Pulmonology

Today’s most prominent medical journals have a “clinical images” section. High- quality, readily accessible digital photography can transport a patient to the journal’s pages, as demonstrated by Grandjean and Huber’s “Thinker sign” images in this issue of the Journal.¹ Images challenge healthcare practitioners to recall diseases via pattern recognition, or to deduce them by higher-order cognition. Images can reinforce prior learning, change perspective, and challenge preconceived notions.

See related article and editorial

I have used clinical images—physical examination findings, skin rashes, blood smears, radiography—for more than 20 years as a medical educator. I have dimmed the lights in conference rooms and lecture halls from Maine to Northern California, challenging students, residents, and faculty to contemplate a snippet of history and describe what they see to arrive at a diagnosis. Images are compelling teaching tools for first-year medical students beginning to make clinical observations, and for seasoned clinicians who have seen thousands of patients.

In my experience, clinical image presentations are consistently engaging. Introducing an audience to 8 to 10 patients in an hour loosely mimics the experience of seeing patients over the course of morning hospital rounds or clinic. The images I use are assembled from a collection of images of patients I have seen during my career in medical education. Showing images of patients I’ve personally cared for consistently prompts people to engage. “Here is a patient I saw last week on the medicine wards” reignites the sagging eyes and fading attention of the audience. In retelling a patient encounter, I create a human connection between a picture on the screen—my patient—and the listener. My patient becomes a patient of anyone in the room, a patient someone might see tomorrow on hospital rounds or in clinic.

Sometimes, instead of presenting a brief clinical history or select physical findings, I tell a story about the patient in the image. Whether sad or funny, these stories often bring learners together, prompting them to wonder how there could ever be a better job than the one they have. A prominent educator once approached me after a clinical images presentation to opine, “What you did with us today is the cure for physician burnout.” Hyperbole, perhaps, but I understood what he meant. Over the course of an hour, the audience had been transported to numerous bedsides and examination rooms, witnessing the interesting and delightfully mundane jewels our patients often bring—true pearls, indeed.

However, as educational, fun, and intellectually challenging as clinical images can be, they can never replace the experience of being at the bedside. There is nothing as engaging as the stories the patients themselves tell us. Unfiltered musings come to life, physical findings are indelibly seared into memory.

But unfortunately, even as trainees spend less time than ever before with their patients,^2,3 bedside rounding has dramatically faded, replaced by rounds in conference rooms and hospital hallways.⁴ The underlying cause is multifactorial—declining physical examination skills, increasing use of radiography and other advanced imaging, the electronic health record, and the overwhelming volume of clinical tasks carried out at a distance from the patient.

But this is not the whole story. I also believe that teachers and leaders fear the “thin ice” of rounding at the patient’s bedside. One never knows what will happen there—what will be said, what will be asked, what will be uncovered. What if, while talking to and examining the patient with the Dahl sign shown in Grandjean and Huber,¹ the patient’s condition would suddenly deteriorate, urgently requiring nebulized beta-2 agonists and transfer to the medical intensive care unit? What if the patient rambles for 5 minutes about extraneous details not relevant to his or her disease? What if the nurse needs to dispense scheduled medications or hang the next dose of antibiotics? What if the patient asks to use the bedpan at the moment digital clubbing was to be pointed out and discussed?

Of course, the patient may have lots to say, or nothing at all. But in those moments when the ice does not break, when the patient is not suddenly wheeled away to radiology, key clinical findings are seen and remembered, often for an entire career. If the ice does not break, the patient, the story, and the clinical finding—otherwise seen on a large screen in a dark room or on a page in a textbook or journal—come together in that moment, in a way nothing else ever quite can.

In this golden age of technology, we must remember that these images portray real patients with stories to tell, sometimes mundane and sometimes profound, but always worth hearing.

Acknowledgment: The author wishes to thank Mark C. Henderson, MD, for his helpful comments on this manuscript.

Today’s most prominent medical journals have a “clinical images” section. High- quality, readily accessible digital photography can transport a patient to the journal’s pages, as demonstrated by Grandjean and Huber’s “Thinker sign” images in this issue of the Journal.¹ Images challenge healthcare practitioners to recall diseases via pattern recognition, or to deduce them by higher-order cognition. Images can reinforce prior learning, change perspective, and challenge preconceived notions.

See related article and editorial

I have used clinical images—physical examination findings, skin rashes, blood smears, radiography—for more than 20 years as a medical educator. I have dimmed the lights in conference rooms and lecture halls from Maine to Northern California, challenging students, residents, and faculty to contemplate a snippet of history and describe what they see to arrive at a diagnosis. Images are compelling teaching tools for first-year medical students beginning to make clinical observations, and for seasoned clinicians who have seen thousands of patients.

In my experience, clinical image presentations are consistently engaging. Introducing an audience to 8 to 10 patients in an hour loosely mimics the experience of seeing patients over the course of morning hospital rounds or clinic. The images I use are assembled from a collection of images of patients I have seen during my career in medical education. Showing images of patients I’ve personally cared for consistently prompts people to engage. “Here is a patient I saw last week on the medicine wards” reignites the sagging eyes and fading attention of the audience. In retelling a patient encounter, I create a human connection between a picture on the screen—my patient—and the listener. My patient becomes a patient of anyone in the room, a patient someone might see tomorrow on hospital rounds or in clinic.

Sometimes, instead of presenting a brief clinical history or select physical findings, I tell a story about the patient in the image. Whether sad or funny, these stories often bring learners together, prompting them to wonder how there could ever be a better job than the one they have. A prominent educator once approached me after a clinical images presentation to opine, “What you did with us today is the cure for physician burnout.” Hyperbole, perhaps, but I understood what he meant. Over the course of an hour, the audience had been transported to numerous bedsides and examination rooms, witnessing the interesting and delightfully mundane jewels our patients often bring—true pearls, indeed.

However, as educational, fun, and intellectually challenging as clinical images can be, they can never replace the experience of being at the bedside. There is nothing as engaging as the stories the patients themselves tell us. Unfiltered musings come to life, physical findings are indelibly seared into memory.

But unfortunately, even as trainees spend less time than ever before with their patients,^2,3 bedside rounding has dramatically faded, replaced by rounds in conference rooms and hospital hallways.⁴ The underlying cause is multifactorial—declining physical examination skills, increasing use of radiography and other advanced imaging, the electronic health record, and the overwhelming volume of clinical tasks carried out at a distance from the patient.

But this is not the whole story. I also believe that teachers and leaders fear the “thin ice” of rounding at the patient’s bedside. One never knows what will happen there—what will be said, what will be asked, what will be uncovered. What if, while talking to and examining the patient with the Dahl sign shown in Grandjean and Huber,¹ the patient’s condition would suddenly deteriorate, urgently requiring nebulized beta-2 agonists and transfer to the medical intensive care unit? What if the patient rambles for 5 minutes about extraneous details not relevant to his or her disease? What if the nurse needs to dispense scheduled medications or hang the next dose of antibiotics? What if the patient asks to use the bedpan at the moment digital clubbing was to be pointed out and discussed?

Of course, the patient may have lots to say, or nothing at all. But in those moments when the ice does not break, when the patient is not suddenly wheeled away to radiology, key clinical findings are seen and remembered, often for an entire career. If the ice does not break, the patient, the story, and the clinical finding—otherwise seen on a large screen in a dark room or on a page in a textbook or journal—come together in that moment, in a way nothing else ever quite can.

In this golden age of technology, we must remember that these images portray real patients with stories to tell, sometimes mundane and sometimes profound, but always worth hearing.

Acknowledgment: The author wishes to thank Mark C. Henderson, MD, for his helpful comments on this manuscript.

Today’s most prominent medical journals have a “clinical images” section. High- quality, readily accessible digital photography can transport a patient to the journal’s pages, as demonstrated by Grandjean and Huber’s “Thinker sign” images in this issue of the Journal.¹ Images challenge healthcare practitioners to recall diseases via pattern recognition, or to deduce them by higher-order cognition. Images can reinforce prior learning, change perspective, and challenge preconceived notions.

See related article and editorial

I have used clinical images—physical examination findings, skin rashes, blood smears, radiography—for more than 20 years as a medical educator. I have dimmed the lights in conference rooms and lecture halls from Maine to Northern California, challenging students, residents, and faculty to contemplate a snippet of history and describe what they see to arrive at a diagnosis. Images are compelling teaching tools for first-year medical students beginning to make clinical observations, and for seasoned clinicians who have seen thousands of patients.

In my experience, clinical image presentations are consistently engaging. Introducing an audience to 8 to 10 patients in an hour loosely mimics the experience of seeing patients over the course of morning hospital rounds or clinic. The images I use are assembled from a collection of images of patients I have seen during my career in medical education. Showing images of patients I’ve personally cared for consistently prompts people to engage. “Here is a patient I saw last week on the medicine wards” reignites the sagging eyes and fading attention of the audience. In retelling a patient encounter, I create a human connection between a picture on the screen—my patient—and the listener. My patient becomes a patient of anyone in the room, a patient someone might see tomorrow on hospital rounds or in clinic.

Sometimes, instead of presenting a brief clinical history or select physical findings, I tell a story about the patient in the image. Whether sad or funny, these stories often bring learners together, prompting them to wonder how there could ever be a better job than the one they have. A prominent educator once approached me after a clinical images presentation to opine, “What you did with us today is the cure for physician burnout.” Hyperbole, perhaps, but I understood what he meant. Over the course of an hour, the audience had been transported to numerous bedsides and examination rooms, witnessing the interesting and delightfully mundane jewels our patients often bring—true pearls, indeed.

However, as educational, fun, and intellectually challenging as clinical images can be, they can never replace the experience of being at the bedside. There is nothing as engaging as the stories the patients themselves tell us. Unfiltered musings come to life, physical findings are indelibly seared into memory.

But unfortunately, even as trainees spend less time than ever before with their patients,^2,3 bedside rounding has dramatically faded, replaced by rounds in conference rooms and hospital hallways.⁴ The underlying cause is multifactorial—declining physical examination skills, increasing use of radiography and other advanced imaging, the electronic health record, and the overwhelming volume of clinical tasks carried out at a distance from the patient.

But this is not the whole story. I also believe that teachers and leaders fear the “thin ice” of rounding at the patient’s bedside. One never knows what will happen there—what will be said, what will be asked, what will be uncovered. What if, while talking to and examining the patient with the Dahl sign shown in Grandjean and Huber,¹ the patient’s condition would suddenly deteriorate, urgently requiring nebulized beta-2 agonists and transfer to the medical intensive care unit? What if the patient rambles for 5 minutes about extraneous details not relevant to his or her disease? What if the nurse needs to dispense scheduled medications or hang the next dose of antibiotics? What if the patient asks to use the bedpan at the moment digital clubbing was to be pointed out and discussed?

Of course, the patient may have lots to say, or nothing at all. But in those moments when the ice does not break, when the patient is not suddenly wheeled away to radiology, key clinical findings are seen and remembered, often for an entire career. If the ice does not break, the patient, the story, and the clinical finding—otherwise seen on a large screen in a dark room or on a page in a textbook or journal—come together in that moment, in a way nothing else ever quite can.

In this golden age of technology, we must remember that these images portray real patients with stories to tell, sometimes mundane and sometimes profound, but always worth hearing.

Acknowledgment: The author wishes to thank Mark C. Henderson, MD, for his helpful comments on this manuscript.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.^24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.⁵ One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.²⁶ In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).²⁷ Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.²⁸ Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.⁵ The prescribing clinician also needs to consider potential of prolongation of the QT interval.²⁶

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD.^29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.⁶ Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.^29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD³¹ found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.⁶

β-Blockers

Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.³² Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.³³

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations.³⁴ Two small, single-center studies,^35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,⁶ which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.³⁷ Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.^24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.⁵ One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.²⁶ In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).²⁷ Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.²⁸ Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.⁵ The prescribing clinician also needs to consider potential of prolongation of the QT interval.²⁶

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD.^29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.⁶ Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.^29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD³¹ found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.⁶

β-Blockers

Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.³² Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.³³

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations.³⁴ Two small, single-center studies,^35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,⁶ which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.³⁷ Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.^24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.⁵ One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.²⁶ In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).²⁷ Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.²⁸ Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.⁵ The prescribing clinician also needs to consider potential of prolongation of the QT interval.²⁶

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD.^29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.⁶ Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.^29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD³¹ found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.⁶

β-Blockers

Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.³² Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.³³

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations.³⁴ Two small, single-center studies,^35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,⁶ which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.³⁷ Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Use of inhaled corticosteroids may lower the risk of lung cancer in patients with chronic obstructive pulmonary disease, and continued use may also reduce lung cancer risk, recent research from the European Respiratory Journal has shown.

“The appropriate use of [inhaled corticosteroids] ICS in [chronic obstructive pulmonary disease] COPD patients is often debated and not all patients might benefit from the use of ICS. The clinical benefits and risk of use in an individual patient must be weighed by the physician,” wrote Adam J.N. Raymakers, MSc, PhD, of the University of British Columbia’s Collaboration for Outcomes Research and Evaluation (CORE), Vancouver, B.C., and colleagues.

“This study, however, indicates that potential benefits may accrue from ICS use in COPD patients in terms of reduced lung cancer risk, and that sustained use may be associated with reduced risk of lung cancer.”

Dr. Raymakers and colleagues did an analysis of 39,676 patients with COPD (mean age, 70.7 years; 53% female) who received ICS between 1997 and 2007 and linked those patients to a registry of cancer patients in British Columbia. The linked databases included the Medical Services Plan (MSP) payment information file, Discharge Abstract Database (DAD), PharmaNet data file, and the British Columbia Cancer Registry (BCCR). The researchers determined a patient had COPD if he or she received three or more prescriptions related to COPD, while ICS exposure was analyzed in the context of a patient’s ICS exposure, cumulative duration, cumulative dose, and weighted cumulative duration and dose.

The analysis revealed 372,075 prescriptions for ICS were dispensed and 71.2% of the patients were “distinct users” of ICS, with patients filling a median of eight prescriptions at mean 5.2 years of follow-up. Fluticasone propionate was the most common ICS prescribed at a dose of 0.64 mg per day, and patients had median 60 days of ICS supplied per person.

Overall, there were 994 cases of lung cancer (2.5%), and exposure to ICS was linked to a 30% reduction in lung cancer risk (hazard ratio, 0.70; 95% confidence interval, 0.61-0.80), while recency-weighted duration of ICS exposure was linked to a 26% reduction in lung cancer risk (HR, 0.74; 95% CI, 0.66-0.87). There was a 43% reduced risk of lung cancer per gram of ICS when the data were measured by recency-weighted cumulative dosage.

In a multivariate analysis, ICS use was associated with a 30% reduction in risk of non–small cell lung cancer (HR, 0.70; 95% CI, 0.60-0.82), which the researchers said suggests ICS provides a protective effect for patients against lung cancer. “These results highlight the importance of properly identifying which patients might be at the highest risk of lung cancer, to enhance the therapeutic benefits of ICS in these COPD patients,” they wrote.

This study received funding from the Canadian Institutes of Health Research. The authors report no conflicts of interest.

SOURCE: Raymakers A, et al. Eur Respir J. 2019. doi: 10.1183/13993003.01257-2018.

Use of inhaled corticosteroids may lower the risk of lung cancer in patients with chronic obstructive pulmonary disease, and continued use may also reduce lung cancer risk, recent research from the European Respiratory Journal has shown.

“The appropriate use of [inhaled corticosteroids] ICS in [chronic obstructive pulmonary disease] COPD patients is often debated and not all patients might benefit from the use of ICS. The clinical benefits and risk of use in an individual patient must be weighed by the physician,” wrote Adam J.N. Raymakers, MSc, PhD, of the University of British Columbia’s Collaboration for Outcomes Research and Evaluation (CORE), Vancouver, B.C., and colleagues.

“This study, however, indicates that potential benefits may accrue from ICS use in COPD patients in terms of reduced lung cancer risk, and that sustained use may be associated with reduced risk of lung cancer.”

Dr. Raymakers and colleagues did an analysis of 39,676 patients with COPD (mean age, 70.7 years; 53% female) who received ICS between 1997 and 2007 and linked those patients to a registry of cancer patients in British Columbia. The linked databases included the Medical Services Plan (MSP) payment information file, Discharge Abstract Database (DAD), PharmaNet data file, and the British Columbia Cancer Registry (BCCR). The researchers determined a patient had COPD if he or she received three or more prescriptions related to COPD, while ICS exposure was analyzed in the context of a patient’s ICS exposure, cumulative duration, cumulative dose, and weighted cumulative duration and dose.

The analysis revealed 372,075 prescriptions for ICS were dispensed and 71.2% of the patients were “distinct users” of ICS, with patients filling a median of eight prescriptions at mean 5.2 years of follow-up. Fluticasone propionate was the most common ICS prescribed at a dose of 0.64 mg per day, and patients had median 60 days of ICS supplied per person.

Overall, there were 994 cases of lung cancer (2.5%), and exposure to ICS was linked to a 30% reduction in lung cancer risk (hazard ratio, 0.70; 95% confidence interval, 0.61-0.80), while recency-weighted duration of ICS exposure was linked to a 26% reduction in lung cancer risk (HR, 0.74; 95% CI, 0.66-0.87). There was a 43% reduced risk of lung cancer per gram of ICS when the data were measured by recency-weighted cumulative dosage.

In a multivariate analysis, ICS use was associated with a 30% reduction in risk of non–small cell lung cancer (HR, 0.70; 95% CI, 0.60-0.82), which the researchers said suggests ICS provides a protective effect for patients against lung cancer. “These results highlight the importance of properly identifying which patients might be at the highest risk of lung cancer, to enhance the therapeutic benefits of ICS in these COPD patients,” they wrote.

This study received funding from the Canadian Institutes of Health Research. The authors report no conflicts of interest.

SOURCE: Raymakers A, et al. Eur Respir J. 2019. doi: 10.1183/13993003.01257-2018.

Use of inhaled corticosteroids may lower the risk of lung cancer in patients with chronic obstructive pulmonary disease, and continued use may also reduce lung cancer risk, recent research from the European Respiratory Journal has shown.

“The appropriate use of [inhaled corticosteroids] ICS in [chronic obstructive pulmonary disease] COPD patients is often debated and not all patients might benefit from the use of ICS. The clinical benefits and risk of use in an individual patient must be weighed by the physician,” wrote Adam J.N. Raymakers, MSc, PhD, of the University of British Columbia’s Collaboration for Outcomes Research and Evaluation (CORE), Vancouver, B.C., and colleagues.

“This study, however, indicates that potential benefits may accrue from ICS use in COPD patients in terms of reduced lung cancer risk, and that sustained use may be associated with reduced risk of lung cancer.”

Dr. Raymakers and colleagues did an analysis of 39,676 patients with COPD (mean age, 70.7 years; 53% female) who received ICS between 1997 and 2007 and linked those patients to a registry of cancer patients in British Columbia. The linked databases included the Medical Services Plan (MSP) payment information file, Discharge Abstract Database (DAD), PharmaNet data file, and the British Columbia Cancer Registry (BCCR). The researchers determined a patient had COPD if he or she received three or more prescriptions related to COPD, while ICS exposure was analyzed in the context of a patient’s ICS exposure, cumulative duration, cumulative dose, and weighted cumulative duration and dose.

The analysis revealed 372,075 prescriptions for ICS were dispensed and 71.2% of the patients were “distinct users” of ICS, with patients filling a median of eight prescriptions at mean 5.2 years of follow-up. Fluticasone propionate was the most common ICS prescribed at a dose of 0.64 mg per day, and patients had median 60 days of ICS supplied per person.

Overall, there were 994 cases of lung cancer (2.5%), and exposure to ICS was linked to a 30% reduction in lung cancer risk (hazard ratio, 0.70; 95% confidence interval, 0.61-0.80), while recency-weighted duration of ICS exposure was linked to a 26% reduction in lung cancer risk (HR, 0.74; 95% CI, 0.66-0.87). There was a 43% reduced risk of lung cancer per gram of ICS when the data were measured by recency-weighted cumulative dosage.

In a multivariate analysis, ICS use was associated with a 30% reduction in risk of non–small cell lung cancer (HR, 0.70; 95% CI, 0.60-0.82), which the researchers said suggests ICS provides a protective effect for patients against lung cancer. “These results highlight the importance of properly identifying which patients might be at the highest risk of lung cancer, to enhance the therapeutic benefits of ICS in these COPD patients,” they wrote.

This study received funding from the Canadian Institutes of Health Research. The authors report no conflicts of interest.

SOURCE: Raymakers A, et al. Eur Respir J. 2019. doi: 10.1183/13993003.01257-2018.

The pediatric hexavalent vaccine (DTaP-[inactivated poliovirus] IPV-[hepatitis B] HepB-[Haemophilis influenzae type b] Hib) should be included as an option in the Vaccines for Children (VFC) program for the infant series at ages 2, 4, and 6 months, according to unanimous votes at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

copyright itsmejust/Thinkstock

The addition of the vaccine to the VFC program required no motions on the part of the committee, but involved separate votes on each component of the vaccine.

Combination vaccination has been associated with increased coverage and more likely completion of the full infant vaccine series, said Sara Oliver, MD, of the CDC’s National Center for Immunization and Respiratory Diseases.

The new vaccine is being developed jointly by Sanofi and Merck, and has been approved by the Food and Drug Administration for use in children through age 4 years.

Dr. Oliver presented evidence that the safety profile of the combination vaccine is consistent with that of the component vaccines. In addition, “use of combination vaccines can reduce the number of injections patient receive and alleviate concern associated with the number of injections,” she said. However, “considerations should include provider assessment, patient preference, and the potential for adverse events.”

The vote does not make any changes to the current vaccination schedule, but adds the combination vaccine as an option in the VFC program, although it will not be available until 2021 in order to ensure sufficient supply, Dr. Oliver noted.

The combination vaccination work group considered whether the new vaccine should be preferentially recommended for American Indian and Alaskan Native populations, but they concluded that post–dose one immunogenicity data are needed before such a preferential recommendation can be made.

The ACIP members had no financial conflicts to disclose.

The pediatric hexavalent vaccine (DTaP-[inactivated poliovirus] IPV-[hepatitis B] HepB-[Haemophilis influenzae type b] Hib) should be included as an option in the Vaccines for Children (VFC) program for the infant series at ages 2, 4, and 6 months, according to unanimous votes at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

copyright itsmejust/Thinkstock

The addition of the vaccine to the VFC program required no motions on the part of the committee, but involved separate votes on each component of the vaccine.

Combination vaccination has been associated with increased coverage and more likely completion of the full infant vaccine series, said Sara Oliver, MD, of the CDC’s National Center for Immunization and Respiratory Diseases.

The new vaccine is being developed jointly by Sanofi and Merck, and has been approved by the Food and Drug Administration for use in children through age 4 years.

Dr. Oliver presented evidence that the safety profile of the combination vaccine is consistent with that of the component vaccines. In addition, “use of combination vaccines can reduce the number of injections patient receive and alleviate concern associated with the number of injections,” she said. However, “considerations should include provider assessment, patient preference, and the potential for adverse events.”

The vote does not make any changes to the current vaccination schedule, but adds the combination vaccine as an option in the VFC program, although it will not be available until 2021 in order to ensure sufficient supply, Dr. Oliver noted.

The combination vaccination work group considered whether the new vaccine should be preferentially recommended for American Indian and Alaskan Native populations, but they concluded that post–dose one immunogenicity data are needed before such a preferential recommendation can be made.

The ACIP members had no financial conflicts to disclose.

The pediatric hexavalent vaccine (DTaP-[inactivated poliovirus] IPV-[hepatitis B] HepB-[Haemophilis influenzae type b] Hib) should be included as an option in the Vaccines for Children (VFC) program for the infant series at ages 2, 4, and 6 months, according to unanimous votes at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

copyright itsmejust/Thinkstock

The addition of the vaccine to the VFC program required no motions on the part of the committee, but involved separate votes on each component of the vaccine.

Combination vaccination has been associated with increased coverage and more likely completion of the full infant vaccine series, said Sara Oliver, MD, of the CDC’s National Center for Immunization and Respiratory Diseases.

The new vaccine is being developed jointly by Sanofi and Merck, and has been approved by the Food and Drug Administration for use in children through age 4 years.

Dr. Oliver presented evidence that the safety profile of the combination vaccine is consistent with that of the component vaccines. In addition, “use of combination vaccines can reduce the number of injections patient receive and alleviate concern associated with the number of injections,” she said. However, “considerations should include provider assessment, patient preference, and the potential for adverse events.”

The vote does not make any changes to the current vaccination schedule, but adds the combination vaccine as an option in the VFC program, although it will not be available until 2021 in order to ensure sufficient supply, Dr. Oliver noted.

The combination vaccination work group considered whether the new vaccine should be preferentially recommended for American Indian and Alaskan Native populations, but they concluded that post–dose one immunogenicity data are needed before such a preferential recommendation can be made.

The ACIP members had no financial conflicts to disclose.

Pneumococcal vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) based on shared clinical decision making is recommended for immunocompetent adults aged 65 years and older who have not previously received PCV13, and all adults aged 65 years and older should continue to receive the pneumococcal polysaccharide vaccine (PPSV23), according to a vote at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

bowdenimages/iStock/Getty Images

The motion passed with an 11-1 vote after members voted down two other options to either discontinue or continue the current recommendation of PCV13 for all immunocompetent adults aged 65 years and older. The current recommendation for PCV13 for adults aged 65 years and older has been in place since 2014.

The pneumococcal work group assessed indirect effects of the pediatric PCV vaccination on older adults prior to 2014 and since 2014, and what additional benefits might be expected if routine vaccination of older adults continued.

“Indirect effects have been observed in all age groups” said Almea Matanock, MD, of the CDC’s National Center for Immunization and Respiratory Diseases. Although there were no safety concerns, the public health impact of continued vaccination of adults was minimal.

Although PCV13 resulted in a 75% reduction in vaccine-type invasive pneumococcal disease and a 45% reduction in vaccine-type nonbacteremic pneumonia in 2014, the annual number needed to vaccinate to prevent a single case of outpatient pneumonia was 2,600, said Dr. Matanock.

Dr. Matanock presented key issues from the Evidence to Recommendations Framework for and against the recommendation for PCV13 in older adults. Work group comments in favor of continuing the recommendation for PCV13 in older adults included effective disease prevention and the potential negative impact on the importance of adult vaccines if the vaccine was no longer recommended. However, some work group members and committee members expressed concern about resource allocation and steering vaccines away from younger age groups in whom they have been more consistently effective.

Paul Hunter, MD, of the City of Milwaukee Health Department, voted against the shared clinical decision making, and instead favored discontinuing the recommendation for PCV13 for older adults. “I think clinicians need a clear message,” he said, adding that “the public health bang for the buck is with the kids.”

“I think there was a recognition that the population level benefit is minimal,” said work group chair Grace Lee, MD.

Although the work group recognized some benefit for older adults, the burden of disease for PCV-specific disease is low, compared with all-cause pneumonia, said Dr. Lee of Lucile Packard Children’s Hospital at Stanford, Calif. However, the recommendation for shared clinical decision making allows for potential insurance coverage of the vaccine for adults who decide after discussion with their health care provider that they would benefit.

“We are still unpacking this construct” of shared clinical decision making, which in this case applies to adults without immunocompromising conditions, and is more of a provider assessment than a risk assessment, she said.

The ACIP members had no financial conflicts to disclose.

Pneumococcal vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) based on shared clinical decision making is recommended for immunocompetent adults aged 65 years and older who have not previously received PCV13, and all adults aged 65 years and older should continue to receive the pneumococcal polysaccharide vaccine (PPSV23), according to a vote at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

bowdenimages/iStock/Getty Images

The motion passed with an 11-1 vote after members voted down two other options to either discontinue or continue the current recommendation of PCV13 for all immunocompetent adults aged 65 years and older. The current recommendation for PCV13 for adults aged 65 years and older has been in place since 2014.

The pneumococcal work group assessed indirect effects of the pediatric PCV vaccination on older adults prior to 2014 and since 2014, and what additional benefits might be expected if routine vaccination of older adults continued.

“Indirect effects have been observed in all age groups” said Almea Matanock, MD, of the CDC’s National Center for Immunization and Respiratory Diseases. Although there were no safety concerns, the public health impact of continued vaccination of adults was minimal.

Although PCV13 resulted in a 75% reduction in vaccine-type invasive pneumococcal disease and a 45% reduction in vaccine-type nonbacteremic pneumonia in 2014, the annual number needed to vaccinate to prevent a single case of outpatient pneumonia was 2,600, said Dr. Matanock.

Dr. Matanock presented key issues from the Evidence to Recommendations Framework for and against the recommendation for PCV13 in older adults. Work group comments in favor of continuing the recommendation for PCV13 in older adults included effective disease prevention and the potential negative impact on the importance of adult vaccines if the vaccine was no longer recommended. However, some work group members and committee members expressed concern about resource allocation and steering vaccines away from younger age groups in whom they have been more consistently effective.

Paul Hunter, MD, of the City of Milwaukee Health Department, voted against the shared clinical decision making, and instead favored discontinuing the recommendation for PCV13 for older adults. “I think clinicians need a clear message,” he said, adding that “the public health bang for the buck is with the kids.”

“I think there was a recognition that the population level benefit is minimal,” said work group chair Grace Lee, MD.

Although the work group recognized some benefit for older adults, the burden of disease for PCV-specific disease is low, compared with all-cause pneumonia, said Dr. Lee of Lucile Packard Children’s Hospital at Stanford, Calif. However, the recommendation for shared clinical decision making allows for potential insurance coverage of the vaccine for adults who decide after discussion with their health care provider that they would benefit.

“We are still unpacking this construct” of shared clinical decision making, which in this case applies to adults without immunocompromising conditions, and is more of a provider assessment than a risk assessment, she said.

The ACIP members had no financial conflicts to disclose.

Pneumococcal vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) based on shared clinical decision making is recommended for immunocompetent adults aged 65 years and older who have not previously received PCV13, and all adults aged 65 years and older should continue to receive the pneumococcal polysaccharide vaccine (PPSV23), according to a vote at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

bowdenimages/iStock/Getty Images

The motion passed with an 11-1 vote after members voted down two other options to either discontinue or continue the current recommendation of PCV13 for all immunocompetent adults aged 65 years and older. The current recommendation for PCV13 for adults aged 65 years and older has been in place since 2014.

The pneumococcal work group assessed indirect effects of the pediatric PCV vaccination on older adults prior to 2014 and since 2014, and what additional benefits might be expected if routine vaccination of older adults continued.

“Indirect effects have been observed in all age groups” said Almea Matanock, MD, of the CDC’s National Center for Immunization and Respiratory Diseases. Although there were no safety concerns, the public health impact of continued vaccination of adults was minimal.

Although PCV13 resulted in a 75% reduction in vaccine-type invasive pneumococcal disease and a 45% reduction in vaccine-type nonbacteremic pneumonia in 2014, the annual number needed to vaccinate to prevent a single case of outpatient pneumonia was 2,600, said Dr. Matanock.

Dr. Matanock presented key issues from the Evidence to Recommendations Framework for and against the recommendation for PCV13 in older adults. Work group comments in favor of continuing the recommendation for PCV13 in older adults included effective disease prevention and the potential negative impact on the importance of adult vaccines if the vaccine was no longer recommended. However, some work group members and committee members expressed concern about resource allocation and steering vaccines away from younger age groups in whom they have been more consistently effective.

Paul Hunter, MD, of the City of Milwaukee Health Department, voted against the shared clinical decision making, and instead favored discontinuing the recommendation for PCV13 for older adults. “I think clinicians need a clear message,” he said, adding that “the public health bang for the buck is with the kids.”

“I think there was a recognition that the population level benefit is minimal,” said work group chair Grace Lee, MD.

Although the work group recognized some benefit for older adults, the burden of disease for PCV-specific disease is low, compared with all-cause pneumonia, said Dr. Lee of Lucile Packard Children’s Hospital at Stanford, Calif. However, the recommendation for shared clinical decision making allows for potential insurance coverage of the vaccine for adults who decide after discussion with their health care provider that they would benefit.

“We are still unpacking this construct” of shared clinical decision making, which in this case applies to adults without immunocompromising conditions, and is more of a provider assessment than a risk assessment, she said.

The ACIP members had no financial conflicts to disclose.

The Food and Drug Administration has approved dupilumab (Dupixent) for the treatment of chronic rhinosinusitis accompanied by nasal polyps in adults.

FDA approval is based on results from a pair of studies involving 724 patients aged 18 years or older with chronic rhinosinusitis with nasal polyps who were symptomatic despite undergoing treatment with intranasal corticosteroids and who received either dupilumab or a placebo. Compared with the placebo group, patients receiving dupilumab had statistically significant reductions in nasal polyp size and nasal congestion; they also had an increased ability to smell and required less nasal polyp surgery and oral steroids.

The most commonly reported adverse events were injection-site reactions and eye and eyelid inflammation, which included redness, swelling, and itching. The drug can cause severe allergic reactions and eye problems, such as conjunctivitis or keratitis; patients should also not receive live vaccines while taking dupilumab.

“Nasal polyps can lead to loss of smell, and often patients require surgery to remove the polyps. Dupixent provides an important treatment option for patients whose nasal polyps are not adequately controlled with intranasal steroids. It also reduces the need for nasal polyp surgery and oral steroids,” said Sally Seymour, MD, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved dupilumab (Dupixent) for the treatment of chronic rhinosinusitis accompanied by nasal polyps in adults.

FDA approval is based on results from a pair of studies involving 724 patients aged 18 years or older with chronic rhinosinusitis with nasal polyps who were symptomatic despite undergoing treatment with intranasal corticosteroids and who received either dupilumab or a placebo. Compared with the placebo group, patients receiving dupilumab had statistically significant reductions in nasal polyp size and nasal congestion; they also had an increased ability to smell and required less nasal polyp surgery and oral steroids.

The most commonly reported adverse events were injection-site reactions and eye and eyelid inflammation, which included redness, swelling, and itching. The drug can cause severe allergic reactions and eye problems, such as conjunctivitis or keratitis; patients should also not receive live vaccines while taking dupilumab.

“Nasal polyps can lead to loss of smell, and often patients require surgery to remove the polyps. Dupixent provides an important treatment option for patients whose nasal polyps are not adequately controlled with intranasal steroids. It also reduces the need for nasal polyp surgery and oral steroids,” said Sally Seymour, MD, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved dupilumab (Dupixent) for the treatment of chronic rhinosinusitis accompanied by nasal polyps in adults.

FDA approval is based on results from a pair of studies involving 724 patients aged 18 years or older with chronic rhinosinusitis with nasal polyps who were symptomatic despite undergoing treatment with intranasal corticosteroids and who received either dupilumab or a placebo. Compared with the placebo group, patients receiving dupilumab had statistically significant reductions in nasal polyp size and nasal congestion; they also had an increased ability to smell and required less nasal polyp surgery and oral steroids.

The most commonly reported adverse events were injection-site reactions and eye and eyelid inflammation, which included redness, swelling, and itching. The drug can cause severe allergic reactions and eye problems, such as conjunctivitis or keratitis; patients should also not receive live vaccines while taking dupilumab.

“Nasal polyps can lead to loss of smell, and often patients require surgery to remove the polyps. Dupixent provides an important treatment option for patients whose nasal polyps are not adequately controlled with intranasal steroids. It also reduces the need for nasal polyp surgery and oral steroids,” said Sally Seymour, MD, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Find the full press release on the FDA website.

lfranki@mdedge.com

SAN ANTONIO – In the clinical opinion of Richard J. Schwab, MD, any hospitalized patient with a body mass index of 35 kg/m² or greater should undergo overnight pulse oximetry testing.

Courtesy Dr. Krishna Sundar

“Many diseases are adversely affected by sleep apnea, including myocardial infarction, hypertension, a cerebrovascular accident, pulmonary hypertension, atrial fibrillation, diabetes, and congestive heart failure,” Dr. Schwab, interim chief of the University of Pennsylvania Perelman School of Medicine’s Division of Sleep Medicine, said at the annual meeting of the Associated Professional Sleep Societies.

“Continuous positive airway pressure [CPAP] may help heart failure patients and reduce 30-day readmission rates, which has important financial implications in the University of Pennsylvania Health system. CPAP may also decrease the rapid responses and cardiac arrests at night,” he said.

A few years ago, Dr. Schwab and his associates set out to determine whether PAP adherence in cardiac patients with sleep-disordered breathing reduced readmission rates 30 days after discharge (J Clin Sleep Med. 2014;10:1051-59). They evaluated 104 consecutive cardiovascular hospitalized patients reporting symptoms of sleep-disordered breathing (SDB) between January of 2012 and March of 2013, and collected demographic data, SDB type, PAP adherence, and data regarding 30-day hospital readmission/ED visits. Apnea was scored when there was a 90% or greater cessation of airflow detected through the nasal pressure sensor. Hypopnea was scored when there was at least a 50% reduction in airflow with an associated 3% or greater oxyhemoglobin desaturation. Central apnea (CSA) was scored when there was a 90% or greater cessation of airflow detected through the nasal pressure sensor and no effort in the thorax and abdomen. If more than 50% of the apneas were central, the SDB was classified as CSA. If more than 50% of apneas were obstructive in nature, it was considered obstructive sleep apnea (OSA).

The mean age of the patients was 59 years, 63% were male, their mean body mass index was 34 kg/m², 87% had heart failure, and 82% had hypertension. Of the 104 patients, 81 had SDB and 23 did not. The 30-day readmission rate was 29% in patients who did not use PAP, 30% in partial users, and 0% in full users (P = .0246).

The researchers found that 81 patients (78%) had sleep disordered breathing. Of these, 65 (80%) had OSA while 16 (20%) had CSA. The study demonstrated that performing inpatient sleep studies was feasible. “Our study indicated that SDB is common in hospitalized cardiac patients, with the majority of patients manifesting OSA,” said Dr. Schwab, medical director of the Penn Sleep Centers. “The data suggest that hospital readmission and ED visits 30 days after discharge were significantly lower in patients with cardiac disease and SDB who adhere to PAP treatment than those who are not adherent.”

Dr. Schwab is part of a research team conducting a longer study with ResMed to examine 30-, 60-, and 90-day readmission rates in cardiac inpatients newly diagnosed with OSA and started on auto-PAP (APAP). They plan to evaluate the ejection fraction during hospitalization and in follow-up, as well as the effect of an in-laboratory sleep study at 1 month. The long-term follow-up is planned for 3 years.

Launching an inpatient sleep apnea consult service in the hospital makes sense, Dr. Schwab continued, because home sleep studies are approved for the diagnosis of sleep apnea, APAP can determine optimal CPAP settings, insurance will cover CPAP with a home or inpatient sleep study, and patients can get CPAP/APAP at or before discharge. “Sleep techs or respiratory therapists can perform these sleep studies,” he said. At Penn, a nurse practitioner (NP) runs this service using the Alice NightOne home sleep testing device and the WatchPAT portable sleep apnea diagnostic device.


The notion of performing in-hospital sleep studies should be an easy sell to cardiologists and hospital administrators, Dr. Schwab said, because the program will decrease hospital readmissions, “which is going to save the hospital a lot of money. In addition, these patients can come back for in-laboratory sleep studies. There is also increased revenue from the consults and progress notes, and the professional fee for sleep study interpretation. The most challenging part of the inpatient sleep consult service is trying to get these patients to follow up in the sleep center with the NP.”

Dr. Schwab is an investigator for the recently launched Penn Medicine Nudge Unit Project, which is funded by the National Institutes of Health. The project includes a multidisciplinary team of providers from the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, and Penn Medicine Risk Management. If an inpatient has a BMI of 35 kg/m² or greater, the clinician will be “nudged” via an enterprise messaging system (EMS) prompt to order an inpatient sleep oximetry. “They have to respond to that nudge,” Dr. Schwab said. “If the oximetry is consistent for sleep apnea, there will be another nudge to consult with the sleep medicine team. If the oximetry is negative, they will be nudged to get an outpatient consult with the sleep medicine team.” For patients undergoing preadmission testing for any type of surgery who score 4 or more on the STOP-Bang questionnaire (Chest 2016;149:631-38), the clinician is “nudged” to order an outpatient sleep consultation.

Benefits to such an approach, he said, include a decrease in resource allocation, shorter hospital stays, patient perceived improvement in quality of sleep, improved patient survey scores, and the fact that apnea treatment may decrease the need for rapid response. “It also reduces medical-legal concerns, improves patient outcomes, decreases readmissions, and generates revenue from inpatient and outpatient sleep studies,” Dr. Schwab said. Barriers to such an approach include the fact that there is no defined pathway at many institutions for recognizing and referring suspected OSA patients. “There is often a lack of care coordination between primary providers and sleep medicine, and sleep is viewed as ambulatory care, not as a part of inpatient care,” he said.

Last year, Dr. Schwab and his colleagues at UPenn conducted a pilot study to develop and test a pathway for identifying OSA in high-risk inpatient and preadmission patient populations. Of 389 patients admitted between Aug. 20 and Sept. 20 of 2018, 43 had a BMI of 35 kg/m² or greater. Of these, 10 were screened with oximetry and 8 were positive for severe apnea. Of these eight cases, five inpatient consults were ordered, one outpatient consult was ordered, one patient had no consult ordered, and one patient was discharged before the consult was ordered.

Dr. Schwab also performed a pilot study in patients undergoing preoperative testing with the STOP-Bang questionnaire. “When we piloted this, there were over 200 patients who could have been sent to the outpatient sleep consult service, and we referred none,” Dr. Schwab said. “We are just starting to implement a program to screen them. We can treat these people for their sleep apnea and prevent chronic adverse sequelae associated with this disease.”

Both the inpatient and outpatient screening programs for sleep apnea are built within their electronic medical record. “Building this within your EMR requires effort, but it’s doable,” he said.

Dr. Schwab disclosed that he has received grants from the National Institutes of Health, ResMed, and Inspire Medical Systems.

dbrunk@mdedge.com

SAN ANTONIO – In the clinical opinion of Richard J. Schwab, MD, any hospitalized patient with a body mass index of 35 kg/m² or greater should undergo overnight pulse oximetry testing.

Courtesy Dr. Krishna Sundar

“Many diseases are adversely affected by sleep apnea, including myocardial infarction, hypertension, a cerebrovascular accident, pulmonary hypertension, atrial fibrillation, diabetes, and congestive heart failure,” Dr. Schwab, interim chief of the University of Pennsylvania Perelman School of Medicine’s Division of Sleep Medicine, said at the annual meeting of the Associated Professional Sleep Societies.

“Continuous positive airway pressure [CPAP] may help heart failure patients and reduce 30-day readmission rates, which has important financial implications in the University of Pennsylvania Health system. CPAP may also decrease the rapid responses and cardiac arrests at night,” he said.

A few years ago, Dr. Schwab and his associates set out to determine whether PAP adherence in cardiac patients with sleep-disordered breathing reduced readmission rates 30 days after discharge (J Clin Sleep Med. 2014;10:1051-59). They evaluated 104 consecutive cardiovascular hospitalized patients reporting symptoms of sleep-disordered breathing (SDB) between January of 2012 and March of 2013, and collected demographic data, SDB type, PAP adherence, and data regarding 30-day hospital readmission/ED visits. Apnea was scored when there was a 90% or greater cessation of airflow detected through the nasal pressure sensor. Hypopnea was scored when there was at least a 50% reduction in airflow with an associated 3% or greater oxyhemoglobin desaturation. Central apnea (CSA) was scored when there was a 90% or greater cessation of airflow detected through the nasal pressure sensor and no effort in the thorax and abdomen. If more than 50% of the apneas were central, the SDB was classified as CSA. If more than 50% of apneas were obstructive in nature, it was considered obstructive sleep apnea (OSA).

The mean age of the patients was 59 years, 63% were male, their mean body mass index was 34 kg/m², 87% had heart failure, and 82% had hypertension. Of the 104 patients, 81 had SDB and 23 did not. The 30-day readmission rate was 29% in patients who did not use PAP, 30% in partial users, and 0% in full users (P = .0246).

The researchers found that 81 patients (78%) had sleep disordered breathing. Of these, 65 (80%) had OSA while 16 (20%) had CSA. The study demonstrated that performing inpatient sleep studies was feasible. “Our study indicated that SDB is common in hospitalized cardiac patients, with the majority of patients manifesting OSA,” said Dr. Schwab, medical director of the Penn Sleep Centers. “The data suggest that hospital readmission and ED visits 30 days after discharge were significantly lower in patients with cardiac disease and SDB who adhere to PAP treatment than those who are not adherent.”

Dr. Schwab is part of a research team conducting a longer study with ResMed to examine 30-, 60-, and 90-day readmission rates in cardiac inpatients newly diagnosed with OSA and started on auto-PAP (APAP). They plan to evaluate the ejection fraction during hospitalization and in follow-up, as well as the effect of an in-laboratory sleep study at 1 month. The long-term follow-up is planned for 3 years.

Launching an inpatient sleep apnea consult service in the hospital makes sense, Dr. Schwab continued, because home sleep studies are approved for the diagnosis of sleep apnea, APAP can determine optimal CPAP settings, insurance will cover CPAP with a home or inpatient sleep study, and patients can get CPAP/APAP at or before discharge. “Sleep techs or respiratory therapists can perform these sleep studies,” he said. At Penn, a nurse practitioner (NP) runs this service using the Alice NightOne home sleep testing device and the WatchPAT portable sleep apnea diagnostic device.


The notion of performing in-hospital sleep studies should be an easy sell to cardiologists and hospital administrators, Dr. Schwab said, because the program will decrease hospital readmissions, “which is going to save the hospital a lot of money. In addition, these patients can come back for in-laboratory sleep studies. There is also increased revenue from the consults and progress notes, and the professional fee for sleep study interpretation. The most challenging part of the inpatient sleep consult service is trying to get these patients to follow up in the sleep center with the NP.”

Dr. Schwab is an investigator for the recently launched Penn Medicine Nudge Unit Project, which is funded by the National Institutes of Health. The project includes a multidisciplinary team of providers from the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, and Penn Medicine Risk Management. If an inpatient has a BMI of 35 kg/m² or greater, the clinician will be “nudged” via an enterprise messaging system (EMS) prompt to order an inpatient sleep oximetry. “They have to respond to that nudge,” Dr. Schwab said. “If the oximetry is consistent for sleep apnea, there will be another nudge to consult with the sleep medicine team. If the oximetry is negative, they will be nudged to get an outpatient consult with the sleep medicine team.” For patients undergoing preadmission testing for any type of surgery who score 4 or more on the STOP-Bang questionnaire (Chest 2016;149:631-38), the clinician is “nudged” to order an outpatient sleep consultation.

Benefits to such an approach, he said, include a decrease in resource allocation, shorter hospital stays, patient perceived improvement in quality of sleep, improved patient survey scores, and the fact that apnea treatment may decrease the need for rapid response. “It also reduces medical-legal concerns, improves patient outcomes, decreases readmissions, and generates revenue from inpatient and outpatient sleep studies,” Dr. Schwab said. Barriers to such an approach include the fact that there is no defined pathway at many institutions for recognizing and referring suspected OSA patients. “There is often a lack of care coordination between primary providers and sleep medicine, and sleep is viewed as ambulatory care, not as a part of inpatient care,” he said.

Last year, Dr. Schwab and his colleagues at UPenn conducted a pilot study to develop and test a pathway for identifying OSA in high-risk inpatient and preadmission patient populations. Of 389 patients admitted between Aug. 20 and Sept. 20 of 2018, 43 had a BMI of 35 kg/m² or greater. Of these, 10 were screened with oximetry and 8 were positive for severe apnea. Of these eight cases, five inpatient consults were ordered, one outpatient consult was ordered, one patient had no consult ordered, and one patient was discharged before the consult was ordered.

Dr. Schwab also performed a pilot study in patients undergoing preoperative testing with the STOP-Bang questionnaire. “When we piloted this, there were over 200 patients who could have been sent to the outpatient sleep consult service, and we referred none,” Dr. Schwab said. “We are just starting to implement a program to screen them. We can treat these people for their sleep apnea and prevent chronic adverse sequelae associated with this disease.”

Both the inpatient and outpatient screening programs for sleep apnea are built within their electronic medical record. “Building this within your EMR requires effort, but it’s doable,” he said.

Dr. Schwab disclosed that he has received grants from the National Institutes of Health, ResMed, and Inspire Medical Systems.

dbrunk@mdedge.com

SAN ANTONIO – In the clinical opinion of Richard J. Schwab, MD, any hospitalized patient with a body mass index of 35 kg/m² or greater should undergo overnight pulse oximetry testing.

Courtesy Dr. Krishna Sundar

“Many diseases are adversely affected by sleep apnea, including myocardial infarction, hypertension, a cerebrovascular accident, pulmonary hypertension, atrial fibrillation, diabetes, and congestive heart failure,” Dr. Schwab, interim chief of the University of Pennsylvania Perelman School of Medicine’s Division of Sleep Medicine, said at the annual meeting of the Associated Professional Sleep Societies.

“Continuous positive airway pressure [CPAP] may help heart failure patients and reduce 30-day readmission rates, which has important financial implications in the University of Pennsylvania Health system. CPAP may also decrease the rapid responses and cardiac arrests at night,” he said.

A few years ago, Dr. Schwab and his associates set out to determine whether PAP adherence in cardiac patients with sleep-disordered breathing reduced readmission rates 30 days after discharge (J Clin Sleep Med. 2014;10:1051-59). They evaluated 104 consecutive cardiovascular hospitalized patients reporting symptoms of sleep-disordered breathing (SDB) between January of 2012 and March of 2013, and collected demographic data, SDB type, PAP adherence, and data regarding 30-day hospital readmission/ED visits. Apnea was scored when there was a 90% or greater cessation of airflow detected through the nasal pressure sensor. Hypopnea was scored when there was at least a 50% reduction in airflow with an associated 3% or greater oxyhemoglobin desaturation. Central apnea (CSA) was scored when there was a 90% or greater cessation of airflow detected through the nasal pressure sensor and no effort in the thorax and abdomen. If more than 50% of the apneas were central, the SDB was classified as CSA. If more than 50% of apneas were obstructive in nature, it was considered obstructive sleep apnea (OSA).

The mean age of the patients was 59 years, 63% were male, their mean body mass index was 34 kg/m², 87% had heart failure, and 82% had hypertension. Of the 104 patients, 81 had SDB and 23 did not. The 30-day readmission rate was 29% in patients who did not use PAP, 30% in partial users, and 0% in full users (P = .0246).

The researchers found that 81 patients (78%) had sleep disordered breathing. Of these, 65 (80%) had OSA while 16 (20%) had CSA. The study demonstrated that performing inpatient sleep studies was feasible. “Our study indicated that SDB is common in hospitalized cardiac patients, with the majority of patients manifesting OSA,” said Dr. Schwab, medical director of the Penn Sleep Centers. “The data suggest that hospital readmission and ED visits 30 days after discharge were significantly lower in patients with cardiac disease and SDB who adhere to PAP treatment than those who are not adherent.”

Dr. Schwab is part of a research team conducting a longer study with ResMed to examine 30-, 60-, and 90-day readmission rates in cardiac inpatients newly diagnosed with OSA and started on auto-PAP (APAP). They plan to evaluate the ejection fraction during hospitalization and in follow-up, as well as the effect of an in-laboratory sleep study at 1 month. The long-term follow-up is planned for 3 years.

Launching an inpatient sleep apnea consult service in the hospital makes sense, Dr. Schwab continued, because home sleep studies are approved for the diagnosis of sleep apnea, APAP can determine optimal CPAP settings, insurance will cover CPAP with a home or inpatient sleep study, and patients can get CPAP/APAP at or before discharge. “Sleep techs or respiratory therapists can perform these sleep studies,” he said. At Penn, a nurse practitioner (NP) runs this service using the Alice NightOne home sleep testing device and the WatchPAT portable sleep apnea diagnostic device.


The notion of performing in-hospital sleep studies should be an easy sell to cardiologists and hospital administrators, Dr. Schwab said, because the program will decrease hospital readmissions, “which is going to save the hospital a lot of money. In addition, these patients can come back for in-laboratory sleep studies. There is also increased revenue from the consults and progress notes, and the professional fee for sleep study interpretation. The most challenging part of the inpatient sleep consult service is trying to get these patients to follow up in the sleep center with the NP.”

Dr. Schwab is an investigator for the recently launched Penn Medicine Nudge Unit Project, which is funded by the National Institutes of Health. The project includes a multidisciplinary team of providers from the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, and Penn Medicine Risk Management. If an inpatient has a BMI of 35 kg/m² or greater, the clinician will be “nudged” via an enterprise messaging system (EMS) prompt to order an inpatient sleep oximetry. “They have to respond to that nudge,” Dr. Schwab said. “If the oximetry is consistent for sleep apnea, there will be another nudge to consult with the sleep medicine team. If the oximetry is negative, they will be nudged to get an outpatient consult with the sleep medicine team.” For patients undergoing preadmission testing for any type of surgery who score 4 or more on the STOP-Bang questionnaire (Chest 2016;149:631-38), the clinician is “nudged” to order an outpatient sleep consultation.

Benefits to such an approach, he said, include a decrease in resource allocation, shorter hospital stays, patient perceived improvement in quality of sleep, improved patient survey scores, and the fact that apnea treatment may decrease the need for rapid response. “It also reduces medical-legal concerns, improves patient outcomes, decreases readmissions, and generates revenue from inpatient and outpatient sleep studies,” Dr. Schwab said. Barriers to such an approach include the fact that there is no defined pathway at many institutions for recognizing and referring suspected OSA patients. “There is often a lack of care coordination between primary providers and sleep medicine, and sleep is viewed as ambulatory care, not as a part of inpatient care,” he said.

Last year, Dr. Schwab and his colleagues at UPenn conducted a pilot study to develop and test a pathway for identifying OSA in high-risk inpatient and preadmission patient populations. Of 389 patients admitted between Aug. 20 and Sept. 20 of 2018, 43 had a BMI of 35 kg/m² or greater. Of these, 10 were screened with oximetry and 8 were positive for severe apnea. Of these eight cases, five inpatient consults were ordered, one outpatient consult was ordered, one patient had no consult ordered, and one patient was discharged before the consult was ordered.

Dr. Schwab also performed a pilot study in patients undergoing preoperative testing with the STOP-Bang questionnaire. “When we piloted this, there were over 200 patients who could have been sent to the outpatient sleep consult service, and we referred none,” Dr. Schwab said. “We are just starting to implement a program to screen them. We can treat these people for their sleep apnea and prevent chronic adverse sequelae associated with this disease.”

Both the inpatient and outpatient screening programs for sleep apnea are built within their electronic medical record. “Building this within your EMR requires effort, but it’s doable,” he said.

Dr. Schwab disclosed that he has received grants from the National Institutes of Health, ResMed, and Inspire Medical Systems.

dbrunk@mdedge.com