General Information

• Definition: persistent airflow limitation that is usually progressive and is associated with a chronic enhanced inflammatory response in the airways and lungs to noxious particles and gases
  • due to airway and/or alveolar abnormalities
• Common, preventable & treatable disease
• Usually caused by significant exposure to noxious particles or gases
  • Developed countries — smoking; developing countries — biomass fuel
• Influenced by host factors including abnormal lung development
• Chronic bronchitis — clinical diagnosis — chronic cough and sputum production
  • epidemiological definition — chronic productive cough on most days during at least 3 months per year for 2 or more consecutive years
  • periods of worsening or exacerbation precipitated by a respiratory tract infection
  • in between exacerbations, residual clinical disease (unlike asthma where symptoms go away in between exacerbations) because chronic bronchitis is not a disease of airway hyperreactivity
  • If clinical features of chronic bronchitis with evidence of airway hyperreactivity → asthmatic bronchitis or asthma-COPD overlap syndrome
• Emphysema — pathological diagnosis — destruction of lung parenchyma and enlargement of air spaces distal to the terminal bronchiole — this is the region from respiratory bronchioles to the alveoli
  • where the destruction is along this path determines the subtype of emphysema
• Chronic bronchitis and emphysema can (and often do) co-exist in a patient therefore the broader term of COPD is used
• Significant comorbidities may have an impact on morbidity and mortality

Associated Anatomy & Physiology

Associated Histology

Epidemiology

Burden of COPD

COPD is underdiagnosed and under-reported

• Prevalence estimates vary widely
  • Global -- 10.1%
• Deaths -- 3.2 million annually
  • Third leading cause of death worldwide
• Prevalence expected to rise over next 4 decades
• Prevalence increasing in women
• 
  • China and India account for more than 50% of all cases of COPD in the world
• Undiagnosed COPD
  • Percentage of undiagnosed COPD in the general population, aged 40 or older with current or past exposure to tobacco (≥10 pack-years) is 70-78%
  • Overall health system burden by undiagnosed COPD still exists and its largely unrecognized
  • Asymptomatic Undiagnosed COPD
    • If FEV₁ <80% (moderate or more severe obstruction) → adverse effects ~ symptomatic COPD
    • Increased risk of exacerbations and pneumonia
  • Symptomatic Undiagnosed COPD
    • increased risk of exacerbations, pneumonia and death
  • i.e. it doesn't matter if they are symptomatic or not, being undiagnosed increases risk of adverse effects

Etiology, Pathogenesis & Pathology

Etiology & Risk Factors

• Early life factors and exposures
  • Maternal smoking
  • Respiratory infections
  • Dysanapsis (Mismatch of airway tree caliber to lung size; develops early in life)
• Tobacco smoke
  • Nearly 80% of all COPD cases can be attributed to smoking
  • 15-20% of 1 pack per day (PPD) smokers and 25% of 2 PPD smokers will develop COPD
• Outdoor and Indoor Pollution
  • Biomass fuel
    • 50% of COPD deaths in developing countries are from biomass smoke
    • 75% are in women
• Occupational exposures
  • May account for 15-20% of COPD
  • Mining, agriculture, textile, paper, wood, chemical, food processing
  • Cadmium fumes can cause emphysema (smelting, batteries)
• Socioeconomic status
• Genetic factors
  • Several GWAS (genome-wide association study) have linked genetic loci with COPD but causality remains uncertain
  • Best documented in Alpha-I Antitrypsin Deficiency
    • SERPINA1 gene mutation

Lung Function Trajectory

• Reduced maximal attained lung function may identify individuals at increased risk
• Incidence of COPD was higher when FEV1 was <80% predicted before age 40 (26% vs 7%; P <0.001)
• 
  • TR1: Normal
  • TR2: Small lungs but no COPD
  • TR3: Normal initial FEV₁ with rapid decline leading to COPD
  • TR4: Small lungs leading to COPD

Dysanapsis

• Associated with incident COPD in older adults
• Develops early in life
• May contribute to COPD susceptibility later in life
• Three trials -- MESA (N=2531), CanCOLD (N=1272), SPIROMICS (N=2726)
• Incidence and prevalence of COPD was highest in the lowest airway to lung ratio quartiles in MESA and CanCOLD
• SPIROMICS participants with COPD in the highest airway to lung ratio quartiles had faster FEV₁ decline as compared to the lowest airway to lung ratio quartile suggesting two different paths for COPD development
• Can lead to Bronchopulmonary Dysplasia

Risk Factors for AECOPD

• Advanced age
• Severity of airflow limitation
• Chronic mucous hypersecretion
• Productive cough
• Duration of COPD
• Pulmonary Hypertension (Pulmonary Artery {PA}: Ascending Aorta {A} ratio >1)
• Blood eosinophil count >340 cells/μL
• Comorbid Conditions
• GERD
• History of antibiotic use
• COPD-related hospitalization in the previous year
  • History of prior exacerbations is the single best predictor, regardless of severity

Etiology of AECOPD

• Causes of exacerbations requiring hospitalization in patients (Papi A, et al. Am J Respir Crit Care Med. 2006;173:1114)
  • Non-infectious 21.8%
  • Bacteria 29.7%
  • Virus 23.4%
  • Bacteria & Virus 25%

Pathogenesis

Inflammation in COPD

T Lymphocytes

• Increase in T lymphocytes in the airway wall and lung parenchyma
  • organize into lymphoid follicles
  • 
    • Collection of bronchial lymphoid tissue with a lymphoid follicle containing a germinal center (GC) surrounded by a rim of darker-staining lymphocytes that extend to the epithelium of both the small airway and alveolar surface
  • Shift in the balance of CD4/CD8 T cell ratio in favor of CD8 → direct toxic effects → alveolar wall destruction
• Number of Th1 and Tc1 cells, which produce interferon-γ increase

Neutrophils

• Release proteases
• Increased in the sputum and distal airspaces of smokers
• Further increase occurs in COPD and is related to disease severity

Macrophages

• Produce inflammatory mediators and proteases
• Increased in number in airway, lung parenchyma and in BAL fluid

B Lymphocytes

• increased in peripheral airways and within lymphoid follicles possibly as a response to chronic infection of the airways

Inflammatory Mediators

• Leukotriene B4
  • Chemoattractant of neutrophils and T cells
  • produced by macrophages, neutrophils, and epithelial cells
• Chemotactic factors (CXC) & Chemokines (IL-8 & growth related oncogene α)
  • produced by macrophages and epithelial cells
  • Chemoattractant of cells from circulation and amplify pro-inflammatory responses
• TNF-α & IL 1β + IL 6 -- Pro-inflammatory cytokines
• TGF-β -- growth factors
  • may cause fibrosis in the airways either directly or through release of another cytokine, connective tissue growth factor

Protease and Antiprotease Imbalance

• Increased production (or activity) of proteases and decreased production (or inactuvation) of antiproteases = imbalance
• Cigarette smoke + inflammation → oxidative stress → primes inflammatory cells → release of proteases and inactivates several antiproteases by oxidation
  • Oxidative stress
    • leads to inactivation of antiproteases & stimulation of mucous production
    • Amplifies inflammation by enhancing transcription factor activation (NFκB) → gene expression of pro-inflammatory mediators
• Main proteases involved
  • Neutrophil produced -- serine proteases, elastase, cathepsin G, and protease 3
  • Macrophage produced -- cysteine proteases, cathepsins E, A, L, and S
  • Matrix metalloproteases -- MMP-8, MMP-9, and MMP-12
• Main antiproteases involved
  • α1 antitrypsin
  • secretory leukoprotease inhibitor
  • tissue inhibitors of metalloproteases
• 

HDAC expression is reduced in COPD

• Histone deacetylase 2 (HDAC2 suppresses inflammatory gene experssion
• Corticosteroids can recruit HDAC and reverse inflammatory process
• HDAC function is impaired by cigarette smoking and oxidative/nitrative stress
• HDAC levls in the lung decrease with increasing COPD severity
• In COPD, there is decreased corticosteroid responsiveness

α-1 Antitrypsin (AAT) Deficiency

• AAT is a protease inhibitor of the proteolytic enzyme elastase
• An imbalance between neutrophil elastase and the elastase inhibitor causes early COPD in smokers (see above)
• COPD occurs later in non-smokers
• Inherited in autosomal co-dominant pattern
  • SERPINA1 gene on Chromosome 14
  • M allele is normal
  • S or Z allele a/w deficiency
• 
• Consider AAT if
  • earlier age of onset (<45 years)
  • emphysema in a nonsmoker or minimal smoker
  • Basal, pan-acinar emphysema
  • Unremitting asthma with persistent airflow limitation
  • Concurrent liver disease/cirrhosis
  • Necrotizing panniculitis
  • C-ANCA positive vasculitis
  • First-degree relative with emphysema, bronhiectasis, panniculitis

Exacerbation-Prone COPD

• Imaging phenotypes (Han MK, et al. Radiology 2011;261(1):274)
  • 
• COPDGene Study
  • Greater lung emphysema and airway wall thickness a/w COPD exacerbations, independent of the severity of airflow obstruction

Pathophysiology

Mucus Hypersecretion & Ciliary Dysfunction

Mucus Hypersecretion

• Results in chronic productive cough
  • Characteristic of chronic bronchitis but not necessarily a/w airflow obstruction
• Not all patients with COPD have symptomatic mucous hypersecretion
• Hypersecretion is due to
  • squamous metaplasia
  • increased # of goblet cells
  • increased size of bronchial submucosal glands in response to chronic irritation by noxious particles and gases

Ciliary Dysfunction

• Ciliary Dysfunction due to
  • squamous metaplasia of epithelial cells
    • Abnormal mucociliary escalator
    • Difficulty in expectorating

Airflow Limitation & Air Trapping (Hyperinflation)

• Inflammation, fibrosis, and luminal exudates occur in small airways (<2 mm in diameter)
  • This is because of inflammation and narrowing (airway remodeling) and inflammatory exudates in the small airways
• 
• Number of small airways is decreased
  • smoking-related or may reflect abnormal early-life lung development
  • 
    • Hogg J. Lancet 2004; 364: 709–21
• Other factors -- loss of lung elastic recoil (due to destruction of alveolar walls) and destruction of alveolar support (from alveolar attachments)
• Hyperinflation occurs early in the disease and is the main mechanism of exertional dyspnea
  • The progressive airway obstruction traps air during expiration resulting in
    • hyperinflation at rest
    • dynamic hyperinflation during exercise
  • Reduces inspiratory capacity → reduction in FRC during exercise → breathlessness & limited exercise capacity

Emphysema & Gas Exchange Abnormalities

• Peribronchiolar destruction of alveolar walls
• Loss of alveolar attachments
• Loss of elastic recoil and airway collapse
• Enlargement of air spaces

Subtypes of Emphysema

Gas Exchange Abnormalities

• Gas exchange abnormalities occur in advanced disease
  • Arterial hypoxemia with or without hypercapnia
    • Anatomical changes in COPD → abnormal distribution of V/Q ratios → abnormal gas exchange
  • Extent of impairment of DLCO per liter of alveolar volume correlates well with the severity of emphysema

Pulmonary Hypertension

• Develops late in COPD at the time of severe gas exchange abnormalities
  • Hypoxia → pulmonary arterial constriction
  • Structural change in pulmonary arterioles
    • Endothelial dysfunction
    • Remodeling of pulmonary arteries (smooth muscle hypertrophy and hyperplasia)
    • Destruction of pulmonary capillary bed
• Hypoxia + Structural changes in pulmonary arterioles → persistent pulmonary hypertension & right ventricular hypertrophy or enlargement and dysfunction (cor pulmonale)
• 

Systemic Effects

• Systemic inflammation + skeletal muscle wasting → limited exercise capacity
  • worsen prognosis irrespective of degree of airflow obstruction
• Increased risk of CV disease → a/w increase in CRP (see below)

Exacerbation Pathophysiology

• Increased neutrophilic inflammation & increased number of eosinophils (in mild exacerbations)
• Caused by infection, air pollution, and changes in ambient temperature
• Mild exacerbation
  • airflow obstruction is unchanged to slightly increased
• Severe exacerbation
  • Worsening pulmonary gas exchange due to V/Q mismatch & Respiratory Muscle Fatigue
  • Worsening pulmonary gas exchange
    • airway inflammation, edema, mucous hypersecretion, and bronchoconstriction → reduce ventilation → hypoxic vasoconstriction of pulmonary arterioles → impairs perfusion
  • Respiratory Muscle Fatigue + Alveolar hypoventilation
    • Result in hypoxemia, hypercapnia, and respiratory acidosis → severe respiratory failure → death
    • Hypoxia + Respiratory acidosis → pulmonary vasoconstriction → increase load on right ventricle + renal and hormonal changes → peripheral edema

History & Physical Exam/Clinical Features

Diagnosis

Consider COPD and Perform Spirometry if:

• Dyspnea -- progressive over time, worse with exercise, persistent
• Chronic Cough -- may be intermittent and dry
• Recurrent Wheezing
• Chronic sputum
• Recurrent respiratory infections
• History of risk factors -- smoke or other noxious, occupational, genetics
• Childhood factors -- prematurity, maternal smoking, low birth weight
• Family history of COPD
• Presence or absence of symptoms (Wheezing, Cough, sputum production or Dyspnea) was not particularly discriminative in diagnosing COPD in the general population

GOLD Grades

• Airflow limitation based on post-bronchodilator FEV₁
  • 
  • Assess airflow limitation first then symptoms & risk of exacerbation
• FEV₁ and Mortality from NHANES 1 data
  • Increasing mortality with increasing severity of airflow limitation
  • Never smokers with moderate-severe COPD were not at increased risk of mortality

Symptom Assessment Tool

mMRC Dyspnea Scale

COPD Assessment Tool (CAT)

• 
• 8 items; scale 1-5
• Scores 0 - 40
  • <10 - Low impact
  • 10-20 - Medium impact
  • 21-30 - High impact

  • 30 - Very high impact

• Fixes limitation with predicting risk of acute exacerbation based on FEV₁
• Assess symptoms plus consequences (activity limitation, sleep, fatigue, self-efficacy)

Additional Investigations to Consider

• α-1 antitrypsin (AAT) screening
  • WHO recommends screening all patients with COPD at least once
• Imaging
• Lung volumes and diffusing capacity
• Oximetry and blood gas measurement
• Exercise testing
• Composite scores (such as BODE index for COPD survival)
  • 
  • B- BMI, O- degree of airflow Obstruction (FEV₁%), D-Dyspnea (mMRC), E-Exercise capacity index (6MWT)
  • BODE is a better predictor of risk of death from any cause and from respiratory causes than is the FEV₁ alone
  • FEV₁ does not adequately reflect all the systemic manifestations of the disease
    • FEV₁ correlates weakly with degree of dyspnea and change in FEV₁ does not reflect the rate of decline in patient's health
  • Degree of dyspnea and health-status scores are more accurate predictors of risk of death than is the FEV₁.
• Biomarkers -- need further study

α1 Anti-Trypsin Deficiency

Diagnosis of AECOPD

Management

Management of Stable COPD

• Goals of COPD Management
  • Reduce Symptoms
    • relieve symptoms of dyspnea
    • improve exercise tolerance
    • improve health status
  • Reduce Risk
    • prevent disease progression
    • prevent and treat exacerbations
    • reduce mortality

Pharmacologic Therapy

• 
• Symptomatic patients with mild to moderate COPD (post-bronchodilator FEV₁ ≥50% predicted), there is significant improvement of annual decline in FEV₁ after bronchodilator use, accompanied by a significant increase in the time to first AECOPD, but no improvement in mortality.
  • Improvement in prebronchodilator FEV₁ and post, mMRC and CAT scores
• SABA and SAMA improve FEV₁ and symptoms
  • SABA + SAMA > SABA or SAMA
• LAMA and LABA improve lung function (FEV₁), dyspnea (symptoms), health status and exacerbations
  • LAMA -- greater effect on exacerbation and hospitalization reduction
  • LAMA -- improve effectiveness of pulmonary rehabilitation
  • LAMA + LABA > LAMA or LABA
• Inhaled Steroids
  • ICS + LABA -- more effective than ICS or LABA in improving lung function, health status and exacerbations
  • Triple inhaled therapy (ICS/LABA/LAMA)
    • improves lung function, symptoms, health status, exacerbations, mortality vs
      • ICS/LABA or LABA/LAMA or LAMA
  • Regular treatment with ICS increases risk of pneumonia, especially in those with severe disease
  • Factors to consider when initiating ICS treatment
    • 
• Data
  • ISOLDE Study (Burge PS, et al. BMJ. 2000;320:1297)
    • ICS (Fluticasone) decreases COPD exacerbation risk by 25%
  • UPLIFT Study (Tashkin DP, et al. N Engl J Med. 2008;359:1543)
    • LAMA (Tiotropium) decreases COPD exacerbation risk by 14%
  • TORCH Study (Calverley PM, et al. N Engl J Med. 2007;356:775)
    • LABA + ICS (Salmeterol + Fluticasone) decreases COPD exacerbation more than ICS or LABA alone
  • POET-COPD Study (Vodelmeier et al. NEJM 2011;364:1093)
    • LAMA (Tiotropium) decreases exacerbations more than LABA (Salmeterol)
  • FLAME Study (Wedzicha et al. NEJM 2016; 374: 2222)
    • LAMA + LABA (Glycopyrronium + Indacaterol) decreases exacerbations more than ICS + LABA (Fluticasone + Salmeterol)
    • Effect independent of baseline blood eosinophil count
    • Higher incidence of pneumonia in ICS group
  • ETHOS Study (Rabe et al. NEJM 2020; 383:35) -- looked at exacerbation rate
    • Large study - 8509 patients with moderate to very severe COPD
      • ≥1 moderate to severe exacerbation in prior year if FEV₁ <50%
      • ≥2 moderate or ≥1 severe exacerbation if FEV₁ 50-65%
    • ICS used was Budesonide 160 and 320
    • Triple therapy with Budesonide 160 had lowest rate of moderate to severe exacerbation compared to triple therapy with Budesonide 320 and ICS + LABA and LAMA + LABA (highest rate) -- surprising that LAMA + LABA had a higher exacerbation rate than ICS + LABA when FLAME study said opposite (potentially a result of the individual drugs used?)
  • IMPACT Study (Lipson et al. AJRCCM 2020) -- looked at mortality
    • Large study - 10355 patients with symptomatic COPD; FEV₁ <50% and at least 1 moderate to severe exacerbation in the prior year; FEV₁ 50 - <80% and at least 1 severe or 2 moderate exacerbations (a little higher cut off than ETHOS study)
    • LAMA + LABA highest all-cause mortality
    • ICS + LABA & triple therapy had similar all-cause mortality at the end of 52 weeks
  • Macrolide Therapy in COPD & Exacerbations
    • Long-term macrolide therapy reduces exacerbations (Seemungal et al. AJRCCM 2008)
      • medium time to 1st exacerbation 271 days macrolide; 89 days for placebo
    • Azithromycin therapy (Albert et al NEJM 2011; 365:689)
      • medium time to exacerbation 266 days azithromycin; 174 days placebo
  • Roflumilast & Exacerbations (Martinez et al Lancet 2015;385:857)
    • All patients had baseline LABA/ICS use
    • 13% reduction in exacerbations

Non-Pharmacologic Therapy

• Smoking cessation
  • Effect on Lung Function (The Lung Health Study at 11 years Anthonisen et al. Am J Respir Crit Care Med. 2002;166:675)
    • Men who quit had an FEV₁ rate of decline of 30 mL/year
    • Men who continued to smoke had an FEV₁ rate of decline of 66 mL/year
  • Effect on Lung Function (The Lung Health Study at 14 years Anthonisen NR, et al. Ann Intern Med. 2005;142:233)
    • Sustained quitters had the least deaths per 1000 person-years followed by intermittent quitters and highest deaths per 1000 person-years for continued smokers
• Immunization
  • Influenza vacciantion reduces serious illness and death in COPD patients
  • PPSV 23 has been shown to reduce the incidence of CAP in
    • COPD patients aged <65 years + FEV₁ <40% predicted
    • Those with comorbidities
  • PCV 13 demonstrated significant efficacy in reducing bacteremia and serious invasive pneumococcal disease in adults ≥65 years
    • No longer recommended by CDC unless specific risk factors
  • Tdap vaccination recommended in adults with COPD who were not vaccinated in adolescence to protect against pertussis
• Pulmonary rehabilitation (Alison et al. Respirology 2017;22(4):800 McCarthy et al. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD003793)
  • Significantly improves exercise capacity and health status (QOL/anxiety/depression/dyspnea)
  • Reduces frequency of exacerbations
  • Reduces the number of readmissions in the year following initiation
  • Reduction in mortality
  • Optimum benefit from programs 6-8 weeks' duration
  • does not improve pulmonary function tests or oxygenation
• Oxygen therapy
  • Long-term oxygen therapy (LTOT) = >15 hours/day
  • Severe chronic resting arterial hypoxemia (PaO₂ ≤55 mm Hg)
    • Long-term oxygen therapy improved survival vs nocturnal-only or no oxygen
  • Moderate chronic resting hypoxemia (PaO₂ 56-59 mm Hg or SpO₂ 88-90%) + cor pulmonale or polycythemia
    • Long-term oxygen therapy improved survival
  • Moderate chronic resting hypoxemia (SpO₂ 89-93%)
    • Long-term oxygen therapy does not lengthen time to death or time to first hospitalization or provide sustained benefit in health status, lung function and 6MWT distance
  • Exercise-Induced Hypoxemia (SpO₂ during 6MWT ≥80% for ≥5 minutes and <90% for ≥10 seconds)
    • Long-term oxygen therapy does not lengthen time to death or time to first hospitalization or provide sustained benefit in health status, lung function and 6MWT distance
      • Use of supplemental oxygen during exercise, however, increases exercise performance
    • SpO₂ 80 to 88% during exercise (Moderate Exercise Hypoxemia), → O₂ during exercise did not improve long term outcomes of hospitalization, QOL, dyspnea
      • Supplemental oxygen may remove the stimulus to hypoxia-compensating mechanisms such as those seen in residents of high-altitude
  • Indications in Stable COPD
    • Resting Hypoxemia
      • PaO₂ ≤55 mm Hg or SaO₂ ≤88%
      • PaO₂ ≤59 mm Hg or SaO₂ ≤ 89% +
        • EKG evidence of cor pulmonale
        • Hematocrit > 55
        • Clinical evidence of right heart failure
    • Exercise-Induced Hypoxemia
      • PaO₂ ≤55 mm Hg during exercise (Severe Exercise Hypoxemia) → O₂ prescribed for use DURING exercise
        • Unknown if this has any effect on long-term outcome benefits
        • Use during exercise did not translate to improvement/benefit in dyspnea or ADLs when not using oxygen
    • Sleep-Induced Hypoxemia
      • PaO₂ ≤55 mm Hg during sleep → O₂ prescribed
      • Also need to evaluate with PSG for underlying sleep-disordered breathing
  • Supplemental oxygen sometimes provides symptomatic dyspnea relief by stimulating a decrease in minute ventilation → may improve activity but does not improve survival
  • COPD + DOE can be from exertional hypoxemia but also from mechanical loading of the respiratory system, deconditioning and concomitant cardiac disease → pulmonary rehabilitation
• Non-invasive positive pressure ventilation
  • In stable hypercapnic COPD improves survival (Kohnlein et al. Lancet Respir Med 2014;2:698)
  • Criteria: GOLD stage IV COPD + PaCO₂ ≥ 52 mm Hg & pH > 7.35
  • Long-term NPPV targeted to reduce hypercapnia
  • 11% reduction in mortality at 1 year
  • In patients admitted for AECOPD requiring NIV and who remain hypoxemic and hypercarbic (PaCO₂ ≥52 mm Hg) 2 weeks following discharge, the addition of goal-directed nocturnal NIV to continous O₂ has been shown to significantly prolong time to hospital readmission and death within 12 months + improved health-related QOL and reduction in AECOPD frequency
    • AECOPD + NIV = poor prognosis w/ median time to readmission or death less than a year
      • benefit from supplemental oxygen
      • use NIV for at least 6 hours at night → reduce nocturnal hypoventilation → reduction in daytime PaCO₂ by 6-8 mm Hg

• Interventional & Surgical Therapy in Stable COPD

  • Surgical Lung Volume Reduction (NETT research group NEJM 2003;348:2059 Naunheim et al. Ann Thorac Surg 2006; 82:431)
    • Upper lobe emphysema a/w improvement in exercise capacity & QOL
    • Upper lobe emphysema + low baseline exercise capacity a/w improvement in survival
  • Bronchoscopic Lung Volume Reduction w/ Endobronchial Valves (EBV) (Criner et al. AJRCCM 2018;198(9):1151 Kemp et al. AJRCCM 2017;196(12):1535 Majid et al. Respiration 2020;99(1):62)
    • Criteria
      • hyperinflation due to severe emphysema
      • symptomatic despite optimal medical therapy and pulmonary rehabilitation
    • EBV placed in lung region with most emphysematous destruction and no collateral ventilation
    • Zephyr duckbill shaped and Spiration umbrella-shaped EBV approved in USA
    • Efficacy -- improved FEV₁, dyspnea, 6MWD, QOL, RV
    • A/E -- significant risk of pneumothorax (25-30%)
    • EBV does not preclude subsequent LVRS or transplant
      | Reduce Exacerbations | Reduce Mortality |
      | --------------------------------- | ---------------------------- |
      | LABA, LAMA, LABA + LAMA | LABA + LAMA + ICS |
      | LABA + ICS, LABA + LAMA + ICS | Smoking Cessation |
      | Roflumilast | LVRS |
      | Chronic macrolide | NIPPV |
      | Smoking Cessation | Pulmonary Rehabilitation |
      | Vaccines | |
      | Pulmonary Rehabilitation | |
      | LVRS | |
      | N-acetylcysteine | |
      | Vitamin D | |

• 

Management of Acute Exacerbations

• SABA with or without SAMA are recommended as initial bronchodilators
• Systemic corticosteroids improve FEV₁, oxygenation and shorten recovery time and duration of hospitalization
  • Duration of therapy no more than 5-7 days
• Antibiotics if signs of bacterial infection
  • shorten recovery time, reduce risk of early relapse and treatment failure, reduce hospital duration
• Methylxanthines not recommended
• NIV for AECOPD
  • If no contraindication, NIV in patients with acute respiratory failure 2/2 AECOPD
    • improves gas exchange
    • reduces work of breathing
    • reduces need for intubation
    • reduces hospital duration and hospital re-admission
    • improves survival

Complication & Prognosis

• Diagnosed COPD
  • Asymptomatic individuals with FEV₁ <80% (moderate or more severe obstruction) experience significant adverse events similar to symptomatic COPD
• Undiagnosed COPD
  • Symptomatic individuals with undiagnosed COPD were found to have an increased risk of exacerbations, pneumonia and death
  • Asymptomatic individuals with undiagnosed COPD had an increased risk of exacerbations and pneumonia

Comorbidities ^4e379d

• Heart failure - prevalence 20-70%
• CAD - increased risk of MI for 30 days after acute exacerbation of chronic bronchitis (AECB)
  • COPD is an independent risk factor for CV disease
    • increased the odds of having CV disease by 2.7
    • 
      • Finkelstein J, et al. Int J Chron Obstruct Pulmon Dis. 2009;4:337
  • Effects of airflow obstruction and systemic inflammation are additive
    • Increase in cardiac infarction injury score as airflow obstruction gets worse
    • (Sin
      • DD & Man SF. Circulation 2003; 107: 1514
• PVD - higher prevalence in COPD (8.8% vs 1.8%)
• Osteoporosis - associated with emphysema, low BMI, low fat-free mass
  • Severity of airflow obstruction predicts osteoporosis
  • Worsening severity of airflow obstruction -> increasing percentage of osteoporosis
    • More prominent in women than men
• Metabolic syndrome - prevalence >30%
• GERD - independent risk factor for exacerbations
• OSA overlap with COPD a/w worse prognosis

Impact on Mortality

• Estimated age-adjusted mortality a/w selected comorbid conditions
• Holguin et al. CHEST 2005;128(4):2005 - National Hospital Discharge Survey 1979-2001; 47 million discharges
• 
  • Those with COPD and comorbid condition had higher in-hospital mortality from the percentage of people that were discharged

Frequent Exacerbations & Decline in Lung Function

• More exacerbations = faster decline in lung function
• Donaldson GC, et al. Thorax. 2002;57:847
• 
• PEFR recovery after exacerbation (Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608)
  • Recovery of PEFR to baseline values was complete in only 75% of exacerbations at 35 day
  • In 7% of exacerbations at 91 days PEFR recovery had not occurred

COPD Exacerbations Impact Survival

• Severe COPD Exacerbations
  • Soler-Cataluña JJ et al Thorax 2005;64:925
  • 304 male patients, hospitalized for AECOPD followed for 5 years
  • Risk of death 4.3 times greater in frequent exacerbators
  • 
• In general exacerbations are a/w increased mortality
  • In patients hospitalized with AECOPD
    • 14% mortality in 3 months
    • 28% mortality in 1 year
  • If AECOPD w/ PaCO₂ > 50 mm Hg, a/w
    • 33% mortality in 6 months
    • 43% mortality in 12 months
  • Roberts et al. Thorax 2002;57(2):137 Connors et al. AJRCCM 1996; 154(4):959 Slenter et al. Respiration 2013;85(1):15 Almagro et al. Respiration 2012;84(1):36

Backlinks

• 01.1. Obstructive Lung Diseases
• Chronic Obstructive Pulmonary Disease
• Acute Respiratory Distress Syndrome
• Hypercapnic Respiratory Failure
• 10.3. Airway Diseases in Critical Care