Early Identification of Exacerbations in Patients With Chronic Obstructive Pulmonary Disease

Abstract

Frequent exacerbations of chronic obstructive pulmonary disease (COPD) place a considerable burden on the health care system and are a major cause of decreased health-related quality of life, accelerated pulmonary decline, and mortality in individual patients. Primary care physicians are usually the first point of contact for patients experiencing an exacerbation and are therefore best placed to prevent, identify, and treat these events in a timely manner. This review addresses the triggers and risk factors for COPD exacerbations, including the exacerbation-prone phenotype. The prevention, prompt diagnosis, and early appropriate pharmacological/nonpharmacological treatment of COPD exacerbations is important, as early recognition of symptoms (as supported by tools for measuring the illness/wellness experience of COPD patients in primary care) and treatment lead to optimal recovery in these patients. The review also highlights the importance of the urgency in identifying exacerbations and the important role played by primary care physicians in the prevention and postexacerbation management of patients with COPD.

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease that affects approximately 13.1 million adults in the United States ¹ and over 65 million people worldwide ² ; however, this disease is underdiagnosed. ³ COPD is now ranked as the third-leading cause of death in the United States ⁴ and is projected to be the third-leading cause of global mortality by 2030. ⁵ Typically, COPD is detected in middle age and is characterized by airflow obstruction that is not fully reversible. COPD is a disease of slow progression interspersed with exacerbations that become more frequent with declining lung function. ⁶ Common symptoms include chronic cough, abnormal sputum production, and dyspnea on exertion. These symptoms may be caused by other conditions, such as cardiac disease, and should not be automatically attributed to COPD but rather confirmed by a patient’s characteristic history (which usually includes smoking, the main risk factor for developing COPD) and postbronchodilator spirometry to confirm the presence of airflow limitation that is not fully reversible. ⁶

An exacerbation is defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as “an acute event characterized by worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medications.” ⁶ Exacerbations range in severity from transient declines in functional status to fatal events. Recurrent episodes of exacerbations are often associated with accelerated pulmonary decline, ⁷ decreased quality of life, ⁸ and, with severe exacerbations, an increase in the risk of mortality. ⁹ Less severe exacerbations (those that are amenable to treatment in a primary care office) appear to come on quickly and are responsive to therapy within 7 days, while more severe episodes require hospitalization with extended recovery periods. Some patients never return to their pre-exacerbation baseline ¹⁰ ; several studies have demonstrated a high rate of recurrence ¹¹ and mortality^12,13 in people with severe COPD exacerbations, requiring hospitalizations.

Hospitalizations due to COPD exacerbations are expensive and account for 50% to 75% of the total costs of the disease (depending on the country), ¹⁴ approaching $50 billion in the United States for 1 year. ¹⁵ Although there is an increasing prevalence of COPD ¹⁶ in the aging US population, ¹⁷ the high health care cost and poor quality of life associated with COPD could be reversed by the prompt identification and treatment of exacerbations.

Primary care physicians are at the forefront of managing patients with COPD and are usually the first point of contact for patients experiencing an exacerbation. Therefore, it is essential for these physicians to understand the importance of prompt diagnosis, as well as the steps to take in the management of COPD exacerbations. This review discusses the importance of urgency in identifying exacerbations and the role that primary care physicians can play in the prevention and diagnosis of these events in patients with COPD.

General Considerations

Triggers and Risk Factors for Exacerbations

Bacterial and viral respiratory tract infections trigger the majority of COPD exacerbations. ¹⁸ Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are examples of bacterial pathogens associated with exacerbations; rhino, influenza, and respiratory syncytial viruses also are implicated in these events. ¹⁸ Additional triggers include exposure to tobacco, occupational dusts, biomass fuel smoke, and environmental pollution. ⁶ Exacerbations are more likely to recur in patient subsets with a history of exacerbations, ⁶ patients with other independent clinical predictors (chronic cough and sputum production), ¹⁹ or patients with physician-diagnosed concomitant asthma. ²⁰ Other medical conditions, such as congestive heart failure, pneumothorax, pulmonary embolism, cardiac arrhythmia, and pleural effusion, can aggravate symptoms or mimic exacerbations in patients with known COPD. ⁶

Classification of Exacerbations

Exacerbations have been classified on the basis of symptomatic (not lung function) criteria ²¹ or graded on the basis of requirements for health care resources ¹⁴ ; however, there is no consensus-based definition for the ranking of exacerbations. Many investigators classify exacerbations according to the symptomatic criteria first proposed by Anthonisen et al in 1987.^21,22 According to these criteria, type 1 exacerbations are characterized by the following symptoms: increased breathlessness, increased sputum volume, and new or increased sputum purulence. Type 2 exacerbations include any 2 of these symptoms, and type 3 exacerbations consist of any 1 of the above symptoms with at least 1 additional feature, including upper respiratory tract infection in the previous 5 days, fever without other cause, increased wheezing or cough, or a 20% increase in respiratory or heart rate compared with baseline. Clinically, this classification system has limited utility for the management of COPD exacerbations. The American Thoracic Society/European Respiratory Society severity scale also can be used in the assessment of exacerbations: level I (mild), patient is treated at home; level II (moderate), patient requires hospitalization; and level III (severe), exacerbation leads to respiratory failure, one of the indicators for intensive care. ¹⁴ While these assessments (determined after the event) may be helpful in future planning or clinical trials, they do not aid the primary care physician in deciding how to routinely proceed during an exacerbation.

The Exacerbation-prone Phenotype

Exacerbations have been shown to increase and become more severe with disease severity. ²³ More precisely, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study ²³ demonstrated that exacerbation rates in the first year of patient follow-up were 0.85 per person for patients with GOLD-defined stage 2 COPD, 1.34 for patients with GOLD-defined stage 3 COPD, and 2.00 for patients with GOLD-defined stage 4 disease. ⁶ Since the most reliable predictor of exacerbations in an affected individual is a history of exacerbations, ²⁴ the authors also investigated the hypothesis that there is a frequent exacerbation phenotype that is independent of disease severity. The ECLIPSE study findings support the hypothesis of a frequent COPD exacerbator phenotype. Overall, 22% of patients with stage II disease, 33% of patients with stage III disease, and 47% of patients with stage IV disease had frequent exacerbations (2 or more in the first year of follow-up). ²³ In the absence of a universal definition, Soler-Cataluña et al ²⁵ proposed a consensual definition for an exacerbation-prone individual or frequent COPD exacerbator as a patient with a mean of 2 or more exacerbations per year. The authors suggest allowing 4 to 6 weeks to elapse following treatment to differentiate between a recurrent event and treatment failure. ²⁵ Frequent COPD exacerbators may require different clinical approaches than do patients whose exacerbations increase in frequency based solely on increasing disease severity. ⁶

Patients may switch from being a frequent to an infrequent exacerbator and vice versa, ²⁶ as was shown among a group of 121 patients. ²⁶ A large clinical trial is warranted for further exploration of this hypothesis. If this theory proves true, it will be very important to determine what can be done to move frequent exacerbators into the infrequent category and prevent the infrequent exacerbators from becoming frequent exacerbators.

Prevention of Exacerbations

Proactive COPD exacerbation management to prevent or delay future events should include pharmacological and nonpharmacological interventions. Nonpharmacological methods include avoiding risk factors for exacerbations, such as tobacco smoke (active or inhaling secondhand smoke), environmental pollution, and interaction with individuals who have viral or bacterial respiratory infections. If the patient has asthma as well as COPD, he or she should avoid allergic triggers, such as pollen and pets. ²⁷ The most effective and cost-effective intervention in most people for stopping COPD progression is smoking cessation ⁶ ; accordingly, all patients with COPD should be offered a smoking cessation program by their physician. ⁶ Physicians should inform patients about the potential triggers of exacerbations as well as approaches to avoiding these triggers. Primary care physicians also should ensure that patients have received annual influenza and pneumonia vaccinations as appropriate. ⁶

Pharmacotherapies to aid in the reduction of future exacerbations include maintenance medications approved by the US Food and Drug Administration. The long-acting anticholinergic tiotropium is indicated to reduce exacerbations in patients with COPD ²⁸ ; the long-acting β₂-agonist/inhaled corticosteroid combination salmeterol/fluticasone is indicated to reduce exacerbations in patients with COPD with a history of exacerbations ²⁹ ; and the oral phosphodiesterase-4 inhibitor roflumilast is indicated to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. ³⁰ Nonpharmacological strategies include teaching patients how to use inhalers and store prescribed medications properly, referring patients for pulmonary rehabilitation after recovery from exacerbations, and educating patients about the importance of adhering to all aspects of their treatment regimens. Patients who are hypoxemic during an exacerbation and after recovery may require long-term supplemental oxygen therapy ⁶ ; primary care physicians will have to facilitate access to oxygen for these patients.

When to Suspect an Exacerbation

An exacerbation diagnosis should be considered for patients with a history of COPD or past exacerbations who experience worsening respiratory symptoms and deteriorating health status as defined by GOLD and other guidelines.^6,14 Patients may not recognize or report their symptoms ³¹ and might delay seeking medical assistance during an exacerbation. ³² Thus, primary care physicians need to educate patients to recognize the early signs of respiratory symptom deterioration (eg, increased cough, change in mucus [color/amount/viscosity], and increased shortness of breath or wheezing) and the limitations in activities of daily living. Primary care physicians who have established a rapport with their patients may be able to initially assess symptom severity via the telephone and may recommend a visit to the emergency department or hospitalization during an exacerbation, especially if the individual has very severe COPD or significant comorbidities, suddenly develops resting dyspnea, has a history of frequent exacerbations, or has insufficient support at home to manage an exacerbation.^6,14 Patients are generally advised to visit their physician if they experience aches and pains and have a cough for 2 or more days so they can receive a thorough evaluation and a referral to a specialist if necessary. Diagnosis by physical assessment encompasses taking a history of baseline and all current symptoms, including malaise, insomnia, fatigue, depression, sleepiness, and confusion. Pulse oximetry to evaluate oxygen saturation, lung and heart examinations, whole blood count, and other laboratory tests also may be carried out. ⁶ When deteriorating symptoms are considered to be less severe exacerbations, the physician can monitor the patient closely and treat him or her as appropriate on an individual basis (Figure 1) owing to the continuity of care that is part of the primary care setting.

Figure 1.

Monitoring a patient at the onset of an exacerbation

Medication management during an exacerbation is beyond the scope of this article (see Anzueto ³³ for a detailed discussion) and therefore only briefly mentioned here. Depending on its severity, prompt treatment of an exacerbation with increased/more frequent doses of existing short-acting bronchodilator therapy with appropriate antibiotic in the event of a bacterial infection and systemic corticosteroids in selected patients may lead to a faster recovery. ⁶

Why Urgent Identification of an Exacerbation Matters

Clinically, it is important to manage exacerbations promptly and accurately, as early recognition of symptoms by patients and early appropriate treatment by physicians improve exacerbation recovery ³⁴ ; however, mistaking symptom variation as an exacerbation may result in unnecessary exposure to therapy. ³⁵ Patients are likely to derive more health-related benefits (greater recovery, fewer hospitalizations, and a better health-related quality of life) from prompt identification and treatment at the start of an exacerbation, compared with those in whom therapy is delayed. ³⁴ However, primary care physicians are faced with a number of challenges in detecting the early signs of an exacerbation and implementing appropriate treatment (eg, patients may delay reporting their own symptoms ³³ or exacerbations in patients with milder COPD may go unrecognized and unreported).^31,32 Moreover, patients who survive severe exacerbations are at high risk of rehospitalization after 1 year (25%) and 5 years (44%). ³⁶ Relapse following initial treatment for acute exacerbations also may lead to prolonged disability. ³⁷ Thus, there is an added need to urgently identify patients most at risk of relapse to implement proactive treatment and closer follow-up. ³⁷

An awareness of the concepts of an exacerbation-prone individual and a high-risk period of recurrence may aid primary care physicians in the management of exacerbations. Emerging data suggest that exacerbations cluster in time and that there is an at-risk period of 8 weeks following an exacerbation in which there is a high likelihood that a second event will occur. ¹¹ Results from a prospective pilot study suggest that domiciliary pulse oximetry may have potential as a tool to distinguish the onset of an exacerbation from normal day-to-day variations. ³⁵ A patient-reported diary ³⁸ could also be useful in assessing the timing, frequency, and duration of exacerbations.

Postexacerbation Management

Primary care physicians should monitor patients for an appropriate time after an exacerbation and, as previously mentioned, educate patients about risk reduction measures. Patients who were hospitalized for an exacerbation should be assessed by their primary care physicians 4 to 6 weeks after discharge. As part of this follow-up assessment, the GOLD guidelines ⁶ recommend that physicians perform spirometry, reassess inhaler technique, and determine whether the patient is able to cope with his or her usual environment, understands the recommended treatment regimen, or requires long-term oxygen therapy or a home nebulizer. ⁶ There are a number of tools that can be used to measure the illness and wellness of COPD patients in primary care, and a review of 9 of these has been published by the International Primary Care Respiratory Group, providing a description and the limitations of each tool, including ease of use, availability, costs, and conditions of use. ³⁹

After an exacerbation, a patient’s lung function will probably never return to baseline, ¹⁰ and, if a patient has multiple exacerbations, his or her lung function will decline from then on. ⁷ Primary care personnel should counsel patients that it can take 2 to 6 weeks (longer with more severe or frequent exacerbations) for their lung function to stabilize ⁷ and that a further decline in lung function may occur if measures are not taken to prevent future exacerbations.

Conclusions

The primary care physician can potentially improve patient outcomes by identifying COPD exacerbations early to minimize the need for acute care and by educating patients about self-management, including the recognition of exacerbation risk factors, signs, and symptoms; the importance of optimal adherence to treatment regimens and prescribed medications; and the need to contact a physician as appropriate.