Topic Discussion: Acute COPD

Exacerbations
August 15, 2023
Ethan Robinson, Pharm.D.
Learning Objectives

1. Describe the signs/symptoms, pathophysiology, risk factors and diagnosis of

COPD.
2. Summarize the recommended inpatient treatment and management of acute
COPD exacerbations based on the 2023 GOLD Guidelines.
3. Determine how three recent randomized controlled trials may be applied to
patient care to effectively treat or reduce the recurrence of COPD
exacerbations.
Defining COPD
Chronic Obstructive Pulmonary Disease is a heterogeneous lung condition with chronic
respiratory symptoms due to airway or alveolar abnormalities resulting in progressive
airflow obstruction.
Signs/Symptoms
● Dyspnea
● Wheezing
● Chest tightness
● Fatigue
● Cough +/- sputum production
● Activity Limitation
Pathophysiology

Increased numbers of macrophages, neutrophils and lymphocytes in the airways,

lung parenchyma and blood vessels release inflammatory mediators and
cytokines (inflammatory cascade and oxidative stress) which leads to structural
changes in the lungs.

● Protease-mediated destruction of elastin (emphysema)

● Peribronchiolar fibrosis due to excessive growth factor production
Risk Factors

#1: Smoking tobacco and marijuana

Others include:

● chronic exposure to pollution/toxins

● abnormal lung development
● frequent/severe respiratory infections
● alpha-1 antitrypsin deficiency (rare genetic mutation of SERPINA1)
Diagnosis

Gold standard: Spirometry

● FEV1/FVC < 0.7 after administration of a bronchodilator

● Non-fully reversible airflow limitation

Defining COPD Exacerbations

An event in which a patient with COPD presents with increased dyspnea or cough
w/sputum that worsens over less than 14 days and is often accompanied by
tachypnea/tachycardia and associated with increased inflammation due to
infection or airway irritants.
Classification

Mild: treated with short-acting bronchodilators only

Moderate: mild treatment + corticosteroids +/- antibiotics

Severe: requiring hospitalization or ER visit (often associated with acute

respiratory failure)
ROME Proposal
Utilizes clinical variables to classify exacerbation severity on arrival.
Mild vs Moderate (3 of 5 criteria)
● Dyspnea VAS Scale (0-10) < or ≥ 5
● Respiratory Rate < or ≥ 24 breaths per minute
● Heart Rate < or ≥ 95 bpm
● CRP < or ≥ 10 mg/L
● O2 Sat ≥ or < 92% OR change ≤ or > 3% (if known)
Severe if ABG shows hypercapnia (PaCO2 > 45 mmHg) and respiratory acidosis
(pH < 7.35)
Non-Pharmacological Management

Supplemental Oxygen → Non-invasive mechanical ventilation → Intubation

Pharmacological Treatment (Bronchodilators)

Short-acting Bronchodilators: beta agonist +/- anticholinergic

● MDI or nebulizer can be used (levalbuterol, albuterol, ipratropium)

● 1-2 puffs every hour for 2-3 doses, then every 2-4 hours
● Continue home meds (LABA, LAMA, ICS or combinations)
Pharmacological Treatment (Steroids)

Steroids (Glucocorticoids)

● Shorten recovery time and improve lung function

● 5-day course of 40 mg prednisone equivalent is recommended (oral or IV)
○ Can use nebulized budesonide in some patients

● Higher eosinophils = greater response

● Caution: increased risk of pneumonia, sepsis, and death
Pharmacological Treatment (Antibiotics)

Infectious Causes can be Viral or Bacterial (rarely fungal)

Antibiotics indicated if patient has 3 cardinal symptoms (dyspnea, increased
sputum volume and purulence) or 2 of 3 if purulent
● Often sputum purulence is used to determine presence of bacteria
○ Sensitivity 94.4%, Specificity 52%
● Using procalcitonin or CRP to determine antibiotic use is not recommended
due to conflicting data
Duration should be no greater than 5 days
Pharmacological Treatment (Antibiotics)

Antibiotic choice based on local susceptibilities and sputum culture results

● amoxicillin/clavulanate or ampicillin/sulbactam
● azithromycin
● doxycycline
● levofloxacin

May need combination therapy if using beta-lactam and want atypical coverage
Discharge Care

May take 4-6 weeks for patient to fully recover from exacerbation.

● Note exacerbations can cause progression of disease

Outpatient follow up within 30 days of discharge and again at 90 days to assess

symptoms, current regimen, and adherence/inhaler technique

Smoking cessation resources/medications

Make sure patient is up to date of pneumonia vaccinations

Vitamin D supplementation if patient has deficiency.

Study #1 Description
Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe
COPD (Rabe et al.)

Phase 3 randomized trial, 4 groups (1:1:1:1)

● ICS (budesonide) 160 mcg, LABA (formoterol) 9.6 mcg & LAMA (glycopyrrolate) 18 mcg
● ICS 320 mcg, LABA 9.6 mcg & LAMA 18 mcg
● ICS 320 mcg & LABA 9.6 mcg
● LAMA 18 mcg & LABA 9.6 mcg

Primary Endpoint: Annual rate of moderate or severe COPD exacerbations

Study #1 Results

Modified intention-to-treat population: 8509 patients

High-dose Triple Therapy
● Rate Ratio compared to ICS/LABA: 0.87, 95% CI (0.79-0.95) p = 0.003
● Rate Ratio compared to LAMA/LABA: 0.76, 95% CI (0.69-0.83) p < 0.001

Low-dose Triple Therapy

● Rate Ratio compared to ICS/LABA: 0.86, 95% CI (0.79-0.95) p = 0.002
● Rate Ratio compared to LAMA/LABA: 0.75, 95% CI (0.69-0.83) p < 0.001

The rate of adverse effects was similar between all 4 groups.

Study #2 Description

Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts

(Bhatt et al.)

Phase 3 double-blind randomized-control trial (1:1)

● Dupilumab 300 mg SQ every 2 weeks vs placebo

● 939 patients with blood eosinophils > 300/mcL

Primary Endpoint: Annualized rate of moderate or severe COPD exacerbations

Study #2 Results

Dupilumab vs Placebo

● Rate Ratio 0.70, 95% CI (0.58-0.86) p < 0.001

Adverse events were balanced between both groups.

Study #3 Description
Two-day versus seven-day course of levofloxacin in acute COPD exacerbation: a
randomized controlled trial (Messous et al.)

● 2 days levofloxacin 500 mg + 5 days placebo + 5 days IV prednisone 40 mg

● 7 days levofloxacin 500 mg + 5 days IV prednisone 40 mg

Primary Endpoint: Cure rate (through 30 day follow up)

Secondary Endpoints: Need for additional abx, ICU admission rate,

Re-exacerbation rate, Death rate, and Exacerbation-free interval (EFI)
Study #3 Results
310 patients randomized (1:1)

Cure rate was 79.3% (2-day) and 74.2% (7-day) OR 1.3, 95% CI (0.78-2.2) p = 0.28

No Secondary Endpoints were statistically significant

● Need for additional abx 3.2% (2-day) and 1.9% (7-day) p = 0.43
● One-year Re-exacerbation rate 34.8% (2-day) and 29% (7-day) p = 0.19
● ICU admission rate 5.1% (2-day) and 3.2% (7-day) p = 0.65

Conclusion: 2 days of levofloxacin is non-inferior to 7 days for treating an acute

COPD exacerbation
References
1. Agusti A, Beasley R, Celli BR, et al., Hadfield R. Global strategy for the diagnosis, management, and prevention of chronic

obstructive pulmonary disease (2023 Report) [Internet]. Version 1.3. Global Initiative for Chronic Obstructive Lung Disease,

Inc.; 2023. [cited 2023 Aug 15]. Available from: https://goldcopd.org/2023-gold-report-2/

2. Rabe KF, Martinez FJ, Ferguson GT, et al. Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe

COPD. N Engl J Med. 2020;383(1):35-48. doi:10.1056/NEJMoa1916046

3. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts. N Engl J

Med. 2023;389(3):205-214. doi:10.1056/NEJMoa2303951

4. Messous S, Trabelsi I, Bel Haj Ali K, et al. Two-day versus seven-day course of levofloxacin in acute COPD exacerbation: a

randomized controlled trial. Ther Adv Respir Dis. 2022;16:17534666221099729. doi:10.1177/17534666221099729