Chronic obstructive pulmonary disease

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This editable Main Article is under development and subject to a disclaimer.

[edit intro]

## Contents

* 1 Signs and symptoms
* 2 Causes
* 2.1 Cigarette smoking
* 2.2 Occupational pollutants
* 2.3 Air pollution
* 2.4 Genetics
* 2.5 Other risk factors
* 3 Pathophysiology
* 3.1 Chronic bronchitis
* 3.2 Emphysema
* 4 Diagnosis
* 4.1 Physical examination
* 4.2 Differential diagnosis
* 5 Management
* 5.1 Smoking cessation
* 5.2 Occupational change
* 5.3 Pharmacotherapy
* 5.3.1 Bronchodilators
* 5.3.1.1 β2 agonists
* 5.3.1.2 M3 muscarinic cholinergic antagonists
* 5.3.1.3 Cromones
* 5.3.1.4 Leukotriene antagonists
* 5.3.1.5 Methylxanthines
* 5.3.2 Corticosteroids
* 5.3.3 Antiboitics
* 5.3.4 Mucolytic agents
* 5.3.5 TNF antagonists
* 5.4 Narcotics
* 5.5 Direct respiratory support
* 5.5.1 Supplemental Oxygen
* 5.5.2 Noninvasive positive pressure ventilation
* 5.6 Vaccination
* 5.7 Pulmonary rehabilitation
* 5.8 Self management
* 5.9 Diet
* 6 Prognosis
* 7 Screening
* 8 Epidemiology
* 9 References

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[edit]

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[edit]

### Cigarette smoking[edit]

A primary risk factor of COPD is chronic tobacco smoking. In the United States of America, 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[edit]

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[edit]

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[edit]

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[edit]

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

## Pathophysiology[edit]

### Chronic bronchitis[edit]

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[edit]

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[edit]

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

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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[edit]

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[edit]

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

## Management[edit]

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[edit]

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[edit]

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[edit]

#### Bronchodilators[edit]

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

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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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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

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|
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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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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

### Vaccination[edit]

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

### Pulmonary rehabilitation[edit]

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[edit]

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

### Diet[edit]

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[edit]

ADO index[56] | 0 points | 1 points | 2 points | 3 points | 4 points | 5 points

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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

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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[edit]

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[edit]

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.

## References[edit]

1. ↑ 1.0 1.1 Devereux G. ABC of chronic obstructive pulmonary disease. Definition, epidemiology, and risk factors. BMJ 2006;332:1142-1144. PMID 16690673
2. ↑ U.S. National Heart Lung and Blood Institute - Signs and Symptoms
3. ↑ MedicineNet.com - COPD signs & symptoms
4. ↑ PatientPlus - Spirometry
5. ↑ eMedicine - Barotrauma
6. ↑ 6.0 6.1 MedicineNet.com - COPD causes
7. ↑ Lokke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: a 25 year follow up study of the general population. Thorax. 2006 Nov;61(11):935-9. PMID 17071833
8. ↑ MedlinePlus Medical Encyclopedia
9. ↑ 9.0 9.1 Longmore M, Wilkinson I, Rajagopalan S (2005). Oxford Handbook of Clinical Medicine, 6ed. Oxford University Press. pp 188-189. ISBN 0-19-852558-3.
10. ↑ 10.0 10.1 10.2 Kumar P, Clark M (2005). Clinical Medicine, 6ed. Elsevier Saunders. pp 900-901. ISBN 0702027634.
11. ↑ 11.0 11.1 Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T et al. (2011). "Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society.". Ann Intern Med 155 (3): 179-91. DOI:10.1059/0003-4819-155-3-201108020-00008. PMID 21810710. Research Blogging.
12. ↑ 12.0 12.1 Rabe KF, Hurd S, Anzueto A, et al (2007). "Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary". Am. J. Respir. Crit. Care Med. 176 (6): 532–55. DOI:10.1164/rccm.200703-456SO. PMID 17507545. Research Blogging.
13. ↑ Holleman DR, Simel DL (1995). "Does the clinical examination predict airflow limitation?". JAMA 273 (4): 313-9. PMID 7815660. [e]
14. ↑ Badgett RG, Tanaka DJ, Hunt DK, et al (1994). "The clinical evaluation for diagnosing obstructive airways disease in high-risk patients". Chest 106 (5): 1427-31. PMID 7956395. [e]
15. ↑ Tillie-Leblond I, Marquette CH, Perez T, et al (2006). "Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors". Ann. Intern. Med. 144 (6): 390–6. PMID 16549851. [e]
16. ↑ Qaseem, Amir; Timothy J. Wilt, Steven E. Weinberger, Nicola A. Hanania, Gerard Criner, Thys van der Molen, Darcy D. Marciniuk, Tom Denberg, Holger Schünemann, Wisia Wedzicha, Roderick MacDonald, Paul Shekelle (2011). "Diagnosis and Management of Stable Chronic Obstructive Pulmonary Disease: A Clinical Practice Guideline Update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society". Annals of Internal Medicine 155 (3): 179 -191. DOI:10.1059/0003-4819-155-3-201108020-00008. Retrieved on 2011-08-03. Research Blogging.
17. ↑ Qaseem A, Snow V, Shekelle P, et al (2007). "Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians". Ann. Intern. Med. 147 (9): 633–8. PMID 17975186. [e]
18. ↑ Wilt TJ, Niewoehner D, MacDonald R, Kane RL (2007). "Management of stable chronic obstructive pulmonary disease: a systematic review for a clinical practice guideline". Ann. Intern. Med. 147 (9): 639–53. PMID 17975187. [e]
19. ↑ 19.0 19.1 19.2 American Thoracic Society / European Respiratory Society Task Force (2005). Standards for the Diagnosis and Management of Patients with COPD. Version 1.2. New York: American Thoracic Society. http://www.thoracic.org/go/copd
20. ↑ Appleton S, Jones T, Poole P, et al. (2006). "Ipratropium bromide versus long-acting beta-2 agonists for stable chronic obstructive pulmonary disease". Cochrane Database Syst Rev 3: CD006101. DOI:10.1002/14651858.CD006101. PMID 16856113. Research Blogging.
21. ↑ 21.0 21.1 Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB (September 2008). "Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease". Ann. Intern. Med. 149 (6): 380–90. PMID 18794557. [e]
22. ↑ 22.0 22.1 Tashkin DP, Celli B, Senn S, et al. (October 2008). "A 4-year trial of tiotropium in chronic obstructive pulmonary disease". N. Engl. J. Med. 359 (15): 1543–54. DOI:10.1056/NEJMoa0805800. PMID 18836213. Research Blogging.
23. ↑ 23.0 23.1 23.2 Singh S, Loke YK, Furberg CD (September 2008). "Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis". JAMA 300 (12): 1439–50. DOI:10.1001/jama.300.12.1439. PMID 18812535. Research Blogging.
24. ↑ 24.0 24.1 24.2 Rodrigo GJ, Nannini LJ, Rodríguez-Roisin R (May 2008). "Safety of Long-Acting {beta}-Agonists in Stable COPD: A Systematic Review". Chest 133 (5): 1079–87. DOI:10.1378/chest.07-1167. PMID 18460518. Research Blogging.
25. ↑ 25.0 25.1 25.2 25.3 25.4 Calverley PM, Anderson JA, Celli B, et al (February 2007). "Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease". N. Engl. J. Med. 356 (8): 775–89. DOI:10.1056/NEJMoa063070. PMID 17314337. Research Blogging.
26. ↑ Nannini LJ, Cates CJ, Lasserson TJ, Poole P (2007). "Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease". Cochrane Database Syst Rev (4): CD006829. DOI:10.1002/14651858.CD006829. PMID 17943918. Research Blogging.
27. ↑ Celli BR, Thomas NE, Anderson JA, et al (August 2008). "Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study". Am. J. Respir. Crit. Care Med. 178 (4): 332–8. DOI:10.1164/rccm.200712-1869OC. PMID 18511702. Research Blogging.
28. ↑ [1]
29. ↑ [2]
30. ↑ Niewoehner DE, Rice K, Cote C, et al. (September 2005). "Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial". Ann. Intern. Med. 143 (5): 317–26. PMID 16144890. [e]
31. ↑ Howell JB, Altounyan RE (1967). "A double-blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma". Lancet 2 (7515): 539–42. PMID 4166895. [e]
32. ↑ Price D, Musgrave SD, Shepstone L, Hillyer EV, Sims EJ, Gilbert RF et al. (2011). "Leukotriene antagonists as first-line or add-on asthma-controller therapy.". N Engl J Med 364 (18): 1695-707. DOI:10.1056/NEJMoa1010846. PMID 21542741. Research Blogging.
33. ↑ BROCKLEHURST WE (1960). "The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock". J. Physiol. (Lond.) 151: 416–35. PMID 13804592. [e]
34. ↑ http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=HomeMolecule\archive\motw_xanthine_arch.html
35. ↑ Duffy N, Walker P, Diamantea F, Calverley PM, Davies L (September 2005). "Intravenous aminophylline in patients admitted to hospital with non-acidotic exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial". Thorax 60 (9): 713–7. DOI:10.1136/thx.2004.036046. PMID 15939732. PMC 1747521. Research Blogging.
36. ↑ Rodrigo GJ, Castro-Rodriguez JA, Plaza V (2009). "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 136 (4): 1029-38. DOI:10.1378/chest.09-0821. PMID 19633090. Research Blogging.
37. ↑ 37.0 37.1 Sin DD, Tashkin D, Zhang X, Radner F, Sjöbring U, Thorén A et al. (2009). "Budesonide and the risk of pneumonia: a meta-analysis of individual patient data.". Lancet 374 (9691): 712-9. DOI:10.1016/S0140-6736(09)61250-2. PMID 19716963. Research Blogging.
38. ↑ de Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA, van den Berg JW (2007). "Oral or IV Prednisolone in the Treatment of COPD Exacerbations: A Randomized, Controlled, Double-blind Study". Chest 132 (6): 1741–7. DOI:10.1378/chest.07-0208. PMID 17646228. Research Blogging.
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