Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)


Not all flares are infectious.


  • Definition: acute exacerbation of chronic obstructive pulmonary disease is an acute worsening of respiratory symptoms that demand additional therapy.
    • Note: symptoms are not specific, develop a differential diagnosis.
      • Most common cause = respiratory infections (viral > bacterial or environmental factors)
    • Exacerbations result in increased inflammation within airways, mucous and more gas trapping.
      • Patients with frequent exacerbations (> 2 per year) have greater morbidity and worse health status.
  • Principles: most exacerbations precipitated by viral upper respiratory tract infections in COPD flares but in those with chronic bronchitis up to half of the acute exacerbations of chronic bronchitis (AECB) are caused by a bacterial infection.
  • Exacerbations of COPD classifications:
    • Mild: treated with short-acting bronchodilators (SABDs), only
    • Moderate: SABD + antibiotics +/- oral corticosteroids
    • Severe: requires hospitalization or ED visit, includes respiratory failure
  • Significant AECB flare: need all 3 (see below)
    • Increased sputum production
    • Increased cough
    • Increased dyspnea
  • PE: increased respiratory rate, wheezing, rhonchi, cyanosis +/- fever.


  • Definitions:
    • Exacerbation of COPD: see above.
    • Chronic bronchitis: irreversible reduction in maximal airflow velocity and productive cough for most days of the most x 3 months over two consecutive years.
    • AECB: an acute event with worsened respiratory symptoms more than usual baseline in cough, sputum, and sputum purulence in patients with chronic bronchitis.
      • Increased cough severity/frequency
      • Increased sputum volume and/or change in character
      • Worsened dyspnea
  • DDx: pneumonia, pneumothorax, pleural effusion, PE, CHF, cardiac arrhythmia.
  • Imaging:
    • Obtain chest X-ray or Chest CT to R/O pneumonia, CHF, effusion, mass lesion or pneumothorax.
  • Lab: sputum Gram stain and culture, not advocated routinely for outpatients; consider for inpatient care and especially in severely ill (ICU).
  • Arterial blood gases or pulse oximetry if pt seriously ill.
  • Spirometry: probably not useful for acute management.
  • Severity: include judgment by pulse oximetry, blood gases, FEV-1.



  • As heterogeneous reasons for AECB flare, the key is supportive care includes bronchodilators (albuterol, ipratropium bromide), corticosteroids, antibiotics (not all), and oxygen (see below).
    • May manage as inpatient or outpatient depending on severity.
  • When indicated, abx shorten the time needed for recovery, reduce relapse/treatment failure and shorten hospital length of stay (LOS).
    • Abx appears to reduce short-term mortality by 77% and treatment failure 53% per systematic review of patients with moderate or severe exacerbations (typically inpatients rather than outpatients)[11].
    • Duration of treatment: 5-7 days
  • Abx indications: severe acute exacerbations with increased cough, sputum volume and sputum purulence.
    • Some studies support use of procalcitonin to initiate abx, limiting use.
    • Antibiotic selection is optimally made based on Gram stain and/or culture, especially for patients with frequent and/or severe exacerbations (e.g., ICU) to help determine if resistant organisms present.
      • The choice should be guided upon local antibiograms.
    • The most commonly used antibiotics for acute bronchitis are azithromycin followed by amoxicillin and clarithromycin.
  • Preferred: (Note: no antibiotic preferred for mild exacerbations). Target typical respiratory pathogens anticipated and local resistance patterns.
    • Uncomplicated flare, no risk factors: age < 65 yrs, FEV1 > 50% of predicted, < 2 exacerbations/year, no cardiac disease
    • Complicated flare: 1 or more risk factors--age > 65 years, FEV1 < 50% of predicted, ≥ 2 exacerbations/year, cardiac disease. Consider sputum analysis to help guide therapeutic choice.
    • Duration: 5-7 days
  • Influenza: efficacy of oseltamivir for ambulatory patients is established and should be given to high patients with COLD even if sx > 48 hrs (CDC recommendation). Check CDC website for latest recommendations: Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza.
    • Oral:
      • Oseltamivir
        • Adult: 75mg PO twice daily
        • Neonates:
          • PMA < 38 weeks: 1 mg/kg/dose PO q12h
          • PMA 38-40 weeks: 1.5 mg/kg/dose PO q12h
          • PMA > 40 weeks: 3 mg/kg/dose PO q12h
        • Infants:
          • Term 0-8 months: 3 mg/kg/dose PO q12h
          • 9-11 months: 3.5 mg/kg/dose PO q12h
        • Children ≥ 1 year old:
          • ≤ 15 kg: 30 mg PO q12h
          • >15-23 kg: 45 mg PO q12h
          • >23-40 kg: 60 mg PO q12h
          • >40 kg: 75 mg PO q12h
        • Duration: 5 days
      • Baloxivir:
        • Weight-based dosing: single-dose administration
          • 40-80 kg: 40 mg PO x 1 dose
          • ≥ 80 kg: 80 mg PO x 1 dose
        • Duration: single dose
    • Avoid zanamivir due to possible exacerbation of wheezing from inhalant powder.
    • Peramivir IV: may consider in critically ill patients, patients unable to take oral agents.

Supportive Care

  • Aspects are more important typically than antibiotic selection. Guidance per GOLD 2020[2].
  • Determine the need for ED evaluation or hospitalization.
  • Assess the severity of symptoms: CXR, blood gases
    • Supplemental oxygen as determined by oxygenation or ABG assessments.
    • Consider oral corticosteroids, need for non-invasive mechanical ventilation, IV fluids, DVT/PE prevention, figure if there are associated conditions also contributing, e.g., PE or CHF.
  • Mangement of Exacerbations:
    • Short-acting inhaled beta2-agonists +/- short-acting anticholinergic are recommended for the initial treatment of flare.
    • O2: use 2-4L/min by nasal cannula; keep pulse oximeter target to 88- 92%. If need increase or pCO2 > 45, use Venturi mask.
      • Risk with higher O2 administration is respiratory failure, so close monitoring recommended if the patient is known CO2 retainer.
      • Ventilatory support: if concern for impending respiratory failure, admit to ICU or respiratory care unit.
        • Non-invasive positive-pressure ventilation; requires a trained physician
    • Systemic corticosteroids yield improvements in FEV1, oxygenation and shorter LOS.
      • Prednisone 40 mg PO daily (no taper)
      • Duration: 5-7 days
      • As effective as intravenous corticosteroids.
    • Non-invasive mechanical ventilation should be first considered in flares of COPD who otherwise do not have a contraindication.
      • This approach lessens the need for intubation, hospital LOS and better survival.
    • Not recommended: methylxanthines (e.g., theophylline or aminophylline), chest PT, mucolytic agents.
  • Smoking: if active, smoking cessation therapies.
    • Opportune time for such intervention.

Selected Drug Comments




Old agent for treatment and prevention of influenza A, but now precludes routine use unless circulating strains known to be sensitive.


Good activity against most S. pneumoniae, performed well in the history of AECB and cheap. Due to concern of rising resistance (5-10% of S. pneumoniae, 30-40% of H. influenzae and 90-95% of M. catarrhalis) now not frequently employed except as amoxicillin/clavulanate


Expands amoxicillin activity to cover all H. influenzae and M. catarrhalis, usually highly active vs. S. pneumoniae.


It seems to work better in patients than in the test tube (susceptibility testing). Resistance rates of S. pneumoniae are high, but relevance debated.


Single-dose drug for influenza based on the half-life of up to 91 hours. It has an FDA indication for treatment of influenza in patients at high risk for complications, and also in one unpublished study works better against influenza B than oseltamivir. It also has less nausea or vomiting compared to oseltamivir. As an end-cap endonuclease inhibitor, it depresses viral shedding faster than oseltamivir. No data in hospitalized patients yet.


A bad choice, poor activity against S. pneumoniae relative to other oral cephalosporins.


Active against most strains of S. pneumoniae and all strains of H. influenzae and M. catarrhalis. About as active as amoxicillin vs. S. pneumoniae. Relatively expensive, well-tolerated.

Cefpodoxime proxetil

Active against most strains of S. pneumoniae and all strains of H. influenzae and M. catarrhalis. Somewhat less active than amoxicillin vs. S. pneumoniae. Relatively expensive, well-tolerated.


Active against most strains of S. pneumoniae and all strains of H. influenzae and M. catarrhalis. Somewhat less active than amoxicillin vs. S. pneumoniae. Relatively expensive; well-tolerated.

Cefuroxime and Cefuroxime axetil

Active against most strains of S. pneumoniae and all strains of H. influenzae and M. catarrhalis. Somewhat less active than amoxicillin vs. S. pneumoniae. Relatively expensive; well-tolerated.


As active as azithromycin and erythromycin vs. S. pneumoniae; activity vs. H. influenzae is debated due to activity ascribed to a metabolic product, which is greater than that of the parent compound. FDA has approved for H. influenzae pneumonia but would not rely on it for severe infection.


Risky choice due to low in vitro activities against S. pneumoniae and H. influenzae, but good historic record for AECB, well-tolerated and cheap. This is usually a good choice for patients who aren’t very sick.


Active against nearly all treatable pathogens except influenza virus including S. pneumoniae, H. influenzae, M. catarrhalis, most S. aureus (MSSA), most GNB, Chlamydophila pneumoniae and Mycoplasma pneumoniae. The drug is easy to take (once daily) and well-tolerated. The major concern is abuse with the consequence of resistance and C. difficile infection. Tendon rupture possible even with short courses, especially if patients are frequently taking systemic corticosteroids or have ESRD.


No longer useful since most strains now resistant, so need to know current CDC recommendations.


Use for the treatment and prophylaxis of influenza virus A and B. Early treatment preferred, should be withing 48 hrs of sx onset -- if possible but use beyond this time frame is justified if severe COLD, severe infection or hospitalized patient. Expensive. Main side effect in GI intolerance and rare cases of self-injury and confusion. See the CDC website for the latest recommendations.


Limited published data but reasonable activity vs. the major pathogen and generally well tolerated except for hypersensitivity reactions to a sulfa moiety.


Neuraminidase inhibitor (NAI) for the treatment of influenza A or B. Given by inhalation, the aerosolized form is contraindicated for persons with reactive airways. Should be given within 48 hrs of the onset of sx if possible, but use later is justified if severe illness or hospitalized patient. Expensive. Main side effect is bronchospasm. The most potent of the NAIs.


  • Common non-bacterial causes of AECB: viral infections, allergens, pollution.
  • Must r/o pneumonia (x-ray), subclinical asthma (PFTs) and respiratory failure (ABG).
  • Antibiotics fall into 3 categories: cheap, old, and proven (TMP/SMX, doxycycline); better activity vs S. pneumoniae and H. influenzae (oral cephalosporins, amoxicillin/clavulanate); drugs w/ clout but concern for abuse and resistance (levofloxacin, moxifloxacin).
  • Main issues: role of H. influenzae and the role of newer drugs to reduce hospitalizations and to delay the next exacerbation?
    • A placebo-controlled trial in > 1000 patients with chronic bronchitis showed prophylactic azithromycin (250 mg/d) reduced the rate of acute exacerbations by 40%. Note that these recommendations must be interpreted with caution due to the crisis of antibiotic resistance attributed primarily to the extensive use of antibiotics. Occasionally considered in patients with frequent AECB as maintenance, but not a first-line current recommendation (GOLD 2017).

Pathogen Specific Therapy

Basis for recommendation

  1. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. http://www.goldcopd.org (accessed 5/18/17)

    Comment: This group is supported by the NHLBI and WHO, and it’s regularly updated guidance comprises a definition of COPD and chronic bronchitis as well as a basis for recommendations in this module.

  2. Global Initiative for Chronic Obstructive Lund Disease (2020 Report). https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2-03Dec19_WMV.pdf (accessed 6/4/20) pp 102-113.


    The GOLD report is revised annually since 2011. Includes definitions, comprehensive treatment recommendations. Antibiotic recommendations are what are incorporated into the ABX module. For the overall management, please launch and view the document for AECB.


  1. Huckle AW, Fairclough LC, Todd I. Prophylactic Antibiotic Use in COPD and the Potential Anti-Inflammatory Activities of Antibiotics. Respir Care. 2018;63(5):609-619.  [PMID:29463692]

    Comment: Similar to bronchiectasis studies, authors look at whether certain drugs (mostly macrolides) have some effect beyond anti-infective properties. Twelve trials w/ 3784 patients reviewed. Authors thought the studies with azithromycin or erythromycin had the greatest effect with improvement on clinical bases.

  2. Vollenweider DJ, Frei A, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2018;10:CD010257.  [PMID:30371937]

    Comment: Systematic review suggests that effects are small and inconsistent for both inpatients and outpatients. Effect of abx best among ICU patients. Data quality is heterogeneous and limited.

  3. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189(12):1503-8.  [PMID:24779680]

    Comment: Role of azithromycin for prevention in COPD remains controversial. The authors here suggest that daily use of drugs was most helpful in older patients and with GOLD scores of 1 or 2 (milder disease). Use of the drug did seem to prevent flares that required both antibiotic and steroid therapy.

  4. Vollenweider DJ, Jarrett H, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;12:CD010257.  [PMID:23235687]

    Comment: Review of trials of abx v. placebo RCTs only (2068 pts), found benefit in patients in ICU while those on non-ICU hospitalizations and outpatients were not consistent. Of note, these trials ranged in years from 1957 to 2012. There was no apparent impact on mortality or LOS in hospital for those patients.

  5. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98.  [PMID:21864166]

    Comment: This is a randomized controlled trial in 1,142 patients with COPD given placebo vs. azithromycin 250 mg/day. azithromycin recipients had a significant reduction in exacerbations (1.5/year vs. 1.8/year; p=< 0.001) and improved lung function.

  6. Dimopoulos G, Siempos II, Korbila IP, et al. Comparison of first-line with second-line antibiotics for acute exacerbations of chronic bronchitis: a metaanalysis of randomized controlled trials. Chest. 2007;132(2):447-55.  [PMID:17573508]

    Comment: First-line agents (ampicillin, TMP-SMX and doxycycline) vs. 2nd line (amox-CA, macrolides, quinolines and 3d gen cephalosporins). First-line agents were inferior (RR 0.5).

  7. Fernaays MM, Lesse AJ, Sethi S, et al. Differential genome contents of nontypeable Haemophilus influenzae strains from adults with chronic obstructive pulmonary disease. Infect Immun. 2006;74(6):3366-74.  [PMID:16714566]

    Comment: The authors, noted authorities on COPD, examined genetic differences between 59 H. influenza strains implicated in exacerbations of COPD and 73 that merely colonized the lower airway in these patients. They noted gene patterns that were associated with exacerbations supporting the thesis that these strains have greater pathogenic potential.
    Rating: Important

  8. Wilson R, Jones P, Schaberg T, et al. Antibiotic treatment and factors influencing short and long term outcomes of acute exacerbations of chronic bronchitis. Thorax. 2006;61(4):337-42.  [PMID:16449273]

    Comment: Patients with AECB were randomized to treatment with moxifloxacin or placebo. Clinical cure was significantly associated with antibiotic treatment (OR 1.5) and negatively associated with age >65, and bronchodilator use. The conclusion was that the benefit of moxifloxacin was seen primarily in those >65 yrs.

  9. Ram FS, Rodriguez-Roisin R, Granados-Navarrete A, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006.  [PMID:16625602]

    Comment: This systematic review examines placebo-controlled studies that are not now frequently pursued by pharma (2020) that show reduced risk of short-term mortality by 77%, treatment failure by 53% and sputum purulence by 44% if antibiotics are received. This supportive evidence applies to moderately or severely ill patients with COPD exacerbations and increased cough and sputum purulence with antibiotics.

  10. Murphy TF, Brauer AL, Grant BJ, et al. Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med. 2005;172(2):195-9.  [PMID:15805178]

    Comment: The Buffalo group has studied this cohort of 104 pts with COPD for 10 years with monthly sputum cultures. In this study they showed M. catarrhalis was newly detected in 57 of 560 exacerbations. This was accompanied by a serologic response and clearance. They conclude M. catarrhalis causes 10% of exacerbations.

  11. Sethi S, Wrona C, Grant BJ, et al. Strain-specific immune response to Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;169(4):448-53.  [PMID:14597486]

    Comment: A longitudinal study of patients with COPD showing some exacerbations are associated with an immune response to a newly acquired strain of H. influenzae. (This supports the role of H. flu as a pathogen in exacerbations).

  12. Murphy TF, Brauer AL, Schiffmacher AT, et al. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170(3):266-72.  [PMID:15117742]

    Comment: Analysis of sequential (monthly) samples of sputum from patients with COPD defined a group with a less than six-month lapse with negative cultures for H flu. The subsequently recovered strain was identical to the initial isolate suggesting it was always there and that sputa culture are unreliable sources of this agent.

  13. Wedzicha JA. Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2004;1(2):115-20.  [PMID:16113423]

    Comment: Viruses implicated in 168 cases in 83 patients are: All viruses - 66 (40%), Rhinovirus - 59% (of the 66), RSV - 29%, Coronavirus -11%, influenza - 16%.

  14. Sethi S. Bacteria in exacerbations of chronic obstructive pulmonary disease: phenomenon or epiphenomenon? Proc Am Thorac Soc. 2004;1(2):109-14.  [PMID:16113422]

    Comment: The author reviews methods and conclusions of studies to determine exacerbations of COPD with 2 categories: 1) Conventional: sputum culture, serology & placebo-controlled trial; 2) New: Bronchoscopic sampling, molecular epi of sputum isolates, immune response & markers of airway inflammation. Most exciting are the new methods which include studies showing a new strain of H. influenzae is associated w/some exacerbations & there is an immune response that is strain-specific to support its potential role.

  15. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(9):1618-23.  [PMID:11719299]

    Comment: Study of 168 exacerbations - viruses found in 67 (40%) - most common were rhinovirus and RSV.

  16. Nouira S, Marghli S, Belghith M, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo-controlled trial. Lancet. 2001;358(9298):2020-5.  [PMID:11755608]

    Comment: Results showed a benefit of ofloxacin with mortality decrease (4% vs 22%) & reduced duration hospitalization & mechanical ventilation. The study raised concerns about the ethics of a placebo control with such seriously ill pts, but the accompanying editorial notes that the benefit of antibiotics had never been clearly shown.
    Rating: Important

  17. Snow V, Lascher S, Mottur-Pilson C, et al. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 2001;134(7):595-9.  [PMID:11281744]

    Comment: Position paper of ACP for managing exacerbations of chronic bronchitis. Indications to Rx: Increased dyspnea, increased cough AND increased sputum purulence. Agents recommended: Amoxicillin, doxycycline, TMP-SMX.

  18. Emerman CL, Cydulka RK. Use of peak expiratory flow rate in emergency department evaluation of acute exacerbation of chronic obstructive pulmonary disease. Ann Emerg Med. 1996;27(2):159-63.  [PMID:8629745]

    Comment: The authors show the ADVANTAGES OF MEASURING FEV-1 AND/OR PEFR for baseline evaluation and response to treatment. Both require patient effort

  19. Emerman CL, Lukens TW, Effron D. Physician estimation of FEV1 in acute exacerbation of COPD. Chest. 1994;105(6):1709-12.  [PMID:7911418]

    Comment: The authors show PHYSICIAN ESTIMATES OF THE SEVERITY OF AIRWAY OBSTRUCTION in exacerbations of COPD correlate poorly with FEV-1 measurements

  20. Jørgensen AF, Coolidge J, Pedersen PA, et al. Amoxicillin in treatment of acute uncomplicated exacerbations of chronic bronchitis. A double-blind, placebo-controlled multicentre study in general practice. Scand J Prim Health Care. 1992;10(1):7-11.  [PMID:1589668]

    Comment: One of many controlled trials of amoxicillin vs. placebo, this one with 262 outpatients with AECB. Analysis by symptom score and peak expiratory flow rate showed NO ADVANTAGE FOR ANTIBIOTICS.

  21. Wiedemann HP, McCarthy K. Noninvasive monitoring of oxygen and carbon dioxide. Clin Chest Med. 1989;10(2):239-54.  [PMID:2661121]

    Comment: The data support use OF PULSE OXIMETRY to evaluate oxygenation except when O2 saturation is < 70%

  22. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106(2):196-204.  [PMID:3492164]

    Comment: There are many trials of antibiotics, but this is THE BEST AND MOST QUOTED TRIAL. Anthonisen et al studied 362 exacerbations and showed that antibiotics have a significant benefit, but only when the exacerbation is relatively severe with at least 2 of the major 3 symptoms--increased cough, sputum, and sputum purulence. Clinical success was noted in this group for 75% of antibiotic recipients vs. 63% of placebo recipients. This is close, but the number of patients was sufficiently high to push it over the p=0.05 threshold for statistical significance.
    Rating: Important

  23. Gump DW, Phillips CA, Forsyth BR, et al. Role of infection in chronic bronchitis. Am Rev Respir Dis. 1976;113(4):465-74.  [PMID:1267252]

    Comment: One of the MOST COMPREHENSIVE STUDIES EVER DONE by culture techniques. The authors followed a group of pts with chronic bronchitis & obtained quantitative bacterial cultures of sputum & viral cx at 2-week intervals. They showed that exacerbations of bronchitis were often due to viral infection (positive cultures in 32% of exacerbations vs. < 1% in periods of stability), sputum bacterial culture showed no significant changes in either frequency of recovery or counts of the big 2--H. flu & S. pneumo). S. pneumo was recovered in 37% of exacerbations & in 33% of control periods; for H. flu, it was 57% & 60%, respectively

  24. Bjerkestrand G, Digranes A, Schreiner A. Bacteriological findings in transtracheal aspirates from patients with chronic bronchitis and bronchiectasis: a preliminary report. Scand J Respir Dis. 1975;56(4):201-7.  [PMID:1198085]

    Comment: The tracheobronchial tree below the larynx is normally sterile. This study using transtracheal aspirations shows that about one-third of patients with chronic bronchitis have COLONIZATION OF THE LOWER AIRWAYS by the same bacteria implicated as the major causes of AECB--H influenzae and S. pneumoniae. This presumably accounts for the common observation that sputum cultures show the same bacteria during stability and during exacerbations.

  25. Pines A, Raafat H, Plucinski K, et al. Antibiotic regimens in severe and acute purulent exacerbations of chronic bronchitis. Br Med J. 1968;2(5607):735-8.  [PMID:4872151]

    Comment: One of the many controlled trials of tetracycline vs. placebo in 149 patients hospitalized for AECB. There was SIGNIFICANT BENEFIT FOR TETRACYCLINE TREATMENT in terms of symptom scores and peak expiratory flow rate.

Last updated: July 3, 2020