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A. Introduction navigator

  1. COPD is a condition of chronic airflow obstruction with some irreversible component
  2. Airflow obstruction is due to bronchitis and/or emphysema
    1. Emphysema a pathologic diagnosis with destruction of lung tissue
    2. Chronic bronchitis is chronic cough for >3 consecutive months in two consecutive years
  3. Majority of cases are associated with smoking tobacco over long periods
    1. Primary tobacco smoking is major risk
    2. Second hand smoke increases risk
    3. Occupational exposures other than tobacco smoke may be minor contributors
  4. Minority of cases have a genetic basis, usually with reduced or absent anti-proteases
  5. Epidemiology [1,4]
    1. Estimated ~24 million in USA have COPD but >50% are not diagnosed
    2. Prevalence of diagnosed cases is 12-15 million in USA
    3. ~85% of COPD is directly attributable to smoking cigarettes
    4. COPD is the 4th leading cause of death (110,000 deaths per year) in USA
  6. Incidence and prevalence increasing worldwide (to ~10%) [45]
  7. PFTs for Screening
    1. PFTs should not be done (for COPD screening) in healthy adults without symptoms [50,51]
    2. PFTs to detect early COPD prior to symptoms even in smokers is not recommended [50,51]

B. Clinical Entities navigator

  1. Chronic Bronchitis
    1. Clinical diagnosis with definition of cough and sputum production as for COPD
    2. Specifically refers to chronic inflammation of the bronchial tubes
    3. Patients with prominant bronchitis are borderline hypoxic but retain CO2 (hypercarbic)
    4. They typically have a compensated respiratory acidosis (that is, with high bicarbonate)
    5. Often referred to as "blue bloaters" (blue because of high CO2 levels)
    6. Cor pulmonale often occurs due to pulmonary hypertension (P-HTN)
    7. Polycythemia is common due to chronic hypoxemia
    8. High dose O2 administration (>2-4L/min) may exacerbate CO2 retention (see above)
    9. PFTs show nearly normal DLCO, increased total lung capacity, reduced FEV1/FVC
  2. Emphysema
    1. Defined as permanent, abnormal distention of air spaces distal to terminal bronchiole
    2. Destruction of alveolar septa also occurs
    3. Centriacinar, panacinar and distal acinar destructive pathologies are seen
    4. Patients are typically hypoxic and hypocarbic, late stage O2 dependent with tachypnea
    5. Cor pulmonale (right heart failure) may occur due to P-HTN
    6. Often referred to as "pink puffer" (pink because CO2 level is low with low normal O2)
    7. PFTs show markedly reduced DLCO, increased residual volume and reduced FEV1/FVC

C. Symptoms and Diagnosis [11]navigator

  1. Cough with sputum production (usually thick, white-yellow, yellow-green)
  2. Tachypnea, shortness of breath, dyspnea on exertion
  3. Most patients >40 years and allergies usually not present
  4. Chronic Symptoms Interrupted by Acute Exacerbations [46]
    1. Exacerbations more common in winter months
    2. Average patient has 1-1.5 exacerbations per year
    3. Cough, sputum production, tachypnea beyond usual baseline
    4. Spirometry (pulmonary function tests, PFTs) should be performed in patients at risk
    5. COPD exacerbations should be treated aggressively to prevent respiratory failure
  5. Right Ventricular (RV) Failure (Cor Pulmonale)
    1. Progressive increases in pulmonary arterial pressures usually occur
    2. This leads to frank pulmonary hypertension
    3. RV hypertrophy
    4. Right bundle branch block (RBBB)
    5. Other ECG abnormalities
    6. Echocardiographic documentation of RV dysfunction and pulmonary hypertension
  6. Diagnosis
    1. Clinical history and physical exam
    2. Must be confirmed by spirometry: FEV1 <80% of normal and FEV1:FVC ratio <0.7
    3. Degree of emphysema assessed with DLCO
    4. Some patients have a low response (<12% FEV1 increase) to albuterol (ß-agonist) challenge
    5. Difficult to clearly distinguish from asthma based on airway hyperresponsiveness
  7. Prognosis [39]
    1. FEV1 is usually considered best predictor for outcomes
    2. BODE score is superior than FEV1
    3. BODE includes body-mass index, airflow obstruction level, dyspnea, exercise capacity
    4. Used for predicting death from respiratory or all causes in COPD

D. Risk Factors [1,2,45] navigator

  1. Smoking
    1. Chronic smoking of tobacco accounts for ~85% of cases of COPD
    2. Current or previous smoking results in much irreversible damage to tissue
    3. Second hand smoke, particularly in closed spaces, is a major risk factor as well
    4. With normal aging, FEV1 declines 15-30mL/year after age 35-40
    5. Smoking increases rate of decline of FEV1 in ~15% of Caucasians and 5% of Asians
    6. Therefore, additional genetic factors likely play a role in determining FEV1 decline
    7. Mutations in microsomal epoxide hydrolase increases risk of CODP ~5X
    8. Persons with heterozygous A1AT deficiency who smoke are at increased COPD risk
    9. Buproprion SR aids in smoking cessation and should be considered in COPD
  2. Air Pollution
    1. May contributes but is generally insufficient to cause COPD
    2. Nitrogen dioxide (NO2) and other pollutants implicated
  3. Occupational exposure to organic dusts or noxious gasses may contribute
  4. Chronic pulmonary infections/inflammation can lead to permanent lung tissue destruction
  5. Increased incidence in elderly due to progressive loss of lung function with aging
  6. alpha1-Antitrypsin (A1AT) Deficiency [5]
    1. Normal A1AT gene, designated M, codes for a trypsin inhibitor ("serpin")
    2. Serum levels A1AT in normal persons (genotype MM) are >2.5g/L
    3. Reduced levels of A1AT (<10% of normal) is designated ZZ genotype
    4. About 15% of persons with A1AT deficiency develop (early onset) emphysema
    5. In addition, these patients may develop chronic hepatitis
    6. Heterozygotes (MZ genotype) have 30% increased risk of developing COPD than MM [6]
    7. Risk of emphysema increases greatly at A1AT serum levels <800 mg/L
    8. Check A1AT for emphysema <50 years of age with little or no smoking history
    9. Intravenous infusion of A1AT raises serum and alveolar levels, may slow disease
  7. Increased airway responsiveness to methacholine or histamine challenge predicts accelerated decline of lung function over 5 years [38]

E. Pathophysiology [1,3] navigator

  1. Chronic inflammation of airways, usually due to toxic irritations
    1. Cigarette smoke, including second hand smoke, is major irritant
    2. Lung tissue is lost as part of the normal aging process
    3. This chronic process is rapidly accelerated by irritants
    4. Non-smokers lose FEV1 at ~20-30mL/year after age 35
    5. Smokers lose FEV1 at 40-60mL/year
    6. When FEV1 goes below a threshhold level (1.5-2.5L), symptoms occur
    7. Hyperinflation at rest, worsening with exercise, also seen in moderate to severe COPD
    8. Hyperinflation prominent during COPD exacerbations
  2. Contributions to Airflow Limitation [24]
    1. Disruption of epithelial barrier with Interference with mucociliarly clearance
    2. Increase in accumulation of inflammatory mucous barier
    3. Infiltration of airway walls with inflammatory cells
    4. Deposition of connective tissue in airway walls
    5. Chronic irritative processes eventually lead to lung tissue destruction
    6. Airflow limitation is most prominant in chronic bronchitis
    7. Emphysema is a pathologic condition of lung tissue destruction
  3. Mechanisms of Lung Tissue Destruction [41]
    1. Destruction occurs primarily in bronchioles and lung parenchyma
    2. Increased numbers of macrophages and CD8+ cytotoxic T lymphocytes
    3. Lymphoid follicles form in septae; infiltration of alveolar walls by leukocytes
    4. Neutrophil numbers are increased, particularly in patients with severe COPD
    5. Neutrophil proteases released during inflammation believed to mediate most destruction
    6. Protease to antiprotease ratio is abnormally high in lungs of patients with COPD
  4. Causes of Inflammation
    1. Destruction of lung tissue reduces ability to clear microorganisms from lungs
    2. Role of bacteria in inducing exacerbations increasingly clear [9]
    3. Reduces vascular beds and normal lung epithelium impair leukocyte migration
    4. Pollutants and cigarette smoke inhibit alveolar macrophage function and ciliary motion
    5. Result is increased bacterial load which leads to chronic inflammation
    6. Bacteria and neutrophils also increase oxidative stress levels
    7. Neutrophils are found in large numbers, leading to supperative inflammation
    8. Sputum may contain prevalent eosinophils, suggesting an allergic component [10]
    9. Thus, inflammation in bronchitis is characterized by sputum overproduction and fibrosis
    10. Contrast with asthma, where inflammation (mainly eosinophils) causes airway constriction
  5. Gene Expression and Disease Severity [19]
    1. Severe COPD associated with perpetual inflammation
    2. Chromatin (histone) acetylation levels determine expression of genes
    3. Reduced histone deacetylase (HDAC) levels found in progressive COPD
    4. Smoking, bacterial pathogens, and other COPD contributors reduces HDAC levels
  6. Protease-Antiprotease Imbalance
    1. Proteases are overexpressed in COPD patients' lungs
    2. Neutrophils and macrophages are major cells responsible for protease production
    3. Matrix metalloproteinases (MMP), neutrophil elastase, proteinase 3, cathepsins implicated
    4. Macrophage MMP-1 (collagenase) and MMP-9 (gelatinase B) particularly destructive
    5. Macrophage metalloelastase (MMP-12) may be induced by tobacco smoke
    6. A variety of antiproteases including alpha-1 antitrypsin protect lung tissue
    7. Tissue inhibitors of MMPs (called TIMP-1, -2, and -3) play major roles
    8. A1-antitrypsin deficiency causes pan-alveolar destruction, pan-lobular emphysema
    9. Smoking reduces functional levels of A1-antitrypsin production (oxidation of enzyme)
    10. However, it is not clear if a1-antitrypsin plays a major protective role in usual COPD
  7. Oxidative Stress
    1. Both pulmonary and systemic oxidative stress found in COPD patients
    2. COPD patients exhale increased levels of hydrogen peroxide (H2O2)
    3. Reactive oxygen species increase local and systemic inflammation
    4. Patients with COPD have elevated circulating levels of Interleukin 6 and CRP
    5. Weight loss in COPD associated with elevelated levels of tumor necrosis factor alpha (TNFa)
    6. Weight loss is largely due to loss of skeletal muscle and waisting of limb muscles
  8. Common Organisms Colonizing Lungs of COPD Patients
    1. Streptococcus pneumoniae
    2. Haemophilus influenza
    3. Moraxella catarrhalis (Brahnamella): G- diplococci
    4. Other gram negative organisms
    5. Thus, antibiotic prescriptions in COPD patients must cover the above organisms
    6. Picornavirus or adenovirus often associated with COPD exacerbations [12]
  9. Result of Pulmonary Parenchyma Destruction is Chronic Hypoxemia [41]
    1. Several mechanisms of hypoxemia exist
    2. Mucous plugging with shunting and V/Q mismatch appears to make major contribution
    3. Accumulation of inflammatory mucous exudeates in lumen and leukocyte accumulation
    4. Lymphoid follicles also form in walls
    5. Destruction of lung tissue prevents O2 exchange
    6. Repair or remodeling of walls leads to thickening and fibrosis
    7. The compensatory responses to hypoxemia lead to chronic cardiopulmonary dysfunction
  10. Response to Hypoxemia
    1. Increased ventilatory drive - decreases pCO2, increases pO2 and work of breathing
    2. Non-pulmonary vascular beds dilate - decreased systemic vascular resistance (SVR)
    3. Decreased SVR induces tachycardia and increased stroke volume (cardiac output up)
    4. Pulmonary vascular resistance (PVR) increases to improve ventilation perfusion matches
    5. This increase in PVR leads to pulmonary hypertension and right heart failure
    6. Hypoxia also leads to increased erythropoietin production, increased red cell mass
    7. The increased RBC mass (erythrocytosis) increases cardiac work
    8. Also increases blood viscosity and may require phlebotomy
    9. Supplemental oxygen, particularly at night, may slow or prevent progression
  11. Etiology of CO2 retention in COPD is unclear
    1. Appears to be mainly due to mucus pluging with V/Q mismatch
    2. Increasing O2 in patients with COPD may increase CO2 retention
    3. Likely due to increased V/Q mismatch and hypoventilation due to reduced hypoxic drive
    4. Respiratory drive in CO2 retainers is mostly pH (not CO2 level) dependent
    5. Chronic CO2 retention is poor prognostic factor for COPD patients
    6. Hypercarbia also increases blood pressure (frank HTN) in COPD exacerbations [14]
  12. Respiratory Muscle Changes
    1. Diaphragm, normally convex, becomes flattened with emphysema
    2. Flattening of diaphragm occurs due to loss of parenchymal elasticity
    3. This leads to loss of diaphragm's ability to expand lung size
    4. Lung reduction surgery can improve convexity of diaphragm and inspiration (see below)
    5. Respiratory muscles will fatigue as well, particularly accessory muslces
    6. Diaphragm muscle fibers adapt to chronic fatigue with molecular changes
    7. These changes include increases in slow and reduction in fast myosin types

F. Stages and Treatment Overview navigator

  1. Chronic disease requires treatment to maintain stability and reduce progression
  2. Quitting smoking is essential to disease improvement and reducing mortality
  3. Various interventions can reduce the number of acute exacerbations
  4. Acute exacerbations must be treated aggressively
  5. Surgical lung resection can sometimes improve cardiopulmonary dynamics significantly
  6. Pneumococcal and annual influenza vaccinations
  7. "GOLD" Stages 0 (at risk) to IV (very severe) [11]
    1. Stages 1-4 all include irreversible obstructive lung disease on spirometry
    2. Note: All spirometry for staging should be done post-bronchodilator
  8. Stage 0
    1. Chronic symptoms
    2. Exposure to risk factors
    3. Normal spirometry
  9. Stage I (mild)
    1. FEV1/FVC <70%
    2. FEV1 >80%
    3. WIth or without symptoms
    4. Generally not treated [4]
  10. Stage II (moderate)
    1. FEV1/FVC <70%
    2. 50% < FEV1 <80%
    3. WIth or without symptoms
  11. Stage III (severe)
    1. FEV1/FVC <70%
    2. 30% < FEV1 <50%
    3. WIth or without symptoms
  12. Stage IV (very severe)
    1. FEV1/FVC <70%
    2. FEV1 <30% OR
    3. FEV1 <50% with chronic respiratory failure
  13. Spirometry should be used frequently to assess treatment response, progression [11]

G. Treatment of Chronic Stable COPD [1,3,4] navigator

  1. Chronic Treatment Overview [4,7,8]
    1. Smoking cessation is essential; pursue aggressively [11]
    2. Inhaled agents mainly for symptomatic COPD with FEV1 <60% [4]
    3. Inhaled agents are mainstay: anticholinergics, glucocorticoids (GC), long-acting ß2-agonists
    4. Inahled GC with long-acting ß-agonist more effective than either alone [17,22]
    5. Inhaled anticholinergics reduce exacerbation rates, resource utilization, and when added to other inhaled agents, improve disease control [21,37]
    6. Mucolytics reduce exacerbations, illness days, antibiotic use in COPD [18]
    7. Pulmonary rehabilitation including exercise beneficial, mainly for FEV1<60% [4,16,32,47]
    8. Interval or continuous high-intensity exercise both highly beneficial in COPD [32]
    9. Supplemental oxygen mainly for patients with paO2 <55mmHg at rest [4]
    10. Intermittant antibiotics only as needed (regular cycling is generally not recommended)
    11. Severe disease requires specific treatments (see below)
  2. Smoking Cessation [11]
    1. Essential to any meaningful treatment response
    2. GOLD Strategies to Intervene: "Ask, Advise, Assess, Assist, Arrange"
    3. Physicians must use anti-smoking agents aggressively to help stop smoking
    4. These agents include varenicline (Chantix®), buproprion (Zyban®) or nicotine replacement
    5. Inverventions are usually 8 or more weeks, with at least several >10 minute sessions
  3. Anticholinergic Agents [40,47]
    1. Used alone in chronic disease or as adjuncts to ß2-agonist therapy in acute and chronic
    2. Combination more effective than ß2-agonist or anticholinergic agents used alone
    3. Ipratropium (Atrovent®) is a nonselective, short acting inhibitor of all three muscarinic acetylcholine receptors (M1, M2, M3)
    4. M1 and M3 are dilatory, but M2 is an inhibitor receptor
    5. Tiotropium (Spiriva®) is a selective M1/M3 agonist with long duration of action [40]
    6. Tiotropium 10µg qd had fever exacerbations, better FEV1, reduced use of ß2-agonists compared with ipratropium 40µg qid
    7. Tiotropium qd superior to salmeterol (Serevent®) bid in COPD patients
    8. Tiotropium qd inhaler reduces COPD exacerbations and may reduce resource use in moderate to severe COPD [44]
    9. Adding tiotropium to salmeterol+fluticasone improves lung function, quality of life, and reduced hospitalizations overall, with variable effects on exacerbations [21,37]
    10. Formoterol beneficial when added to tiotropium [20]
    11. Inhaled anticholinergics have no or only mild cardiac effects
    12. Ipratroprium (Atroven®) dose is 2-4 puffs (40-80µg) po qid
  4. ß2-Agonists [47]
    1. In chronic COPD treatment, efficacy of ipratropium is better than short- (but not long-) acting ß2-agonists
    2. Long acting ß2-agonist salmeterol (Serevent®) superior to ipratroprium on FEV1, dyspnea rating
    3. Tiotropium appears to be more active than long- and short-acting ß2-agonists
    4. Long acting ß2-agonists salmeterol or formoterol (Foradil®) should be used
    5. Nebulized arformoterol (Brovana®) and formoterol (Perforomist®) are available for patients who cannot tolerate dry powder inhalers [45,48]
    6. Formoterol nebulization 20µg bid improved FEV1 and reduced COPD exacerbations [48]
    7. Formoterol added to tiotropium is superior to tiotropium alone in COPD [20,40]
    8. Short acting ß2 agonists such as albuterol (Ventolin®) are mainly effectiv in exacerbations
    9. Combivent® (albuterol + ipratropium) is more effective than single agents alone
    10. Fluticasone + salmeterol (Advair®) bid provided improved FEV1 superior to either alone over 12 months of therapy [17,22]
    11. Advair Diskus® (blister: 100, 250 or 500µg fluticasone /50µg salmeterol) 1 inhalation bid
    12. Advar HFA® (dose: 45, 115, or 230µg fluticasone / 21µg salmeterol) 2 inhalations bid
    13. Budesonide + formoterol (Symbicort®): 80 or 160µg/4.5µg per inhalation; 2 puffs bid [48]
  5. Glucocorticoids (GC; see below)
    1. Inhaled GC benefit in chronic COPD treatment, not during exacerbations
    2. High dose systmic GC in COPD exacerbations - initially given IV
    3. Oral GC for stable COPD will benefit ~10% of patients
    4. Patients with prevalent eosinophils in sputum may benefit most from GC [10]
  6. Theophylline
    1. Weak bronchodilator which may increase respiratory muscle strength mildly (~10%)
    2. Use in difficult / severe cases is strongly recommended
    3. May prevent overnight attacks
    4. Improvement in exercise tolerance in moderate to severe COPD cases
    5. Improvement often seen on patients on ventilator with low tidal volume and/or apnea
  7. Antibiotic Therapy
    1. In most patients, there is no benefit to chronic suppressive therapy with antibiotics
    2. In general, antibiotics should be reserved for mild to moderate exacerbations
    3. Antibiotics used in exacerbations must cover the organisms described above
    4. Since many of these produce ß-lactamases, appropriate drugs should be used (see below)
  8. Decongestants
    1. Pseudoephedrine
    2. Entex® or Deconsal® (Pseudoephedrine with Gauifenesin)
    3. Anti-histamines are not recommended (dry up secretions)
  9. Mucolytics [18]
    1. N-Acetylcysteine (NAC, Mucomist®): to thin out thick secretions, make easier to clear
    2. NAC did not slow progression of COPD or reduce exacerbations (3 years, 600mg qd) [42]
    3. Organiden: iodonated mucolytic, thins mucus, easier to clear
  10. Supplemental Oxygen [4,23,47]
    1. Usually for patients with pO2 at rest of <55-60mm Hg
    2. Clear benefits in exercise tolerance when given over long term
    3. Improvement in cardiac function (including right heart pressures)
    4. Reduction in mortality in most studies
    5. Some patients do not respond at all, and there are currently no predictors of response
    6. Strongly recommend a trial of supplemental oxygen for patients with pO2 <55mm
  11. Pulmonary Rehabilitation [25]
    1. Continuum of services dedicated to evaluation and management of respiratory problems
    2. Mainly indicated for FEV1<50% [4]
    3. Initial goal is improvement in activities of daily living (ADL)
    4. In addition, improved functional capacity beyond ADL are sought
    5. Definite benefits of pulmonary rehabilitation programs in short and long terms
  12. Noninvasive ventilation mainly for acute exacerbations

H. Inhaled Glucocorticoids (GC) in COPD [47] navigator

  1. Essentially all COPD patients should be treated with chronic inhaled GC
  2. Efficacy [26]
    1. Inhaled GC improve mortality in COPD patients
    2. Inhaled GC reduced rate of COPD exacerbation 25-30% [7,27]
    3. Inhaled GC do not slow decline of or FEV1 / lung function in COPD [26]
    4. Inhaled GC + long acting ß-agonist reduced exacerbations ~5% versus either agent alone [7]
    5. Smoking MUST be discontinued to receive benefit from inhaled GC
    6. Osteoporosis should be evaluated and appropriate prevention/treatment instituted
  3. Inhaled Fluticasone in Stable COPD
    1. Study in current or ex-smokers with COPD (all FEV1 <70%)
    2. Fluticasone 500µg bid versus placebo for 6 months
    3. Fluticasone group had improved FEV1, FVC, and mid-expiratory flow, reduced exacerbations
    4. Fluticasone group also had reduced sputum and cough, improved exercise tolerance
    5. Fluticasone + salmeterol bid improved FEV1 and patient well-being, reduced mortality, exacerbations, superior to either alone; slight increase in pneumonia risk [17,22]
  4. Inhaled Budesonide in Smokers with Mild COPD [28]
    1. Study in continuing smokers with mild COPD (FEV1 mean 77%)
    2. Comparison of inhaled budesonide versus placebo inhaler
    3. During first 6 months of treatment, budesonide improved FEV1 versus drop with placebo
    4. After 6 months of treatment, pulmonary function declined in both groups
    5. Thus, inhaled budesonide does not reduce the long term consequences of smoking
  5. Inhaled Triamcinolone in Stable COPD [29]
    1. Patients (1116 total) with COPD and FEV1 30-90% of predicted value
    2. Triamcinolone (Azmacort®) 600µg (6 puffs) bid versus placebo for mean of 40 months
    3. No improvement in FEV1 in triamcinolone versus placebo group
    4. However, triamcinolone group had reduced hospitalizations, illness, airway reactivity
    5. Triamcinolone group had reduced bone density compared with placebo

I. New Treatments for COPD [2,13]navigator

  1. Antileukotrienes
    1. Receptor antagonists
    2. 5-lipoxygenase inhibitors
  2. CXCR2 Antagonists: Groalpha or Interleukin 8 Antagonists
  3. TNFa Blockade
    1. Monoclonal antibodies
    2. Soluble TNFa-Receptor
    3. TNFa-converting enzyme (TACE) inhibitors
  4. Antioxidants have not shown benefits to date
  5. Protease Inhibitors
    1. MMP Inhibitors
    2. Elastase inhibitors
    3. Cathepsin inhibitors
    4. alpha1-antitrypsin (purified / recombinant)
    5. Elafin
  6. Phosphodiesterase 4 (PDE4) Inhibitors [15,30]
    1. PDE4 is main enzyme involved in degration of cyclic AMP in various cell types
    2. Main role of PDE4B isoform in immune, inflammatory, and airway smooth muscle cells
    3. Cilomilast and roflumilast are specific PDE4 inhibitors
    4. Cilomilast in patients with FEV1 <50% and FEV1/FVC~55%
    5. Cilomilast 15mg po bid improved trough FEV1, FVC, and PEF substantially
    6. No improvement in quality of life measures or rates of serious adverse events
    7. Nausea, diarrhea, abdominal pain (likely due to PDE4D isoform effects)
    8. Roflumilast is more selective for PDE4B than PDE4D
    9. Roflumilast 250µg and 500µg po qd for 24 weeks reduced exacerbations and significantly imporved FEV1 after bronchodilator therapy, without bronchodilator effects [15]
    10. Main side effects of roflumilast are nausea and diarrhea (mainly at 500µg qd)
  7. Other Antiinflammatory Agents
    1. Nuclear factor kappa B (NFkB) inhibitors
    2. Leukocyte Adhesion Molecule Blockade
    3. Mitogen activated (MAP) kinase (p38) inhibitors
    4. Interleukin 10
    5. PI3K gamma inhibotrs
    6. PPAR activators
  8. Nitric Oxide [31]
    1. Bronchial and arterial vasodilator
    2. Investigated in patients with pulmonary hypertension and COPD
    3. Chronic, pulsed, inhaled nitric oxide may reduce pulmonary pressures in COPD
  9. Lung Regeneration Agents - retinoids, stem cells

J. Surgical Treatment of COPD [33,34]navigator

  1. Types
    1. Bullectomy
    2. Volume Reduction Surgery (pneumoplasty)
    3. Lung Transplantation
  2. Indications
    1. Incapacitating dyspnea
    2. Compression of relatively normal lung parenchyma by diseased lung tissue
  3. Bullectomy
    1. Removal of large bullae improves respiratory mechanics, exercise tolerance
    2. Resection in upper lobes is most effective
  4. Volume Reduction Pneumoplasty
    1. Volume reduction surgery (pneumoplasty ± bullectomy) are performed
    2. About 30% of lung is excised with aim to reduce total lung capacity and residual volume
    3. Allows diaphragmatic contour to return to near baseline concavity
  5. Medical Therapy versus Surgery (Initial Study) [35]
    1. Carefully screened patients
    2. Average initial FEV1 0.75L and median shuttle distance 215 meters
    3. Surgery increased FEV1 by 70mL and shuttle distance by 50 meters on average
    4. Surgery increased quality of life as well
    5. Patients randomized to continued medical therapy rather than sugery declined
    6. Patients with FEV1<20%, DLCO <20%, or homogeneous emphysema have increased mortality with surgery versus medical therapy [35]
    7. Surgery is recommended ONLY for selected patients with severe emphysema
  6. Lung Volume Reduction Surgery versus Medical Therapy [33,34]
    1. 1218 patients with severe emphysema
    2. Patients undergo pulmonary rehabilitation and randomized to surgery or medications
    3. Mortality similar in both groups
    4. Surgery improved exercise capacity better than medical therapy
    5. Patients with high baseline exercise capacity are poor candidates for surgery
    6. Surgery is very expensive and QALY range from about $100K-300K [36]
    7. Surgery should probably be reserved only for baseline low exercise capacity
  7. Indications for Lung Transplantation in COPD
    1. FEV1<25% of predicted after bronchodilator
    2. Clinically significant hypoxemia or hypercapnia
    3. Clinically significant pulmonary hypertension (P-HTN)
    4. Rapid decline in lung function
    5. Frequent, severe exacerbations
  8. Bilateral lung transplant leads to longer survival than single transplant, particular in age <60 [49]

Resources navigator

calcAlveolar Gas Equation

References navigator

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