CONTENTS

• Definitions
• Epidemiology & risk factors
• Symptoms
• Clinical examination
• Laboratory evaluation
• PFTs in COPD
• Radiology:
  • Hyperinflation on radiography
  • Centrilobular emphysema
  • Paraseptal emphysema
  • Panlobular (panacinar) emphysema
  • Chronic bronchitis
  • Bronchiectasis-COPD overlap syndrome (BCOS) ➡️
• Diagnosis of COPD
  • Differential diagnosis
  • Differentiation of asthma vs. COPD
  • Disorders causing emphysema (without tobacco exposure)
• Management
  • Integrated approach to COPD therapies
    • (Inhalation devices & optimization ➡️)
  • Phosphodiesterase inhibitors
    • Roflumilast
    • Ensifentrine
  • Azithromycin
  • Oxygen
  • Nocturnal BiPAP & COPD-OSA overlap syndrome
  • Lung volume reduction
    • Surgical
    • BLVR (bronchoscopic lung volume reduction)
  • Transplantation ➡️
• Prognosis
• Related topics
  • Alpha-1 antitrypsin deficiency (AATD)
  • Bullous lung disease
  • CPFE (combined pulmonary fibrosis and emphysema) ➡️
  • Secondary spontaneous pneumothorax due to COPD ➡️
• Questions & discussion

abbreviations used in this chapter:

• SABA = Short-Acting Beta Agonist.
• LABA = Long-Acting Beta Agonist.
• SAMA = Short-Acting Muscarinic Antagonist.
• LAMA = Long-Acting Muscarinic Antagonist.
• ICS = Inhaled corticosteroid.

abbreviations used in the pulmonary section: 4

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• CF: Cystic fibrosis 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OHS: Obesity hypoventilation syndrome 📖
• OP: Organizing pneumonia 📖
• OSA: Obstructive sleep apnea 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

---

definitions

(back to contents)

---

• COPD: A heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause permanent and often progressive airflow obstruction. (GOLD 2024)
• Emphysema: Radiologic/pathologic term describing abnormal, permanent enlargement of airspaces distal to terminal bronchioles, with destruction of the airway walls in the absence of fibrosis. Emphysema is generally associated with COPD, but some patients with emphysema may have preserved airflow (pre-COPD, not meeting the definition of COPD).
• Chronic bronchitis: Chronic productive cough for at least three months in each of two successive years, in whom other etiologies of chronic cough have been excluded. About a third of patients with COPD have chronic bronchitis. However, chronic bronchitis without airflow obstruction doesn't meet the definition of COPD (rather, it is another form of pre-COPD). (Gold 2024) 

---

epidemiology

(back to contents)

---

risk factors for COPD

• Smoking is the primary risk factor:
  • It's unusual for COPD to develop with <20 pack-years exposure.
  • Most patients with COPD have >40 pack-years exposure.
• Alpha-1 antitrypsin deficiency. ⚡️
• Occupational exposures (e.g., sculptors, gardeners, and warehouse workers). (GOLD 2024)
• Domestic cooking with biomass fuels (e.g., wood, animal dung, or crop residues). (Shah 2019) 
• Impaired lung maturation (e.g., developmental abnormalities, low birthweight, prematurity, childhood respiratory infections). (GOLD 2024)

general epidemiology

• COPD is enormously common (e.g., third-leading cause of death globally). (35533707)
• Chronic bronchitis might be more common than emphysema. About a third of smokers age 35-60 have chronic bronchitis, with increasing prevalence over time. However, the majority of patients with COPD have some combination of both emphysema and chronic bronchitis.

---

symptoms

(back to contents)

---

Core symptoms are dyspnea, cough, wheezing, and chest tightness. These symptoms may be chronic, or worsen transiently during disease exacerbations.

dyspnea

• Chronic dyspnea is the most characteristic symptom of COPD. (GOLD 2024)
• Dyspnea is progressive and persistent (unlike asthma, wherein dyspnea is more episodic).
• Dyspnea is worse with exertion.

chronic cough

• Cough may be a relatively early manifestation (often the initial symptom).
• Cough often progresses to occur throughout the day.
• Chronic sputum production may occur (but rarely is daily sputum production >60 ml). Sputum production may initially be insidious, only occurring in the morning. If large volumes of sputum occur this may suggest the possibility of bronchiectasis, or an acute exacerbation of COPD.

wheeze and chest tightness

• Symptoms may fluctuate over time.

symptoms of more advanced disease

• Chronic hypercapnia:
  • May cause morning headache and drowsiness.
  • On examination, hypercapnia may cause asterixis. Patients may also complain of asterixis (referring to it as a “tremor”).
• Weight loss may occur in advanced emphysema, due to persistent work of breathing and difficulty eating.
• Cor pulmonale may cause peripheral edema.

---

clinical examination

(back to contents)

---

• Physical examination is insensitive for the diagnosis of COPD.
• Wheezing may be present.
• Hyperinflation may cause:
  • Increased anterior-posterior chest dimension (“barrel chest”).
  • Decreased heart and breath sounds.
• Cor pulmonale may occur in advanced disease, leading to:
  • Peripheral edema.
  • Jugular vein distension.
• (Clubbing 📖 is not a sign of COPD. If clubbing is present this should raise concern regarding the possibility of lung cancer.)

---

laboratory evaluation

(back to contents)

---

• Polycythemia may occur in patients with chronic hypoxemia.
• Metabolic alkalosis may be seen as chronic compensation for hypercapnia.
• Peripheral eosinophils:
  • >~200/uL may predict responsiveness to steroid.
  • >300/uL may predict increased risk of exacerbations. (GOLD 2024)
  • ⚠️ During acute illness, physiological stress and cortisol release may temporarily reduce the eosinophil count. When possible, review the patient's eosinophil count longitudinally over time.
• Alpha-1 antitrypsin levels may be used to screen for alpha-1 antitrypsin deficiency. ⚡️

---

PFTs in COPD

(back to contents)

---

---

spirometry in COPD

roles of spirometry in COPD

• Diagnosis of COPD (discussed below).
• Assessment of disease severity.
• Consider alternative diagnoses when symptoms >> obstruction. (GOLD 2024)
• Identification of decline over time (e.g., candidacy for lung transplantation).

spirometry is a cornerstone of COPD diagnosis 

• Diagnostic criteria for COPD require a post-bronchodilator FEV1/FVC ratio of <0.7 (GOLD 2024)
• If FEV1/FVC is between 0.6 – 0.8, repeat spirometry on a separate occasion should be performed to confirm the result (some patients may have varying results over time). (GOLD 2024)
• (Further discussion of obstruction in pulmonary function tests: 📖)

severity of airflow obstruction

• FEV1 >80% predicted = Mild (GOLD 1)
• FEV1 50-80% predicted = Moderate (GOLD 2)
• FEV1 30-50% predicted = Severe (GOLD 3)
• FEV1 <30% predicted = Very severe (GOLD 4)

change in FEV1 over time

• Generalizations:
  • Healthy nonsmokers over ~30-40 years of age lose ~30 ml/year in the FEV1.
  • Patients with COPD who smoke may lose ~45-70 ml/year in their FEV1, but there is substantial variability. (Fishman 2023)
  • Smoking cessation reduces the rate of FEV1 loss, as shown above.
• ⚠️ However, loss of lung function is very heterogeneous, with some patients having little or no decline in FEV1 over time. (Fishman 2023) Therefore, disease prognostication based solely on FEV1 is prone to error.

---

flow-preserved emphysema

• Patients with early emphysema may have preserved FEV1. Such patients may display:
  • Reduction in DLCO.
  • Evidence of centrilobular emphysema on CT scan.
  • Reduced expiratory flows at low lung volumes (e.g., reduced FEV3/FVC).
• FEV1 largely reflects abnormalities in the larger airways, so this may be insensitive to early emphysema.
• Despite a normal FEV1/FVC, patients may have substantial clinical impairment.
• Another diagnostic possibility to consider is CPFE (combined pulmonary fibrosis and emphysema). 📖
• 💡 Normal FEV1/FVC doesn't necessarily exclude emphysema.

---

bronchial hyperresponsiveness in COPD

• Bronchial hyperresponsiveness refers to improvement in airflow following bronchodilator therapy. This measurement shouldn't alter management. (GOLD 2024)
  • Within a single patient, bronchial hyperresponsiveness varies over time.
  • Responsiveness doesn't differentiate COPD versus asthma.
  • Responsiveness doesn't predict the response to therapy with inhaled bronchodilators or steroid. (GOLD 2024)
• (Bronchial hyperresponsiveness is discussed further in the chapter in PFTs: 📖)

---

radiology in COPD

(back to contents)

---

Emphysema refers to loss of lung parenchyma, leading to a reduction of attenuation on CT scan. Emphysema may have various distributions, as discussed below. Unlike cystic lung disease, emphysema doesn't lead to the formation of definable walls around areas of missing lung.

---

hyperinflation on chest radiography

frontal radiograph

• Flattened, low diaphragms.
• Unusually large number of ribs visible:
  • >6 anterior ribs.
  • >10 posterior ribs.

lateral radiograph

• (1) Flattened diaphragms may be seen.
  • Diaphragm arch height may be measured as shown below. Normally this should be >2.5 cm. Height <1.5 cm is considered clearly pathological. (Bell, radiopaedia)
  • In severe cases, diaphragm may assume a concave upwards configuration (opposite to its normal curvature).
• (2) Increased retrosternal clear space between the aorta and sternum.
• Barrel configuration of chest may be notable (with increased anterior-posterior diameter).

differential diagnosis: causes of hyperinflation

• COPD.
• Asthma.
• Bronchiectasis (including cystic fibrosis).
• Bronchiolitis (including bronchiolitis obliterans).
• Diffuse cystic airway diseases (e.g., lymphangioleiomyomatosis).
• Large airway obstruction.

---

centrilobular emphysema 

basics

• The disease process begins with the central bronchioles and gradually spreads outwards (eventually involving the entire pulmonary lobule).
• This is the most common radiographic finding among patients with emphysema.

chest radiograph

• Increased biapical lucency may be seen. (Rosado-de-Christenson 2022)
• Hyperinflation may be noted.

CT scan

• Patchy, focal areas of lung tissue are missing (generating a moth-eaten appearance).
• Lucencies begin in the center of the pulmonary lobule. Eventually, the entire lobule may be destroyed, leaving behind only centrilobular arterioles.
  • Centrilobular arterioles may remain as small dots within involved secondary lobules (central dot sign). These structures are helpful in differentiating centrilobular emphysema from cystic lung disease (since cysts are empty).
• The lobes most frequently involved are the posterior and apical segments of the upper lobe, and the superior segment of the lower lobe. (Fishman 2023)

clinical significance

• Centrilobular emphysema is the most common pattern of emphysema seen among patients with COPD.
• Centrilobular emphysema can also occur due to industrial dust exposure (e.g., silica). (Rosado-de-Christenson 2022)

---

paraseptal emphysema

radiology of paraseptal emphysema

• Areas of emphysema occur at the lung periphery and occasionally the fissures. This causes numerous subpleural air-filled spaces (blebs) which may vary from 0.5-2 cm. (Shah 2019)
• There is usually an upper-lobe distribution.
• Only a single row of blebs as usually present (differentiating this from honeycombing).

epidemiology: causes of paraseptal emphysema

• COPD: Paraseptal emphysema commonly occurs in combination with centrilobular emphysema.
• Tall, thin people have a greater tendency to develop paraseptal emphysema (due to the effects of gravitational pull on the lungs, with a greater negative pleural pressure at the lung apices). (Walker 2019)
• Marfan syndrome, Ehlers-Danlos syndrome.

clinical significance

• Paraseptal emphysema usually has a minimal effect on pulmonary function.
• Subpleural blebs may increase the risk of pneumothorax.
  • Paraseptal emphysema may be related to primary spontaneous pneumothorax. This frequently occurs in patients who don't use tobacco (but it is associated with smoking marijuana). (Fishman 2023)

---

panlobular (panacinar) emphysema

radiology

• Unlike centrilobular emphysema, focal areas of missing lung tissue usually are not observed. Instead, the entire lung is abnormally hypodense.
• Panlobular emphysema may involve the entire lung, but it often has a lower lobe predominance. (Walker 2019) 
  • Coronal projections may be ideal to appreciate reduced density of the lower lung, in comparison to the upper lung.

clinical significance

• Panlobular emphysema is seen in only ~1% of patients with COPD.
• Causes of panlobular emphysema:
  • alpha-1 antitrypsin deficiency. ⚡️
  • Intravenous methylphenidate abuse (“Ritalin lung”).
  • Hypocomplementemic urticarial vasculitis syndrome.
  • Elastin abnormalities (e.g., Ehlers-Danlos syndrome, cutis laxa).

---

radiology of chronic bronchitis

chest radiograph

• Chest radiograph is usually normal.
• Bronchial wall thickening may be seen:
  • Peribronchial cuffing
  • Increased interstitial markings.
• Hyperinflation may be noted.

CT scan

• Bronchial wall thickening.
• Mosaic attenuation.
• Mucus may be seen within the tracheobronchial tree. (Rosado-de-Christenson 2022)
• Evidence of pulmonary hypertension and right ventricular failure may be seen.

differential diagnosis of bronchial wall thickening includes:

• Airway diseases:
  • Asthma.
  • Cystic fibrosis.
  • ABPA (allergic bronchopulmonary aspergillosis).
  • Bronchiectasis.
  • Acute bronchitis.
  • Chronic bronchitis.
  • Bronchiolitis obliterans (including DIPNECH, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia).
  • Diffuse panbronchiolitis.
  • RBILD (respiratory bronchiolitis interstitial lung disease).
  • Airway complication from inflammatory bowel disease.
• Infections, including:
  • Acute bronchitis or bronchopneumonia.
  • Mycobacterial infection.
• Other:
  • Heart failure.
  • Obstructive sleep apnea.
  • Sarcoidosis.
  • Organizing pneumonia. (Muller 2019)

---

diagnosis of COPD

(back to contents)

---

⚠️ Not all patients with chronic airflow obstruction have COPD!

the diagnosis of COPD is generally based on several pieces of information:

• Three cornerstones of diagnosis:
  • (1) Risk factors for COPD. ⚡️
  • (2) Symptoms of COPD. ⚡️
  • (3) Post-bronchodilator FEV1/FVC <0.7 ⚡️
• Other features may also require consideration:
  • Competing diagnoses (see the section below).
  • Review of any radiological data.

---

differential diagnosis

(back to contents)

---

COPD is very common, so there is a tendency to over-diagnose COPD in patients who actually have less common disorders. 

COPD

• Slowly progressive symptoms.
• >20 pack-years of smoking exposure, or an alternative risk factor for COPD ⚡️.

asthma

• Discussed further in the section below.

heart failure

• Both COPD and heart failure may cause chronic dyspnea and peripheral edema (COPD may be associated with cor pulmonale).

bronchiectasis

• Bronchiectasis is suggested by greater sputum production.
• CT scan is diagnostic for bronchiectasis.
• (Note that one third of patients with COPD may have comorbid bronchiectasis, so these disorders are not mutually exclusive.)

bronchiolitis obliterans (BO)

• Patients present with dyspnea and fixed airway obstruction.
• Lack of smoking history may be a useful clue.
• CT scan with expiratory images may show mosaic attenuation.
• Patients usually have an associated cause (e.g., transplantation, connective tissue disease).

diffuse panbronchiolitis

• History may include chronic bronchitis and cough productive of substantial volumes of sputum (>50 ml/day).
• CT may show diffuse tree-in-bud opacities.
• Chronic sinusitis is generally present.
• Diffuse panbronchiolitis is rare and occurs predominantly in people with Asian (or especially Japanese) ancestry.

---

differentiation of asthma vs. COPD

(back to contents)

---

It may be impossible to distinguish between the two diagnoses (and indeed, some patients may have both disorders: asthma-COPD overlap). In situations where it's impossible to sort out the diagnosis, the management should be similar to the treatment of asthma. (GOLD 2024)

differentiating factors

• Age:
  • Asthma often occurs in younger people (but can occur at any age).
  • COPD is rare below ~45 years old.
• Smoking history:
  • <20 pack-year smoking exposure makes COPD unlikely.
  • Very extensive smoking exposure makes COPD increasingly likely.
• Atopy and eosinophilia:
  • The presence of allergies, rhinitis, or eczema may suggest a diagnosis of atopic asthma.
  • Family history of asthma or atopy may support a diagnosis of asthma.
  • Substantial blood eosinophilia and/or elevated IgE may support a diagnosis of asthma.
  • Elevated exhaled nitric oxide may support a diagnosis of asthma.
• Fluctuation over time:
  • Asthmatics tend to vary more over time (e.g., periodic abrupt episodes of bronchospasm).
  • COPD symptoms are usually more slowly progressive (although exacerbations may occur).
• Nocturnal symptoms:
  • More commonly seen in asthma.
• Sputum production:
  • Sputum production is less common in asthma.
  • Chronic productive cough would be more supportive of a diagnosis of chronic bronchitis.
• CT scan:
  • If seen, centrilobular emphysema supports a diagnosis of COPD.
• PFTs:
  • Bronchodilator and/or methacholine responsiveness may be seen in both asthma and COPD.
    • If patients are broncho-responsive, this is nonspecific.
    • Lack of bronchodilator or methacholine responsiveness may largely exclude asthma, so this finding would support a diagnosis of COPD.
  • DLCO reduction would suggest a diagnosis of emphysema. Alternatively, DLCO tends to be elevated in asthma.
  • If FEV1 is normal (either at baseline or following bronchodilation), this may favor a diagnosis of asthma. However, it is possible for some patients with emphysema to have a normal FEV1 (flow-preserved emphysema 📖).

---

disorders causing emphysema without tobacco exposure

(back to contents)

---

list of possibilities

• Alpha-1 antitrypsin deficiency ⚡️.
• HIV.
• Intravenous drug use:
  • Methylphenidate or methadone may cause basilar emphysema.
  • Cocaine or heroin may cause an apical distribution.
• Chronic hypersensitivity pneumonia (especially farmer's lung).
• Anorexia nervosa. (34743855)
• Genetic connective tissue abnormality:
  • Cutis laxa.
  • Marfan syndrome.
  • Ehlers-Danlos syndrome.
• HUVS (hypocomplementemic urticarial vasculitis syndrome) – history may be notable for urticarial rash and angioedema (discussed further below).
• Salla syndrome (autosomal recessive; also causes intellectual disability, ataxia, nystagmus). 📄

---

HUVS (hypocomplementemic urticarial vasculitis syndrome)

basics

• Immune complex-mediated vasculitic disorder that may involve several organ systems.
• Caused by anti-C1q autoantibodies, which activate the classical complement pathway. (27726442) 

epidemiology

• Usually occurs in patients ~30-40 years old.
• 8:1 female predominance. (25644915)
• May be familial or acquired (due to viral infection, lupus, monoclonal gammopathy, or Sjogren syndrome). (34743855)

clinical features

• Pulmonary involvement:
  • Panlobular emphysema occurs in most patients.
  • Reversible airway obstruction consistent with asthma can also occur. (27726442) 
  • Symptoms may include cough, pleuritis, and hemoptysis. (27726442) 
• Recurrent angioedema is the presenting feature in ~50% of patients. Patients may have urticaria and laryngeal edema.
• Raynaud phenomenon.
• Glomerulonephritis.
• Peripheral neuropathy.
• Abdominal pain.
• Uveitis, episcleritis.
• Arthritis.

radiological findings

• Basilar emphysema is usually seen. Other causes of basilar emphysema include alpha-1 antitrypsin disorder ⚡️ or illicit injection of methylphenidate (“Ritalin lung”). (27726442) 

laboratory tests

• Low C4 and C1q levels.
• Positive test for C1q precipitin antibody (nearly ubiquitous in this disorder). (27726442)
• About half of patients also have positive ANA (antinuclear antibody), sometimes with high titers. (25644915)

invasive diagnostic testing

• Skin biopsy of urticarial lesions shows leukocytoclastic vasculitis and direct immunofluorescence reveals immunoglobulin and complement deposition in a granular pattern. (25644915)

differential diagnosis

• Alpha-1 antitrypsin deficiency ⚡️.
• Lupus (most patients meet diagnostic criteria for SLE, however they should not have anti-dsDNA antibodies). (25644915)

management

• Immunosuppression may improve nonpulmonary features.
• Pulmonary disease is often rapidly progressive without transplantation. (34743855)

---

assessment of disease severity & risk

(back to contents)

---

The two key dimensions of assessment are the current symptom burden and the risk of exacerbation.

disease symptoms

• Symptom severity may be assessed using the MRC dyspnea scale (Medical Research Council) or the CAT assessment (COPD Assessment Test). The CAT assessment may be a more accurate evaluation of varying symptoms related to COPD.
• MRC Dyspnea scale:
  • 0 = I only get breathless with strenuous exercise.
  • 1 = I get short of breath when hurrying on level ground or walking up a slight hill.
  • 2 = I walk slower than people of the same age on the level because of breathlessness, or I have to stop for breath when walking on my own pace on the level.
  • 3 = I stop for breath after walking about 100 meters or after a few minutes on the level.
  • 4 = I am too breathless to leave the house or I am breathless when dressing or undressing.
• CAT assessment is shown below. All the points are summed to create a total score ranging from 0-40.

exacerbation risk

• The primary risk factor for future exacerbations is a history of prior exacerbations.
• Blood eosinophil level >300/uL might also predict an increased risk of exacerbations. (GOLD 2024)

integration of symptoms and risk

• GOLD guidelines combine symptoms and exacerbations to classify patients into three groups as shown below: (GOLD 2024)

---

management of chronic COPD, overview

(back to contents)

---

• Basic supportive care:
  • Reduce risk factor exposure:
    • Smoking cessation.
    • Avoid air pollution (e.g., occupational irritants or biomass-burning stoves).
  • Vaccinations (e.g., influenza, Pneumococcus, COVID, RSV, TDAP).
  • Nutritional support for patients with malnutrition.
• Medications:
  • Bronchodilators.
  • Inhaled steroid.
  • Inhalation devices & optimization ➡️
• Oxygen.
• Interventional therapies:
  • Lung volume reduction surgery (LVRS).
  • Transplantation.
• Pulmonary rehabilitation.

---

integrated approach to COPD therapies

(back to contents)

---

abbreviations

• SABA = Short-Acting Beta Agonist.
• LABA = Long-Acting Beta Agonist.
• SAMA = Short-Acting Muscarinic Antagonist.
• LAMA = Long-Acting Muscarinic Antagonist.
• ICS = Inhaled corticosteroid.

---

initial therapy

Below is a general initial approach to COPD therapy. Over time, therapies may be adjusted based on clinical response. (GOLD 2024) 

group A (mild symptoms, low risk of exacerbation)

• Either a short- or long-acting bronchodilator may be utilized.
• A long-acting bronchodilator is generally preferred (except in patients with very occasional dyspnea).

group B (severe symptoms, low risk of exacerbation)

• SABA+SAMA: As a PRN reliever medication, combined SABA (short-acting beta-agonist) plus SAMA (short-acting muscarinic antagonist) is most effective (e.g., albuterol/ipratropium).
• LABA+LAMA is preferred combination therapy.
• An RCT on this group of patients demonstrated superior outcomes with LABA+LAMA as compared with LAMA or LABA monotherapy. (31666084)

group E (severe symptoms, high risk of exacerbation)

• SABA+SAMA: As a PRN reliever medication, combined short-acting beta-agonist plus short-acting muscarinic agonist is most effective (e.g., albuterol/ipratropium).
• LABA+LAMA combination therapy is superior to monotherapy to reduce exacerbations. (30521694)
• LABA+LAMA+ICS: indications & contraindications for this are discussed further below.

---

follow-up therapy

---

further discussion of individual components

short-acting PRN bronchodilators

• Combination therapy with a SABA (short-acting beta-agonist) plus SAMA (short-acting muscarinic antagonist) may have greater bronchodilator response and reduce the frequency of exacerbations, as compared to albuterol monotherapy. (8181328, 9404747, 9782217)
• Albuterol/ipratropium may be a good choice (e.g., Combivent).
• If combination therapy isn't available, ipratropium may actually be slightly more effective than albuterol. (16625543) 

LAMA (long-acting muscarinic antagonist)

• Tiotropium has been shown to reduce exacerbations and hospitalizations, as well as improve lung function.
• LAMAs > LABAs: LAMAs have greater efficacy at exacerbation and hospitalization reduction. (GOLD 2024) For example, when compared with salmeterol, tiotropium was more effective at reduction of exacerbations. (23102611)
• LAMA monotherapy may be adequate for patients with mild disease (e.g., group A above). However, a LABA+LAMA combination is generally preferred over LAMA monotherapy. (GOLD 2024)

LABA+LAMA combination 

• When initiating therapy with long-acting bronchodilators, the preferred choice is generally a combination of LABA+LAMA. (GOLD 2024)
• Advantages of combination therapy: (GOLD 2024; 16055868)
  • Improved FEV1.
  • Reduced symptoms.
  • Reduced exacerbations.
• Potential side effects:
  • LABA may rarely promote tachycardia or tremor.
  • LAMA may cause dry mouth.
• Examples of LABA+LAMA:
  • Formoterol/glycopyrronium (Bevespi Aerosphere).
  • Indacaterol/glycopyrronium (Utibron Neohaler).
  • Vilanterol/umeclidinium (Ellipta).
  • Olodaterol/tiotropium (Respimat).
• (More on LABAs in the asthma chapter here: 📖).

LABA-LAMA-ICS

• If there is an indication for ICS, LABA+LAMA+ICS is preferred (rather than to use a LABA+ICS combination). (GOLD 2024) 
• Benefits of triple therapy may include:
  • Improved lung function, symptoms, and reduced exacerbation.
  • May reduce mortality among symptomatic COPD patients with a history of frequent and/or severe exacerbations. (GOLD 2024; 35921883)
• Factors to consider when initiating ICS therapy center around exacerbation risk and eosinophil count: (GOLD 2024)
  • Strongly favors ICS use:
    • History of hospitalization(s) for exacerbations of COPD.
    • ≧ 2 moderate exacerbations of COPD per year (despite appropriate long-acting bronchodilator maintenance therapy).
    • Blood eosinophils >300/uL. Eosinophilia serves as a biomarker for patients with a more asthmatic/atopic phenotype. This may be the strongest predictor of benefit from inhaled steroid. (35921883)
    • History of, or concomitant, asthma.
  • Favors ICS use:
    • One moderate exacerbation of COPD per year (despite appropriate long-acting bronchodilator maintenance therapy).
    • Blood eosinophils between 100-300/uL.
  • Against ICS use:
    • Blood eosinophils <100/uL (this correlates with greater presence of proteobacteria, including Haemophilus, which may correlate with an increased risk of pneumonia). (GOLD 2024)
    • Repeated pneumonia events.
    • History of mycobacterial infection.
• Dose: Low- or medium-dose inhaled steroid probably offers the greatest benefit/risk ratio.
• Examples of combination inhalers:
  • Fluticasone/umeclidinium/vilanterol (Trelegy Ellipta).
  • Budesonide/formoterol/glycopyrrolate (Breztri).
• (More information about inhaled steroid here: 📖)

evidence for inhaled steroid in COPD

• TORCH trial (Calverley PMA et al. 2007; 17314337)
  • Randomized patients to salmeterol 50 ug BID, fluticasone 500 ug BID, or both.
  • Patients treated with combination therapy had improved pulmonary function and fewer exacerbations compared to other groups. Mortality seemed to be lowest among patients in the combination therapy group.
  • Patients receiving steroid did have an increased rate of pneumonia.
• Triple therapy trial (Aaron et al. 2007; 17310045)
  • 449 patients with moderate to severe COPD were randomized to tiotropium, tiotropium plus salmeterol, or tiotropium plus salmeterol plus fluticasone.
  • Triple therapy reduced hospitalizations.
• IMPACT trial (Lipson et al. 2018; 29668352)
  • 10,355 patients were randomized to receive triple therapy (fluticasone/umeclidinium/vilanterol), fluticasone-vilanterol, or umeclidinium-vilanterol. The fluticasone dose utilized was 100 micrograms daily (a low dose).
  • Inclusion criteria included symptomatic COPD plus either:
    • FEV1 <50% plus at least one moderate or severe exacerbation in the prior year.
    • FEV1 50-80% plus at least two moderate or severe exacerbations in the prior year, or one severe exacerbation.
  • Triple therapy reduced the frequency of exacerbations.
  • Inhaled steroid was associated with an increased rate of pneumonia (7-8% vs. 5%). However, inhaled steroid use was also associated with a reduction in all-cause mortality.

---

phosphodiesterase inhibitors

(back to contents)

---

---

roflumilast (oral PDE-4 inhibitor)

evidence & indications

• Summary: Guidelines recommend the addition of roflumilast for patients with chronic bronchitis, severe or very severe airflow obstruction (FEV1 < 50% predicted), and a history of exacerbations. (GOLD 2024) Roflumilast is generally utilized as add-on therapy for patients who are already on triple therapy with a LABA, LAMA, and inhaled steroid. (ERS handbook 3rd ed.)
• REACT trial:
  • Roflumilast was evaluated among patients with: (25684586)
    • Severe airflow obstruction (post-bronchodilator FEV1 <50% predicted).
    • Symptoms of chronic bronchitis.
    • At least two exacerbations in the prior year.
    • Failure of inhaled steroid plus long-acting beta-agonist (with or without tiotropium).
  • The addition of roflumilast was shown to reduce exacerbations, reduce hospital admissions, and improve FEV1.
• Meta-analysis of several trials suggests that the benefit of roflumilast is greatest among patients with one or more of the following characteristics: (29763572)
  • Hospitalization for a COPD exacerbation in the prior year.
  • More than two exacerbations in the prior year.
  • Baseline eosinophils >150-300/uL.

adverse effects

• The main side effects are gastrointestinal (nausea, anorexia, diarrhea, bloating, and weight loss), sleep disturbances, psychiatric reactions, and headache.
• Side effects tend to settle over time but may be problematic among patients with baseline cachexia. However, weight loss may be beneficial for patients with diabetes and obesity. (Fishman 2023)

---

ensifentrine (nebulized PDE3/4 inhibitor)

• Ensifentrine is a nebulized dual PDE3 and PDE4 inhibitor:
  • PDE3 inhibition causes smooth muscle relaxation and bronchodilation.
  • PDE4 inhibition reduces inflammation and mucus production.
• ENHANCE-1 and ENHANCE-2 trials:
  • Multicenter RCTs investigating adults 40-80 years with post-bronchodilator FEV1 30-70% predicted, dyspnea, and smoking history >10 pack years.
  • Exclusion criteria included using LAMA/LABA or LAMA/LABA/ICS.
  • Ensifentrine improved FEV1 slightly and decreased the risk of COPD exacerbation.
• The current role in therapy for COPD is unclear for most patients (since LAMA/LABA is supported by greater evidence, and the utilization of ensifentrine in combination with LAMA/LABA is unknown). Logistically, the cost of ensifentrine is high, and administration requires a nebulizer.
• Ensifentrine might be considered as an alternative to roflumilast among patients unable to tolerate roflumilast due to systemic side effects.

---

azithromycin

(back to contents)

---

• Among patients with a history of exacerbations, daily azithromycin reduced the frequency of exacerbations. (21864166) 
• Azithromycin may be considered for patients with persistent exacerbations despite other therapies (e.g., maximal inhaled treatments, including inhaled steroids). This may be most appropriate for patients with a chronic bronchitis phenotype. A post-hoc analysis suggested reduced benefits in active smokers. (GOLD 2024)
• Chronic azithromycin use may increase the risk of hearing loss or tinnitus.
• ⚠️ Continuation of therapy beyond >1 year hasn't been evaluated. (GOLD 2024)

---

oxygen

(back to contents)

---

long-term oxygen therapy 

• Long-term oxygen therapy (>15 hours/day) is one of the only therapies which has been shown to improve mortality in COPD. (6110912, 6776858)
• Indications for long-term oxygen therapy:
  • PaO2 <55 mm or saturation <88%.
  • PaO2 56-59 mm or saturation <90% plus one of the following:
    • Evidence of pulmonary hypertension.
    • Right ventricular dysfunction (e.g., peripheral edema). (GOLD 2024)
    • Polycythemia (hematocrit >55%).
• Oxygen is titrated for a target saturation >90%.
• Ideally saturation should be monitored at rest, during exertion, and overnight.

isolated nocturnal desaturation

• Patients with isolated nocturnal desaturation have not been shown to benefit from supplemental oxygen. (INOX trial 2020; 32937046)

isolated desaturation with activity 

• The Long-Term Oxygen Treatment Trial (LOTT) evaluated patients with moderate exercise-induced desaturation (80-90%). The prescription of oxygen with exercise and sleep didn't affect mortality, hospitalization, quality of life, lung function, or six-minute walk distance.
• Supplemental oxygen provided during activity may improve exercise performance. However, this doesn't seem to have other benefits, so oxygen should only be utilized in this fashion if the patient strongly desires it.

---

nocturnal BiPAP & COPD-OSA overlap syndrome

(back to contents)

---

---

role of nocturnal BiPAP for COPD 

potential benefits of chronic nocturnal BiPAP:

• Reduction of the composite endpoint of hospital readmission or mortality.
• Reduced daytime PaCO2.
• Improved functional activity, 6-minute walk distance, dyspnea, and quality of life.

inclusion criteria for chronic nocturnal BiPAP:

• Persistent hypercapnia (PaCO2 >53 mm) after the patient has stabilized following an exacerbation (>2-4 weeks after an exacerbation):
  • The HOT-HMV trial demonstrated benefit among patients who remained hypercapnic >2-4 weeks after discharge from an exacerbation of COPD. (28528348)
• Absence of untreated OSA (obstructive sleep apnea).

---

COPD-OSA (+/- OHS) overlap syndrome 

basics

• OSA may have a weak association with moderate-to-severe COPD. However, the existence of COPD-OSA overlap syndrome is largely due to the fact that both disorders are common.
  • Overlap syndrome may occur in 29-66% of patients with COPD. (33610579)
• COPD-OSA overlap syndrome may initially be misdiagnosed as uncomplicated COPD.

clues to the diagnosis of OSA/OHS in patients with COPD

• (1) Clinical features of OSA (e.g., witnessed apneas, daytime somnolence).
• (2) If treated with nocturnal oxygen therapy alone, patients may experience worsening hypercapnia.
• (3) The severity of hypoxemia, hypercapnia and pulmonary hypertension may be disproportionately severe, as compared to the severity of airflow obstruction on pulmonary function tests.
  • In severe cases, patients may have features of OHS (e.g., morbid obesity, right ventricular failure, and peripheral edema). This has been referred to as a “blue bloater” phenotype, in reference to cyanosis and systemic congestion.

diagnosis

• Sleep study may help clarify the extent of comorbid OSA.
• Home sleep apnea testing hasn't been validated in patients with COPD. Therefore, in-lab polysomnography with carbon dioxide monitoring is generally preferred (especially if hypercapnia is anticipated). (Murray 2022)

treatment

• Optimization of COPD therapy.
• PAP (positive airway pressure) therapy:
  • CPAP should be utilized for OSA-COPD overlap in the absence of hypercapnia.
  • BiPAP may be needed in patients with significant hypercapnic respiratory failure.
• Supplemental oxygen should be added if hypoxemia persists despite stabilization of the sleep disordered breathing.

---

lung volume reduction

(back to contents)

---

---

LVRS (lung volume reduction surgery)

basics

• For selected patients, resection of hyperinflated upper lobes may improve lung function (by promoting reinflation of the lower lobes). However, this involves an invasive surgical procedure that does increase short-term mortality (due to perioperative mortality).
• Inclusion criteria for LVRS surgery are based on the landmark NETT trial (listed below). In practice, few patients actually meet these criteria.
• Lung volume reduction surgery may be most beneficial for patients undergoing thoracic surgery for another indication (e.g., pleurodesis, or resection of an upper lobe tumor).
• Ideally LVRS should be performed at centers with extensive experience with this procedure. It's unknown whether the benefits observed in the NETT trial could be replicated by smaller centers, with lower surgery volumes.

inclusion criteria for LVRS (based on the NETT trial)

• Upper-lobe emphysema.
• Cardiopulmonary exercise test (CPET) showing poor exercise capacity despite 6-10 weeks of pulmonary rehabilitation (<40 Watts or <25 Watts output for men or women, respectively).
• Sufficiently preserved PFTs to tolerate the procedure (FEV1 >20% and DLCO >20%).
• Age <70 years old.
• Pulmonary artery systolic pressure <50 mm.
• No history of thoracic surgery.
• No bronchiectasis with chronic sputum production.

---

BLVR (bronchoscopic lung volume reduction)

overview

• Endobronchial valves may be used to induce compressive atelectasis in segments or lobes of the lung, thereby functioning analogously to lung volume reduction surgery.
• Overall, the net risk/benefit of endobronchial valve placement remains unclear. Valve insertion may improve pulmonary function and symptomatology, but this comes at a risk of pneumothorax and possibly death.
• Evidence regarding endobronchial valve placement is discussed below. Please note that procedural outcomes performed in the community are likely to be inferior to those obtained within the context of an RCT performed at high-volume centers.

Klooster K et al. (2015)

• This RCT enrolled 68 patients with emphysema, residual volume >150% predicted, post-bronchodilator FEV1 <60%, total lung capacity higher than predicted, Medical Research Council scale dyspnea of 2-4, and a complete fissure between the target lobe and the adjacent lobe.
• Valve placement improved FEV1 by ~140 ml and FVC by ~347 ml.
• Valve placement is associated with an increase in serious treatment-related adverse events (including pneumothorax in 18% of patients, replacement of valves in 12% of patients, and removal of valves in 15% of patients). (26650153)

LIBERATE trial (2018)

• This multicenter RCT enrolled 190 patients. Inclusion criteria included:
  • Age 40-75 years old.
  • Post-bronchodilator FEV1 15-45% predicted.
  • Total lung capacity >100% predicted.
  • Residual volume >175% predicted.
  • DLCO >20% predicted.
  • 6-minute walk distance 100-500 meters after a supervised pulmonary rehabilitation program.
  • Sophisticated imaging selection of patients with heterogeneous emphysema and lack of collateral ventilation.
• Endobronchial valve placement resulted in improved pulmonary function tests (average improvement in FEV1 of 100 ml), reduced symptoms, and improved six-minute walk distance.
• Complications:
  • Mortality: During the treatment period, four patients (3%) who received endobronchial valves died (compared to none in the standard-of-care group). Three deaths were related to pneumothorax, whereas one was related to respiratory failure.
  • Pneumothorax: One-third of patients treated with valves developed pneumothorax (as compared to none in the control group). Most pneumothoraces develop within a few days after valve insertion.  (29787288)

inclusion criteria to consider BLVR

• General candidacy:
  • Failing optimal medical therapy.
  • Nonsmoking and not vaping.
  • Post-rehabilitation.
  • Persistent, substantial symptoms that are attributable to emphysema.
  • No prior lung surgery (lobectomy, pneumonectomy, or lung transplant).
  • No significant comorbidities affecting performance and survival (expected survival <1 year is a relative contraindication). (de Moraes 2024)
  • Not on maintenance anticoagulation (e.g., oral anticoagulation or P2Y12 inhibitors). (26910845) Not all sources list this, so it may be a relative contraindication. 
• PFTs:
  • FEV1 between 15-20% and 45-50% predicted.
  • RV >175% predicted.
  • DLCO >20% predicted.
  • Total lung capacity >100% predicted.
  • 6-minute walk distance of 100-500 meters.
• ABG:
  • No severe hypercapnia (PaCO2 <60 mm on room air).
  • No severe hypoxemia (PaO2 >45 mm on room air).
• Radiology:
  • Complete fissures on CT scan.
  • No large bullae are present adjacent to the target lobe. (de Moraes 2024)
  • Absence of clinically significant bronchiectasis.
  • (Note: BLVR can be done with either homogeneous or heterogeneous emphysema, but results are generally better with heterogenous emphysema.)
• Echocardiography:
  • No significant pulmonary hypertension (e.g., PA systolic pressure <45-50 mm).
  • No heart failure (e.g., LV ejection fraction >40%).

favorable characteristics for the lobe to target

• Complete fissure.
• Little interlobar collateral ventilation.
• High emphysematous destruction.
• Large volume (which implies compression of other lobes).
• Low perfusion.
• Low intralobar heterogeneity. (de Moraes 2024)

---

prognosis

(back to contents)

---

BODE index for COPD 🧮

• B = BMI
  • BMI < 21 = 1 point
• O = Obstruction
  • FEV1 50-65% = 1 point.
  • FEV1 35-49% = 2 points.
  • FEV1 < 35% = 3 points.
• D = Dyspnea
  • 1 point = MRC score 2 = Walks slower than people of the same age due to dyspnea, or has to stop for breath when walking at own pace.
  • 2 points = MCR score 3 = Stops for breath after walking 100 yards, or after a few minutes.
  • 3 points = MRC score 4 = Too dyspneic to leave the house, or breathless when dressing.
• E = Exercise (6-minute walk distance)
  • 250-349 meters = 1 point.
  • 150-249 meters = 2 points.
  • <149 meters = 3 points.
• Interpretation: (14999112)
  • 0-2 = ~20% 4-year mortality.
  • 3-4 = ~30% 4-year mortality.
  • 5-6 = ~40% 4-year mortality.
  • >6 = ~80% 4-year mortality.

---

alpha-1 antitrypsin deficiency (AATD)

(back to contents)

---

basics

• Alpha-1 antitrypsin is a serine protease inhibitor that normally protects the lungs from proteolytic damage caused by neutrophil elastase. (26803352) Genetic deficiency of alpha-1 antitrypsin renders the lungs at increased risk of smoking-induced lung disease, often leading to emphysema. The most common disease-causing mutation (PI-ZZ) additionally causes the accumulation of misshapen proteins in hepatocytes, which may cause cirrhosis.
• AATD is more common among patients with European ancestry. It may cause ~2% of COPD in the United States. (Fishman 2023)

---

clinical features of alpha-1 antitrypsin deficiency

pulmonary manifestations

• Emphysema:
  • AATD usually causes panacinar emphysema. 📖 However, ~30% of patients with AATD may have centrilobular emphysema. Therefore, panacinar emphysema may be a useful clue to consider the diagnosis of AATD, but centrilobular emphysema doesn't exclude the possibility of AATD. (Shah 2019; ERS handbook 3rd ed) 
  • Symptoms usually develop between ~40-60 years of age. Patients are especially sensitive to the development of emphysema due to smoking.
• Asthma may also be more common among patients with AATD. (35000711) 
  • Many patients may have asthma-COPD overlap. 📖
• Bronchiectasis: (17872489)
  • Radiographic evidence of bronchiectasis is often seen.
  • Clinically significant bronchiectasis is much less common, affecting perhaps ~25% of patients. A subset of patients may have severe bronchiectasis with only mild emphysema. (29493335)
• Red flags to consider AATD:
  • 🚩 Emphysema with <20 pack-years tobacco exposure (and especially in a nonsmoker).
  • 🚩 Emphysema onset <45 years old.
  • 🚩 Emphysema with lower lobe predominance or uniform distribution from the apex to the base (panlobular emphysema 📖).
  • 🚩 Strong family history of emphysema or known family history of AATD.
  • 🚩 Combination of COPD, cirrhosis, and bronchiectasis (without another explanation).
  • 💡 ATS guidelines recommend screening for alpha-1 antitrypsin deficiency for any patient with persistent airflow obstruction. (14522813)

nonpulmonary manifestations

• Cirrhosis often occurs at an older age, with a relatively poor prognosis. (26803352)
• Necrotizing panniculitis may rarely occur (causing erythematous, tender, subcutaneous nodules).
• ANCA-associated vasculitis may correlate with AATD.

---

diagnosis of pulmonary AATD

[#1/3] alpha-1 antitrypsin level (+/- CRP level)

• This may be utilized as a screening test.
• ⚠️ Alpha-1 antitrypsin is an acute-phase reactant, which will be elevated in patients with acute inflammation. It may be reasonable to obtain a simultaneous CRP (C-reactive protein). If the C-reactive protein is elevated, this may reflect systemic inflammation that could cause a falsely normal alpha-1 antitrypsin level – so levels may be repeated when inflammation has subsided.
• Interpretation of alpha-1 antitrypsin level (100-190 mg/dL is normal):
  • >110 mg/dL with a normal CRP indicates normal AAT status. (32268028)
  • <60 mg/dL (<11 uM) indicate alpha-1 antitrypsin deficiency. (26803352)
  • If CRP is elevated and the AAT level is borderline, consider repeating the test following the resolution of acute inflammation.

[#2/3] genetic testing

• Genetic testing may be helpful, especially among patients with borderline serum enzyme levels.
• Individual genes:
  • Z = abnormal gene, most frequently associated with AATD.
  • O = Null (doesn't cause any secretion of enzyme).
  • M = Normal.
  • S = Common variant.
  • F = enzyme is dysfunctional (serum protein levels may be relatively preserved, but enzyme function is impaired). (32469648)
• Interpreting genetic results:
  • PI-ZZ or PI-ZO causes classic AATD disease.
  • PI-MM is normal.
  • PI-MZ or PI-SZ doesn't appear to increase the risk of emphysema. (Even if such patients have mildly reduced levels of alpha-1 antitrypsin, they may not benefit from augmentation therapy.)(35000711)

[#3/3] evidence of emphysema

• Clinically active pulmonary AATD disease requires the presence of fixed airflow obstruction on pulmonary function tests and/or emphysema.
• If neither of these components is present, then: (35000711)
  • It's doubtful that AATD is contributing to a patient's pulmonary symptomatology.
  • Alpha-1 antitrypsin augmentation is not indicated.

---

management

smoking cessation

• This is absolutely pivotal.
• See the chapter on smoking cessation: 📖

COPD management

• Treatment is similar to that of other patients with COPD, as outlined above.
• One minor difference is that patients may develop severe COPD at a young age, improving their fitness to undergo lung transplantation. Unfortunately, the allograft will be affected by alpha-1 antitrypsin deficiency.

alpha-1 antitrypsin augmentation therapy

• This may be used to restore serum alpha-1 antitrypsin levels. To date, there is no definitive evidence that augmentation therapy is beneficial. Disease progression can occur despite alpha-1 antitrypsin augmentation therapy, possibly reflective of localized elastase activity. (26803352) Thus, the appropriate use of this therapy is uncertain.
• Criteria to receive augmentation therapy might include the following:
  • Alpha-1 antitrypsin level <11 uM.
  • High-risk genotypes (PI-ZZ or PI-ZO).
  • Patients who are not currently smoking.
  • Patients with airflow obstruction or emphysema on CT scan.

liver disease management (PiZZ)

• Counseling regarding avoidance of hepatotoxins (e.g., alcohol).
• Consider vaccination for HAV and HBV.
• If possible, avoid obesity and metabolic syndrome (may function synergistically with PI-ZZ to cause cirrhosis). (32268028)
• Screening and treatment for cirrhosis.

---

bullous lung disease

(back to contents)

---

---

definitions & differential diagnosis

definitions of a bulla

• Pathological definition: An air-containing space within the lung parenchyma that arises from destruction, dilation, and confluence of airspaces distal to the terminal bronchioles and is >1 cm in diameter. (Fishman 2023)
• Radiological features: Sharply demarcated area that is >1 cm in diameter with a <1 mm thick wall.
• Bullae are usually associated with COPD, but there are a variety of other causes as well.

differential diagnosis of a bulla

• Pneumothorax: This is an important difference to sort out because pneumothorax is an indication for chest tube insertion, whereas insertion of a chest tube into a bulla could be catastrophic.
• Cystic lung disease
  • Histologically, cysts have an epithelial lining whereas bullae do not.
  • Radiologically, a cyst should have a well-defined wall, whereas a bulla lacks a wall. In practice, cysts and bullae may look very similar radiologically. The differentiation may be based on the size, distribution, and context of the lesion.
• Bleb: This is an accumulation of air between the two layers of the visceral pleura. (Fishman 2023)

---

causes of bullae

• Primary:
  • Vanishing lung syndrome (parenchyma rapidly replaced by multiple bullae; may be associated with tobacco use, inhaled marijuana, and HIV).
  • Single giant bulla (occupies >1/3 of the hemithorax). (33965156)
  • Bullous lung disease.
• Emphysema (most common): Usually occurs in patients over ~45 years old with >10 pack-years tobacco exposure:
  • Paraseptal emphysema.
  • Panlobular emphysema.
  • Centrilobular emphysema.
  • Alpha-1 antitrypsin disorder. ⚡️
• Marijuana smoking.
• Fibrotic lung disorders, including:
  • Sarcoidosis.
  • Fibrotic tuberculosis.
  • IPF (idiopathic pulmonary fibrosis).
  • Progressive massive fibrosis.
• Genetic disorders (these disorders typically cause small apical blebs):
  • Ehlers-Danlos syndrome.
  • Marfan disease.
  • Fabry disease.
  • Cutis laxa.
  • Salla disease. (Fishman 2023)

---

clinical manifestations

• Rupture of a superficial bulla may cause pneumothorax.
• Enlargement of a bulla may cause restrictive physiology, causing dyspnea (giant tension bulla). This may occur via various mechanisms:
  • (a) Airplane travel may cause enlargement, due to a reduction in ambient pressure.
  • (b) A ball-valve mechanism may cause air to accumulate within a bulla, leading to a giant tension bulla.
• Superinfection of a bulla may occur (e.g., in the context of adjacent pneumonia).
• Hemoptysis may occur due to rupture of blood vessels within the bulla wall.
• Chest pain may result from tension that the bulla places on the pleura.

---

radiology

chest radiograph

• Small bullae may not be visible.
• Larger bullae may be seen to have “hairline shadows” partially surrounding them. They may cause contralateral shifting of the mediastinum (mimicking a tension pneumothorax).
• Serial chest radiographs may be useful for monitoring patients with giant bullae.

CT scan

• Bullae are generally empty and have a thin wall.
• Usually underlying emphysema may be seen, supporting the diagnosis of bullae.
• Giant bullae are usually located in a subpleural location within the upper lobes. However, among patients with alpha-1 antitrypsin deficiency ⚡️, bullae are usually in the lung bases. (Fishman 2023)

ultrasound

• Ultrasound may not be helpful in differentiating a giant bulla from a pneumothorax. The bulla wall is very thin and often exhibits relatively little tidal movement, which makes detection of lung slide difficult. (33965156)

---

management

medical management

• Bullae may enlarge or shrink in an unpredictable fashion. Serial chest radiographs may be used to surveil the disease, in addition to clinical follow-up.
• Any underlying lung disease should be treated using standard therapies (e.g., COPD, alpha-1 antitrypsin deficiency ⚡️).
• Patients should be advised to avoid activities that could cause rupture of the bullae (scuba diving, contact sports, and possibly air flight).

bronchoscopic management

• Endobronchial valve insertion is supported by case series-level evidence.
• A series of 27 patients suggested that valve therapy is more likely to be successful in patients where the bullae are actually being ventilated (as revealed by concordance between lung volumes measured using body plethysmography and gas dilution). (28444339)

surgical bullectomy

• Patient selection for surgical bullectomy is complex. The following attributes would describe an optimal surgical candidate: (Fishman 2023)
• (1) Reasonable fitness to undergo surgery:
  • Absence of significant pulmonary hypertension.
  • Absence of cachexia.
  • FEV1 >40% predicted.
  • DLCO isn't severely reduced.
  • Absence of significant chronic hypercapnia.
• (2) Patient would physiologically benefit from bullectomy:
  • Bulla is large (e.g., >1/3 of the hemithorax) and well-defined.
  • FEV1 <80% predicted.
  • Parenchyma surrounding bulla seems reasonably preserved.
  • Surrounding lung tissue seems to be compressed radiographically.

management of pneumothorax

• ⚠️ Care is required to differentiate between a pneumothorax and bullae. These may mimic one another radiographically.
• Pneumothorax tends to cause a prolonged air leak (ongoing bronchopleural fistula).
• Pleurodesis may help facilitate pneumothorax resolution and prevent recurrence. In some cases, surgical pleurodesis may be combined with simultaneous surgical bullectomy (discussed above).
• (Further discussion of the management of bronchopleural fistula: 📖)

---

questions & discussion

(back to contents)

---

To keep this page small and fast, questions & discussion about this post can be found on another page here.

Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
• = Link to supplemental media.