MC, et al. Am J Respir Crit Care Med. 2022;789-790). We’ve also yet to fully explain the factors driving differences in lung function between races. If socioeconomic factors explained the entirety of the difference, it would be easier to argue for elimination of using race/ethnicity in our equations. Currently, the etiology is thought to be multifactorial and is yet to be fully explained (Braun L, et al. Eur Respir J. 2013;41:1362-1370).

The more we look for institutional racism, the more we will find it. As we realize that attaining health and wellness is more difficult for the disenfranchised, we need to ensure our current practices are part of the solution.

The ERS/ATS guidelines suggest eliminating fixed correction factors for race but do not require elimination of race/ethnicity as a co-variate in the equations selected for use. This seems very reasonable given what we know now. As pulmonary medicine academics and researchers, we need to continue to study the impact integrating race/ethnicity has on precision, accuracy, and clinical outcomes. As pulmonary medicine clinicians, we need to be aware of the reference equations being used in our lab, understand how inclusion of race/ethnicity affects findings, and act accordingly, depending on the clinical situation.
 

Dr. Ghionni is a Pulmonary/Critical Care Fellow, and Dr. Woods is Program Director – PCCM Fellowship and Associate Program Director – IM Residency, Medstar Washington Hospital Center; Dr. Woods is Associate Professor of Medicine, Georgetown University School of Medicine, Washington, DC.

Point-of-care ultrasound (POCUS) is a useful, practice-changing bedside tool that spans all medical and surgical specialties. While the definition of POCUS varies, most would agree it is an abbreviated exam that helps to answer a specific clinical question. With the expansion of POCUS training, the clinical questions being asked and answered have increased in scope and volume. The types of exams being utilized in “point of care ultrasound” have also increased and include transthoracic echocardiography; trans-esophageal echocardiography; and lung, gastric, abdominal, and ocular ultrasound. POCUS is used across multiple specialties, including critical care, anesthesiology, emergency medicine, and primary care.

Villalobos_Nicholas_web.jpg

Not only has POCUS become increasingly important clinically, but specialties now test these skills on their respective board examinations. Anesthesia is one of many such examples. The content outline for the American Board of Anesthesiology includes POCUS as a tested item on both the written and applied components of the exam. POCUS training must be directed toward both optimizing patient management and preparing learners for their board examination. A method for teaching this has yet to be defined (Naji A, et al. Cureus. 2021;13[5]:e15217).

One question – how should different specialties approach this educational challenge and should specialties train together? The answer is complicated. Many POCUS courses and certifications exist, and all vary in their content, didactics, and length. No true gold standard exists for POCUS certification for radiology or noncardiology providers. Additionally, there are no defined expectations or testing processes that certify a provider is “certified” to perform POCUS. While waiting for medical society guidelines to address these issues, many in graduate medical education (GME) are coming up with their own ways to incorporate POCUS into their respective training programs (Atkinson P, et al. CJEM. 2015 Mar;17[2]:161).

Who’s training whom?

Over the past decade, several expert committees, including those in critical care, have developed recommendations and consensus statements urging training facilities to independently create POCUS curriculums. The threshold for many programs to enter this realm of expertise is high and oftentimes unobtainable. We’ve seen emergency medicine and anesthesia raise the bar for ultrasound education in their residencies, but it’s unclear whether all fellowship-trained physicians can and should be tasked with obtaining official POCUS certification.

While specific specialties may require tailored certifications, there’s a considerable overlap in POCUS exam content across specialties. One approach to POCUS training could be developing and implementing a multidisciplinary curriculum. This would allow for pooling of resources (equipment, staff) and harnessing knowledge from providers familiar with different phases of patient care (ICU, perioperative, ED, outpatient clinics). By approaching POCUS from a multidisciplinary perspective, the quality of education may be enhanced (Mayo PH, et al. Intensive Care Med. 2014;40[5]:654). Is it then prudent for providers and trainees alike to share in didactics across all areas of the hospital and clinic? Would this close the knowledge gap between specialties who are facile with ultrasound and those not?

Determining the role of transesophageal echocardiography in a POCUS curriculum

This modality of imaging has been, until recently, reserved for cardiologists and anesthesiologists. More recently transesophageal echocardiography (TEE) has been utilized by emergency and critical care medicine physicians. TEE is part of recommended training for these specialties as a tool for diagnostic and rescue measures, including ventilator management, emergency procedures, and medication titration. Rescue TEE can also be utilized perioperatively where the transthoracic exam is limited by poor windows or the operative procedure precludes access to the chest. While transthoracic echocardiography (TTE) is often used in a point of care fashion, TEE is utilized less often. This may stem from the invasive nature of the procedure but likely also results from lack of equipment and training. Like POCUS overall, TEE POCUS will require incorporation into training programs to achieve widespread use and acceptance.

A deluge of research on TEE for the noncardiologist shows this modality is minimally invasive, safe, and effective. As it becomes more readily available and technology improves, there is no reason why an esophageal probe can’t be used in a patient with a secured airway (Wray TC, et al. J Intensive Care Med. 2021;36[1]:123).

Ultrasound for hemodynamic monitoring

There are many methods employed for hemodynamic monitoring in the ICU. Although echocardiographic and vascular parameters have been validated in the cardiac and perioperative fields, their application in the ICU setting for resuscitation and volume management remain somewhat controversial. The use of TEE and more advanced understanding of spectral doppler and pulmonary ultrasonography using TEE has revolutionized the way providers are managing critically ill patients. (Garcia YA, et al. Chest. 2017;152[4]:736).

In our opinion, physiology and imaging training for residents and fellows should be required for critical care medicine trainees. Delving into the nuances of frank-starling curves, stroke work, and diastolic function will enrich their understanding and highlight the applicability of ultrasonography. Furthermore, all clinicians caring for patients with critical illness should be privy to the nuances of physiologic derangement, and to that end, advanced echocardiographic principles and image acquisition. The heart-lung interactions are demonstrated in real time using POCUS and can clearly delineate treatment goals (Vieillard-Baron A, et al. Intensive Care Med. 2019;45[6]:770).

Documentation and billing

If clinicians are making medical decisions based off imaging gathered at the bedside and interpreted in real-time, documentation should reflect that. That documentation will invariably lead to billing and possibly audit or quality review by colleagues or other healthcare staff. Radiology and cardiology have perfected the billing process for image interpretation, but their form of documentation and interpretation may not easily be implemented in the perioperative or critical care settings. An abbreviated document with focused information should take the place of the formal study. With that, the credentialing and board certification process will allow providers to feel empowered to make clinical decisions based off these focused examinations.

Dr. Goertzen is Chief Fellow, Pulmonary/Critical Care; Dr. Knuf is Program Director, Department of Anesthesia; and Dr. Villalobos is Director of Medical ICU, Department of Internal Medicine, San Antonio Military Medical Center, San Antonio, Texas.

Point-of-care ultrasound (POCUS) is a useful, practice-changing bedside tool that spans all medical and surgical specialties. While the definition of POCUS varies, most would agree it is an abbreviated exam that helps to answer a specific clinical question. With the expansion of POCUS training, the clinical questions being asked and answered have increased in scope and volume. The types of exams being utilized in “point of care ultrasound” have also increased and include transthoracic echocardiography; trans-esophageal echocardiography; and lung, gastric, abdominal, and ocular ultrasound. POCUS is used across multiple specialties, including critical care, anesthesiology, emergency medicine, and primary care.

Villalobos_Nicholas_web.jpg

Not only has POCUS become increasingly important clinically, but specialties now test these skills on their respective board examinations. Anesthesia is one of many such examples. The content outline for the American Board of Anesthesiology includes POCUS as a tested item on both the written and applied components of the exam. POCUS training must be directed toward both optimizing patient management and preparing learners for their board examination. A method for teaching this has yet to be defined (Naji A, et al. Cureus. 2021;13[5]:e15217).

One question – how should different specialties approach this educational challenge and should specialties train together? The answer is complicated. Many POCUS courses and certifications exist, and all vary in their content, didactics, and length. No true gold standard exists for POCUS certification for radiology or noncardiology providers. Additionally, there are no defined expectations or testing processes that certify a provider is “certified” to perform POCUS. While waiting for medical society guidelines to address these issues, many in graduate medical education (GME) are coming up with their own ways to incorporate POCUS into their respective training programs (Atkinson P, et al. CJEM. 2015 Mar;17[2]:161).

Who’s training whom?

Over the past decade, several expert committees, including those in critical care, have developed recommendations and consensus statements urging training facilities to independently create POCUS curriculums. The threshold for many programs to enter this realm of expertise is high and oftentimes unobtainable. We’ve seen emergency medicine and anesthesia raise the bar for ultrasound education in their residencies, but it’s unclear whether all fellowship-trained physicians can and should be tasked with obtaining official POCUS certification.

While specific specialties may require tailored certifications, there’s a considerable overlap in POCUS exam content across specialties. One approach to POCUS training could be developing and implementing a multidisciplinary curriculum. This would allow for pooling of resources (equipment, staff) and harnessing knowledge from providers familiar with different phases of patient care (ICU, perioperative, ED, outpatient clinics). By approaching POCUS from a multidisciplinary perspective, the quality of education may be enhanced (Mayo PH, et al. Intensive Care Med. 2014;40[5]:654). Is it then prudent for providers and trainees alike to share in didactics across all areas of the hospital and clinic? Would this close the knowledge gap between specialties who are facile with ultrasound and those not?

Determining the role of transesophageal echocardiography in a POCUS curriculum

This modality of imaging has been, until recently, reserved for cardiologists and anesthesiologists. More recently transesophageal echocardiography (TEE) has been utilized by emergency and critical care medicine physicians. TEE is part of recommended training for these specialties as a tool for diagnostic and rescue measures, including ventilator management, emergency procedures, and medication titration. Rescue TEE can also be utilized perioperatively where the transthoracic exam is limited by poor windows or the operative procedure precludes access to the chest. While transthoracic echocardiography (TTE) is often used in a point of care fashion, TEE is utilized less often. This may stem from the invasive nature of the procedure but likely also results from lack of equipment and training. Like POCUS overall, TEE POCUS will require incorporation into training programs to achieve widespread use and acceptance.

A deluge of research on TEE for the noncardiologist shows this modality is minimally invasive, safe, and effective. As it becomes more readily available and technology improves, there is no reason why an esophageal probe can’t be used in a patient with a secured airway (Wray TC, et al. J Intensive Care Med. 2021;36[1]:123).

Ultrasound for hemodynamic monitoring

There are many methods employed for hemodynamic monitoring in the ICU. Although echocardiographic and vascular parameters have been validated in the cardiac and perioperative fields, their application in the ICU setting for resuscitation and volume management remain somewhat controversial. The use of TEE and more advanced understanding of spectral doppler and pulmonary ultrasonography using TEE has revolutionized the way providers are managing critically ill patients. (Garcia YA, et al. Chest. 2017;152[4]:736).

In our opinion, physiology and imaging training for residents and fellows should be required for critical care medicine trainees. Delving into the nuances of frank-starling curves, stroke work, and diastolic function will enrich their understanding and highlight the applicability of ultrasonography. Furthermore, all clinicians caring for patients with critical illness should be privy to the nuances of physiologic derangement, and to that end, advanced echocardiographic principles and image acquisition. The heart-lung interactions are demonstrated in real time using POCUS and can clearly delineate treatment goals (Vieillard-Baron A, et al. Intensive Care Med. 2019;45[6]:770).

Documentation and billing

If clinicians are making medical decisions based off imaging gathered at the bedside and interpreted in real-time, documentation should reflect that. That documentation will invariably lead to billing and possibly audit or quality review by colleagues or other healthcare staff. Radiology and cardiology have perfected the billing process for image interpretation, but their form of documentation and interpretation may not easily be implemented in the perioperative or critical care settings. An abbreviated document with focused information should take the place of the formal study. With that, the credentialing and board certification process will allow providers to feel empowered to make clinical decisions based off these focused examinations.

Dr. Goertzen is Chief Fellow, Pulmonary/Critical Care; Dr. Knuf is Program Director, Department of Anesthesia; and Dr. Villalobos is Director of Medical ICU, Department of Internal Medicine, San Antonio Military Medical Center, San Antonio, Texas.

Point-of-care ultrasound (POCUS) is a useful, practice-changing bedside tool that spans all medical and surgical specialties. While the definition of POCUS varies, most would agree it is an abbreviated exam that helps to answer a specific clinical question. With the expansion of POCUS training, the clinical questions being asked and answered have increased in scope and volume. The types of exams being utilized in “point of care ultrasound” have also increased and include transthoracic echocardiography; trans-esophageal echocardiography; and lung, gastric, abdominal, and ocular ultrasound. POCUS is used across multiple specialties, including critical care, anesthesiology, emergency medicine, and primary care.

Villalobos_Nicholas_web.jpg

Not only has POCUS become increasingly important clinically, but specialties now test these skills on their respective board examinations. Anesthesia is one of many such examples. The content outline for the American Board of Anesthesiology includes POCUS as a tested item on both the written and applied components of the exam. POCUS training must be directed toward both optimizing patient management and preparing learners for their board examination. A method for teaching this has yet to be defined (Naji A, et al. Cureus. 2021;13[5]:e15217).

One question – how should different specialties approach this educational challenge and should specialties train together? The answer is complicated. Many POCUS courses and certifications exist, and all vary in their content, didactics, and length. No true gold standard exists for POCUS certification for radiology or noncardiology providers. Additionally, there are no defined expectations or testing processes that certify a provider is “certified” to perform POCUS. While waiting for medical society guidelines to address these issues, many in graduate medical education (GME) are coming up with their own ways to incorporate POCUS into their respective training programs (Atkinson P, et al. CJEM. 2015 Mar;17[2]:161).

Who’s training whom?

Over the past decade, several expert committees, including those in critical care, have developed recommendations and consensus statements urging training facilities to independently create POCUS curriculums. The threshold for many programs to enter this realm of expertise is high and oftentimes unobtainable. We’ve seen emergency medicine and anesthesia raise the bar for ultrasound education in their residencies, but it’s unclear whether all fellowship-trained physicians can and should be tasked with obtaining official POCUS certification.

While specific specialties may require tailored certifications, there’s a considerable overlap in POCUS exam content across specialties. One approach to POCUS training could be developing and implementing a multidisciplinary curriculum. This would allow for pooling of resources (equipment, staff) and harnessing knowledge from providers familiar with different phases of patient care (ICU, perioperative, ED, outpatient clinics). By approaching POCUS from a multidisciplinary perspective, the quality of education may be enhanced (Mayo PH, et al. Intensive Care Med. 2014;40[5]:654). Is it then prudent for providers and trainees alike to share in didactics across all areas of the hospital and clinic? Would this close the knowledge gap between specialties who are facile with ultrasound and those not?

Determining the role of transesophageal echocardiography in a POCUS curriculum

This modality of imaging has been, until recently, reserved for cardiologists and anesthesiologists. More recently transesophageal echocardiography (TEE) has been utilized by emergency and critical care medicine physicians. TEE is part of recommended training for these specialties as a tool for diagnostic and rescue measures, including ventilator management, emergency procedures, and medication titration. Rescue TEE can also be utilized perioperatively where the transthoracic exam is limited by poor windows or the operative procedure precludes access to the chest. While transthoracic echocardiography (TTE) is often used in a point of care fashion, TEE is utilized less often. This may stem from the invasive nature of the procedure but likely also results from lack of equipment and training. Like POCUS overall, TEE POCUS will require incorporation into training programs to achieve widespread use and acceptance.

A deluge of research on TEE for the noncardiologist shows this modality is minimally invasive, safe, and effective. As it becomes more readily available and technology improves, there is no reason why an esophageal probe can’t be used in a patient with a secured airway (Wray TC, et al. J Intensive Care Med. 2021;36[1]:123).

Ultrasound for hemodynamic monitoring

There are many methods employed for hemodynamic monitoring in the ICU. Although echocardiographic and vascular parameters have been validated in the cardiac and perioperative fields, their application in the ICU setting for resuscitation and volume management remain somewhat controversial. The use of TEE and more advanced understanding of spectral doppler and pulmonary ultrasonography using TEE has revolutionized the way providers are managing critically ill patients. (Garcia YA, et al. Chest. 2017;152[4]:736).

In our opinion, physiology and imaging training for residents and fellows should be required for critical care medicine trainees. Delving into the nuances of frank-starling curves, stroke work, and diastolic function will enrich their understanding and highlight the applicability of ultrasonography. Furthermore, all clinicians caring for patients with critical illness should be privy to the nuances of physiologic derangement, and to that end, advanced echocardiographic principles and image acquisition. The heart-lung interactions are demonstrated in real time using POCUS and can clearly delineate treatment goals (Vieillard-Baron A, et al. Intensive Care Med. 2019;45[6]:770).

Documentation and billing

If clinicians are making medical decisions based off imaging gathered at the bedside and interpreted in real-time, documentation should reflect that. That documentation will invariably lead to billing and possibly audit or quality review by colleagues or other healthcare staff. Radiology and cardiology have perfected the billing process for image interpretation, but their form of documentation and interpretation may not easily be implemented in the perioperative or critical care settings. An abbreviated document with focused information should take the place of the formal study. With that, the credentialing and board certification process will allow providers to feel empowered to make clinical decisions based off these focused examinations.

Dr. Goertzen is Chief Fellow, Pulmonary/Critical Care; Dr. Knuf is Program Director, Department of Anesthesia; and Dr. Villalobos is Director of Medical ICU, Department of Internal Medicine, San Antonio Military Medical Center, San Antonio, Texas.