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CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Treatment Guideline Chart

Chronic obstructive pulmonary disease (COPD) is an inflammatory respiratory disease characterized by reversible airflow limitation.

The patient usually has chronic cough, sputum production or dyspnea with or without history of risk factors for the disease.

The chronic airflow limitation is caused by a combination of small airways disease and parenchymal destruction.

It is a preventable and treatable disease.

Chronic%20obstructive%20pulmonary%20disease Treatment

Principles of Therapy

  • Goals of therapy
    • Prevention and control of symptoms
    • Reduction of the frequency and severity of exacerbations
    • Improvement of health status
    • Improvement of exercise tolerance
  • Drug therapy for COPD is determined by individualized assessment of symptoms and exacerbation risk
  • Based on studies, the existing pharmacotherapy for COPD do not modify the long-term decline in lung function; however, limited evidence suggests that regular treatment with long-acting beta2-agonists, inhaled corticosteroid and its combination can decrease the rate of decline in lung function

Initial Treatment

  • The following table summarizes treatment recommendations by patient category of COPD:

Patient Category

Recommended Initial Treatment*

A

Short-acting anticholinergic or short-acting beta2-agonist monotherapy

B

Long-acting anticholinergic or long-acting beta2-agonist monotherapy

C

Long-acting anticholinergic monotherapy

D

Long-acting anticholinergic or

Long-acting anticholinergic+ long-acting beta2-agonist or

Inhaled corticosteroid + long-acting beta2-agonist

*Adapted from: Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2021 report.

Follow-up Treatment

  • Should be based on the predominant symptom, either for dyspnea or persistent exacerbations, irrespective of the patient's GOLD grouping 
  • Inhaler technique and treatment adherence should be investigated in every follow-up
  • Patients may be considered for an additional long-acting bronchodilator if breathlessness or exercise limitation is still present despite inhaled bronchodilator monotherapy
  • Dual combination therapy with 2 long-acting inhaled bronchodilators or long-acting beta2-agonist plus an inhaled corticosteroid should be considered in patients previously given short-acting bronchodilators or long-acting inhaled bronchodilator monotherapy who show disease progression
  • Triple combination therapy should be offered to patients with disease progression despite treatment with a bronchodilator and corticosteroid combination therapy
  • Roflumilast or Azithromycin may be given to patients suffering from persistent exacerbations previously given bronchodilator combination therapy and with eosinophil count of <100 cells/μL
  • Roflumilast should be considered in patients with FEV1 <50% predicted and chronic bronchitis
  • Azithromycin may be added for patients who are ex-smokers
Recommended Follow-up Regimens After Initial Therapy Based on Predominant Symptom: Dyspnea

  • Adjust therapy based on current maintenance therapy

    		•
    Initial Therapy Follow-up Therapy
    Long-acting anticholinergic or long-acting beta2-agonist Long-acting anticholinergic + long-acting beta2-agonist
    Long-acting anticholinergic + long-acting beta2-agonist
  • Consider switching agents or devices
  • Investigate & treat other etiologies
    		•
    Long-acting beta2-agonist + inhaled corticosteroid
  • Triple therapy: Long-acting anticholinergic + long-acting beta2-agonist + inhaled corticosteroid combination or
  • Long-acting anticholinergic + long-acting beta2-agonist1
  • Consider switching agents or devices
  • Investigate & treat other etiologies
    		•

    1For patients with adverse effects (eg pneumonia) or unresponsive to inhaled corticosteroids, or if initial indication is unclear

    Recommended Follow-up Regimens After Initial Therapy Based on Predominant Symptom: Exacerbations or Both Dyspnea and Exacerbations

  • Adjust therapy based on current maintenance therapy

    		•
    Initial Therapy Follow-up Therapy
    Long-acting anticholinergic or long-acting beta2-agonist
  • Long-acting anticholinergic + long-acting beta2-agonist
  • Long-acting beta2-agonist + inhaled corticosteroids1
    		•
    Any dual-agent combination therapy
  • Switch agents
  • Triple therapy
  • Add Roflumilast or Azithromycin if eosinophil count <100 cells/µL
    		•
    Triple therapy
  • Add Roflumilast
  • Add Azithromycin
  • Discontinue inhaled corticosteroids2
    		•

    1Consider in patients with blood eosinophil count ≥300 cells/microliter or with ≥100 cells/microliter and ≥2 moderate exacerbations per year or 1 severe exacerbation requiring hospitalization
    2For patients with adverse effects (eg pneumonia) or unresponsive to inhaled corticosteroids, or if initial indication is unclear


    Pharmacotherapy

    Bronchodilators

    • Classes (listed alphabetically): Anticholinergics, beta2-agonists, methylxanthines
    • All bronchodilators increase exercise capacity
    • Inhaled bronchodilators are recommended for all symptomatic patients with stable COPD with FEV1 of <60%
      • May also be used for symptomatic stable COPD patients with predicted FEV1 of 60-80%
      • Inhaled therapy is preferred to oral, because of better efficacy, faster onset and decreased likelihood of adverse effects
    • Short-acting bronchodilators are given on a “when required” basis for immediate relief of symptoms and long-acting bronchodilators are administered on a regular basis to prevent or reduce symptoms
    • Regular treatment with long-acting bronchodilators is more effective and convenient but can be more expensive
      • When possible, therapy should be via the inhaled route but if cost is a barrier, then oral bronchodilators (beta2-agonists) can be considered
      • Inhaled bronchodilators are preferred to Theophylline because of the latter’s low bronchodilating effect and high potential for toxicity
    • Choice of drugs will depend on the patient’s response and preference, together with drug’s side effects and cost

    Anticholinergics

    • Eg Long-acting: Aclidinium, Glycopyrronium, Tiotropium, Umeclidinium; Short-acting: Ipratropium, Oxitropium
    • Block the effects of acetylcholine on M2 and M3 (short-acting), and M1 and M3 (long-acting) receptors
    • Long-acting inhaled anticholinergics are recommended for symptomatic patients with FEV1 of <60% predicted
    • Short-acting anticholinergics generally have a longer duration of bronchodilatation than short-acting beta2-agonists
    • Based on a large, long-term, randomized, controlled study in patients with moderate to very severe COPD, Tiotropium with concurrent respiratory medication other than another inhaled anticholinergic agent, resulted in the following benefits:
      • Positive effects on quality of life
      • Reduced risk of exacerbations and exacerbation-related hospitalizations
      • Reduced respiratory morbidity including respiratory failure and cardiac morbidity
    • Have been shown to be very safe at a wide range of doses
    • Based on short-term, clinical studies in patients with moderate to severe COPD, combination of short-acting anticholinergic and short-acting beta2-agonist may provide superior bronchodilatation than either medication alone
    • Aclidinium and Glycopyrronium have effects on lung function and breathlessness comparable to that of Tiotropium but further studies are needed

    Beta2-agonists

    • Eg Long-acting: Arformoterol, Formoterol, Indacaterol, Olodaterol, Salmeterol, Tulobuterol, Vilanterol (given as combination therapy); Short-acting: Fenoterol, Levalbuterol, Salbutamol (Albuterol), Terbutaline
    • Long-acting inhaled beta2-agonists are recommended for symptomatic patients with FEV1 of <60% predicted
    • Relax airway smooth muscle by stimulating beta2-adrenergic receptors
    • Salmeterol and Formoterol significantly improves FEV1, lung function, dyspnea, quality of life and exacerbation rate
    • Vilanterol, in combination with Umeclidinium or Fluticasone, showed improved lung function and slower decline in FEV1
    • Based on several clinical trials, combination of long-acting beta2-agonists (eg Salmeterol) and inhaled corticosteroids (eg Fluticasone) may reduce COPD exacerbation and may improve lung function and quality of life better than when each drug is used alone
    • Inhaled beta2-agonists have a faster onset of action and less side effects than oral preparations

    Methylxanthines

    • Eg Aminophylline, Theophylline
    • May act as non-selective inhibitor of phosphodiesterase, but have also been observed to exert a range of non-bronchodilator actions
    • Though have modest effect in COPD, inhaled bronchodilators are preferred to Theophylline, owing to the latter’s poor bronchodilating property and potential toxicity
    • Combination of a beta2-agonist, an anticholinergic and Theophylline may produce additional improvements in health status and lung function
    • All studies that have shown efficacy of Theophylline in COPD made use of slow-release preparations

    Combination Bronchodilator Therapy

    • Available as single inhaler are Fenoterol/Ipratropium, Salbutamol/Ipratropium, Formoterol/Aclidinium, Formoterol/Glycopyrronium, Indacaterol/Glycopyrronium, Vilanterol/Umeclidinium, Olodaterol/Tiotropium
    • Bronchodilator-corticosteroid combinations (eg Formoterol/Beclometasone, Formoterol/Budesonide, Formoterol/Mometasone, Salmeterol/Fluticasone propionate, Vilanterol/Fluticasone furoate, Fluticasone/Umeclidinium/Vilanterol, Beclometasone/Formoterol/Glycopyrronium, Budesonide/Formoterol/Glycopyrrolate) are also available
    • Combination therapy with inhaled long-acting anticholinergics, long-acting beta2-agonists, or corticosteroids are recommended for symptomatic patients with stable COPD and FEV1 of <60% predicted
    • Combining drugs with different mechanisms of action may increase bronchodilatation with less side effects compared to simply increasing the dose of a bronchodilator
    • Compared to monotherapy combination treatment of short-acting beta2-agonist and short-acting anticholinergics improves FEV1 and symptoms
    • Compared to monotherapy combination treatment of long-acting beta2-agonist and long-acting anticholinergics increases FEV1, decreases symptoms and reduces exacerbation

    Corticosteroids

    • Eg Inhaled: Beclomethasone, Budesonide, Fluticasone, Mometasone; Systemic: Prednisolone, Methylprednisolone
    • Regular treatment with inhaled corticosteroids alone does not change the long-term decline of FEV1
    • Regular treatment with inhaled corticosteroids is appropriate in patients with FEV1 <50% predicted or ≥2 exacerbations/year and repeated exacerbations (eg 3 exacerbations in the last 3 years)
      • May reduce airway hyper-reactivity in these patients and decrease symptoms of COPD including exacerbations
    • Inhaled corticosteroid in combination with 1 or 2 long-acting bronchodilators is recommended in patients with:
      • History of hospitalizations for COPD exacerbations despite appropriate maintenance therapy with long-acting bronchodilator
      • ≥2 moderate COPD exacerbations per year despite appropriate maintenance therapy with long-acting bronchodilator
      • History of, or concomitant asthma
      • Blood eosinophil count >300 cells/microliter
    • In patients with more advanced COPD and repeated exacerbation, treatment with inhaled corticosteroids can be beneficial
    • Dose-response relationships and long-term safety of inhaled corticosteroids in COPD are not known
    • On a 3-year period treatment in COPD patients with high prevalence of osteoporosis, therapy with high-dose Fluticasone alone or in combination with Salmeterol was not associated with decreased bone mineral density (BMD) compared with placebo
      • Previous long-term trials investigating BMD in COPD patients produced conflicting results
    • The use of combination therapy with inhaled corticosteroids and long-acting beta2-agonist is more effective in reducing exacerbations and improving pulmonary function than either medication alone
      • In patients with FEV1 <60%, treatment with long-acting beta2-agonist, inhaled corticosteroids and its combination have been shown to reduce the rate of decline of pulmonary function; addition of the combination to an anticholinergic (eg Tiotropium) appears to provide additional benefits
    • Addition of a long-acting anticholinergic to combination therapy of inhaled corticosteroid and long-acting beta2-agonist (triple inhaled therapy) has been shown to improve lung function, symptoms and health status, and reduce exacerbations compared to combination therapy of inhaled corticosteroid and long-acting beta2-agonist, long-acting beta2-agonist and long-acting anticholinergic, or monotherapy with a long-acting anticholinergic
    • Long-term monotherapy with inhaled corticosteroids is not recommended 
    • Long-term use of oral corticosteroids is not recommended
    • Short-course trials of oral corticosteroids may not reliably predict which patients will respond to inhaled corticosteroids

    Phosphodiesterase-4 Inhibitor

    • Eg Roflumilast
    • Reduce inflammation through inhibition of the breakdown of intracellular cyclic AMP
    • Has no direct bronchodilator effects but has been shown to improve FEV1 in patients treated with Tiotropium or Salmeterol
    • Roflumilast has been shown to reduce exacerbations in patients with severe to very severe COPD (FEV1 <50% predicted) with chronic bronchitis treated with oral corticosteroids
      • Same effect on exacerbation reduction has been noted when added to long-acting bronchodilators
    • Roflumilast can not be administered with Theophylline
    • Has more side effects compared to inhaled medications

    Other Pharmacologic Agents

    Alpha-1 Antitrypsin Augmentation Therapy

    • May help halt the development and progression of pulmonary disease in patients with AATD
    • Studies demonstrated a reduction in spirometric progression with alpha-1 antitrypsin augmentation therapy in patients with FEV1 35-49% predicted 
    • Especially recommended for nonsmoking patients or those who stopped smoking with FEV1 35-60% predicted
    • Further studies are needed to prove the efficacy versus cost of this treatment

    Antibiotics

    • Not recommended except for treatment of infectious bacterial exacerbations
    • Treatment with macrolides (eg Azithromycin) may be considered for previous smokers with moderate to severe exacerbations despite inhaled bronchodilator therapy

    Cough and Cold Preparations

    • Eg Ambroxol, Carbocysteine, Erdosteine, N-acetylcysteine
    • Antitussives are not recommended because cough has a protective effect in COPD
    • Expectorants and mucolytics were seen to have benefits in few patients with viscous mucous, but overall benefits seem to be very small
      • May be considered in patients with chronic cough productive of sputum
      • Therapy may be continued if there is a decrease in the frequency of cough and sputum production
    • Regular treatment with Carbocysteine or N-acetylcysteine may help reduce exacerbations in COPD patients without inhaled corticosteroid treatment

    Vaccines

    Influenza Vaccine

    • May decrease morbidity and mortality rates due to influenza
    • Should be given yearly, 1-2 months prior to anticipated peak influenza season, because of new antigens and waning immunity from the previous years
    • Associated with reduced risk of all-cause mortality

    Pneumococcal Vaccines

    • Eg 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23)
    • Recommended in COPD patients ≥65 years old and in younger patients with significant comorbidities (eg cardiac disease, chronic pulmonary disease)
    • PPSV23 reduces occurrence of community-acquired pneumonia (CAP) in patients <65 years old with FEV1 <40% predicted or comorbidities
    • Studies showed that PCV13 exhibited significant efficacy for both CAP and vaccine-type invasive pneumococcal disease in adults ≥65 years old with efficacy lasting for at least 4 years
      • Possesses comparable or even greater efficacy when compared to the immunogenicity of PPSV23
    • Generally given only once, but revaccination may be considered in 5-10 years

    Inhalation Devices

    • Effective drug delivery and training in inhaler technique should be emphasized and re-checked as necessary
    • Choice of device depends on price, availability, the prescribing doctor, and the skills and ability of the patient
    • Metered dose inhaler (MDI)
      • COPD patients may have poorer coordination and experience more difficulty with MDI use
      • Use of spacers with the MDI may be advised for patients who find it hard to master MDI inhaler technique
    • Dry powder inhaler (DPI)
      • Breath-activated and may therefore require less hand-and-mouth coordination
      • May be more convenient and may provide improved deposition of the drug
    • Nebulizer
      • Not recommended for routine use because of greater cost of treatment
    • Assessment of inhaler technique should be done prior to modifying current therapy

    ACUTE EXACERBATION OF COPD
    Bronchodilators

    • Long-acting selective beta2-agonist bronchodilators include Arformoterol, Bambuterol, Formoterol, Indacaterol, Olodaterol, Salmeterol and Tulobuterol
    • Short-acting selective beta2-agonist bronchodilators include Clenbuterol, Fenoterol, Hexoprenaline,Levalbuterol, Orciprenaline, Procaterol, Salbutamol (Albuterol), Terbutaline and Trimetoquinol
    • Long-acting anticholinergic bronchodilators: Aclidinium, Glycopyrronium, Tiotropium, Umeclidinium
    • Short-acting anticholinergic bronchodilators: Ipratropium, Oxitropium

    Hospital Management

    • Short-acting inhaled beta2-agonists, with or without short-acting anticholinergics are typically preferred for treating acute COPD exacerbations
    • An anticholinergic may be added if the patient does not respond immediately to short-acting inhaled beta2-agonists
    • Long-acting bronchodilators can be used with or without inhaled corticosteroids during exacerbation or as a maintenance therapy that should be started as soon as possible before hospital discharge

    Home Management

    • The dose and/or frequency of ongoing bronchodilator treatment should be increased
    • An anticholinergic, if not yet in use, may be added until improvement is noted
    • High-dose nebulized therapy may be given when required for several days
      • Long-term use of nebulizer therapy after an exacerbation is not recommended

    Corticosteroids

    • Improves oxygenation and lung function, and reduces risk for relapse, treatment failure and length of hospital stay

    Hospital Management

    • Oral or IV corticosteroids are recommended as an addition to bronchodilator therapy, in the absence of significant contraindications
      • Oral route is preferred, as no significant difference in efficacy was seen when compared to parenteral administration
      • IV route may be used in patients with severe exacerbation and with contraindications for oral medications
    • Shorten recovery time and help hasten restoration of lung function
    • Duration of therapy with oral corticosteroid must not exceed 5-7 days, as there is no advantage to prolonged therapy and the risk of side effects is increased

    Home Management

    • Addition of oral corticosteroid to existing bronchodilator therapy may be considered if patient’s baseline FEV1 is <50% predicted
    • Nebulized Budesonide alone or in combination with Formoterol may be used as an alternative to oral corticosteroids; may cause significant reduction of complications (eg hyperglycemia)

    Antibiotics

    • Given in patients who presents with increased purulence of sputum together with increase in dyspnea and sputum volume or in patients who need mechanical ventilation
    • May reduce recovery time, interval to relapse, treatment failure, and duration of hospital stay
    • Local antibiotic sensitivity patterns for Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis must be taken into account when choosing an antibiotic agent
    • Recommended oral antibiotic agents include:
      • 1st-line: Amoxicillin, Doxycycline and Clarithromycin
      • 2nd-line: Co-amoxiclav, Levofloxacin, Co-trimoxazole, Azithromycin, Cefuroxime axetil
        • Given if no improvement seen or with clinical deterioration after 72 hours of treatment initiation
    • Recommended IV antibiotic agents include Co-amoxiclav, Clarithromycin, Piperacillin/tazobactam
    • Recommended duration of antibiotic therapy is 5-7 days

    Heparin (SC/Low Molecular Weight)

    • Consider administration of SC/LMW Heparin to reduce the risk of pulmonary embolism in patients with polycythemia or dehydration, with or without a history of thromboembolic disease

    Non-Pharmacological Therapy

    Pulmonary Rehabilitation

    • Multidisciplinary program for patients with chronic respiratory impairment that is individually designed to maximize a patient’s physical and social performance and autonomy
      • In regions with limited resources, simplified pulmonary rehabilitation programs are useful and are recommended
    • Includes exercise training, nutrition counseling, education and psychological support
    • Recommended for symptomatic patients with FEV1 of <50% predicted
      • May also be considered in symptomatic patients with FEV1 of >50% predicted with exercise limitations, patients with mMRC >1, and following acute exacerbations
    • Program should last 6-8 weeks to be effective; no additional benefit is seen in extending the program to 12 weeks

    Site of Care

    Please refer to the Symptom and Risk Evaluation of COPD table for characteristics per patient category

    • Patients belonging to category A or B may be managed on an outpatient basis during exacerbations
    • Patients belonging to category C or D may require hospitalization and more aggressive management during exacerbations

    Indications for Hospital Treatment for Chronic Obstructive Pulmonary Disease Exacerbations

    • Significant increase in signs and symptoms (eg sudden development of resting dyspnea, SaO2 <90%, changes in chest X-ray, arterial pH <7.35, arterial PaO2 <7 kPa, <53 mmHg)
    • Acute lung failure
    • Onset of new symptoms (eg cyanosis, peripheral edema, impaired level of consciousness)
    • Absence of response to initial medical treatment
    • Significant comorbidities (eg heart failure or newly occurring arrhythmias)
    • Frequent exacerbations
    • Older age
    • Lack of home support
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