Chronic%20obstructive%20pulmonary%20disease Treatment

• 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 and 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 and 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

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

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 PaO^₂ <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