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The Proceedings of the American Thoracic Society 3:252-256 (2006)
© 2006 The American Thoracic Society

Clinical Assessment, Staging, and Epidemiology of Chronic Obstructive Pulmonary Disease Exacerbations

Jørgen Vestbo

North West Lung Centre, South Manchester University Hospital Trust, Manchester, United Kingdom; and Department of Cardiology and Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark

Correspondence and requests for reprints should be addressed to Jørgen Vestbo, M.D., Ph.D., North West Lung Centre, South Manchester University Hospital Trust, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. E-mail: jorgen.vestbo{at}manchester.ac.uk

ABSTRACT

Patients presenting with an exacerbation of chronic obstructive pulmonary disease (COPD) are initially assessed to ensure that a proper diagnosis has been made and that relevant differential diagnoses are excluded. Although guidelines provide indicators for use, very little systematic research has been done in initial assessment of COPD exacerbations. Next, the assessment should aim at stratifying patients for risk of poor outcome. For this, predictors of poor prognosis as well as knowledge of favorable treatments can be used. However, no formal and validated staging system exists today. Given the frequency and impact of COPD exacerbations, there seems to be a need for systematic research in this area.

Key Words: biomarkers • blood gases • chronic obstructive pulmonary disease • lung function • prognosis

Exacerbations of chronic obstructive pulmonary disease (COPD) are often described and discussed with a focus on definition, etiology, treatment, and outcomes. Less focus is usually aimed at the clinical assessment of the patient with an acute exacerbation, probably because this is seen as one of every clinician's basic medical skills. However, exacerbations are frequent, especially in patients with severe and very severe COPD, and exacerbations leading to hospitalization are among the leading causes of acute admission in Europe and the United States (1, 2). For this reason, it can be argued that developing means of patient assessment with a view to improving outcomes is desirable to achieve better understanding of exacerbations of COPD.

ASSESSMENT

The primary goal of the initial assessment of a patient with an exacerbation of COPD is to ensure that a proper diagnosis has been made. This often requires that differential diagnoses are excluded quickly and that, subsequently, severity of the exacerbation as well as the underlying COPD and the impact of comorbidities are ascertained. The classical differential diagnoses include heart failure, arrhythmia, pneumonia, lung cancer, pneumothorax, and pulmonary embolism. The latter is especially likely to be overlooked. Indeed, the seasonal variation in deep venous thrombosis and pulmonary embolism (3) is not often considered when the "COPD exacerbations epidemic" sets in by late autumn or early winter. Pneumonia, either alone or in combination with atrial fibrillation, frequently occurs in moderate to severe COPD, and both conditions are seen more often in patients with COPD than in others (4, 5). A thorough history is required—also in the patient well known to the clinician presenting for the fifth time in a short period—and should be supplemented with a physical examination and relevant tests. The history as well as findings from a physical examination can also help in the staging of the patient and thus decide whether there is a need for hospital admission, and if so, in what setting. Although recent guidelines have all provided guidance for these choices (6–8), "relevant tests" are not easily defined. In a recent review, Borrill and colleagues found the evidence base for most of our clinical tools for diagnosis and monitoring of respiratory disease to be surprisingly weak (9). Although mainly treatment trials were looked at for COPD, most such tests have not necessarily been sufficiently validated in spite of their widespread use. Some guidance can be obtained from thorough literature reviews. As an example, the 2001 review by the American College of Chest Physicians stated that an admission chest X-ray is worthwhile, whereas spirometry was not found to provide any help for diagnosis or assessment of severity of acute exacerbation of COPD (10). This was based mainly on one study showing that in 21% of COPD cases, diagnosis or treatment or both were altered as a result of the chest X-ray report (11).

It is, nevertheless, worth noting that no obviously useful laboratory test for an exacerbation exists. There are currently no known biomarkers of acute exacerbation that are the equivalent of the troponin-t test for myocardial infarction or D-dimer in pulmonary embolism. This can be due to a number of reasons but most likely it reflects that, just like the underlying disease, exacerbations of COPD are heterogeneous events. The most common causes of exacerbation are shown in Table 1.


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  		TABLE 1. CAUSES OF EXACERBATIONS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 
After having established the diagnosis of an exacerbation of COPD, attention to the cause of the exacerbation is warranted. If diagnostic criteria are vague, the notion of establishing the cause of the exacerbation is at least as controversial. It is clear that an exact cause often cannot be established. Regardless, at the least, an attempt should be made to distinguish exacerbations due to infections from noninfectious exacerbations as treatments may differ. Different tests have been suggested for differentiating types of exacerbations (12), mainly for identifying those needing antibiotic treatment. Although the usual markers of inflammation in blood such as leukocyte count and C-reactive protein are all usually increased during an exacerbation of COPD, none of them seem likely to differentiate infectious episodes from noninfectious episodes in the individual patient.

Sputum color has been shown to predict neutrophilic inflammation in the airways (13), presence of bacteria in Gram stains, growth of bacteria in sputum cultures (14), and, to some extent, effect of antibiotics (15). Biochemical markers in sputum, such as myeloperoxidase, neutrophil elastase, tumor necrosis factor-{alpha}, and interleukin-8, have been found to be elevated (16–19), but whether they add to the information gained from scoring purulence is unclear. Noninvasive biomarkers such as those in exhaled breath and breath condensate have to some extent been tested. They would seem well suited as they could reflect immediate changes in degree and type of airway inflammation, oxidative stress, and epithelium damage. However, findings so far have not been encouraging. Whereas measurements of nitric oxide (NO) reflect degree of airway inflammation in asthma (20) and can be used to guide antiinflammatory therapy (21), changes in exhaled NO in COPD are less impressive and more difficult to interpret. Cigarette smoking down-regulates NO production (22, 23) and exhaled NO may, therefore, only be used reliably in ex-smokers. Furthermore, although exhaled NO has been shown to increase during exacerbations (24) and remains elevated for at least a week (25), the level of exhaled NO has not been associated with cause of exacerbation or response to treatment. A number of biomarkers can be measured in exhaled breath condensate but their role is uncertain regarding type of exacerbation, response to treatment, or value as markers of prognosis. Future needs in this area include better diagnostic tools as well as measures enabling us to identify patients with significant viral or bacterial infection and also measures that can better guide novel therapies.

STAGING

Once the diagnosis of acute exacerbation has been established, an important further aim of the assessment should be to assess severity. This has two purposes: first, severity can potentially be used to stage exacerbations based on prognosis, and second, severity will often relate to level and intensity of treatment as well as need for observation. The initial assessment is done to establish if the patient requires hospital admission. All recent guidelines have provided indicators of need for hospitalization (6–8). A summary list is shown in Table 2. Recent studies of hospital-at-home services have identified patients at low risk for whom treatment at home is safe—and often preferred by the patient (26–29).


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  		TABLE 2. SUMMARY LIST OF INDICATORS OF NEED FOR HOSPITALIZATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 
Few scales for severity staging of COPD exacerbation exist for inpatients. The often-quoted staging by Anthonisen and colleagues was conducted in outpatients for the purpose of evaluating the efficacy of antibiotics in exacerbations of COPD; it provided a three-stage system (30). Thus, three principal symptoms were looked at: increase in sputum volume, increase in sputum purulence, and increase in shortness of breath. The most severe exacerbations were labeled type 1 and characterized by the presence of all three symptoms; type 2 exacerbations had two of the three symptoms, and type 3 exacerbations had one of the three symptoms as well as at least one of the following: an upper respiratory tract infection lasting 5 d, fever, increase in wheeze, increase in cough, or increase in heart rate by 20% or more. This type of scaling works well for predicting effect of antibiotic treatment; in type 1 exacerbations, antibiotics clearly reduced the risk of treatment failure, whereas the effect of antibiotics was virtually absent from type 3 (30).

For predictive purposes, however, symptoms are far from ideal. They are not assessed uniformly, patients' perception of symptoms vary, and, in the most severely ill, they can often not be assessed accurately. We know that age, reduced lung function (e.g., FEV1), presence of chronic mucus hypersecretion, smoking, frequent previous exacerbations, low body mass index, low PaO2, high PaCO2, high respiratory rate, lack of pulmonary rehabilitation, and lack of proper inhaler technique all increase risk of frequent and/or severe exacerbations (31–37). We also know that maintenance treatment with inhaled corticosteroids and long-acting bronchodilators reduces the risk of exacerbations (38–42), but this does not automatically mean that they can also be used as prognostic markers during an exacerbation.

From follow-up studies of patients who have had COPD exacerbations, we do know something about predictors of mortality. In unselected consecutive patients, their age, a high PaCO2, a low PaO2, maintenance treatment with oral corticosteroids, and presence of cor pulmonale have been shown recently to predict a poor prognosis (43, 44). In a study of selected patients with severe COPD, a low body mass index, a high Acute Physiology and Chronic Health Evaluation score, a high Activities of Daily Living score, a low albumin level, and congestive heart failure were additional predictors of poor prognosis (45). Lung function in itself has little value although an initial increase in FEV1 after treatment may indicate a more favorable prognosis (46). These measures could potentially be combined in a score similar to the scores used for the initial assessment of patients with pneumonia (47–49). Until formally tested, the value of a "severity score" or of "exacerbation staging" remains unknown. Intuitively, it makes more sense to focus on parts of an assessment that can quickly identify patients for whom effective treatment is available. In "the real world," this primarily means assessment of arterial blood gases. Knowledge of pH, PaO2, and PaCO2 after initial treatment enables identification of patients requiring noninvasive ventilation, either in the intensive care unit or elsewhere as well as the patient requiring immediate transfer to an intensive care unit for intubation. The evidence base for noninvasive ventilation is now so strong that lack of assessing arterial blood gases in patients admitted to hospital with an exacerbation of COPD is a major flaw (50).

Thus, for the clinician working in a hospital setting, the exact number and composition of initial tests remains a challenge. Help can, nevertheless, be found in guidelines for treating COPD. The most recent guidelines (6–8) all provide guidance on assessment, albeit in varying detail. Table 3 shows the author's compilation of the advice provided by guidelines.


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  		TABLE 3. SUMMARY LIST OF GUIDELINE RECOMMENDATIONS FOR ASSESSMENT OF PATIENTS HOSPITALIZED FOR EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 
In conclusion, however, it is fair to say that given the enormous impact of COPD exacerbations on our health care systems, we have surprisingly little knowledge on the best modes of assessment and staging of this disorder. It is hoped that our evidence base will expand in this area in the near future.

EPIDEMIOLOGY

Having looked at the available evidence and guidance for the assessment of exacerbations in COPD, we may want to ask how frequent they are. Surprisingly, this simple question is difficult to answer. A detailed overview of the epidemiology of exacerbations can be found elsewhere (51) and only a few points will be raised here. Several national hospital registers can provide data on hospital admission rates, and by register linkage give us data on prognosis, readmission rates, and changes in treatment before or immediately after an exacerbation leading to hospital admission. However, it seems fair to assume that the vast majority of exacerbations are treated outside hospital and are often not even brought to the attention of doctors and health care workers. Thus, data have to be collected from other sources including patient series—or patient cohorts—and from groups of patients participating in clinical trials in which exacerbation rates are outcomes of interest. Such data are bound to be biased, not just because of the different criteria used to define exacerbations but also because of the varying inclusion criteria used in the published studies. However, Figure 1 gives some indication of the association between level of lung function and frequency of exacerbations based on data from clinical trials (52–58).


Figure 1
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  		Figure 1. Rate of exacerbations of chronic obstructive pulmonary disease annually according to baseline mean FEV1. Numbers refer to References. Modified by permission from Reference (51).

 
In a Canadian register linkage study the rate of exacerbations leading to either prescription of a combination of antibiotics and oral corticosteroids or hospitalization was 1.12 per person per year among patients identified from an administrative health database (59), fitting well with the picture in Figure 1. Although often quoted, many of the most recent large-scale trials in COPD cannot be used for the above exercise as recent exacerbations requiring treatment have often been among the inclusion criteria used, thus enriching the patient sample with "frequent exacerbators" (38–40). Clearly, more studies are needed in this area.

In conclusion, exacerbations of COPD are frequent and pose a continued challenge to clinicians in all parts of the world. In addition to more research in basic mechanisms and biomarkers there is ample opportunity for sound clinical research in exacerbations management as well as in epidemiology of COPD exacerbations.

FOOTNOTES

Conflict of Interest Statement: J.V. received $10,000 in 2003, $10,000 in 2004, and $8,000 in 2005 for speaking at conferences organized by GlaxoSmithKline (GSK); $7,000 in 2003, $2,000 in 2004, and $5,000 in 2005 for speaking at conferences organized by AstraZeneca; and $1,000 in 2004 and $1,000 in 2005 for speaking at a conference organized by Boehringer-Ingelheim. He has served on advisory boards for GSK, receiving $2,000 annually in 2003–2005; and in 2005, he received $500 from AstraZeneca for a COPD advisory board meeting. His wife (Inge Vestbo) was an employee of GSK from 1988 to January 2004 and currently works for Ferring International. Neither he nor his wife has shares or options in GSK or any other pharmaceutical company.

(Received in original form October 19, 2005; accepted in final form December 23, 2005)

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