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 Typical chest radiograph at exacerbation of COPD. Note the features of underlying COPD, including hyperexpansion and prominent pulmonary vasculature suggestive of pulmonary hypertension, but no evidence of conditions that may mimic or complicate exacerbation (e.g., pneumothorax, pneumonia, cardiac failure).

There is no accepted method of assessing exacerbation severity because it represents the combined severity of the underlying disease and the exacerbation insult. Quantifying changes in symptoms or lung function requires knowledge of the patient at baseline and is difficult to achieve and not generally helpful. Consequently, the degree of health care utilization has been used as a surrogate assessment of severity: mild exacerbations require no more than an increase in inhaled bronchodilators, moderate exacerbations require antibiotics and corticosteroids in the community, and patients with severe exacerbations require hospital admission. The pH is the best indicator of an acute change in alveolar ventilation, and most exacerbations associated with respiratory failure will require hospital assessment. However, the decision to admit a patient depends on more than the severity of the exacerbation and would include, for example, the social circumstances and support available to the patient at home.

Treatment

Pharmacotherapy

The principles of therapy at the time of COPD exacerbation are twofold: to modify the course of the event and to support the patient’s respiratory function so that disease-modifying therapies can work. Treatment is given in proportion to the clinical severity of the event, and the sequential approach is illustrated in Figure 43-4. Many guidelines exist to guide appropriate therapy, including recently updated evidence-based statements from the UK National Institute for Clinical Excellence (NICE). Attention to comorbidities is also important, and in the recovery phase the clinician should consider interventions that may reduce the risk of subsequent exacerbations.

Figure 43-4 Summary of stepwise therapeutic approach to COPD exacerbation, with increasing severity of the exacerbation presentation. NIV, noninvasive ventilation.

Inhaled Bronchodilators

An increase in the dose or frequency of inhaled short-acting bronchodilators is the mainstay of COPD exacerbation therapy. The bronchodilator effect is similar between the β₂-agonist albuterol (salbutamol) and the anticholinergic drug ipratropium bromide. Although often used in combination, there is little evidence to suggest an additive benefit. Also, no evidence indicates that nebulization is more effective than administering these drugs by inhaler and large-volume spacer. However, nebulizers are often preferred in dyspneic patients and may be less demanding on nursing time. Nebulizers for COPD should be driven on compressed air.

Patients prescribed long-acting bronchodilators normally continue these therapies, but evidence is minimal to support the introduction of long-acting agents as exacerbation therapy, and short-acting drugs are preferred. The recommended approach is therefore to increase the dose and frequency of either a short-acting β₂-agonist or an anticholinergic, with both drugs used together in the event of inadequate clinical response.

Corticosteroids

Systemic corticosteroids are indicated in all COPD exacerbations except milder events that respond to an increase in inhaled bronchodilators alone. A number of randomized trials, now summarized in systematic reviews, demonstrate a more rapid improvement in FEV₁ after administration of steroids, although effects on outcomes such as oxygenation, hospitalization, and length of stay are more variable, with no definite evidence of a mortality benefit. Guidelines vary in their specific recommendations, generally suggesting oral prednisone, 30 to 40 mg for 10 to 14 days. Prolonged courses provide no additional benefit (and increase the risk of side effects), and no evidence suggests that tapering the dose is advantageous. Some physicians choose to give the first dose of prednisone intravenously. Nebulized budesonide results in similar improvements in lung function to oral dosing but is more expensive than prednisone.

Intriguingly, the use of systemic steroids may delay the time to subsequent exacerbation. Although initiation of inhaled steroids has no role at exacerbation, inhaled corticosteroids have an important role in exacerbation prevention, as discussed later.

Antibiotics

Anthonisen’s seminal work on antibiotics at COPD exacerbation demonstrated benefit only when patients had an increase in at least two of three symptoms: breathlessness, sputum volume, and sputum purulence. Sputum purulence reliably indicates the presence of bacteria at exacerbation. More recently, a meta-analysis has confirmed a small but statistically significant benefit in favor of antibiotics. Local resistance patterns and antibiotic policies will dictate the choice of drug, but coverage should include the common pathogens Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Streptococcus pneumoniae. An oral aminopenicillin, macrolide, or tetracycline is therefore an appropriate empirical choice. Comparative data across drug classes are sparse. Intravenous antibiotics are rarely required. Data on the optimal duration of therapy are minimal. Antibiotic use at exacerbation may also prolong the time to subsequent exacerbations, perhaps by modulating airway bacterial load.

Noninvasive Ventilation

Noninvasive ventilation (NIV) refers to the provision of ventilatory support using a nasal or full-face mask and the patient’s own upper airway, in the absence of an endotracheal tube. Evidence now supports the use of NIV for patients with hypercapnic respiratory failure caused by exacerbation of COPD. The benefit in mortality with additional reduction in hospital stay and complications may largely be attributed to the reduced need for sedation, intubation, and invasive ventilation. In addition, and in contrast to invasive ventilation, NIV may be used earlier and intermittently, which facilitates communication, nutrition, and physiotherapy. NIV is usually administered as pressure-cycled bilevel positive airway pressure in which the inspiratory and expiratory pressures may be independently varied.

However, NIV is not a substitute for invasive ventilation when required. Therefore, the management plan should consider suitability for invasive ventilation should NIV fail, and some patients may have relative contraindications to NIV or can have respiratory failure of such severity that they should be immediately assessed for invasive ventilation (Box 43-2). Most patients suitable for NIV are able to tolerate the treatment (Figure 43-5).

Box 43-2

Indications and Relative Contraindications for Noninvasive Ventilation in Patients with COPD Exacerbation

Indications

Exacerbation with hypercapnic respiratory failure

PaCO₂ >45 mm Hg

pH <7.35 but >7.25

Relative Contraindications

More severe acidemia

Life-threatening hypoxemia

Inability to protect airway

Hemodynamic instability

Inability to clear secretions

Undrained pneumothorax

Impaired consciousness or agitation

Figure 43-5 Application of noninvasive ventilation by nasal mask in patient with exacerbation of COPD. Note the addition of entrained oxygen.

Clinical Course and Prevention

Using analysis of symptoms and lung function changes, the median length of an exacerbation in the COPD patient is 7 to 10 days, although there is wide variability and a proportion of exacerbations take considerably longer. Some patients never seem to recover their preexacerbation lung function. Patients admitted have an in-hospital mortality of about 10%, and for patients with hypercapnic respiratory failure, mortality approaches 50% at 2 years. Some patients may be suitable for early supported discharge, associated with similar outcomes but apparently no more cost-effective than standard care.

Given the importance of exacerbations and having managed the acute event, it is important to consider instituting a range of preventative measures to reduce the risk of further exacerbations in the COPD patient. Mounting evidence suggests that a number of drug classes are able to reduce exacerbation rates, including the long-acting β₂-agonists (LABAs), long acting anticholinergics, and inhaled corticosteroids (ICS), at least for those with moderately severe underlying disease. Combination therapy with LABAs and ICS appears superior to the use of either alone. Oral corticosteroids are ineffective at preventing exacerbations and have no effect on other outcomes measures, so these also are not indicated in stable COPD. Mucolytics may reduce exacerbation frequency in those with milder disease not taking ICS.

Ongoing trials are reexamining the role of antibiotics in reducing exacerbation frequency. Some evidence indicates antibiotic may be effective, but many trials included patients with simple chronic bronchitis; also, the drugs used were older, and any benefit must be balanced against the possibility of promoting drug resistance. Macrolides hold particular promise given their recognized antiinflammatory action.

Vaccination against influenza and pneumococcus (S. pneumoniae) is recommended.

Underprescription of long-term oxygen therapy in those requiring such treatment is associated with hospital readmission. Home NIV therapy may reduce admissions in those with chronic hypercapnic respiratory failure, although a specific effect on reducing exacerbations has not been demonstrated. Pulmonary rehabilitation has also been shown to reduce hospitalization in patients with COPD. Furthermore, early treatment that might be included in a patient education program can reduce exacerbation length.

The finding that exacerbation susceptibility varies among COPD patients means it is particularly important to target exacerbation reduction interventions at those most likely to develop these events. The simplest way is to ask patients how many courses of systemic (antibiotic and corticosteroid) therapy they received for exacerbations over the past 12 months. Patients receiving two or more such courses (“frequent exacerbators”) are likely to remain frequent exacerbators in the future and should be offered all appropriate exacerbation reduction interventions (see Figure 43-1).

Therefore, a variety of measures may be instituted to reduce the number and consequences of exacerbations, and COPD patients most in need can be identified by asking about prior exacerbation history. For this reason, and for further assessment of patients who present in respiratory failure, it is usually appropriate to review patients in an ambulatory care setting after admission with an acute exacerbation.

Conclusion

Research into exacerbations of COPD is moving rapidly. Not many years ago, these events were considered nothing more than “troublesome” deteriorations in symptoms without long-term consequence. We now know this is not true, but many unanswered questions remain. We still understand little about how bacterial and viral pathogens interact. More effective antiinflammatory agents are required, and the optimal role of antibiotics in preventing exacerbations remains to be defined. We currently have no effective interventions targeting viral pathogens, especially rhinovirus. Understanding why some patients appear more susceptible to exacerbations could lead to the development of new therapeutic approaches. Also, it is now recognized that COPD is associated with systemic inflammation that may cause considerable cardiovascular comorbidity, and ways to assess and manage this may reduce the number and impact of exacerbations in patients with chronic obstructive pulmonary disease.