Epidemiology

It would be difficult to exaggerate the importance of exacerbations in patients with chronic obstructive pulmonary disease (COPD). COPD is the fifth leading cause of death worldwide, and the mortality and morbidity are often associated with episodes of symptom deterioration termed exacerbations. Furthermore, whereas death rates in other prevalent conditions are falling, mortality from COPD continues to rise. Exacerbations of COPD account for about 1 in 10 emergency medical admissions to the hospital, and the in-hospital mortality is 10%. Exacerbations are consequently responsible for 70% of the direct costs attributable to COPD.

Exacerbations generally become both more frequent and more severe as the severity of the underlying COPD progresses. On average, patients with moderate to severe COPD, typical of those attending secondary care, will have one or two exacerbations requiring additional treatment annually. However, annual exacerbation incidence rates differ greatly among individual patients, and those prone to more frequent exacerbations experience a particular burden of disease (Figure 43-1). The best determinant of future exacerbation history is past exacerbation frequency, such that some patients appear more intrinsically susceptible and some more resistant to these important events.

Figure 43-1 Consequences of exacerbations in COPD.

Pathophysiology

The World Health Organization defines COPD as a disease state having a pulmonary component characterized by airflow limitation that is progressive, not fully reversible, and associated with an abnormal inflammatory response to noxious particles or gases. Airway inflammation is even greater at exacerbation, and the assumption has been that this additional inflammation provokes symptoms such as worsening dyspnea and sputum production, through mechanisms relating to airway tone, airway wall edema, and mucus production. The resultant air trapping increases the work of breathing and causes additional impairment to respiratory muscle function. Triggers of increased airway inflammation are therefore the causes of exacerbation, predominantly tracheobronchial infection, with a lesser role for pollutants. However, the effects of increased inflammation at exacerbation require further clarification, because a direct relationship between the clinical severity of the exacerbation and the degree of airway inflammation has never been conclusively demonstrated.

Defining the role of airway infection in causing COPD exacerbation is problematic. Recent advances in molecular biology have isolated respiratory viruses and potentially pathogenic bacteria from the airways of most patients during exacerbations (Box 43-1). However, certainly for patients with more severe underlying disease, bacteria also are often present in the stable state (bacterial colonization). Therefore the presence of an organism at exacerbation does not assume a role in causing that exacerbation. More recent studies suggest that a change in the colonizing bacterial strain may be the precipitating cause. However, not all strain changes are associated with exacerbation, and vice versa. Reflecting this, as discussed later, antibiotics are not of universal benefit during exacerbations. Rhinovirus is the most often identified viral pathogen, and thus exacerbations are more common during the winter months, when viral circulation in the community is higher. The role of atypical organisms such as Chlamydia and Mycoplasma species appears minimal.

Regarding pollutants in causing COPD exacerbation, large epidemiologic studies link rises in pollutant levels with increases in hospital admission for respiratory disease. Particulate matter less than 10 µm in size (PM₁₀) appears particularly important. Pollutants and microorganisms may interact to amplify the risk of exacerbation.

Because some COPD patients seem more susceptible to exacerbations, there may be genetic determinants of exacerbation frequency. In support of this, susceptibility to exacerbation has a familial component, but no single polymorphism has yet been reported to explain the variance in exacerbation frequency observed in COPD patients.

It is now recognized that COPD is associated with upregulated systemic inflammation, and there is now ample evidence to demonstrate heightened systemic inflammation during exacerbations. This may be important given the association between cardiovascular death and elevated systemic inflammatory markers, and because many patients with COPD die from cardiovascular disease. This systemic inflammation is thought to represent “spillover” from the lung.

Understanding the pathophysiology of exacerbations in COPD explains the rationale for the various therapies employed. Bronchodilators may be helpful for increased bronchoconstriction and hyperinflation, corticosteroids may reduce airway inflammation, and antibiotics may be appropriate in exacerbations caused by bacteria (Figure 43-2).

Figure 43-2 Pathophysiology of COPD exacerbation provides rationale for understanding therapies for exacerbations. NIV, noninvasive ventilation; V/Q, ventilation/perfusion ratio.

Clinical Features

The cardinal feature of COPD exacerbation is an increase in respiratory symptoms beyond what is usual for the patient. Typically, such symptoms include dyspnea, sputum volume, sputum purulence, cough, and wheezing, perhaps accompanied by upper respiratory tract symptoms such as rhinorrhea. Clinical signs are nonspecific but may include tachycardia, tachypnea, cyanosis, use of accessory respiratory muscles, polyphonic expiratory wheeze or crackles on auscultation, and features of carbon dioxide retention or cor pulmonale.

Exacerbations are heterogeneous events, and the clinical features vary widely. It may be best to consider the severity of the presentation, which represents the combined severity of the underlying COPD and the exacerbation. Patients with mild underlying disease may experience no more than a troublesome worsening of symptoms, whereas those with more severe COPD are at significant risk of respiratory failure. Furthermore, other conditions occurring in patients with underlying COPD may mimic or complicate exacerbations. Proper assessment, as described next, is therefore important.

Diagnosis

Exacerbation of COPD is a clinical syndrome, and there is no confirmatory diagnostic test. Although controversy surrounds how exactly to define an exacerbation, and such differences are important when interpreting study results, it is now widely accepted that an exacerbation is a sustained worsening of a patient’s symptoms that is acute in onset, is beyond day-to-day variation, and may necessitate a change in therapy.

Although investigations are not helpful in the diagnosis of exacerbation, diagnostic tests help assess the severity of the presentation and exclude other conditions in patients with underlying COPD that may mimic or complicate exacerbation. Such diagnoses include pneumonia, pneumothorax, pulmonary embolus, and cardiac failure, and appropriate investigations include chest radiography, electrocardiography, oxygen saturation (SaO₂) values, and arterial blood gas (ABG) analysis. Simple venous blood tests include complete blood count, urea and electrolytes, and C-reactive protein. A typical chest radiograph at exacerbation (Figure 43-3) should appear much the same as the patient’s radiograph in the stable state. Spirometry is not generally helpful because absolute values may be misleading, changes at exacerbation are small, and patients acutely dyspneic have difficulty performing the maneuvers. Sputum microscopy and culture may help to refine empirical antibiotic therapy in those not initially improving. For the patient with mild exacerbation responding to an increase in inhaled bronchodilators, it may be appropriate to omit further investigation.

Figure 43-3

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