Care of patients with chronic diseases is often challenging. Nevertheless, many disease states known to cause severe debilitation and increased mortality have been identified and modified. Disease management programs have been developed for illnesses such as hypertension, cardiac diseases, and diabetes mellitus, leading to significant improvements in patient outcomes [1-3]. Key to these disease management strategies is awareness of risk factors, early identification, and early intervention in an attempt to prevent disease progression [4].
Chronic obstructive pulmonary disease (COPD) is a major chronic disease causing ever greater degrees of morbidity and mortality throughout the world [5,6]. Despite international awareness of this disease and its impact on society and health care, little has occurred to date to change the course of this disease [7]. Many factors contribute to this problem, each an obstacle to overcome. However, new information suggests that there is reason for hope in modifying the outcomes of COPD. This, in turn, opens up needed opportunities for changes in COPD disease management, including new rationales for early diagnosis and early intervention in this disease.
COPD has long been recognized as a chronic progressive disease of airflow limitation. In the United States, it is estimated that only one half of patients with COPD are diagnosed [6]. Other epidemiological studies support similar results throughout the world [8]. This is especially true for COPD patients with mild and moderate disease [9]. The burden of COPD, both recognized and unrecognized, is marked. Separate from the morbidity and mortality of patients diagnosed with COPD [10], epidemiological studies repeatedly identify significant symptoms, functional limitations, and health care utilization in patients, young and old, with previously undiagnosed disease [11,12].
Many reasons can be identified for past failures to significantly alter COPD outcomes, including difficulties with disease identification and diagnosis to generally held beliefs that no effective interventions were available to alter disease progression, making early identification of COPD unnecessary. Indeed, attempts at early diagnosis were considered to possibly lead to added costs, risks of misdiagnosis, and even increased disease burden by providing a diagnosis for which no effective disease-modifying intervention was available. Consequently, most recommendations and guidelines, past and present, have focused on smoking cessation, symptom control, and end-stage disease management [13-17].
Although these areas remain essential to COPD care and much more information is still needed, new evidence suggests that disease modification is possible in COPD and that various therapeutic interventions are available and useful, even for patients with mild and moderate COPD. It is proposed that this new information dictates reconsideration of past COPD management principles and that COPD should again fall into the area of all chronic diseases, focusing on early identification and early intervention as key parts to its disease management.
DIAGNOSIS
Although appearing to be a straightforward disease, the diagnosis of COPD is fraught with difficulties. Even when suspected, COPD is diagnosed by a constellation of common symptoms plus an effort-dependent physiological measurement. Common COPD symptoms of cough, sputum, and dyspnea are often only recognized as abnormal late in the course of the disease and are otherwise attributed to aging, deconditioning, or other health-related problems [18,19]. Indeed, even patients with a known diagnosis of COPD often deny the presence of symptoms limiting their function and quality of life [20]. Confusion with a diagnosis of asthma, especially early in the disease course can also limit disease identification [21]. A residual perception that COPD is a self-inflicted disease and that smoking cessation is the only recommended therapy for mild or moderate COPD reinforces a lack of need for aggressive intervention in patients who may have COPD [17]. COPD guidelines also contribute to difficulties in diagnosis, with varying definitions for disease severity failing to provide meaningful recommendations for COPD care to practicing physicians [22]. Finally, inappropriate diagnosis or misdiagnosis of COPD commonly occurs due to a lack of definitive workup, with most diagnoses of COPD in the United States made without patients ever undergoing simple spirometry [23]. Likely, similar problems are present throughout the world.
RECOMMENDATIONS FOR TREATMENT
Guidelines are well established for COPD, recommending stepwise therapy for its management [14-17]. Overall, there is strong concordance between guidelines of specialty and primary organizations, although some primary care guidelines suggest therapy for COPD should not be considered until forced expiratory volume in 1 s (FEV1) airflows are below 60% of predicted [17]. In contrast, there is significant discordance between guideline recommendations, especially with FEV1-based disease staging for the selection of specific therapies and clinical practice [22].
Smoking cessation continues to be an essential part of COPD management at all disease stages, with evidence clearly identifying disease modification and improved survival with sustained smoking cessation [24-26]. Bronchodilators remain the mainstay of symptomatic treatment, with initial recommendations for rescue inhalers followed by the addition of long-acting bronchodilators and inhaled corticosteroids based on severity of disease [27]. Multiple studies have examined the roles of various bronchodilators and inhaled corticosteroids, many undertaken by pharmaceutical companies to evaluate their individual products. Review of these clinical trials highlight that most studies assessing COPD treatment focus on patients with severe and very severe COPD, with maximum FEV1% predicted values allowed for these studies typically <65%, and average study population FEV1 values about 45% predicted [28-31].
More recently, clinical work in COPD has focused on disease modification, including mortality and rates of decline in lung function over time [32,33]. Although some results remain controversial, data from several large long-term trials suggest that outcomes other than symptoms and quality of life can be impacted by regular COPD therapies [34]. In particular, reductions and/or prevention of COPD exacerbations, with all of their attendant complications, including quality of life, health care utilization, morbidity, and mortality, have now been repeatedly demonstrated [35-37].
Current understanding of mild and moderate chronic obstructive pulmonary disease
Pathology
Recent studies have examined the pathology of COPD, including patients with mild and moderate disease. Although COPD pathology continues to include those changes associated with emphysema in the alveoli and chronic inflammation change in the large airways, much of recent pathological findings have focused on the small airways, especially bronchioles <1 mm in diameter [38,39]. Indeed, these pathological findings not only describe significant inflammatory changes leading to airway narrowing, mucous plugging, and fibrosis, they also demonstrate very significant active pathological changes in the very early stages of COPD, likely contributing to the ongoing disease progression observed in COPD. Interestingly, recent bronchoscopic biopsy findings following pharmacological treatment in patients with mild and moderate COPD suggest improvement in small airway inflammatory profiles, suggesting a response to these therapies and a potential pathophysiological mechanism for disease intervention and possible modification in patients with milder COPD [40,41].
Clinical disease
Although severity of symptoms, functional capability, and quality of life clearly worsen as COPD progresses, there is now significant evidence that patients with mild and moderate COPD are also impacted by their disease in many ways. Several studies identify an increased risk for exacerbations, health care utilization, FEV1 rates of decline, and even mortality in these patients with milder disease [42-44]. These rates seem to further increase in patients with active respiratory symptoms, whether recognized by the patient or not [45,46].
Pharmacological treatments
As noted earlier, most studies and recommendations for COPD therapy focus on patients with more severe COPD. Certainly, data from clinical studies of patients with more severe COPD may not be generalizable to the population of untreated patients with milder COPD. Indeed, even when data are available for patients with less severe COPD, they still tend toward moderate rather than mild disease. Often, only limited numbers of patients with moderate COPD are available in these studies, making clinical assessment of results challenging.
Until recently, only smoking cessation has been shown to be of benefit in the treatment of mild COPD. Earlier studies attempting to modify disease progression as measured by rates of decline in FEV1 over time using inhaled corticosteroids have been negative [47,48]. Nevertheless, recent studies in mild and moderate COPD, in conjunction with the previously mentioned clinical and pathological information from patients with milder COPD, are starting to address questions about treatment in this milder population. Dynamic hyperinflation during exercise and its attendant negative impact on lung volumes and dyspnea have been identified in patients with mild COPD (Figure 1) [49]. In addition, studies limited to patients with mild and moderate COPD have now shown significant improvements in airflow in patients with milder symptoms (Figure 2) [50,51]. Furthermore, it has been shown that starting treatment in patients with COPD previously naive to medical therapy, whether due to failure to make a diagnosis or previously determined to not require medical therapy because of having milder disease, is beneficial [52]. Importantly, post hoc analysis of large subpopulations with mild and moderate COPD, which are within very large long-term trials assessing disease modification, are now being undertaken to determine whether disease modification, such as reduced exacerbation rates and FEV1 decline, can also be found in patients with milder disease [32,33]. Whether other COPD therapies such as pulmonary rehabilitation are of value to patients with milder symptoms remains to be determined [53,54].
 | Figure 1. Physiological effect of exercise on healthy patients and patients with mild chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 s [FEV1]/forced vital
capacity [FVC] ratio <70% and FEV1 ≥80% of predicted post-bronchodilator).
(Reproduced with permission from Ofir D, Laveneziana P, Webb KA, Lam YM, O'Donnell DE. Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage I
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:622-629) |
 | Figure 2. Effect of long-acting bronchodilators on patients with mild chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 s [FEV1]/ forced vital capacity [FVC] ratio <70% and FEV1 ≥65% of predicted).
(Reproduced with permission from Johansson G, Lindberg A, Romberg K, Nordström L, Gerken F, Roquetd A. Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD. Prim Care Respir J 2008;17:169-175) |
TECHNIQUES FOR DIAGNOSIS
Early identification of COPD is now considered a key part of its management. Although early detection has been proposed for many years, pushes for early diagnosis and proposals for early detection have been variously adopted or rejected by different practicing organizations [55,56]. Although not formally endorsing specific early COPD detection guidelines [55], the information cited earlier has lead most current COPD guidelines to recommend that a clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors and that the diagnosis should be confirmed by spirometry [14].
Screening spirometry and spirometry case finding
Controversy has long shrouded the use of spirometry in the diagnosis of COPD, for many reasons. One area of controversy stems from earlier recommendations that spirometry should be routinely used as a screening tool. By definition, a screening tool is used in apparently healthy individuals to detect those patients at risk or with disease. A screening test must be simple to perform (for both those performing the test and patients being tested), accurate (within and between testing devices), reproducible (providing similar values on repeated testing over time), affordable, safe, sensitive (positive in the presence of disease), and relatively specific (negative in the absence of disease) [57]. Arguments against the use of spirometry as a COPD screening tool have ranged from past concerns over a lack of any effective interventions if a diagnosis of mild COPD is made [58] to concerns that a new diagnosis of COPD in an otherwise unsuspecting individual can lead to a backlash in patient response with decreasing function [59], to multiple concerns over technical problems with office spirometry and the attendant risks associated with bad test results [60-62]. A recommendation to provide well-trained technicians available to primary care offices has been suggested as a way of overcoming these technical issues of spirometry [63].
In contrast to screening spirometry, the notion of case finding or performing spirometry testing only in those patients at an increased risk for COPD based on patient symptoms, exposures, and/or other risk factors has gained much wider acceptance. Indeed, such diagnostic testing has been shown to improve the diagnosis of COPD and improve care, both through earlier detection of disease and institution of appropriate medical therapies based on patients’ disease severity [64]. The success of COPD case-finding in the primary care setting has been validated and recommended in several countries [65,66].
Spirometry and smoking cessation
Several studies have now investigated the impact of spirometry testing results on smoking cessation rates. In general, these studies suggest that the addition of spirometry information, whether a simple statement about being normal or abnormal to more elaborate results describing a patient’s “lung” age can significantly improve smoking cessation rates [66-69]. The mechanisms of how this information influences smoking cessation rates are unclear, as smoking cessation rates are often not correlated to the severity of lung function identified [69]. Evidence also suggests that use of spirometry information in a confrontational manner does not increase smoking cessation rates [70]. It is important to realize that tobacco addiction is a chronic relapsing disorder and that additional ongoing smoking methods beyond spirometry information are required if long-term success is to be achieved.
Questionnaires
With concerns over the failure to effectively identify and diagnose patients with COPD and with ongoing issues pertaining to the routine use of spirometry as a screening tool in a primary care setting, simple questionnaires capable of being self-administered to patients in a primary care setting have been suggested as an alternative method for identifying patients with COPD. Multiple different questionnaires have been proposed, analyzed, and validated [71-73]. Most questionnaires focus on symptoms known to be common to patients with COPD. However, by using these symptoms in an organized, standardized fashion, study results suggest that the questionnaires can enhance awareness of patients at risk for COPD and facilitate diagnosis [74]. Whether the questionnaires are any better than astute clinical questioning during a routine clinic visit is uncertain [75]. Nevertheless, when used in a primary care setting, a significant number of previously unidentified patients were recognized. Indeed, common clinical questions thought to identify patients with COPD may actually have poor discriminatory value when mild disease is present and can actually mislead practitioners away from a COPD diagnosis [76]. A key concern with questionnaires is whether they are sufficient to make a diagnosis, without additional testing. Results suggest that they are relatively sensitive for the detection of COPD, but are less specific and may not be sufficient as a single tool for diagnosing COPD. Whether simple questionnaires can also be used to assess disease control in COPD is also being investigated [77].
Combining questionnaires with spirometry
Using simple COPD case-finding rules for identifying patients at risk for COPD, especially when relying on an abnormal respiratory history alone as the basis for obtaining pulmonary function tests, carries a risk of missing many patients with low lung function, especially in current smokers [78]. In contrast, use of simple self-administered patient questionnaires has been shown to identify patients with a high likelihood of having COPD, for whom spirometry testing is particularly important. Thus, screening with COPD questionnaires has been suggested as a means of enhancing the efficiency and diagnostic accuracy of spirometry as a part of COPD case-finding efforts [79]. Several studies have now extended the natural progression of information obtained from questionnaires and spirometry to evaluate the sequential use of these methods to optimally identify patients with COPD [80,81]. Indeed, the use of questionnaires is an effective means of COPD case-finding and appears to both identify patients appropriate for spirometry testing and reduce the likelihood of false-positive test results from the overuse of screening spirometry alone (Figure 3 and Table 1) [80,81]. The combination of abnormal symptoms and abnormal spirometry not only has a greater chance of identifying disease earlier, but also predicts the likelihood of disease development and disease progression [82].
 | Figure 3. Study diagram and outcomes in patients aged 35 to 70 years undergoing primary care evaluation for airflow obstruction using screening questionnaires and spirometry.
(Reproduced with permission from Buffels J, Degryse J, Heyrman J, Decramer M. Office spirometry significantly improves early detection of COPD in general practice: the DIDASCO Study. Chest 2004;125;1394-1399) |
 | TABLE 1. Severity of chronic obstructive pulmonary disease (COPD) in primary care patients detected with airflow obstruction following screening questionnaires and spirometry |
Alternative methods for diagnosing chronic obstructive pulmonary disease
Various other methods have been suggested in the past as a means for earlier detection of airflow limitation and COPD, ranging from novel measurements of small airways to exhaled gases [83,84]. However, none of these techniques have been shown to have meaningful sensitivities, specificities, or predictive values. In comparison, results from trials assessing computed tomography (CT) scanning of the lungs as a means of identifying and quantifying emphysema have been promising [85,86]. Indeed, CT scanning can detect emphysema changes in patients with otherwise unsuspected COPD, even when airflows are normal. However, the implication of emphysema changes identified on CT scanning in patients without other clinical or physiological abnormalities associated with COPD remains to be evaluated. It is uncertain whether the implications associated with earlier detection and treatment of COPD previously mentioned can be extended to those patients with only CT evidence of emphysema.
CONCLUSION
COPD continues to be a major health care problem in the world today, with many patients continuing to be undiagnosed and/or untreated. These patients typically experience significant symptoms that are unrecognized and/or minimized. Although less frequent than in patients with more severe symptoms, patients with mild COPD are at increased risk for exacerbations and significant disease progression. In spite of an increasing awareness of COPD, many barriers continue to exist in the diagnosis and management of COPD. Therapies for COPD have improved dramatically over the last few years, improving patient’s symptoms and function. Recent efforts have focused on interventions to modify disease progression, focusing in particular on COPD exacerbations and their attendant impact on quality of life, health care expenditure, and risk for morbidity and early mortality. In the past, most information on therapy for COPD was directed at patients with more severe disease. However, information is now becoming available suggesting that current COPD therapies may also significantly impact patients with milder degrees of COPD.
With limited health care resources, efficient and effective management of COPD ideally requires identifying and focusing efforts on individuals at particular risk. This may best be accomplished by simple screening questionnaires identifying patients warranting additional testing with spirometry. Lessons should be learned from the evolution of guidelines and management of cardiovascular diseases, which parallel COPD in terms of prevalence, prognosis, and impact on patient quality of life [87]. It is critical to develop effective programs designed to reduce the impact of COPD on all patients. Practitioners need to become more aware of patients with COPD and actively seek to identify people with mild disease. Guidelines should continue to direct appropriate care practices in COPD. However, as additional information becomes available, care recommendations for patients with mild disease may need to change. An alternative framework for assessing disease severity and disease impact on patients also should be considered; it should integrate pragmatic clinical disease management practices, including the use of symptoms and exacerbations as criteria for therapy, rather than FEV1 alone [88]. Additional trials in COPD are still needed to provide clinical evidence determining optimal methods for early disease identification and optimal treatments for patients with mild disease.
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