Chronic obstructive pulmonary disease

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Chronic obstructive pulmonary disease (COPD), also known as chronic obstructive airway disease (COAD), is an obstructive lung disease that is characterized by the pathological limitation of airflow in the airway that is not fully reversible. This contrasts to asthma, an obstructive lung disease in which the obstruction is reversible.

COPD is the umbrella term for chronic bronchitis, emphysema and a range of other lung disorders. It is most often due to tobacco smoking,[1] but can be due to other airborne irritants such as coal dust, asbestos or solvents, as well as congenital conditions such as alpha-1-antitrypsin deficiency.

Signs and symptoms

The main symptoms of COPD include dyspnea (shortness of breath) lasting for months or perhaps years, possibly accompanied by wheezing, and a persistent cough with sputum production.[2] It is possible the sputum may contain blood (hemoptysis), usually due to damage of the blood vessels of the airways. Severe COPD could lead to cyanosis (bluish decolorization usually in the lips and fingers) caused by a lack of oxygen in the blood. In extreme cases it could lead to cor pulmonale due to the extra work required by the heart to get blood to flow through the lungs.[3]

COPD is particularly characterised by the spirometric measurement of a ratio of forced expiratory volume over 1 second (FEV1) to forced vital capacity (FVC) being < 0.7 and the FEV1 < 70% of the predicted value [4] as measured by a plethysmograph. Other signs include a rapid breathing rate (tachypnea) and a wheezing sound heard through a stethoscope. Pulmonary emphysema is NOT the same as subcutaneous emphysema, which is a collection of air under the skin that may be detected by the crepitus sounds produced on palpation.[5]

Causes

Cigarette smoking

A primary risk factor of COPD is chronic tobacco smoking. In the United States, around 90% of cases of COPD are due to smoking.[6] Not all smokers will develop COPD, but continuous smokers have at least a 25% risk.[7]

Occupational pollutants

Some occupational pollutants, such as cadmium and silica, have shown to be a contributing risk factor for COPD. The people at highest risk for these pollutants include coal workers, construction workers, metal workers and cotton workers, amongst others. However, in most cases these pollutants are combined with cigarette smoking further increasing the chance of developing COPD.[6] These occupations are commonly associated with other respiratory diseases, particularly pneumoconiosis (black lung disease). Asbestosis can appear even with minimal exposure.

Air pollution

Urban air pollution may be a contributing factor for COPD as it is thought to impair the development of the lung function. In developing countries indoor air pollution, usually due to biomass fuel, has been linked to COPD, especially in women.[1]

Genetics

Very rarely, there may be a deficiency in an enzyme known as alpha 1-antitrypsin which causes a form of COPD.[8]

Other risk factors

Increasing age, male gender, allergy, repeated airway infection and general impaired lung function are also related to the development of COPD.

Pathophysiology

Chronic bronchitis

Chronic bronchitis is defined in clinical terms as a cough with sputum production on most days for 3 months of a year, for 2 consecutive years.[9]

Chronic bronchitis is hallmarked by hyperplasia (increased number) and hypertrophy (increased size) of the goblet cells (mucous gland) of the airway, resulting in an increase in secretion of mucus which contributes to the airway obstruction. Microscopically there is infiltration of the airway walls with inflammatory cells, particularly neutrophils. Inflammation is followed by scarring and remodeling that thickens the walls resulting in narrowing of the small airway. Further progression leads to metaplasia (abnormal change in the tissue) and fibrosis (further thickening and scarring) of the lower airway. The consequence of these changes is a limitation of airflow.[10].

Emphysema

For more information, see: Emphysema.

Emphysema is defined histologically as the enlargement of the air spaces distal to the terminal bronchioles, with destruction of their walls.[9]

The enlarged air sacs (alveoli) of the lungs reduces the surface area available for the movement of gases during respiration. This ultimately leads to dyspnea in severe cases. The exact mechanism for the development of emphysema is not understood, although it is known to be linked with smoking and age.

Diagnosis

Clinical practice guidelines by a collaboration of American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society address diagnosis.[11]

The diagnosis of COPD is suggested by symptoms; it is a clinical diagnosis and no single test is definitive. A history is taken of smoking and occupation, and a physical examination is done. Measurement of lung function with a spirograph can reveal the loss of lung function.

The severity of COPD can be classified as follows using post-bronchodilator spirometry (see above)[12]:

Severity Post-bronchodilator FEV1 /FVC FEV1 % predicted
At risk >0.7 ≥80
Mild COPD ≤0.7 ≥80
Moderate COPD ≤0.7 50-80
Severe COPD ≤0.7 30-50
Very Severe COPD ≤0.7 <30 or 30-50 with Chronic Respiratory Failure symptoms

Physical examination

A systematic review by the Rational Clinical Examination concluded that no single medical sign or symptom can adequately exclude the diagnosis of COPD.[13] One study found that the presence of either "a history of smoking more than 30 pack-years, diminished breath sounds, or peak flow less than 350 L/min" has a sensitivity of 98 percent.[14]

Differential diagnosis

25% of patients with "unexplained exacerbation of chronic obstructive pulmonary disease" may have pulmonary embolism.[15]

Management

Although COPD is not curable, it can be controlled in a variety of ways. Clinical practice guidelines by Global Initiative for Chronic Obstructive Lung Disease (GOLD)[12], a collaboration including the American National Heart, Lung, and Blood Institute and the World Health Organization, as well as guidelines by the American College of Physicians published in 2011[16] and 2007[17][18] are available.

Smoking cessation

For more information, see: Smoking cessation.

Smoking cessation is one of the most important factors in slowing down the progression of COPD. Even at a late stage of the disease it can reduce the rate of deterioration and prolong the time taken for disability and death.[10]

Occupational change

Workers may be able to transfer to a significantly less contaminated area of the company depending on circumstances. Often however, workers may need complete occupational change.

Pharmacotherapy

Bronchodilators

There are several types of bronchodilators used clinically with varying efficacy: β2 agonists, M3 antimuscarinics, leukotriene antagonists, cromones and xanthines.[19] These drugs relax the smooth muscles of the airway allowing for improved airflow. Patients may feel less breathless after taking bronchodilators.

Older studies showed:

  • The β2 agonists and M3 antimuscarinics probably have similar efficacy[20]
  • All cause mortality may be worse for antimuscarinic according to a nested case-control study.[21]

More recent studies conclude differently and are in the table.

Major meta-analyses and randomized controlled trials of
bronchodilators for reducing all-cause mortality from COPD.[22][23][24][25]
Study/design Patients Intervention Outcome Results Comments
Treatment group Control group
Uplift study.[22]
Randomized controlled trial, 2008
5993 patients Tiotropium All-cause mortality at 4 years 14.9% † 16.5% The Uplift study was too recent to be in the Singh meta-analysis.
"tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV1"
Singh et al.[23]
Meta-analysis, 2008
14,783 in 17 trials Inhaled anticholinergics All-cause mortality 2% 1.6% "Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD"
Rodrigo et al.[24]
Meta-analysis, 2008
20,527 in 27 trials Long-Acting β-Agonists All-cause mortality 4.9% 6.5% "did not confirm previous data about an increased risk for respiratory deaths"
TORCH Study.[25]
Factorial randomized controlled trial, 2007
6112 patients Long-Acting β-Agonists combined with inhaled corticosteroids All-cause mortality at 3 years 12.6% 15.2% This is the major trial in the Rodrigo meta-analysis
Long-Acting β-Agonists 13.5% 15.2%
Inhaled corticosteroids 16.0% 15.2%
Notes:
† Statistically significant difference.
β2 agonists
For more information, see: Adrenergic beta-agonist.

There is a tendency for long acting β2 agonists to reduce death, especially if they are combined with an inhaled corticosteroid.[26][24][25] β2 agonists may slow progression of airway obstruction[27].

An increased risk is associated with long acting β2 agonists among patients with asthma due to decreased sensitivity to inflammation so generally the use of a concomitant corticosteroid is indicated [28][29].

There are several highly specific β2 agonists available. Salbutamol (Ventolin) is the most widely used short acting β2 agonist to provide rapid relief and should be prescribed as a front line therapy for all classes of patients. Other β2 agonists are Bambuterol, Clenbuterol, Fenoterol, and Formoterol. Longer acting β2 agonists such as Salmeterol act too slowly to be used as relief for dypsnea so these drugs should be used as a secondary therapy.

M3 muscarinic cholinergic antagonists

Antagonists of the acetylcholine receptor include inhaled antimuscarinics. Antimuscarinics specific for M3 muscarinic recetpro the have the advantage of avoiding endocrine and exocrine M1 receptors. The quaternary M3 muscarinic antagonist Ipratropium can be prescribed alone or is offered combined with salbutamol (Combivent) and with fenoterol (Duovent). Tiotropium provides improved specificity for M3 muscarinic receptors and has been beneficial in trials.[30]

Anticholinergics may increase adverse effects.[21][23]

Cromones

Cromones are mast cell stabilizers that are thought to act on a chloride channel found on mast cells that help reduce the production of histamine and other inflammatory factors. Chromones are also thought to act on IgE-regulated calcium channels on mast cells. Cromoglicate and Nedocromil, which has a longer half-life, are two chromones available.[31]

Leukotriene antagonists

More recently leukotriene antagonists block the signaling molecules used by the immune system.[32] Montelukast, Pranlukast, Zafirlukast are some of the leukotrienes antagonists.[33]

Methylxanthines

Theophylline is the prototype of the methylxanthine[34] class of drug. Teas are natural sources of theophylline and caffeine while chocolate is a source of theobromine. Caffeine is approximately 16% metabolized into theophylline. Relatively little used, aminophylline as a derivative of theophylline, which can be given intraveously (IV).

Nebulized theophylline has uncertain value when used in the EMR for treatment of dyspnea (Difficulty in breathing).[35] Patients need continual monitoring as theophylline has a narrow therapeutic range. More aggressive EMR interventions include IV H1 antihistamines and IV glucocorticoids.

Corticosteroids

Although inhaled corticosteroids can reduced the forced expiratory volume when added to long acting adrenergic beta-agonists, they have uncertain benefit on clinical outcomes and may increase pneumonia[36] Budesonide may not increase the risk of pneumonia due to quicker clearing from the airways according to a separate meta-analysis.[37]

A factorial randomized controlled trial in the preceding meta-analyses compared salmeterol and fluticasone alone and in combination and found that the combination group tended to have the least mortality but that "the reduction in death from all causes among patients with COPD in the combination therapy group did not reach the predetermined level of statistical significance".[25]

Inhaled fluticasone may increase the risk of pneumonia.[25] Budesonide may not share this risk due to quicker clearing from the airways according to a meta-analysis.[37]

Corticosteroids may be combined with bronchodilators in a single inhaler. Some of the more common inhaled steroids in use are beclomethasone, mometasone, and fluticasone.

Oral or intravenous corticosteriods can help treat exacerbations of COPD.[38][39]

Antiboitics

Antibiotics for acute exacerbations of COPD accelerate improvement of symptoms.[40]

Antibiotics may prevent exacerbations.

Randomized controlled trials af antibiotics to prevent exacerbations of COPD.[41][42]
Trial Patients Intervention Comparison Outcome Results Comment
Intervention Control
COPD Clinical Research Network[41]
2011
1577 patients
• 22% current smokers
azithromycin orally 250 mg daily Placebo Mean number of exacerbations at 12 months 1.48 1.83 p = 0.01
Seemungal[42]
2008
109 patients
• 48% current smokers
erythromycin orally 250 mg twice daily Placebo Median number of exacerbations at 12 months 1 2 p = 0.006

Mucolytic agents

Mucolytic agents such as N-acetylcysteine (NAC) 400 mg daily up to 600 mg daily, especially patients not already using inhaled corticosteroids.[43]

TNF antagonists

Tumor necrosis factor-alpha antagonists (TNF-a) are the most recent class of medications designed to deal with refractory cases. TNF-a is a cachexin or cachectin. Its inhibitors, all monoclonal antibodies; they are immunosuppressive with attendant risks. These rather expensive drugs include infliximab, adalimumab and etanercept.[44]

Narcotics

For more information, see: Palliative care#Dyspnea.

Narcotics may relieve dyspnea according to a systematic review[45] and more recent narrative review[46].

Direct respiratory support

Appropriate oxygen therapy is different in acute and chronic COPD. "Oxygen is widely used but poorly studied in emergency medicine, with a limited evidence base for its use in specific conditions. There are safety concerns about the underuse of oxygen in patients with critical illness and its overuse in conditions such as .." COPD [47]

Supplemental Oxygen

Excessive oxygen can produce hypercapnia and hypercapnic acidosis in patients with acute exacerbations of COPD. In 2006, 30 patients with a history of previous hypercapnic acidosis with a Pao2 >10.0 kPa—indicating that oxygen may have worsened the hypercapnia— were given “O2 Alert” cards and a 24% Venturi mask. so that field and emergency room personnel do not cause iatrogenic hypercapnia. [48] A larger recent prospective trial in prehospital care randomized patients to receive high-flow oxygen or titrated oxygen. [49]

  • Titrating the oxygen, compared with high flow oxygen. lowered the risk of death for all patients by 58% for all patients (relative risk 0.42, 95% confidence interval 0.20 to 0.89; P=0.02). Overall mortality was 9% (21 deaths) in the high flow oxygen arm compared with 4% (7 deaths) in the titrated oxygen arm; mortality in the subgroup with confirmed COPD was 9% (11 deaths) in the high flow arm compared with 2% (2 deaths) in the titrated oxygen arm. and by 78% for the patients with confirmed chronic obstructive pulmonary disease (0.22, 0.05 to 0.91; P=0.04).
  • The risk of death was significantly lower in the titrated oxygen arm compared with the high flow oxygen arm for all patients (high flow oxygen n=226; titrated oxygen n=179) and for the subgroup of patients with confirmed COPD (high flow n=117; titrated n=97).
  • Patients with COPD who received titrated oxygen according to the protocol were significantly less likely to have respiratory acidosis (mean difference in pH 0.12 (SE 0.05); P=0.01; n=28) or hypercapnia (mean difference in arterial carbon dioxide pressure −33.6 (16.3) mm Hg; P=0.02; n=29) than were patients who received high flow oxygen.

Long-term administration of oxygen is usually reserved for individuals with COPD who have arterial hypoxemia (PaO2 less than 55 mm Hg), or a PaO2 between 55 and 60 mm Hg with evidence of pulmonary hypertension, cor pulmonale, or secondary erythrocytosis (hematocrit >55%). In these patients, continuous home oxygen therapy (for >15 h/d) sufficient to correct hypoxemia has been shown to improve survival.[50]

Noninvasive positive pressure ventilation

Noninvasive positive pressure ventilation, without raising the oxygen level, (NPPV) may help severe episodes.[51][52]

Vaccination

Patients with COPD should be routinely vaccinated against influenza, pneumococcus and other diseases to prevent illness and the possibility of death.[19]

Pulmonary rehabilitation

Pulmonary rehabilitation is a program of disease management, counseling and exercise coordinated to benefit the individual.[53] Pulmonary rehabilitation has been shown to relieve difficulties breathing and fatigue. It has also been shown to improve the sense of control a patient has over their disease as well as their emotions.[54]

Clinical practice guidelines address the use of pulmonary rehabilitation.[11]

Self management

Self management may help the patients who are successful in learning management.[55]

Diet

A recent French study conducted over 12 years with almost 43,000 men concluded that eating a Mediterranean diet "halves the risk of serious lung disease like emphysema and bronchitis". [3]

Prognosis

ADO index[56]
  0 points 1 points 2 points 3 points 4 points 5 points
FEV1 ≥65% 36% - 64% ≤ 35%
Dyspnea (MRC dyspnea scale) 0 - 1 2 3 4
Age (years) 40 - 49 50 - 59 60 - 69 70 - 79 80 - 89 ≥ 90
From Table 6[56]
ADO (age, dyspnea, obstruction) index and 3 year mortality[56]
  0 points 1 points 2 points 3 points 4 points 5 points 6 points 7 points 8 points 9 points 10 points
Patients with longstanding and severe COPD 7% 10% 14% 18% 24% 31% 39% 47% 56% 64% 72%
Patients after first hospitalization 3% 4% 5% 7% 10% 13% 17% 22% 28% 34% 42%
From Table 7[56]

Various clinical prediction rules are available to estimate prognosis.[56]

Chronic airway obstruction may be an independent risk factor for coronary heart disease.[57]

Screening

Chronic obstructive pulmonary disease should not be screened for according to clinical practice guidelines by the American College of Physicians[58] and the Agency for Healthcare Research and Quality[59] This is due to the current lack of treatment for asymptomatic COPD and the inability of spirometric results to motivate smoking cessation.

"Telling smokers their lung age significantly improves the likelihood of them quitting smoking, but the mechanism by which this intervention achieves its effect is unclear" according to a randomized controlled trial. [60]

Epidemiology

According to the World Health Organization (WHO), 80 million people suffer from moderate to severe COPD and 3 million died due to it in 2005. The WHO predicts that by 2030, it will be the 4th largest cause of mortality worldwide.[61]

Since COPD is not diagnosed until it becomes clinically apparent, prevalence and mortality data greatly underestimate the socioeconomic burden of COPD.[19] In the UK, COPD accounts for about 7% of all days of sickness related absence from work.[10]

Smoking rates in the industrialized world have continued to fall, causing rates of emphysema and pulmonary neoplasms to slowly decline.

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