Emphysema Evaluation, Management, and Treatment (2024)

RELEASE DATE

July 1, 2024

EXPIRATION DATE

July 31, 2026

FACULTY

Katherine Hale, PharmD, BCPS, MFA
Clinical Pharmacist
Tri-Cities, Washington

FACULTY DISCLOSURE STATEMENTS

Dr. Hale has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data

ACCREDITATION STATEMENT

TARGET AUDIENCE

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
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DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL

To update pharmacists regarding current concepts in emphysema evaluation, management, and prevention.

OBJECTIVES

After completing this activity, the participant should be able to:

1. Review risk factors, clinical presentation, assessment, and diagnosis of emphysema.
2. Understand the pathophysiology of emphysema.
3. Discuss potential medication and/or surgical interventions for the management of emphysema-related symptoms.
4. Recognize the role of the pharmacist in emphysema management.

ABSTRACT: Often asymptomatic in its early stages, emphysema is a progressive respiratory disease resulting from structural damage to the lung tissue due to inflammatory processes. Cigarette smoking is a primary risk factor in emphysema development, but other environmental and occupational exposures may play a role. Global prevalence of emphysema is 1.8%. Currently, no cure exists for emphysema, which is one component of chronic obstructive pulmonary disease. Therapy goals focus on disease prevention and reducing symptoms, exacerbations, and disease progression. To relieve dyspnea, pharmacologic options include short- and long-acting beta-2 agonists and short- and long-acting antimuscarinic antagonists. Surgical options, such as lung volume–reduction surgery, have been used to relieve severe symptoms.

Most commonly associated with chronic obstructive pulmonary disease (COPD), emphysema occurs due to gradual damage to lung tissue, affecting alveoli and causing them to rupture. Alveolar rupture forms a single, large air pocket, resulting in decreased lung volume. Air becomes trapped in the damaged tissues, preventing oxygen from moving to the bloodstream. Lung hyperinflation makes breathing difficult, with shortness of breath the hallmark sign of emphysema.^1-7

Global prevalence of emphysema has been reported to be 1.8% (95% CI, 1.3%-2.6%).^8,9 From 2002 to 2018, the reported prevalence of emphysema in adults in the United States fluctuated, with the highest rate of 21 cases per 1,000 population in 2009 and the lowest in 2017 (12 cases per 1,000).¹⁰ Global prevalence of COPD is estimated to be 10.3% (95% CI, 8.2%-12.8%), with up to 3 million deaths per year.¹ Incidence, morbidity, and mortality increase with age. In the U.S., the percentage of COPD, emphysema, or chronic bronchitis for adults aged 18 years and older was 4.6% to 5% from 2019 to 2022.¹¹

Death rates from emphysema appear to be on a slow decline, with a range 2.8 to 10 per 100,000 population for the period of 1999 to 2018 versus 9.5 to 10.9 per 100,000 population for the period of 1979 to 1998.¹⁰ The CDC reports 2.2 deaths per 100,000 population from 2018 to 2021.¹² Prevalence is highest in white adults and appears consistently higher in males versus females.¹⁰

Literature evaluating economic and societal burdens of emphysema alone is limited. Rather, data are available for COPD. Management remains costly, with $49 billion spent on COPD in 2020 alone.¹³ It is estimated that the economic burden of COPD in the next 20 years will increase by $40 billion per year.¹ From 1990 to 2010, COPD was the fourth leading cause of years of life lost and the sixth leading cause of years lived with disability.¹⁴

RISK FACTORS

Cigarette smoking is the primary risk factor for the development of emphysema.^1,2,4,15 Secondhand smoke exposure, dust exposure from coal and hardrock mining (e.g., cadmium, silica), and occupational exposure to dust, gas, fumes, and/or smoke are additional risk factors. A possible role of longstanding asthma in emphysema development (per CT scan) has been proposed.¹⁵

PATHOPHYSIOLOGY

The pathogenesis of emphysema is complex, involvingmany inflammatory processes. Cigarette smoking, a primary cause of emphysema and COPD, causes oxidative stress within the lung. Reactive oxygen and nitrogen species increase, and antioxidants (e.g., glutathione, vitamins A and E, superoxide dismutase, and catalase) decrease, affecting nuclear-factor erythroid 2–related factor (Nrf2)enzymatic processes.¹⁶ Nrf2 is a transcription factor that regulates multiple antioxidant enzymes involved in reducing oxidative stress. Additionally, histone deacetylase inactivation leads to ongoing proinflammatory gene expression.¹⁶ It should be noted that oxidative stress also plays a role in multiple chronic health conditions (e.g., diabetes, cancer, general aging, and cardiovascular, neuropsychiatric, and neurodegenerative diseases).^16,17

The role of proteinases in emphysema and COPD development was identified in the 1960s.¹⁶ Specifically, matrix metalloproteinases (MMPs), such as MMP-1, MMP-9, and MMP-12, have been linked to emphysema. MMPs are classified as extracellular matrix–degrading enzymes. Overexpression increases lung tissue destruction and inflammation.^16,18

Emphysema causes structural damage to lung tissue via alveolar septal cell death. Airspaces permanently enlarge due to a decrease in the number of alveolar cells available as a result of apoptosis and/or autophagy.^1,3,16 Loss of alveolar attachments to small airways decreases lung elastic recoil, which can lead to static lung hyperinflation. Emphysematous parenchymal destruction of the lung is one component leading to expiratory flow obstruction in COPD.^1,3

Three emphysema subtypes have been identified and are determined based on the affected part of the acinus.^4,19 A summary of emphysema subtypes is provided in TABLE 1. Each subtype may occur alone or in conjunction with another. Centrilobular and panlobular emphysemas are associated with increased dyspnea and hyperinflation, decreased walking distance, and lower diffusing capacity.¹⁹

Alpha-1 Antitrypsin Deficiency

Genetics plays a role in emphysema and COPD development.^{1,3,5, 22,23} Alpha-1 antitrypsin (AAT) is a serine protease inhibitor synthesized in the liver that protects against elastase degradation. AAT deficiency (AATD) is rare. It accounts for less than 1% of COPD cases but results in onset of COPD at an earlier age (20-50 years).³ AATD is an autosomal recessive genetic disorder that occurs when an abnormal AAT gene is inherited from each parent. Multiple phenotypes of AATD exist, defined by plasma AAT levels and function. S and Z mutations are most prominent, resulting in different serum AAT levels. hom*ozygous Z mutations (ZZ) are at the highest risk of emphysema development due to AAT levels at 10% of those of individuals without mutations. In contrast, serum AAT levels are 40% of normal in heterozygous Z variations (SZ).^3,22 While AATD increases the risk of early-onset emphysema, this does not mean that all individuals with AATD will develop emphysema. Exposure to cigarette smoking, history of other respiratory health conditions, occupational exposures, and parental history of COPD further increase emphysema risk.^3,5,22,24

AATD typically presents as panlobular basal emphysema in individuals aged younger than 45 years. One-time screening for AATD is recommended by the World Health Organization for adults and their family members diagnosed with COPD.¹ It may also be considered for those with adult-onset asthma.²⁵ hom*ozygous deficiency is likely if AAT levels are less than 20%.^1,3,22

Augmentation therapy involving IV administration of exogenous AAT derived from human blood products is available.²⁶ There are limited data for the use of AAT augmentation therapy for those with severe AATD. It appears to be most effective for patients with predicted forced expiratory volume in 1 second (FEV₁) of 35% to 49% and may reduce progression identified via spirometry.^1,25

DIAGNOSIS AND EVALUATION

In the early stages of emphysema, individuals are most likely asymptomatic. Breathlessness or shortness of breath becomes the primary symptom as emphysema worsens. Individuals may present with exertional dyspnea occurring with significant physical activity. If emphysema is severe, dyspnea may occur with activities of daily living (ADLs) or even at rest.^1,3-5 Moderate-to-severe dyspnea is reported by more than 40% of patients with COPD diagnosis in primary care.^1,27 Other presenting symptoms may include cough with or without sputum production, wheezing and chest tightness, fatigue, and/or weight loss.^1-5 These symptoms indicate changes in lung function, increased inflammatory mediators, progression to COPD, and/or worsening of COPD.^1,3 Physical examination is usually unremarkable in the early stages of emphysema. As emphysema worsens, increased resonance on percussion typically indicates hyperinflation.⁵

Evaluation should include occupational and/or environmental exposure history. A detailed patient history regarding tobacco use, history of cigarette smoking, and use of electronic cigarettes and/or vaping is important, as cigarette smoking has the strongest link to emphysema development.^1,3-5 This history should include age at start of inhaled nicotine product use, cigarette pack-year history, and quit date (if applicable). Tobacco-cessation therapies and counseling are strongly recommended for all patients with current use of nicotine products.^1,3

Because emphysema is most frequently a component of COPD, evaluation and assessment primarily follow recommended techniques that are specific to COPD.^1-5 Diagnosis is guided by symptom presentation, spirometry, and history of exacerbations and/or hospitalizations. Dyspnea may be measured objectively by the modified Medical Research Council (mMRC) dyspnea scale.^1,28 Higher scores have been linked to higher healthcare costs and healthcare resource use.¹ The mMRC ranges from grade 0 (breathless with strenuous exercise only) to grade 4 (too breathless to leave house or while dressing or undressing).^1,28-30 Additional questionnaires evaluate dyspnea within assessment of COPD symptoms. A widely used example is the eight-item CAT tool (COPD Assessment Test).^1,31 Use of the mMRC and CAT questionnaires may assist in monitoring changes in dyspnea levels over time and identifying potential exacerbations.

Additional testing is recommended if symptom presentation and airflow obstruction levels conflict. Testing may include measurement of lung volume, lung carbon monoxide diffusing capacity (DLco), oximetry, arterial blood gases, exercise testing, and physical activity assessments (such as self-paced walking distance).^1,2 Imaging techniques include an x-ray of the chest and high-resolution CT. The chest x-ray is often a first step in COPD evaluation but is not diagnostic of emphysema. Chest x-rays may be helpful primarily if emphysema is severe, with the diaphragm appearing flatter and the heart appearing tubular and elongated due to hyperinflation and air trapping.^1,2,4

Emphysema severity is based on symptom presentation, spirometry results, and additional testing as noted above. Characteristics of severe emphysema may include FEV₁ of less than 45% and 75% or more of lung zone involvement identified via highresolution CT imaging.³²

Spirometry

Spirometry evaluates presence or absence of airflow limitations and reversibility. Obtaining spirometry pre- and postbronchodilator use identifies whether airflow limitation is reversible, partially reversible, or not reversible.^1,3 COPD occurs when airflow limitation is partially or fully irreversible. Spirometry follows standardized processes for respiratory measurements and is used for diagnosis and monitoring of respiratory health conditions and disability or impairment.³¹

Spirometry measures the forced vital capacity (FVC) and FEV₁. If FEV₁/FVC is less than 0.7 after bronchodilator use, it is considered diagnostic of COPD.¹ If a postbronchodilator FEV₁/FVC ratio is less than 0.6, repeat spirometry is not recommended. However, if a postbronchodilator FEV₁/FVC is between 0.6 and 0.8, it is recommended to obtain repeat spirometry on a different day for airflowobstruction confirmation.¹ Reference values are based on age, height, and sex.^1,4,33

It is important to note that individuals with emphysema may not have airflow limitations per spirometry but may still report respiratory symptoms or have identified structural or functional abnormalities. These individuals may exhibit obstructive symptoms without bronchodilator use (FEV₁/FVC less than 0.7) and symptom improvement after bronchodilator use (FEV₁/FVC less than 0.7).³⁴ The early stages of emphysema may fall into this category. Progression to persistent airflow limitation may or may not occur.^1,4,7,35,36

CT Scan in Emphysema

CT scan, especially high-resolution CT, is sensitive and specific in determining presence or absence of emphysema and can be used to distinguish between different types of emphysema. It may be used if spirometry is unavailable, and it has been correlated with the presence and severity of emphysema compared with pulmonary function tests.^1,4,37 Qualitative CT provides a visual assessment of altered lung structure and identifies patterns of alteration.³⁸ Quantitative CT identifies and evaluates the extent of destroyed lung, airway changes, and air trapping.³⁸ Areas of abnormally low attenuation are indicative of emphysema and may be used to distinguish between subtypes. Centrilobular emphysema appears most severe in the upper lung and is interspersed within the normal lung and near the secondary pulmonary lobule in diffuse areas.³⁷ Panacinar emphysema is mainly in the lower lung with minimal interspersion into normal lung. Distal acinar emphysema has low attenuation in subpleural lung regions and adjacent to vessels and interlobular septa. Panacinar emphysema recognition on CT is more difficult.^37,39 CT scan is primarily indicated as a presurgical assessment.¹

PHARMACOTHERAPY OPTIONS

No specific pharmacotherapy is recommended for emphysema alone. Rather, treatment choice is guided by the Global Initiative for Chronic Lung Disease (GOLD) for the management of COPD due to the nature of emphysema and COPD progression.^1,3-5 Because lung damage is not reversible, overall therapy goals focus on symptom reduction, preventing exacerbations, and reducing disease progression.¹ Additional goals include improving exercise tolerance, preventing and treating complications, and decreasing morbidity and mortality.³

Initial pharmacotherapy choice is based on symptom presentation and GOLD group staging. Individuals are categorized as GOLD group A, B, or E depending on mMRC and CAT scores and the number of exacerbations in the past 12 months, with hospitalization for exacerbation considered. GOLD group staging and pharmacotherapy recommendations are summarized in TABLE 2. As-needed, short-acting bronchodilator rescue therapy is recommended for all patients with COPD, regardless of stage.¹ If hospitalization occurs due to exacerbation or if a patient experiences two or more exacerbations with or without hospitalization, the individual falls into GOLD group E and should be treated with combination therapy of an inhaled long-acting beta-2 agonist (LABA) with a long-acting antimuscarinic (LAMA). Triple therapy with LABA plus LAMA plus inhaled corticosteroids (ICS) may be indicated for GOLD group E if blood eosinophil counts are 300 cells/μL or greater.¹ A detailed review of COPD guidelines and the pharmacologic management of COPD symptoms was previously summarized and may also be found within the 2024 GOLD guidelines.^1,40

Shortness of breath and dyspnea are hallmark characteristics of emphysema. Initial pharmacotherapy should include a bronchodilator, which includes short- or long-acting beta-2 agonists (SABA or LABA) or muscarinic-receptor antagonists (SAMA or LAMA). Short-acting therapies are indicated when dyspnea is intermittent and are used on an as-needed basis only. If dyspnea worsens or occurs consistently, a LABA or LAMA is indicated. If continued worsening occurs, combination therapy of LABA plus LAMA is recommended.^1,5

Bronchodilators reduce limitations to airflow by relaxing airway smooth muscle tone. Beta-2 agonists do this by increasing formation of cyclic adenosine monophosphate (cAMP) via stimulation of the adenyl cyclase enzyme. In contrast, muscarinic antagonists promote bronchodilation by binding to M1, M2, and M3 receptors in the smooth muscle and mucus glands of the airway. In addition to bronchodilation, mucus secretion decreases.³

ICS addition may be considered if COPD is present, one or more moderate COPD exacerbations occur, and blood eosinophil count is 100 cells/μL to 300 cells/μL or more, with the recommendation to deescalate ICS use where possible.¹ A summary of inhaled therapies is provided in TABLE 3. If exacerbations occur, oral corticosteroids, roflumilast (phosphodiesterase-4 inhibitor), and macrolide antibiotics may also be used.¹ A detailed review of these therapies is outside the scope of this article.

Multiple devices exist for inhaled medication delivery.⁴² These include dry powder inhalers (DPI), metered-dose inhalers (MDI), soft-mist inhalers (Respimat), and nebulizers. Respimat devices and nebulizers are propellent free. A list of commonly used types of inhaler devices and patient-education materials (written and visual) are available for reference.^43-45

Monitoring parameters include therapy effectiveness and symptom control, inhaler technique, use of a spacer device when applicable, potential for drugdrug interactions, side effects, and potential cost limitations.

MEDICATION ADHERENCE

Medication adherence is challenging to achieve and is influenced by many factors (TABLE 4). Greater adherence to therapy has been shown to decrease hospitalizations and spending outcomes. Low adherence rates are associated with an increase in symptoms, higher prescription costs, increased hospitalization, and higher mortality rates.^51,52 Choice of inhaler device and appropriate education in technique may improve adherence. Age may be a determining factor in inhaler choice. DPIs require sufficient peak inspiratory force (PIF) to obtain appropriate medication dosing. Reports suggest that one in five patients with COPD has decreased PIF rates. Regardless of respiratory status, decreased PIF has been associated with older age, female sex, and shorter stature.^46,47 Continued follow-up with frequent assessment of inhaler technique is recommended. A spacer device should be considered for use with all compatible inhalers to improve inhaler technique and medication delivery (TABLE 3).^1,42-46

NONPHARMACOLOGIC MANAGEMENT

Nonpharmacologic management of emphysema includes tobacco cessation, self-management education programs, supplemental oxygen (targeted to oxygen saturation of 92% to 95%) for severe emphysema and COPD with chronic hypoxemia, noninvasive positive pressure ventilation, and pulmonary rehabilitation.^1,3-5

Surgical Treatments

In cases of severe emphysema, surgical treatments may be considered and include options such as lung volume–reduction surgery (LVRS), bullectomy, or endoscopic lung volume reduction.¹ Surgical treatments may decrease hyperinflation and reduce symptoms.^1,3,53

LVRS involves resection of emphysematous tissue from the lung to decrease hyperinflation and improve lung elastic recoil.^1,3,53,54 Perhaps the most widely known trial evaluating LVRS is the National Emphysema Treatment Trial (NETT), which is considered one of the largest LVRS trials.^32,55,56

Using extensive inclusion/exclusion criteria, NETT randomized 1,218 adults with severe emphysema to receive LVRS or continued medical therapy.^32,56,57 Continued medical therapy included smoking cessation, bronchodilators, oxygen therapy to maintain saturations of 90% or higher during ADLs, immunizations, and additional measures specific to the patient. All patients completed pulmonary rehabilitation prior to randomization. Mortality and maximal exercise capacity at 24 months were the primary endpoints.^56,57

Results from NETT indicate that for the non–highrisk group, 30-day and 90-day mortality rates were 2.2% and 5.2% versus 0.2% and 1.5% in the LVRS and medical therapy groups, respectively (P <.001; P = .001). Two-year total mortality was 0.09 death per person-year for the LVRS group versus 0.10 death per person-year in the medical therapy group (risk ratio 0.89; P = .31). Exercise capacity significantly improved in the LVRS group compared with the medical therapy group (16% vs. 3%; P <.001). Distance walked in 6 minutes, percent predicted FEV₁, quality of life, and dyspnea were also found to favor the LVRS group compared with medical therapy.^56-58

Long-term follow-up at 5 years demonstrated a risk ratio of 0.86 (P = .02) for death, indicating an overall survival advantage for the LVRS group.^58,59 Maximal exercise (through 3 years) and health-related quality of life (through 4 years) improvement also increased in the LVRS group.^58,59

It should be noted that the risk of death with LVRS is higher in patients with FEV₁ 20% or less than predicted and either DLco 20% less than predicted or hom*ogenous emphysema distribution on CT.⁶⁰ In this group, the 30-day mortality rate post LVRS was 16% versus 0% in the medical therapy group (95% CI, 8.2%-26.7%; P <.001). The overall mortality was 0.43 deaths per person-year versus 0.22 deaths per person-year in LVRS versus medical therapy groups, respectively (RR 3.9; 95% CI, 1.9-9.0). Due to this finding, these patients were excluded from NETT in the early part of the trial.⁶⁰

A 2016 systematic review of LVRS in diffuse emphysema evaluated 11 studies, with a single study accounting for 68% of participants.⁵³ This systematic review found higher short-term mortality with LVRS compared with controls (OR 6.15, 95% CI 3.22-11.79). However, LVRS was favored compared with control groups in long-term mortality (overall response [OR] 0.76, 95% CI 0.61-0.95). Favorable outcomes were higher for individuals with emphysema predominantly in the upper lobe with low baseline exercise capacity. LVRS reported more adverse effects.⁵³

Overall costs of LVRS are higher when compared with standard medical therapy. The NETT calculated an initial cost-effectiveness ratio of $193,000 per quality-adjusted life year gained for LVRS versus medical therapy groups. At 10 years, this ratio was $53,000 per quality-adjusted life year gained.⁶¹

COMPLICATIONS AND PROGNOSIS

Long-term prognosis of emphysema is individualized and dependent on severity of emphysema (radiologic and symptomatic), progression of COPD, concurrent health conditions, and presence/absence of AATD. Concurrent health conditions that may influence prognosis include cardiovascular disease, congestive heart failure, ischemic heart disease, arrhythmias, peripheral vascular disease, and obstructive sleep apnea.^1,4

The frequency and severity of COPD exacerbations also influence prognosis. COPD exacerbations often occur due to respiratory illness (e.g., rhinovirus, influenza, SARS-CoV-2), leading to worsening of respiratory symptoms and increased dyspnea and hyperinflation.¹ Arterial hypoxemia with or without hypercapnia may occur. Long-term complications include potential for chronic respiratory failure and hypercapnia.¹ Hospitalization for COPD exacerbation is associated with a poor prognosis long-term, as is the need for oxygen therapy at discharge.¹ The BODE index is a predictive tool that may be used to determine the risk of death from any cause and from respiratory causes in COPD.^62,63 The BODE index evaluates percent predicted FEV₁, distance walked in 6 minutes in meters, the mMRC dyspnea scale, and BMI.⁶² Disease severity increases with increasing BODE scores, and survival rate decreases.⁴ Two of the four components evaluated are specific to emphysema.

Emphysema has a strong link to lung cancer.^1,4,64-66 Risk of lung cancer increases if both pulmonary nodules and emphysema are present. The presence of quantitative emphysema on low-dose CT has been found to be independently associated with the incidence and mortality of lung cancer.⁶⁴

CONCLUSION

Emphysema is one component of COPD and is often asymptomatic for many years before symptoms develop. Currently, no cure for emphysema exists. Goals of therapy include symptom management and reducing progression to severe disease. Pharmacologically, inhaled bronchodilator therapy is the mainstay of treatment for emphysema symptoms, with short- and/or long-acting beta-2 agonists or muscarinic antagonists. For current smokers, tobacco cessation is key, and it should be maintained in those who have quit. Emphysema is linked to lung cancer and many other concurrent health conditions.

Pharmacists may play a role in emphysema management by assisting in inhaler selection based on symptom presentation, GOLD group staging, patient dexterity and possible PIF, inhaler technique, and potential need for a spacer device. Pharmacists may also evaluate regimens for potential drug-drug or drug-disease interactions and assist with dosing parameters. Pharmacists may assist with self-management education and education regarding appropriate medication use, inhaler technique, and use of a spacer with applicable devices. Pharmacists are problem solvers and may work with patients and providers to improve long-term adherence to medication therapy, reduce medication burden by optimizing combination inhaler therapy where appropriate, and reduce medication costs where possible. Pharmacist-led tobacco-cessation and immunization programs (e.g., influenza, pneumococcal, SARS-CoV-2, and respiratory syncytial virus) are an integral part of interdisciplinary collaboration in emphysema prevention and management.

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