Treating and preventing acute exacerbations of COPD

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ABSTRACTAcute exacerbations of chronic obstructive pulmonary disease (COPD)—characterized by shortness of breath, increased sputum production, increased purulence, or a combination of these signs—are costly and can have major impacts on the patient’s health. Corticosteroids, antibiotics, and bronchodilators are the cornerstones of prevention and therapy, with mucolytics, oxygen supplementation, and ventilatory support also advisable for some patients. Treatment should be evidence-based and tailored to the patient’s history and present needs.


  • COPD exacerbations usually start with an infection.
  • A short course of corticosteroids (eg, prednisone 40 mg daily for 5 to 7 days) improves outcomes with low risk.
  • The choice of antibiotic depends on severity and frequency of exacerbations and the patient’s age and condition.
  • Inhaled albuterol 2.5 mg, every 1 to 4 hours, should be prescribed with or without a nebulized anticholinergic.
  • Ventilation support is important for patients with acute respiratory acidosis (pH < 7.35).
  • Exacerbations can be prevented with some combination of inhaled agents (long-acting beta-2 agonist, corticosteroid, long-acting antimuscarinic), roflumilast (an oral phosphodiesterase inhibitor), and a mucolytic, depending on the patient’s needs.



In contrast to stable chronic obstructive pulmonary disease (COPD),1 acute exacerbations of COPD pose special management challenges and can significantly increase the risk of morbidity and death and the cost of care.

This review addresses the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.


The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines a COPD exacer­bation as “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.”2 It further categorizes acute exacerbations by severity:

  • Mild—treated with increased frequency of doses of existing medications
  • Moderate—treated with corticosteroids or antibiotics, or both
  • Severe—requires hospital utilization (either emergency room treatment or admission).

Although descriptive and useful for retrospective analyses, this current definition poses ambiguities for clinicians. Day-to-day variation in symptoms is not routinely assessed, so deviations from baseline may be difficult to detect. Although clinical tools are available for assessing symptoms in stable and exacerbated states (eg, the COPD assessment test3 and the Exacerbations of Chronic Pulmonary Disease Tool [EXACT]4), they have not been widely adopted in daily practice. Also, according to the current definition, the severity of an exacerbation can be classified only after the course of action is determined, so the severity is not helpful for forming a management strategy at bedside. In addition, physicians may have different thresholds for prescribing antibiotics and corticosteroids.

An earlier definition categorized a COPD exacerbation by the presence of its three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence):

  • Type I—all three symptoms present
  • Type II—two symptoms present
  • Type III—one symptom present, accompanied by at least one of the following: upper respiratory tract infection within the past 5 days, unexplained fever, increased wheezing or cough, or 20% increased respiratory rate or heart rate from baseline.

This older definition was successfully used in a prospective clinical trial to identify patients who benefited most from antibiotics for COPD exacerbations.5

COPD exacerbation: an acute worsening of respiratory symptoms

Despite these caveats regarding a definition, most clinicians agree on the clinical presentation of a patient with COPD exacerbation: ie, having some combination of shortness of breath, increased sputum volume, and purulence. By the same token, patients with COPD who present with symptoms not typical of an exacerbation should be evaluated for another diagnosis. For instance, Tillie-Leblond et al6 reported that 49 (25%) of 197 patients hospitalized with an “unexplained” exacerbation of COPD were eventually diagnosed with pulmonary embolism.


The care of patients with COPD places a great burden on the healthcare system. Using multiple national databases, Ford et al7 estimated that medical costs in the United States in 2010 attributable to COPD and its complications were $32.1 billion.

The largest component of direct healthcare costs of COPD is exacerbations and subsequent hospitalizations.8 Data from a predominantly Medicare population indicate that the annualized mean COPD-related cost for a patient with no exacerbations was $1,425, compared with $12,765 for a patient with severe exacerbations.9 The investigators estimated that reducing exacerbations from two or more to none could save $5,125 per patient per year.


COPD exacerbations are associated with a faster decline in lung function,10 reduced quality of life,11 and lost workdays.7 A single exacerbation may cause a decline in lung function and health status that may not return to baseline for several months, particularly if another exacerbation occurs within 6 months.12,13 COPD exacerbations have also been linked to poor clinical outcomes, including death.

In a prospective study in 304 men with COPD followed for 5 years, those who had three or more COPD exacerbations annually were four times as likely to die than patients who did not have an exacerbation.14 Nevertheless, the relationship with mortality may not be causal: Brusselle pointed out in an editorial15 that established mortality predictors for COPD do not include exacerbations, and symptomatic patients with COPD without any history of exacerbations are at greater risk of death than those who are asymptomatic but at high risk for exacerbations.


An acute COPD exacerbation can be viewed as an acute inflammatory event superimposed on chronic inflammation associated with COPD. Inflammation in the airways increases resistance to air flow with consequent air trapping. Increased resistance and elastic load due to air trapping place respiratory muscles at a mechanical disadvantage and increase the work of breathing.

Infection starts the process

Infections are thought to be the major instigators of COPD exacerbation

Infections, particularly bacterial and viral, are thought to be the major instigators of COPD exacerbation, although environmental factors such as air pollution may also play a role.16

Airway inflammation is markedly reduced when bacterial infection is eradicated. But if bacterial colonization continues, inflammatory markers remain elevated despite clinical resolution of the exacerbation.17 Desai et al18 found that patients with COPD and chronic bronchitis with bacterial colonization had a larger symptom burden than patients without colonization, even without an exacerbation.

Allergic profile increases risk

Although most studies indicate that infection is the main cause of exacerbations, clinicians should consider other mechanisms of inflammation on an individual basis. COPD exacerbations may be phenotyped by measuring inflammatory markers, perhaps as a starting point for tailored therapies.

Bafadhel et al19 studied 145 patients with COPD over the course of a year and recorded various biomarkers at baseline and during exacerbations. Exacerbations had an inflammatory profile that was predominantly bacterial in 37%, viral in 10%, and eosinophilic in 17%, and had limited changes in the inflammatory profile in 14%. The remaining episodes were combinations of categories. In another study,20 multivariate analysis conducted in two cohorts with COPD found that patients who had an allergic phenotype had more respiratory symptoms and a higher likelihood of COPD exacerbations.

Frequent COPD exacerbations are increasingly recognized as being associated with an asthma-COPD overlap syndrome, consisting of symptoms of increased airflow variability and incompletely reversible airflow obstruction.21

Inflammation as a marker of frequent exacerbations

Evidence is accumulating that supports systemic inflammation as a marker of frequent exacerbations. The Copenhagen Heart Study tested for baseline plasma C-reactive protein, fibrinogen, and white blood cell count in 6,574 stable patients with COPD.22 After multivariable adjustment, they found a significantly higher likelihood of having a subsequent exacerbation in patients who had all three biomarkers elevated (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9–7.4), even in patients with milder COPD and those without previous exacerbations.

Past exacerbations predict risk

A history of exacerbation is the best predictor of future exacerbation

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study23 found that a history of acute COPD exacerbation was the single best predictor of future exacerbations. This risk factor remained stable over 3 years and was present across the severity of COPD, ie, patients at lower GOLD stages who had a history of frequent exacerbations were likely to have exacerbations during follow-up.


COPD exacerbations increase the risk of cardiovascular events, particularly myocardial infarction.24 During hospitalization for acute exacerbation of COPD, markers of myocardial injury and heart failure may be elevated and are a predictor of death.25

Patel et al26 measured arterial stiffness (aortic pulse wave velocity, a validated measure of cardiovascular risk) and cardiac biomarkers (troponin and N-terminal B-type natriuretic peptide) at baseline in 98 patients and longitudinally during and after a COPD exacerbation. In addition to increased levels of cardiac biomarkers, they found a significant rise in arterial stiffness during the exacerbation event without return to baseline levels over 35 days of follow-up. The arterial stiffness increase was related to airway inflammation as measured by sputum interleukin 6, particularly in patients with documented lower respiratory tract infection.

Retrospective analysis suggests a reduced all-cause mortality rate in COPD patients who are treated with beta-blockers.27

Recommendation. We recommend that patients already taking a selective beta-blocker continue to do so during a COPD exacerbation.


Treatment with a combination of a corticosteroid, antibiotic, and bronchodilator addresses the underlying pathophysiologic processes of an acute exacerbation: inflammation, infection, and airway trapping.

Short course of a corticosteroid improves outcomes

A single exacerbation may worsen health status for several months

A 10-day systemic course of a corticosteroid prescribed for COPD exacerbation before discharge from the emergency department was found to offer a small advantage over placebo for reducing treatment failure (unscheduled physician visits, return to emergency room for recurrent symptoms) and improving dyspnea scores and lung function.28 Even just a 3-day course improved measures of respiration (forced expiratory volume in the first second of expiration [FEV1] and arterial oxygenation) at days 3 and 10, and reduced treatment failures compared with placebo.29

Corticosteroid prescription should not be taken lightly, because adverse effects are common. In a systematic review, one adverse effect (hyperglycemia, weight gain, or insomnia) occurred for every five people treated.30

Identifying subgroups of patients most likely to benefit from corticosteroid treatment may be helpful. Corticosteroids may delay improvement in patients without eosinophilic inflammation and hasten recovery in those with more than 2% peripheral eosinophils.31 Siva et al32 found that limiting corticosteroids to patients with sputum eosinophilia reduced corticosteroid use and reduced severe exacerbations compared with standard care.32

Recommendation. For an acute exacerbation, we prescribe a short course of corticosteroids (eg, prednisone 40 mg daily for 5 to 7 days). Tapering dosing is probably unnecessary because adrenal insufficiency is uncommon before 2 weeks of corticosteroid exposure. Clinicians should weigh the merits of tapering (reduced corticosteroid exposure) against patient inconvenience and difficulty following complicated instructions.

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