Chronic Obstructive Pulmonary Disease (COPD)

Definitions

  • Relationship Between Obstructive Airway Diseases

VENN


Epidemiology

  • COPD is the 4th most common cause of death in patients age 65-84 y/o in the US
  • COPD is the most common cause of chronic airflow obstruction
  • COPD is the most common cause of cor pulmonale
  • COPD exacerbation is the most common cause of acute ventilatory failure in US adults

Risk Factors for COPD

  • Tobacco Use
  • Environmental Pollutants
  • Alpha-1 Antitrypsin Deficiency (see xxxx, [[Alpha-1 Antitrypsin Deficiency]])
  • Inflammatory Bowel Disease (IBD) (see Inflammatory Bowel Disease, [[Inflammatory Bowel Disease]]): chronic bronchitis is associated with UC
  • Positive Family History of COPD [MEDLINE]

Physiology

Dynamic Compression

  • Dynamic compression limits maximum expiratory flow in a volume‐dependent manner 
    in normal subjects

    • This is exaggerated in patients with COPD due to multiple factors
      • Loss of elastic recoil of the lung
      • Loss of radial traction on airways due to destruction of lung tissue
      • Decreased small airway diameter due to bronchospasm and mucous hypersecretion
  • Weak expiratory muscles would NOT likely exaggerate dynamic compression because maximum expiratory flow is independent of effort even in normal subjects (and depends on volume). 

Chronic Bronchitis: chronic or recurrent secretion of mucus into bronchial tree

  • Mucus originates from submucosal mucus glands (major source) and goblet cells (minor source)
  • Mucus gland are enlarged, due to hyperplasia (major source of enlargement) and hypertrophy (minor source of enlargement)
  • Reid Index: quantifies mucus gland size, defined as ratio of thickness of bronchial mucus glands: thickness of bronchial wall (measured from BM to inner cartilage)
    • Normal Reid Index: 0.35
    • Chronic Bronchitis Reid Index: 0.51
  • Volume Proportion of Mucus Glands: also used to quantify the mucus gland size
  • Other pathologic changes: goblet cell metaplasia of surface epithelium, chronic inflammation (mononuclear cells, neutrophils), smooth muscle hyperplasia

Emphysema: defined by NHLBI workshop as condition of the lung characterized by abnormal permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis

  • Destruction : non-uniformity in respiratory airspace enlargement so that the orderly appearance of the acinus and its components is disturbed or lost
  • Degree of emphysema is the most important correlate of airflow obstruction in cigarette smokers with moderate or severe COPD

Classification of Emphysema

  • Proximal Acinar (Centrilobular)
    • Most common/primary feature is enlargement of respiratory bronchioles Causes/(Associations)
  • Typical COPD (Upper Lung Zones: Sup/Post UL and Sup Seg-LL)—————————————————-Cigarette Smoking
  • Simple Coal Worker s Pneumoconiosis (Upper Lung Zones: Sup/Post UL and Sup Seg-LL)———————Occupational Coal Dust Exposure
  • Panacinar (Panlobular)
  • Widespread (Most Severe in Lower Zones)——————————————————————————-Alpha1-Antitrypsin Deficiency (Homo PiZ, Homo PiS, and PiSZ)
  • Lower Zones——————————————————————————————————————–Centrilobular Emphysema and COPD, IVDA
  • Lower Zones (In Anterior Margins)—————————————————————————————–Variant of Aging (in 7th-9th Decades)
  • Unilateral Swyer-James Syndrome—————————————————————————————–(Associated with Bronchiolar Obstruction)
  • Distal Acinar (Paraseptal): least common form/only rarely associated with clinical airflow obstruction
  • Upper Zones (In Anterior and Posterior Margins)————————————————————————Spontaneous Pneumothorax

Small Airways Disease

  • Small Airways Disesase defined by Macklem [Ann Int Med, 1971] as patient with clinical features of chronic obstructive airways disease without evidence of emphysema or chronic bronchitis
  • Pathology: non-specific pattern of peribronchiolar inflammation with varying concentric peribronciolar fibrosis/thickening of walls of terminal and respiratory bronchioles
  • There is a correlation between small airway wall thickness and the degree of emphysema

Pulmonary Hypertension

  • pulmonary HTN due to COPD (Chronic Bronchitis > Emphysema)/ Cystic Fibrosis/ Bronchiectasis
  • Anatomic lung blood vessel distortion/ pulmonary vascular destruction/ hypercapnia and hypoxia-induced vasoconstriction/ increased blood viscosity due to polycythemia
  • PA pressure usually increases with exercise
  • PA pressure usually decreases (but not to normal) with oxygen therapy

Respiratory Mechanics in COPD

  • Hyperinflation with Flattened Diaphragms
    • Increases diaphragmatic muscle tension -> increased impedance to diaphragmatic blood flow
    • Flattening results in compromised inspiratory force generation
    • Horizontal orientation of diaphragm (and loss of zone of apposition between chest wall and diaphragm) -> results in diaphragmatic force vector on rib cage becoming more inward, rather than cephalad
      • Hoover Sign: paradoxic inward inspiratory movement of lower lateral rib cage
  • Recruitment of Accessory Muscles: increases oxygen consumption
  • Development of Auto-PEEP: due to airway obstruction (with increased airway resistance)
    • Results in inspiratory pressure load that diaphragm must overcome with each inspiration

Pathology

  • Marked lymphocytic infiltration of adventitia

Diagnosis

Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

  • Polycythemia: in COPD patients with daytime and/or nocturnal hypoxemia

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

  • Hypoxemia (with elevated A-a gradient in most cases, although 1991 study suggests that gradient may normalize in severe COPD with increasing hypercapnia due to shifted oxyHb dissociation curve and V/Q mismatching)
  • Hypercapnia does not usually occur until FEV1 is <1.3 L

Sputum Culture

  • Exacerbations are most commonly associated with Moraxella Catarrhalis/H Flu/Pneumococci
  • By protected brush, sputum C/S is positive for organisms in 25% of stable COPD patients (and in 52% of acute COPD exacerbation cases: in these, 24% of this group had >104 organisms per ml)

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • Obstructive Pattern
  • FEV1: decreased
    • Bronchodilator responsiveness (by standard ATS criteria: >12% increase and >200 ml increase in FEV1) is seen in <50% of COPD patients
    • Bronchodilator testing by spirometry in COPD is not consistent over time (while baseline FEV1 values are fairly consistent over time)
  • FVC:
  • FEV1/FVC ratio: decreased
  • VC:
  • TLC:
  • FRC:
  • RV:
  • DLCO: decreased
  • Raw:
  • Disparity Between TLC Measured by Body Box (higher) and Helium Dilution (lower): suggests a non-communicating gas space (bulla)
    -The rare bulla which communicates with airways (as demonstrated by a lesser disparity between body box and helium dilution TLC) contributes more to dead space ventilation, worsening dyspnea

6-Minute Walk Test (see 6-Minute Walk Test, [[6-Minute Walk Test]])

  • ECLIPSE Trial (2013) [MEDLINE]: 30 m (98.4 ft) decline in 6-minute walking distance in the first year was associated with an increased risk for mortality in the subsequent 2 years
    • No Significant Association with Hospitalization Due to Exacerbation
    • Weak Associations with Decline in FEV1
    • Weak Association with Decline in St George’s Respiratory Questionnaire (SGRQ) Criteria

Exercise Test (see Exercise Test, [[Exercise Test]])

  • xxxx

Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])

  • Bronchoalveolar Lavage (BAL)

CXR Patterns (see Chest X-Ray, [[Chest X-Ray]])

  • Hyperinflation with Flattened Diaphragms
  • Enlarged Pulmonary Arteries: right PA >16mm
  • Enlarged Right Ventricle with Loss of Retrosternal Air Space
  • Enlarged Superior Vena Cava and Azygous Vein
  • “Pruned Tree” Pulmonary Vasculature

Chest CT Patterns (see Chest Computed Tomography, [[Chest Computed Tomography]])

  • Emphysematous Changes on Chest CT Without Spirometrically-Defined Obstruction (Ann Int Med, 2014) [MEDLINE]: presence of emphysematous changes on CT imaging in patients without spirometrically-defined COPD are linearly associated with increased all-cause mortality (even after adjusting for confounding variables, such as cardiovascular risk factors and FEV1)
    • The association was of greatest magnitude among smokers

High-Resolution Chest CT (HRCT) (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]])

  • Emphysematous Changes

Electrocardiogram (EKG) (see Electrocardiogram, [[Electrocardiogram]])

  • RVH Strain Pattern
    • Epidemiology: seen in 57-60% of COPD patients with cor pulmonale
    • Features: ST-Segment Depression and T-Wave Inversion in the Leads Corresponding to the Right Ventricle
      • Right Precordial Leads: V1-V3 (and often V4)
      • Inferior Leads: II/III/AVF (most pronounced in III, as this is the most rightward-facing lead)
  • Right Ventricular Hypertrophy (RVH)
    • Epidemiology
      • Observed in 2-27% of all COPD patients
      • Observed in 28-75% of patients with COPD + cor pulmonale
  • Right Axis Deviation >90 Degrees
    • Epidemiology
      • Observed in 46-85% of all COPD patients
      • Observed in 18-79% of patients with COPD + cor pulmonale
    • Features
      • Usually present in association with RVH
      • May be seen without RVH in cases of pure emphysema with associated hyperinflation (RV swings more anteriorly and LV swings more posteriorly)
  • P-Pulmonale: may be seen
  • S1S2S3 Pattern
    • Epidemiology: least sensitive but most specific pattern for COPD (observed in 2-5% of all COPD patients)
      • Unrelated to COPD disease severity
    • Features: distinct S waves in I/II/III
  • Left Axis Deviation
    • Epidemiology: seen in 2-10% of all COPD patients
    • Features: usually in the range of -80 to -120°, as opposed to the -30 to -60° typically seen in LAD associated with LV disease
  • Right Bundle Branch Block (RBBB)
    • Epidemiology: seen in 2% of all COPD patients

Ventilation/Perfusion (V/Q) Scan (see Ventilation-Perfusion Scan, [[Ventilation-Perfusion Scan]])

  • Useful to exclude acute PE/ chronic thromboembolic disease

Pulmonary Angiogram (see Pulmonary Angiogram, [[Pulmonary Angiogram]])

  • Useful to define anatomy and to exclude CTEPH

Echocardiogram (see Echocardiogram, [[Echocardiogram]])

  • RVE with often decreased RV-EF/ TR/ PR/ normal LV-EF
  • Doppler: quantification of TR jet allows estimation of PA pressure
  • Bubble study: useful to exclude intracardiac shunt (VSD/ASD/etc)

Swan-Ganz Catheterization (see Swan-Ganz Catheter, [[Swan-Ganz Catheter]])

  • RA: normal (at rest)
  • RV-SYS: elevated (with normal RV-EDP)
  • PA-SYS: mild-moderately ele-vated (PA-SYS usually <30-50 mm Hg in COPD)
  • PA-DIA: usually elevated
  • PA-MEAN: mild-moderately elevated
  • PCWP: normal (reflects normal LA and LV-EDP)
  • CO: normal at rest (does not rise appropriately with exercise)

Cardiac Catheterization (see Cardiac Catheterization, [[Cardiac Catheterization]])

  • May be useful to exclude intracardiac shunt

Clinical Manifestations

Cardiovascular Manifestations

  • Cardiac Arrhythmias: occur during severe nocturnal REM-associated desaturations
  • Increased Risk of Acute Myocardial Infarction (see Coronary Artery Disease, [[Coronary Artery Disease]])
    • Epidemiology: 3.5-fold increased risk [MEDLINE]

Neurologic Manifestations

  • Anxiety (see Anxiety, [[Anxiety]])
  • Depression (see Depression, [[Depression]])
  • Increased Risk of Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]])
    • Epidemiology: 3-fold increased risk [MEDLINE]
  • Neuropsychiatric Consequences of Hypoxemia: frequency correlate with the degree of hypoxemia

Pulmonary Manifestations

General Pulmonary Manifestations

  • Accessory Muscle Use
  • Chronic Cough (see Cough, [[Cough]])
  • Dyspnea (see Dyspnea, [[Dyspnea]])
  • Hoover Sign: paradoxic inward inspiratory movement of lower lateral rib cage
  • Tachypnea (see Tachypnea, [[Tachypnea]])

Hypoxemia (see Hypoxemia, [[Hypoxemia]])

Nocturnal Hypoxemia

  • Generally closely related to need for daytime oxygen: occurs in 27% of COPD patients with awake pO2 >60 mm Hg
  • Normal subjects demonstrate small increases in pCO2 and small decreases in pO2 during sleep: these are accentuated in COPD patients
  • Nocturnal desaturations in COPD are most marked in REM (probably due to decreased alveolar ventilation, inhibited respiratory muscles, decreased VT, decreased FRC with worsened V/Q mismatching during REM): typically worse in later REM periods
  • Predictors of Nocturnal Hypoxemia in COPD
    • Daytime pCO2 >45 mmg Hg
    • Daytime pO2 <65 mm Hg

Obstructive Sleep Apnea (OSA) (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]])

  • Epidemiology: occurs in 10-15% of COPD patients

Pulmonary Hypertension/Cor Pulmonale (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

  • Physiology: due to chronic hypoxemia
  • Symptoms of right-sided CHF (variable)
  • Absence of Kussmaul sign

Acute COPD Exacerbation

  • Epidemiology
  • Microbiology: clinical features cannot reliably distinguish bacterial from viral episodes (although presence of sputum neutrophilia more likely suggests a bacterial etiology)
    • 80% of all exacerbations are due to infection = 30% viral + 50% bacterial
    • Most Common Bacterial Etiologies: non-typable Moraxella, H Flu, and Pneumococci
    • Mycoplasma is rarely isolated
    • Chlamydia pneumoniae is uncommonly isolated (5-10% of outpt cases and 18% of mechanically ventilated cases)
    • Gram-Negative Rod (Pseudomonas, Stenotrophomonas, and PCN-Resistant Pneumococcus) are isolated 30% of the time in patients with the most severe exacerbations (those that require mechanical ventilation)
  • Clinical

Acute Respiratory Failure (see Respiratory Failure, [[Respiratory Failure]])

  • Epidemiology
    • COPD exacerbation is the most common cause of acute ventilatory failure in US adults
    • Approximately 33% of COPD exacerbations admitted to an acute care hospital develop acute ventilatory failure: risk is highest in those with FEV1 <50% pred
  • Clinical
    • Acute Hypoxemic Respiratory Failure
    • Acute Hypercapnic/Ventilatory Failure
  • Treatment
    • xxxx

Chronic Hypoventilation (see Chronic Hypoventilation, [[Chronic Hypoventilation]])

  • CO2 retention in patients with COPD typically occurs when the FEV1 falls below 1L
    • However, not all COPD patients with FEV1 <1L develop hypercapnia (due to multifactorial variability)
  • Etiology of Acute Worsening of Pre-Existing Hypercapnia in COPD:
    • Acute Pulmonary Embolism (PE)
    • Pneumonia/Acute Bronchitis
    • CHF
    • Sedatives: such as antihistamines, benzodiazepines, etc.
      • Zolpidem (which is an imidazopyridine) does not cause significant respiratory depression
  • Mechanisms of Supplemental O2 Administration Worsening Pre-Existing Hypercapnia in COPD:
    • Worsened V/Q Mismatch (Primary Etiology)
      • Release of hypoxic vasoconstriction -> increase in blood flow to poorly ventilated lung segments -> increase in dead space and decrease in effective alveolar ventilation
    • Release of Hypoxic Drive
      • Decrease in VT + RR occurs transiently (usually for 15 min) and then increases back to pre-supplemental O2 baseline
    • Haldane Effect
      • Administration of oxygen causes concurrent decrease in the CO2 carrying capacity of the hemoglobin molecule -> resulting in a slight increase in pCO2

[Aubier M, Murciano D, Milic-Emili J, et al. Effects of the administration of O2 on the ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis 1980; 122:747-754
Agusti A, Carrera M, Barbe F, et al. Oxygen therapy during exacerbations of chronic obstructive pulmonary disease. Eur Respir J 1999; 14:934-939
Murciano D, Armengaud M, Cramer P, et al. Acute effects of zolpidem, triazolam, flunitrazepam on arterial blood gases and control of breathing in severe COPD. Eur Respir J 1993; 6:625-629]

Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

  • In patients with parenchymal lung disease, pulmonary hypertension is generally modest (mean PAP 25-35 mm Hg) [MEDLINE]
  • However, in some patients, PAP elevations can be more substantial (mean PAP 35-50 mm Hg) [MEDLINE]
    • In such patients, particularly those with only moderate pulmonary mechanical impairment, this is considered “out-of-proportion” pulmonary hypertension
    • In a retrospective study of 998 COPD patients who underwent Swan, only 1% had severe pulmonary hypertension (mean PAP >40 mm Hg) [MEDLINE]
    • The authors described an unusual pattern of cardiopulmonary abnormalities in the patients with more severe PH, including mild to moderate airway obstruction, severe hypoxemia, hypocapnia, and a very low diffusing capacity for carbon monoxide
    • As with pulmonary hypertension out of proportion to left heart disease, large randomized, controlled studies of medications approved for pulmonary hypertension are not available for PH out of proportion for parenchyma lung disease.
  • Prognosis: PA-mean pressure >45 mm Hg has a significantly worse 5–year survival (<10% versus >90%) [MEDLINE]

Other Manifestations

  • Cachexia: occurs in 20% of COPD outpatients, in 35% of pulm rehab candidates, and in 70% of COPD patients with acute respiratory failure
    • Muscle wasting in COPD is associated with systemic inflammation (with low anabolic hormone levels and catabolism), rather than simple starvation and nutritional imbalance
    • Cachexia iis associated with greater duration of mechanical ventilation after LVRS, lower exercise capacity, lower muscle strength, greater need for mechanical ventilation in acute exacerbation, impaired health status, increased rate of ealr nonelective readmission after an exacerbation, increased duration of ventilation post-lung transplant, increased hospital admission rates (in those on home oxygen), and worse survival rate

Treatment

General Measures

Oxygen (see Oxygen, [[Oxygen]])

  • Indications: pO2 <55 or pO2 <59 + cor pulmonale or polycythemia
  • Physiology: flow is highest during the early part of inspiration (this is when most of the oxygen is delivered to the alveoli)
  • Daytime O2: prevents polycythemia/variably decreases PA pressure acutely but, long-term prevents increases in PA pressure/improves survival (when used for at >18 hrs per day, per data from NOTT Trial)/increases exercise endurance/decreases dyspnea
  • Nocturnal O2: blunts increases in PA pressures that occur with nocturnal desaturations/inhibits development of polycythemia/prolongs survival
    • Nocturnal use alone does not significantly prevent the development of pulmonary hypertension
  • Prognostic Factors in COPD Patients on Chronic O2 (Chailleux; Chest, 1996):
    • Good Prognosis: stable pCO2 >55 (but rising pCO2 portends poor prognosis, represents progressing cor pulmonale)
    • Poor Prognosis: older age/male gender/lower BMI/lower pO2/lower FEV1 (as %pred)
  • NOTT Trial: data suggested that 45% of those discharged with oxygen (for pO2 <55) no longer required oxygen when assessed later (1 month) after discharge, therefore reevaluation is necessary
  • Transtracheal O2 Delivery: results in decreased oxygen requirements (due to more efficient delivery), decreased work of breathing (possibly due to wash out of anatomic dead space with less CO2 reinspired and possiblt less demanding pattern of breathing), decreased sleep apneas/hypopneas (possibly due to oxygen delivery even during obstructive events or increased mean airway pressure), and decreased dyspnea (unclear if it affects the rate of COPD exacerbations)
  • Impact of Oxygen Therapy in COPD with Chronic Hypercapnia: excessive oxygen therapy in the setting of chronic hypercapnia may result in worsened CO2 retention and respiratory failure
    • Excess oxygen may blunt the hypoxic ventilatory drive and/or increase physiologic dead space (due to oxygen-induced bronchodilation in poorly-perfused areas of the lung)

Short-Acting β2-Adrenergic Receptor Agonists (SABA) (see β2-Adrenergic Receptor Agonists, [[β2-Adrenergic Receptor Agonists]])

  • Indicated

Long-Acting ß2-Adrenergic Agonists (LABA) (see β2-Adrenergic Receptor Agonists, [[β2-Adrenergic Receptor Agonists]])

  • Long-Acting Beta 2 Agonist Monotherapy in COPD: controversial
    • In asthma they are contraindicated, but not so in COPD
    • A Cochrane review found monotherapy with the long-acting beta agonist salmeterol to confer efficacy in terms of improvement in symptoms and exercise tolerance similar to that of the anticholinergic ipatropium bromide, although combination therapy of the two agents produced somewhat better results, particularly in terms of quality-of-life measurement.

Anticholinergic (Muscarinic Antagonist) Agents (see Muscarinic Antagonists, [[Muscarinic Antagonists]])

Theophylline (see Theophylline, [[Theophylline]])

  • Benefit of Theophylline in COPD is Unclear [MEDLINE]

HMG-CoA Reductase Inhibitors (Statins) (see HMG-CoA Reductase Inhibitors, [[HMG-CoA Reductase Inhibitors]])

  • Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) Trial (NEJM, 2014) [MEDLINE]
    • Study: randomized, controlled trial of simvastatin (40 mg daily) versus placebo -> primary outcome: annual exacerbation rate
    • Main Findings: simvastatin had no effect on exacerbation rate, time to a first exacerbation, or cardiac events

Inhaled Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • Clinical Efficacy-Exacerbation Rate in COPD
    • ISOLDE Trial in Moderate-Severe COPD (Br Med J, 2000) [MEDLINE]: fluticasone decreased exacerbation rate, increased FEV1 slightly, and resulted in a slower decline in health status
    • Torch Trial Data. Trial of Salmeterol and Fluticasone in COPD (NEJM, 2007) [MEDLINE]: salmeterol and fluticasone did not impact mortality rates, but decreased the exacerbation rate
      • Salmeterol and fluticasone increased rates of pneumonia
    • Systematic Review of Combination Corticosteroid + LABA Inhaler in COPD (2013) [MEDLINE]: combination corticosteroid + LABA inhaler decreased the exacerbation rate and decreased all-cause mortality (although latter finding was due primarily to the TORCH trial)
      • Combination corticosteroid + LABA inhaler increased the pneumonia rate (but without an increase in exacerbations, hospitalizations or deaths)
      • Inadequate data to determine superiority of one combination over another
        Clinical Efficacy-Risk of Pneumonia in COPD
    • TORCH Study (2009)* [MEDLINE]: inhaled corticosteroids increase the risk of pneumonia in COPD
  • Clinical Efficacy-Withdrawal of Inhaled Corticosteroids
    • WISDOM Trial Examining Withdrawal of Inhaled Corticosteroids in Severe Stable COPD, Managed with Tiotropium and Salmeterol (NEJM, 2014) [MEDLINE]
      • Withdrawal had no effect on risk of moderate-severe exacerbations or dyspnea, but led to a minimal decrease in FEV1 (38 mL)

Mucolytics

  • Pharmacology: decrease mucus viscosity, facilitating airway mucus clearance
  • Cochrane Database Systematic Review of Mucolytic Effect on COPD Exacerbation Rate (2012) [MEDLINE]
    • Main Findings: in chronic bronchitis or COPD, mucolytics may produce a small decrease in acute exacerbations, but have little or no effect on the overall quality of life (the effect on COPD exacerbation rate demonstrated in early trials was larger than that found in the more recent studies, possibly due to these earlier smaller trials having higher risk of selection or publication bias)
  • PANTHEON N-Acetylcysteine Trial (2014) [MEDLINE]
    • Study: prospective, randomized, double-blind, placebo-controlled trial of N-Acetylcysteine (see N-Acetylcysteine, [[N-Acetylcysteine]]) performed in China, n = 1006 -> primary endpoint was the annual COPD exacerbation rate
    • Main Findings: in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg PO BID decreases the number of exacerbations (especially in disease of moderate severity)
    • Conclusions: probably exerts its effect via a mucolytic action: N-acetylcysteine cleaves disulfide bonds which cross-link glycoproteins in mucus -> results in decreased mucus viscosity, facilitating airway mucus clearance
      • Other potential mechanisms, such as inhibition of generation or neutralization of reactive species (with a potential anti-inflammatory effect), are less supported by the available data

Azithromycin (Zithromax) (see Azithromycin, [[Azithromycin]])

  • Pharmacology: macrolide antibiotic (see Macrolides, [[Macrolides]])
  • Administration: 250 mg PO qday x 1 year
  • Clinical Efficacy
    • COPD Clinical Research Network Daily Azithromycin Trial (2011) [MEDLINE]
      • Study: randomized, placebo-controlled trial (n = 1577) with daily azithromycin (250 mg PO) x 1 year
      • Exclusion Criteria: asthma, a resting HR >100 beats, prolonged QTc >450 msec, use of medications that prolong the QTc or are associated with torsades (with the exception of amiodarone), and hearing impairment
      • Main Findings
        • Azithromycin decreased COPD exacerbations (1.48 vs 1.83 per year)
        • Azithromycin improved QOL
        • Azithromycin decreased colonization with selected respiratory pathogens (but increased colonization with macrolide-resistant organisms)
        • Azithromycin resulted in a small increase in hearing decrements (25% vs 20% of subjects)
        • No clear impact on microbial resistance patterns
    • Predictors of COPD Exacerbation Reduction in Response to Daily Azithromycin Therapy (Am J Resp Crit Care Med, 2014) [MEDLINE]: azithromycin is most effective in preventing COPD exacerbations in patients requiring both antibiotic and steroid treatment
      • Variables Which Did Not Affect Azithromycin Efficacy: sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy
      • Variables Associated with Increased Azithromycin Efficacy: older age, milder Global Initiative for Chronic Obstructive Lung Disease stage
      • Variables Associated with Decreased Azithromycin Efficacy: current tobacco abuse
  • Adverse Effects
    • Hearing Loss (see Hearing Loss, [[Hearing Loss]]): with azithromycin x 1 year, hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04)
    • Drug-Induced Pulmonary Eosinophilia (see Drug-Induced Pulmonary Eosinophilia, [[Drug-Induced Pulmonary Eosinophilia]])
    • Increased General Cardiovascular Risk
    • Increased Risk of Acute Myocardial Infarction (MI) (see Coronary Artery Disease, [[Coronary Artery Disease]])
    • Risk of Q-T Prolongation with Definite Association with Torsade (see Torsade, [[Torsade]])

Roflumilast (Daliresp, Daxas) (see Roflumilast, [[Roflumilast]])

  • Pharmacology: phosphodiesterase type 4 inhibitor (PDE4 Inhibitor) (see Phosphodiesterase Type 4 Inhibitors, [[Phosphodiesterase Type 4 Inhibitors]])
  • Administration: 500 ug PO qday
  • Clinical Efficacy
    • REACT Trial in Patients with Severe COPD and Chronic Bronchitis Who are at Risk of Frequent and Severe Exacerbations Despite Inhaled Corticosteroids/LABA/Tiotropium (2015) [MEDLINE]: roflumilast decreases exacerbations/hospital admissions
    • Cardiovascular Safety of Roflumilast in COPD (2013) [MEDLINE]: roflumilast decreases the rates of non-fatal acute MI and non-fatal stroke
  • Adverse Effects

Pulmonary Rehabilitation (see Pulmonary Rehabilitation, [[Pulmonary Rehabilitation]])

  • Indications: GOLD criteria suggest that any patient beyond stage 1 may benefit from pulm rehabilitation
    • Limited Ability to Perform ADL’s (except those that are wheelchair-bound)
  • Benefits of Pulmonary Rehab in Patients with COPD Exacerbations
    • Improved Quality of Life (QOL)
    • Decreased Hospital Admissions
    • Decreased Mortality Rate
  • Effect of Smoking: smokers experience same benefit from pulm rehab as non-smokers, but are less likely to complete the program
  • MRC Grade 5 Dyspnea Patients: least likely to experience significant improvement with pulm rehab -> however, they should not be excluded from program
  • 1997 ACCP Task Force Conclusions
    • Grade A Evidence: Lower extremity exercise improves exercise endurance
    • Grade A Evidence: Pulm rehab decreases dyspnea
    • Grade B Evidence: Upper extremity exercise improves exercise endurance
    • Grade B Evidence: Ventilatory muscle training improves exercise endurance
    • Grade B Evidence: Pulm rehab improves health-related QOL and decreases hospitalizations
    • Grade C Evidence: Pulm rehab psychosocial training may improve psychosocial functioning
    • Grade C Evidence: Pulm rehab may improve mortality
  • Impact on Need for Lung Volume Reduction Surgery (LVRS)
    • Improvement during pulm rehab led 14% of NETT patients to forego further evaluation for LVRS

Bronchoscopic Lung Volume Reduction

Endobronchial Valve Therapy

  • Product: Zephyr endobronchial valve (Emphasys Medical/Pulmonyx)
  • Technique: duckbill valve mechanism placed unilaterally via bronchoscopy
  • Clinical Efficacy
    • Modest Improvement in Symptoms/Lung Function After Zephyr Placement: best candidates are probably those with intact inter lobar fissures and no collateral ventilation
      • Exclusion Criteria: FEV1 <20% pred, hypercapnia, pulmonary hypertension, DLCO <25% pred
    • Endobronchial Valve (Zephyr) for Emphysema Palliation Trial (VENT) Trial (NEJM, 2010) [MEDLINE]: randomized multi-center trial of endobronchial valves in heterogeneous emphysema (n = 321)
      • At 90 days: endobronchial valve treatment resulted in increased rates of COPD exacerbations (requiring hospitalization) and hemoptysis
      • At 6 mos: endobronchial valve treatment resulted in modest improvements in FEV1 and 6-minute walk test, but increased mortality (2.8% vs 0% in control group)
      • At 12 mos: endobronchial valve treatment resulted in 4.2% pneumonia rate in target lobe, but no change in complication rates or mortality
    • Retrospective Analysis from Multicenter Registry
    • STELVIO Dutch Trial of Endobronchial Valves (from Pulmonyx) in Patients without Interlobar Collateral Ventilation (NEJM, 2015) [MEDLINE]: at 6 mos, endobronchial valves improved PFT’s and 6-minute walk test in patients without interlobar collateral ventilation (as assessed by complete fissure on HRCT), although adverse event rate was higher (with 1 death in the valve group)

Intrabronchial Valve Therapy

  • Product: Spiration implantable Intrabronchial valve (Spiration)
  • Technique: umbrella-shaped nitinol frame with synthetic polymer cover placed through flexible bronchoscope

Nitinol Coil Therapy

  • Technique spring-like device delivered via bronchoscope

Biologic Lung Volume Reduction Therapy

  • Technique: application of sealant/remodeling system to collapse areas of emphysematous lung

Thermal Airway Ablation Therapy

  • Technique: steam vapor applied to segmental airways

Airway Bypass Procedure

  • Technique: extra-anatomic bronchial fenestration is used to decompress areas of emphysema (stent placed through bronchial wall into an area with severe emphysema decompresses the emphysematous area)

Lung Volume Reduction Surgery (LVRS)

  • Indications: maximal exercise tolerance <50W
  • Current Criteria for Ideal Candidates for LVRS: 50% of these candidates demonstrate significant improvement in lung function post-operatively
    • Predominantly Upper Lobe Disease
    • Absence of Significant Pulmonary Hypertension
    • Absence of Hypercapnia
    • FEV1 >20% Pred with DLCO >20% Pred
  • Technique
    • Operative Mortality: <10% (in experienced centers)
  • Clinical Efficacy
    • Improved Mortality
    • Improved Symptoms
    • Improved Lung Function/Functional Status
    • Improved BMI [MEDLINE]: especially in COPD patients who had prior low BMI

Bullectomy

Criteria for Ideal Candidates for Bullectomy

  • Bulla is >1/3 of Hemithorax
    • The rare bulla which communicates with airways (as determined by disparity between body box and helium dilution TLC) is more likely to lead to improvement with bullectomy (as it contributes more to dead space ventilation, worsening dyspnea)
  • Absence of Generalized Emphysematous Changes in Remaining Lung: the best test for this is a inspiratory/expiratory chest CT scan
    • Presence of generalized emphysema predicts poor results
  • FEV1 Around 50% Predicted: most benefit in this group
    • Those with higher FEV1 generally have few symptoms (with little room for improvement)
    • Those with lower FEV1 generally have generalized emphysema

Post-Operative Outcome from Bullectomy

  • Prediction of Post-Op Outcomes: bronchography, exercise testing, and quantitative V/Q scanning do not predict post-operative outcome from bullectomy
  • Post-Op Outcomes
    • Most patients without severe emphysema show improved FEV1 and FVC post-operatively
    • DLCO is improved, if the compressed lung is better perfused
    • Post-op ventilatory capacity and oxygen consumption (at anaerobic threshold and maximal exercise) are both improved

Non-Invasive Positive Pressure Ventilation (NIPPV)

  • German/Austrian Randomized Trial of NIPPV in Stable Hypercapnic COPD (2014) [MEDLINE]
    • Study: randomized German/Austrian trial of NIPPV (n = 195 from 36 centers)
      • NIPPV was used for at least 6 hrs per day (preferably during sleep)
      • NIPPV was provided using ventilator set to pressure support mode with a backup rate, or alternately assisted ventilation (if high backup rates were not tolerated)
      • NIPPV was targted to decrease pCO2 by at least 20%
    • Main Findings: addition of long-term NIPPV to standard COPD treatment improved survival of patients with hypercapnic, stable COPD when the NIPPV is targeted to significantly reduce hypercapnia (1-year mortality was 12% in the NIPPV group vs 33% in the control group; hazard ratio 0.24 (95% CI 0.11-0.49; p=0.0004)

Nutrition

  • Despite prevalence of cachexia in COPD, there is no evidence that enhanced nutrition improves body wieght, lung function, exercise capacity, or survival

Scuba Diving with Chronic Obstructive Pulmonary Disease

  • Contraindicated: due to risk of pneumothorax

Treatment of Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

  • Calcium Channel Blockers (see Calcium Channel Blockers, [[Calcium Channel Blockers]]): Nifedipine decreases exercise PA pressure and CO (effects last up to 9 weeks but symptoms are unchanged)
    • Verapamil is not an effective pulmonary vasodilator
  • Prazosin (see Prazosin, [[Prazosin]]): decreases PA pressure and increases CO in COPD (effects last for 8 weeks but cause a decrease in pO2 and worsened dyspnea)

Treatment of Polycythemia (see Polycythemia, [[Polycythemia]])

  • If patient is polycythemic, treatment decreases PA pressure, decreases PVR, and increases RV-EF

Specific Treatment of Chronic Obstructive Pulmonary Disease Exacerbation

Oxygen (see Oxygen, [[Oxygen]])

  • Oxygen Therapy: judicious oxygen therapy is crucial
    • Excessive oxygen therapy in COPD exacerbation in the setting of chronic hypercapnia may result in worsened CO2 retention and respiratory failure
      • Excess oxygen may blunt the hypoxic ventilatory drive and/or increase physiologic dead space (due to oxygen-induced bronchodilation in poorly-perfused areas of the lung)

Bronchodilators

Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • Considered a standard treatment for COPD exacerbation
  • Systematic Review of Different Durations of Corticosteroid Therapy in Acute COPD Exacberation (2014) [MEDLINE]: five days of oral corticosteroids is likely to be sufficient for treatment of adults with acute COPD exacerbation
  • REDUCE Trial (2013) [MEDLINE]
    • Main Findings: 5-day treatment with systemic steroids was non-inferior to 14-day treatment -> no change in re-exacerbation rates within 6 months
      • No difference in time to death
      • No difference in the combined end point of exacerbation, death, or both
      • No difference in recovery of lung function
      • No difference in treatment-associated adverse reactions (hyperglycemia, hypertension)

Antibiotics

  • Indications for antibiotics in chronic bronchitis include sputum purulence, increased sputum volume, and increased dyspnea
  • Antibiotics have been shown to decrease days of illness, symptoms, and increase flow rates (benefit of antibiotics is greatest when all 3 are present, of lesser benefit when only 2 are present, and of no benefit when only 1 is present)
  • Microbiologic Coverage in Simple Chronic Bronchitis (<65 y/o, <4 exacerbations per year): cover Moraxella/H Flu/Pneumococci/possibly atypicals
  • Microbiologic Coverage in Complicated Chronic Bronchitis (>65 y/o, >4 exacerbations per year, FEV1 <50% pred, presence of underlying comorbid condition, COPD for >10 years): cover above organisms + GNR

Noninvasive Positive-Pressure Ventilation (NIPPV) (see Noninvasive Positive-Pressure Ventilation, [[Noninvasive Positive-Pressure Ventilation]])

  • History : first used to treat COPD excerbation in the early 1990’s
  • Mechanisms
    • CPAP decreases auto-PEEP during COPD exacerbation -> decreases inspiratory load and work of breathing
    • Pressure support decreases work of breathing in COPD
    • Combined CPAP + pressure support (NIPPV) decreases transdiaphragmatic pressure more than each alone
  • Clinical Efficacy in COPD Exacerbation
    • NIPPV decreases pCO2, heart rate, respiratory rate, and dyspnea within the first hour of treatment
    • NIPPV decreases encephalopathy scores
      • The presence of hypercapneic encephalopathy or coma in COPD exacerbation is not a contraindication to NIPPV
    • NIPPV decreases intubation rate from 75% -> 25% of cases
    • NIPPV decreases mortality rate from 30% -> 10% of cases
      • Mortality rate may not be decreased in the subset of patients with pH <7.30 (at least in patients treated on general medical wards, outside of the ICU): this study suggested that patients with moore severe COPD exacerbation might have better outcomes if treated in the ICU, suggesting the importance of appropriate monitoring of NIPPV [MEDLINE]
      • Decreased mortality rate may not be observed with the USE of NIPPV in milder COPD exacerbations [MEDLINE]
      • Decreases mortality rate in the setting COPD exacerbation with concomitant pneumonia [MEDLINE]
    • NIPPV decreases complication rates and hospital length of stay

Mechanical Ventilation (see Mechanical Ventilation, [[Mechanical Ventilation]])

  • Indications: respiratory failure unresponsive to NIPPV (or if patient is not a candidate for NIPPV)

Treatments with No Demonstrated Clinical Benefit in Acute COPD Exacerbation

  • Intravenous Magnesium Sulfate (see Magnesium Sulfate, [[Magnesium Sulfate]])
  • Systematic Review of Magnesium Sulfate in Acute COPD Exacerbation (Ann Thorac Med, 2014) [MEDLINE]: trials were cited as poor -> further study is required
    • Intravenous Magnesium Sulfate: did not have an immediate bronchodilatory effect, but potentiates the bronchodilatory effect of inhaled beta-2 agonists
    • Nebulized Magnesium Sulfate: no benefit (in terms of FEV1 or need for hospital admission), as compared to salbutamol alone
    • Combined Intravenous and Nebulized Magnesium Sulfate: no benefit in terms of hospital admission/intubation/death, as compared to nebulized ipratropium bromide (but the nebulized ipratropium bromide group had a better bronchodilator effect and improvement in arterial blood gas parameters)
  • Nebulized Magnesium Sulfate (see Magnesium Sulfate, [[Magnesium Sulfate]])
    • Australian New Zealand Clinical Trials Registry Study of Nebulized Magnesium Sulfate Added to Salbutamol in Acute COPD Exacerbation (Thorax, 2013) [MEDLINE]: no benefit (in terms of FEV1 or need for hospital admission), as compared to salbutamol alone
    • Systematic Review of Magnesium Sulfate in Acute COPD Exacerbation (Ann Thorac Med, 2014) [MEDLINE]: trials were cited as poor -> further study is required
      • Intravenous Magnesium Sulfate: did not have an immediate bronchodilatory effect, but potentiates the bronchodilatory effect of inhaled β2 agonists
      • Nebulized Magnesium Sulfate: no benefit (in terms of FEV1 or need for hospital admission), as compared to salbutamol alone
      • Combined Intravenous and Nebulized Magnesium Sulfate: no benefit in terms of hospital admission/intubation/death, as compared to nebulized ipratropium bromide (but the nebulized ipratropium bromide group had a better bronchodilator effect and improvement in arterial blood gas parameters)
  • Combined Intravenous and Nebulized Magnesium Sulfate (see Magnesium Sulfate, [[Magnesium Sulfate]])
    • Systematic Review of Magnesium Sulfate in Acute COPD Exacerbation (Ann Thorac Med, 2014) [MEDLINE]: trials were cited as poor -> further study is required
      • Intravenous Magnesium Sulfate: did not have an immediate bronchodilatory effect, but potentiates the bronchodilatory effect of inhaled beta-2 agonists
      • Nebulized Magnesium Sulfate: no benefit (in terms of FEV1 or need for hospital admission), as compared to salbutamol alone
      • Combined Intravenous and Nebulized Magnesium Sulfate: no benefit in terms of hospital admission/intubation/death, as compared to nebulized ipratropium bromide (but the nebulized ipratropium bromide group had a better bronchodilator effect and improvement in arterial blood gas parameters)

Prognosis

Predictors of Risk of Death in Chronic Obstructive Pulmonary Disease

BODE Index

  • BMI: low BMI
  • Obstruction: degree of airway obstruction by PFT’s
  • Dyspnea
    • Medical Research Council (MRC) Dyspnea Scale
      • Grades 1 and 2 = mild disability, while grades 3-5 = moderate to severe disability
        • Grade 1) I only get breathless with strenuous exercise
        • Grade 2) I get short of breath when hurrying on the level or walking up a slight hill
        • Grade 3) 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
        • Grade 4) I stop for breath after walking about 100 yards or after a few minutes on the level
        • Grade 5) I am too breathless to leave the house or I am breathless when dressing or undressing
  • Exercise Capacity: poor exercise capacity (as assessed by clinical symptoms or 6-minute walk test)

Prediction of COPD Mortality with 6-Minute Walk Test (see 6-Minute Walk Test, [[6-Minute Walk Test]])

  • ECLIPSE Trial (2013) [MEDLINE]: 30 m (98.4 ft) decline in 6-minute walk distance in the first year was associated with an increased risk for mortality in the subsequent 2 years

Emphysematous Changes Noted on Chest CT Predict All-Cause Mortality

  • Cohort Study Examining the Predictive Value of Emphysematous Changes on Chest CT (Ann Int Med, 2014) [MEDLINE]: presence of emphysematous changes on CT imaging in patients without spirometrically-defined COPD were linearly associated with increased all-cause mortality (even after adjusting for confounding variables, such as cardiovascular risk factors and FEV1)
    • The association was of greatest magnitude among smokers

References

General

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  • Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax 1981;36:752–8 [MEDLINE]
  • Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999;54(7):581-586
  • The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005-1012.
  • Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest 2005;127:1531–6 [MEDLINE]
  • Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:189–94 [MEDLINE]
  • The modified BODE index: validation with mortality in COPD. Eur Respir J. 2008;32(5):1269-1274
  • Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease Updated 2008. Available at: http://www.goldcopd.org/Guidelineitem.asp?l1=2&l2=1&intId=2003. Accessed December 15, 2009
  • Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax. 2010;65(11):956–962 [MEDLINE]
  • Family History Is a Risk Factor for COPD. Chest 2011; 140 (2): 343-350 [MEDLINE]
  • ECLIPSE Trial. Six-minute-walk test in chronic obstructive pulmonary disease: minimal clinically important difference for death or hospitalization. Am J Respir Crit Care Med 2013;187:382-386 [MEDLINE]
  • Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095-2128 [MEDLINE]
  • Association between emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: A cohort study. Ann Intern Med 2014;161:863-873 [MEDLINE]

Treatment of Acute Chronic Obstructive Pulmonary Disease Exacerbation

  • Different durations of corticosteroid therapy for exacerbations of COPD. Cochrane Database Syst Rev 2011;(10) CD00697 [MEDLINE]
  • Short-term vs conventional glucocorticoid therapy in acute exacerbations of COPD: The REDUCE randomized clinical trial. JAMA 2013; 309: 2233-2231 [MEDLINE]
  • Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double-blind placebo-controlled trial. Thorax. 2013 Apr;68(4):338-43. doi: 10.1136/thoraxjnl-2012-202225. Epub 2013 Jan 7 [MEDLINE]
  • Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014 Dec 10;12:CD006897. doi: 10.1002/14651858.CD006897.pub3 [MEDLINE]
  • Magnesium for acute exacerbation of chronic obstructive pulmonary disease: A systematic review of randomised trials. Ann Thorac Med. 2014 Apr;9(2):77-80. doi: 10.4103/1817-1737.128844 [MEDLINE]

Pharmacologic Treatment

  • Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 2001;119:1661-1670 [MEDLINE]
  • Ipratropium bromide versus long-acting beta-2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006 Jul 19;3:CD006101
  • Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006;47:2554-2560 [MEDLINE]
  • Azithromycin for Prevention of Exacerbations of COPD. NEJM 2011; 365(8): 689-698 [MEDLINE]
  • Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Aug 15;8:CD001287 [MEDLINE]
  • Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Jul 11;7:CD009285. doi: 10.1002/14651858.CD009285.pub2 [MEDLINE]
  • Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease. The REDUCE Randomized Clinical Trial. JAMA. 2013 Jun 5;309(21):2223-31. doi: 10.1001/jama.2013.5023 [MEDLINE]
  • Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013; 144(3):758–765 [MEDLINE]
  • Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013;11:CD003794 [MEDLINE]
  • Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2014 Mar;2(3):187-94 [MEDLINE]
  • Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med 2014;189:1503-1508 [MEDLINE]
  • STATCOPE Trial. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014 Jun 5;370(23):2201-10. doi: 10.1056/NEJMoa1403086. Epub 2014 May 18 [MEDLINE]
  • Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015 Mar 7;385(9971):857-66. doi: 10.1016/S0140-6736(14)62410-7. Epub 2015 Feb 13 [MEDLINE]
  • Roflumilast: a review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2016 Jan 6;11:81-90. doi: 10.2147/COPD.S89849. eCollection 2016 [MEDLINE]

Inhaled Cortisosteroids

  • Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297-303 [MEDLINE]
  • Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775-89 [MEDLINE]
  • Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD. 2009;6(5):320-329
  • Safety and efficacy of combined long-acting beta-agonists and inhaled corticosteroids vs long-acting beta-agonists monotherapy for stable COPD: a systematic review. Chest. 2009;136(4):1029-1038
  • Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009; 34(3):641-647 [MEDLINE]
  • Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013;11:CD003794 [MEDLINE]
  • WISDOM Investigators. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014;371:1285-1294 [MEDLINE]

Endobronchial Valves

  • VENT Study Research Group. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med 2010;363(13):1233-1244 [MEDLINE]
  • Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation (STELVIO). N Engl J Med 2015; 373:2325-2335December 10, 2015DOI: 10.1056/NEJMoa1507807 [MEDLINE]

Lung Volume Reduction

  • Weight gain after lung reduction surgery is related to improved lung function and ventilatory efficiency. Am J Respir Crit Care Med 2012;186:1109-1116 [MEDLINE]

Ventilation-Based Treatment

  • Noninvasive ventilatory support does not facilitate recovery from acute respiratory failure in chronic obstructive pulmonary disease. Eur Respir J. 1996 Jun;9(6):1240-5 [MEDLINE]
  • Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized evaluation of noninvasive ventilation. Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 1):1585-91 [MEDLINE]
  • Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial. Lancet. 2000 Jun 3;355(9219):1931-5 [MEDLINE]
  • Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ. 2003 Jan 25;326(7382):185 [MEDLINE]
  • Which patients with acute exacerbation of chronic obstructive pulmonary disease benefit from noninvasive positive-pressure ventilation? A systematic review of the literature. Ann Intern Med. 2003 Jun 3;138(11):861-70 [MEDLINE]
  • Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive pulmonary disease: a prospective, multicentre, randomised, controlled clinical trial. Lancet Respir Med. 2014 Sep;2(9):698-705. doi: 10.1016/S2213-2600(14)70153-5. Epub 2014 Jul 24 [MEDLINE]

Other Treatment

  • Out-patient rehabilitation improves activities of daily living, quality of life and exercise tolerance in chronic obstructive pulmonary disease. Eur Respir J. 1997;10(12):2801-2806
  • Bronchoscopic lung volume reduction for end-stage emphysema: report on the first 98 patients. Chest 2006;129:518-526 [MEDLINE]
  • Pulmonary Rehabilitation: Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines. Chest. 2007;131(5 Suppl):4S-42S
  • Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. A Cochrane systematic review. Eura Medicophys. 2007;43(4):475-485
  • Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD005305