Chronic Obstructive Pulmonary Disease

Selena Abboud

Definition

• Common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.

Epidemiology

• Third leading cause of death.

• Mortality rate in Male vs Female ??

• The mortality rate is higher in whites compared with that in blacks.

• Prevalence is higher in smokers and previous smokers.

• Prevalence is higher in those > 40 years.

Chronic bronchitis (clinical)

• Chronic inflammation of lower respiratory tract with chronic cough and phlegm for at least 3 consecutive months in 2 consecutive years.

• Excess mucus production narrows the airways.

• Patients often have a productive cough.

• Inflammation and scarring in airways, enlargement

in mucous glands, and smooth muscle hyperplasia

lead to obstruction.

Emphysema (pathological) • Destruction of the lung alveoli with abnormal permanent enlargement of the airways distal to the terminal bronchioles.

• Destruction of alveolar walls is due to relative excess in protease (elastase) activity or relative deficiency of antiprotease (α1-antitrypsin) activity in the lung.

• Elastase is released from polymorphonuclear neutrophils (PMNs) and macrophages

and digests human lung. This is inhibited by α1-antitrypsin.

• Tobacco smoke increases the number of activated PMNs and macrophages, inhibits α1-antitrypsin and increases oxidative stress on the lung by free radical production.

• Centrilobular/ centriacinar emphysema: Most common type, seen in smokers (rarely in nonsmokers) Destruction limited to respiratory bronchioles (proximal acini) with little change in distal acini Predilection for upper lung zones • Panlobular/ panacinar emphysema: Seen in patients with α1-antitrypsin deficiency Destruction involves both proximal and distal acini Predilection for lung bases • Paraseptal emphysema Emphysematous lesions in the parenchyma adjacent to the pleural surfaces

Clinical features

• Cough, sputum production

• Dyspnea (Chronic and progressive)/ (on exertion or at rest depending on severity)

• Wheezing and chest tightness

• Others – including fatigue, weight loss, anorexia, syncope, rib fractures, ankle swelling, depression, anxiety. ( Malignancy/TB)

• Edema (exacerbation)

• Morning headache (hypercapnia)

History

• Pattern of symptom development

• Impact of disease on patient’s life

• Patient’s exposure to risk factors

• Past medical history (asthma, allergy, sinusitis, polyps, infections)

• Family history of COPD or other chronic respiratory disease.

• History of exacerbations or previous hospitalizations for respiratory disorder

• Presence of comorbidities

• Social and family support available to the patient.

• Possibilities for reducing risk factors, especially smoking cessation

COPD Assessment Test (CATTM)

Signs

A. Prolonged expiratory time with pursed lip breathing

B. Auscultation: end-expiratory wheeze, decreased breath sounds, and/or inspiratory crackles

C. Tachypnea, tachycardia

D. Cyanosis

E. Use of accessory respiratory muscles

F. Hyperresonance and distant heart sounds

G. Signs of cor pulmonale

H. Finger clubbing is not a feature of COPD. (lung cancer or fibrosis).

• The goal of COPD assessment is to determine:

1- The level of airflow limitation

2- The impact of disease on the patient’s health status

3- The risk of future events (such as exacerbations, hospital admissions, or death) in order to guide therapy.

Investigations

1- Pulmonary function test/ Spirometry

• FEV1/FVC ratio is <0.70

• FEV1 is decreased.

• TLC is increased.

• Peak expiratory flow rate is decreased.

• Residual volume is increased.

• Vital capacity is low.

Post-bronchodilator FEV1

2- Chest X-ray

• To identify alternative diagnoses such as cardiac failure, interstitial lung disease and other complications of smoking such as lung cancer .

• Severe emphysema: Hyperinflation due to hyperexpansion

flattened diaphragm and enlarged retrosternal space

Diminished vascular markings due to parenchymal loss

• Acute exacerbation to rule out complications like pneumonia and pneumothorax

3- α1-antitrypsin assay in younger patients (<40) with predominantly basal emphysema and those with family history.

4- ABGs (Chronic PCO2 retention, decreased PO2) and pulse oximetry (O2 saturation)

5- Blood count to exclude anemia or document polycythemia

6- CT scan

• Bronchial wall thickening

• Air trapping (small airway obstruction)

• Narrowing of the trachea in the coronal plane

• Pulmonary artery enlargement in pulmonary

Hypertension

• Bulla

Panlobular

paraseptal

7- Lung volume measurement (assessment of hyperinflation) performed by helium dilution technique

• In patients with severe COPD and large bullae body plethysmography is preferred because the use of helium may under-estimate lung volumes.

• The presence of emphysema is suggested by a low gas transfer

8- Exercise tests (exercise tolerance) to provide a baseline to judge the response to bronchodilator therapy or rehabilitation programs and help in assessing prognosis.

Low symptoms, High risk

Low symptoms, Low risk High symptoms, Low risk

High symptoms, High risk

• Group A patients: bronchodilator either short or long acting .

-This should be continued if benefit is documented.

• Group B patients: long acting bronchodilator.

-superior to short acting bronchodilators and taken as needed.

-There is no evidence to recommend one class of long acting bronchodilators over another for initial relief of symptoms in this group of patients. In the individual patient, the choice should depend on the patient’s perception of symptom relief

-For patients with severe breathlessness initial therapy with two bronchodilators may be considered

- Investigate for comorbidities.

• Group C: single bronchodilator.

-LAMA was superior to the LABA regarding exacerbation prevention.

-Therefor we recommend starting therapy with LAMA in this group

• Group D: LAMA (has effect on breathlessness and exacerbations)

• For patients with more severe symptoms (CAT>=20), especially driven by greater dyspnea and/or exercise limitation, LAMA/LABA may be chosen as initial treatment.

• An advantage of LABA/LAMA over LAMA for exacerbation prevention has not been consistently demonstrated, so the decision to use LABA/LAMA as initial treatment should be guided by the level of symptoms

• In some patients, initial therapy with LABA/ICS may be the first choice for reducing exacerbations, in patients with blood eosinophil counts >= 300 cells/µL.

• LABA/ICS may also be the first choice in COPD patients with history of asthma

• ICS may cause side effects such as pneumonia, so should be used as initial therapy only after the possible clinical benefits versus risk have been considered.

• The choice of inhaler device has to be individually tailored according to access, cost, prescriber, patients ability and preference.

• Instructions for proper inhaler technique and re-check every visit.

• Check adherence to therapy before modification.

• Inhaled bronchodilators are preferred over oral bronchodilators.

• Theophyline is not preferred unless other long term treatment bronchodilators are unavailable or unaffordable.

• Tiotropium improve the effectiveness of pulmonary rehabilitation.

• LAMA and LABA are preferred over short agents except for people with occasional dyspnea and patients who need immediate relief of symptoms and are on maintenance with long acting bronchodilators.

• Alpha 1 antitrypsin IV augmentation therapy may slow down emphysema progression.

• No evidence for benefit from antitussives.

• Vasodilators don’t improve outcome and worsen oxygenation.

• Long term monotherapy with ICS is not recommended.

• In severe to very severe airflow limitation, chronic bronchitis and exacerbation, add PDE4 inhibitor to a treatment with long acting bronchodilator with/without inhaled corticosteroid.

Sympathomimetics (β2-Selective Agonists) • cause relaxation of bronchial smooth muscle and bronchodilation and may also

improve mucociliary clearance.

• Administration via metered-dose inhaler (MDI) or dry-powder inhaler (DPI).

• Short-acting β2-agonists (SABA) are preferred over other short-acting sympathomimetics (isoproterenol, metaproterenol, isoetharine) because they have greater β2 selectivity and longer durations of action (4–6 hours).

• Inhalation is preferred over oral and parenteral.

• SABA can be used for acute relief of symptoms or on a scheduled basis to prevent or reduce symptoms. If patients do not achieve adequate control with a SABA alone, add ipratropium bromide. Recommended doses of SABA are as follows: • ✓ Albuterol inhalation aerosol (Proventil HFA, Ventolin HFA, ProAir HFA) and inhalation

powder (ProAir RespiClick) 1 to 2 inhalations every 4 to 6 hours • ✓ Levalbuterol inhalation aerosol (Xopenex HFA) 1 to 2 inhalations every 4 to 6 hours • ✓ Terbutaline oral tablets 2.5 to 5 mg 3 times daily, 6 hours apart (maximum 15 mg/day)

• Long-acting β2-agonists (LABA) are dosed every 12 to 24 hours.

• More Convenient for patients with persistent symptoms, produce similar or superior improvements in lung function, symptom relief, reduced exacerbation Frequency and need for hospitalization.

• Not recommended for acute relief of symptoms.

• Recommended doses by inhalation for maintenance therapy:

• ✓ Salmeterol inhalation powder (Serevent) 1 inhalation every 12 hours

• ✓ Formoterol inhalation powder (Foradil) 1 inhalation every 12 hours

• ✓ Arformoterol inhalation solution (Brovana) 1 × 15 mcg/2 mL vial by nebulization every 12 hours

• ✓ Indacaterol inhalation powder (Arcapta) 1 inhalation once daily

• ✓ Olodaterol inhalation spray (Striverdi Respimat) 2 inhalations once daily

• ✓ Vilanterol is available in the U.S. only as a combination product with fluticasone

Anticholinergics • Anticholinergics / muscarinic antagonists produce bronchodilation by competitively inhibiting

cholinergic receptors in bronchial smooth muscle.

• Short-acting muscarinic antagonists (sama) include primarily ipratropium bromide.

• Slower onset of action than SABA (15–20 min vs 5 min for albuterol).

• Less suitable for as-needed use.

• Has a more prolonged effect than SABA, with the peak effect occurring in 1.5 to 2 hours and duration up to 8 hours.

• If there is no adequate control with ipratropium alone combine it with a saba.

• Side effects: dry mouth, nausea, and metallic taste.

• Because it is poorly absorbed systemically, anticholinergic side effects are uncommon (eg, blurred vision, urinary retention, nausea, and tachycardia).

• The recommended doses for maintenance treatment :

• ✓ ipratropium bromide inhalation aerosol (atrovent hfa) 2 inhalations four times per day (maximum 12 inhalations/day). Doses are often titrated upward to 24 inhalations per day.

• ✓ Ipratropium bromide nebulization solution 500 mcg every 6 to 8 hours

• Long-acting muscarinic antagonists (LAMA)

• Recommended doses for maintenance treatment are as follows:

✓ Tiotropium bromide inhalation spray (Spiriva Respimat) 2 inhalations once daily or inhalation powder (Spiriva HandiHaler) one capsule (with 2 inhalations) once daily

✓ Umeclidinium inhalation powder (Incruse Ellipta) 1 inhalation once daily

✓ Aclidinium bromide inhalation powder (Tudorza Pressair) 1 inhalation twice daily

✓ Glycopyrrolate inhalation powder (Seebri Neohaler) 1 inhalation twice daily

Combination Anticholinergics and Sympathomimetics • Inhaled anticholinergic and β2-agonist (for disease progression and symptoms worsening).

- Allow the lowest effective doses to be used and reduce adverse effects from individual agents.

- Combination of both short- and long-acting β2-agonists with anticholinergics provides added symptomatic relief and improvements in pulmonary function.

• Recommended doses for maintenance therapy:

• ✓ Ipratropium plus albuterol inhalation spray (combivent respimat) 1 inhalation four to six times per day

• ✓ ipratropium plus albuterol nebulization solution (duoneb) one 3-ml vial four times per day by nebulization with up to two additional 3-ml doses allowed per day, if needed.

• Combination products containing a laba and lama are available. Recommended doses for maintenance treatment are as follows:

✓ vilanterol/umeclidinium inhalation powder (anoro ellipta) 1 inhalation once daily

✓ olodaterol/tiotropium bromide inhalation spray (stiolto respimat) 2 inhalations once daily

✓ indacaterol/glycopyrrolate inhalation powder (Utibron Neohaler) 1 inhalation twice daily

Methylxanthines

• Theophylline and aminophylline (bronchodilation by inhibiting phosphodiesterase).

• Chronic theophylline use may improve lung function, including vital capacity and FEV1. Subjectively, theophylline reduces dyspnea, increases exercise tolerance, and improves respiratory drive.

• Methylxanthines have a very limited role in COPD therapy because of drug interactions and interpatient variability in dosage requirements.

• Theophylline may be considered in patients intolerant of or unable to use inhaled bronchodilators. It may also be added to the regimen of patients not achieving optimal response to inhaled bronchodilators.

• Sustained-release theophylline preparations improve adherence and achieve more consistent serum concentrations than rapid-release products.

• Initiate with 200 mg twice daily and titrate upward every 3 to 5 days; most patients require 400 to 900 mg daily.

• Therapeutic range of 8 to 15 mcg/ml (44.4–83.3 μmol/L (to minimize risk of toxicity).

• Once a dose is established, monitor concentrations once or twice a year unless the disease worsens, medications that interfere with theophylline metabolism are added or toxicity is suspected.

• Theophylline side effects include dyspepsia, nausea, vomiting, diarrhea, headache, dizziness, and tachycardia. Arrhythmias and seizures may occur at toxic concentrations.

• Factors that may decrease theophylline clearance and lead to reduced dosage requirements include advanced age, bacterial or viral pneumonia, heart failure, liver dysfunction, hypoxemia from acute decompensation, and drugs such as cimetidine, macrolides and fluoroquinolone antibiotics.

• Factors that may enhance theophylline clearance and result in need for higher doses include tobacco and marijuana smoking, hyperthyroidism, and drugs such as phenytoin, phenobarbital, and rifampin.

Corticosteroids • Reduce capillary permeability to decrease mucus, inhibit release of

proteolytic enzymes from leukocytes and inhibit prostaglandins.

• (1) short-term systemic use for acute exacerbations (2) inhalation therapy for chronic stable COPD in select patients.

• Inhaled corticosteroid therapy may be beneficial in patients with severe COPD and at high risk of exacerbation (groups c and d) who are not controlled with inhaled bronchodilators.

• Side effects of inhaled corticosteroids are mild and include hoarseness, sore throat, oral candidiasis, and skin bruising. Less but severe side effects such as adrenal suppression, osteoporosis, and cataract formation.

• Combination of inhaled corticosteroids and long-acting bronchodilators is associated with greater improvements in FEV1, health status, and exacerbation frequency than either agent alone.

• Recommended doses for COPD maintenance include: •

• ✓ Budesonide plus formoterol inhalation aerosol (Symbicort) 160 mcg/4.5 mcg, 2 inhalations twice daily

• ✓ Fluticasone plus salmeterol inhalation powder (Advair Diskus DPI) 250 mcg/50 mcg, 1 inhalation twice daily

• ✓ Fluticasone plus vilanterol (Breo Ellipta) inhalation powder 100 mcg/25 mcg, 1 inhalation once daily)

• For patients with more symptoms and at high risk of exacerbation

(category D), triple therapy (LABA plus LAMA plus inhaled corticosteroid) may be considered as a first or second choice.

Phosphodiesterase Inhibitors/ PDE4 • Roflumilast (Daliresp) is indicated to reduce risk of exacerbations in patients

with severe COPD associated with chronic bronchitis and a history of exacerbations.

• The dose is 500 mcg orally once daily, with or without food.

• Major adverse effects include weight loss and neuropsychiatric effects such as suicidal thoughts, insomnia, anxiety, and new or worsened depression.

• Roflumilast is metabolized by CYP3A4 and 1A2; coadministration with strong CYP P450 inducers is not recommended due to potential for subtherapeutic plasma concentrations. Use caution when administering roflumilast with strong CYP P450 inhibitors due to potential for adverse effects.

• Beneficial in patients with severe or very severe COPD who are at high risk of exacerbation (Group C and D) and are not controlled by inhaled bronchodilators.

• It may also be considered for patients who are intolerant or unable to use inhaled bronchodilators or corticosteroids.

• Roflumilast is not recommended for use with theophylline because the drugs share similar mechanisms.

Complications

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