Strategies for Management of the Early Chronic Obstructive Lung Disease.

Lung function reportedly declines with age and that this decline is accelerated during disease progression. However, a recent study showed that the decline might peak in the mild and moderate stage. The prognosis of chronic obstructive pulmonary disease (COPD) can be improved if the disease is diagnosed in its early stages, prior to the peak of decline in lung function. This article reviews recent studies on early COPD and the possibility of applying the U.S. Preventive Services Task Force recommendation 2008 and 2015 for early detection of COPD in Korea.

Introduction

The prevalence of chronic obstructive pulmonary disease (COPD) in persons aged >40 years was 13.4% based on the 2008 Korea National Health and Nutrition Examination Survey (KNHANES), and approximately 94% of the cases were classified as mild and moderate COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document1. Most of these cases were not diagnosed and/or treated as COPD. Indeed, subjects with early COPD have minor or no symptoms at all. However, their pathophysiological conditions and socioeconomic burdens are known to be similar to those of subjects with more-severe COPD. For this reason, reducing the disease burden is important by detection of subjects with early COPD and treatment with drugs combined with behavioral treatment such as smoking cessation, education, and air pollution control, which also can prevent disease progression. However, studies that investigate whether detection and treatment of early COPD lessen the disease burden are rare. This statement is based on a recent literature review conducted for evaluation of the effectiveness of detection, research, and treatment of early COPD.

Definition of Early COPD in Terms of Severity

Early COPD has not been defined clearly because of the variability of airflow within and across a population, and the reduction of lung volume with age23. However, most often, postbronchodilation 1 second forced expiratory volume (FEV1)-to-forced vital capacity (FVC) ratio ≤0.7 and FEV1 >50% of the predicted normal value were used in spirometry regardless of respiratory symptoms4. In South Korea, substantial agreement on the definition of early COPD has not been reached yet. However, suggestion have been made by using the spirometric criteria (FEV1/FVC ≤0.7 and FEV1 >60% of the normal predicted value) according to the Korean COPD Guideline, considering criteria of the group "ga," "na," and "da" and using the term "very early COPD" rather than "early COPD" to avoid confusion with foreign reports.

Early-Onset COPD

Early-onset COPD is sometimes interpreted as COPD occurring at an early age. Generally, COPD has been known to occur in persons older than 40 years and adult smokers. However, considering subjects who do not visit physicians and the individual variability of lung function, it is not entirely impossible to develop COPD at a young adult age. It is interesting that compared with healthy people, these patients are characterized by low peak lung function in their twenties. A common cause of low peak lung function is childhood asthma5 and maternal smoking during pregnancy6. The National Heart, Lung, and Blood Institute reports that 12 million Americans have COPD and that another 12 million Americans are estimated to have the disease without knowing it7. According to the report of a pre-specified post hoc analysis of 356 patients aged ≤50 years who had COPD and enrolled in the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study, the number of women in the ≤50 year age group was higher but disease severity as classified based on GOLD stage was similar to that in the total population. About half of the subjects in the ≤50-year-old cohort continued to smoke, whereas the percentage of continuing smokers progressively decreased with age8. Despite the similar objective indexes of disease severity, health-related quality of life was substantially poorer in the patients aged <50 years8. In another study by Sanchez-Salcedo et al.9, the disease severity distribution and progression (lung function decline) in younger patients with COPD were similar to those in older patients9. Hence, the response of young patients with COPD to pulmonary rehabilitation was similar to that of old patients10.

Importance of Early COPD

In South Korea, the KNHANES performed spirometry in all subjects aged >40 years and found that the incidence of COPD was 13.4% in a 2008 study11. Among the patients, about 94% had mild-to-moderate COPD (early COPD) according to the GOLD staging system, with little or without apparent symptoms11. In the 2008 KNHANES report, only 2.4% (9/353) of subjects were diagnosed by a physician and only 2.1% (8/353) underwent treatment1. This means that although the prevalence of COPD in Korea is high, most of the cases were underdiagnosed and undertreated. Another study in the United States, which was conducted during the period from 2007 through 2010 by the National Health and Nutrition Examination Survey (NHANES), also suggested that the overall age-adjusted prevalence of any obstructive lung disease was 13.5% and reported that 50% of cases were early COPD12.

Owing to the rare symptoms and relatively favorable pulmonary function, subjects with early COPD have the tendency to not visit a hospital. In primary health-care institutions in Korea, spirometry, which is the most important diagnostic study for COPD, has not been performed effectively. Hence, subjects with early COPD could lose the opportunity undergo diagnosis and treatment before disease manifestation. Even subjects with early COPD are known to have pathological changes13, and more-severe systemic inflammation14 and more comorbidities than healthy subjects with conditions compatible with established COPD15.

According to the basic data investigation for the medical cost of treatment of early COPD (FEV1 >50% of the predictive value), the 2012 domestic study reported that each subject spent Korean won (KRW) 890,000 per year (Policy Development Research Work Report of The Development of Strategies for the Prevention and Control of COPD7), showing a high medical care expenditure.

In addition, patients with early COPD have been known to experience acute exacerbation. In registered subjects in well-known cohorts such as those of the TORCH, UPLIFT, and ECLIPSE studies, those who met the criteria of FEV1/FVC ≤0.7 and FEV1 >50% of the predicted normal value were reported to have acute exacerbation at a maximum of 0.9 time, roughly 1 time per year16. Traditionally, lung function decline in patients with COPD has been known to be accelerated as the disease progresses over time17. However, a recent paper showed that the annual decline of pulmonary function was more severe in patients with early COPD than in those with severe to very severe COPD18. Therefore, early detection and active treatment before lung function decline, that is, progression to a more severe status, is important for reducing acute exacerbation, which improves quality of life, and decreases medical expenditure and mortality.

Even with their minor symptoms, subjects with early COPD have the same level of socioeconomic burden as those with severe COPD, but studies that investigate, for example, treatment effectiveness among these subjects are rare. The overseas representative cohort of patients with COPD is limited to those with the most severe cases in the ECLIPSE and COPD gene research. Research about early COPD is limited. In particular, early COPD is registered in relation to the concept of control of progression to severe COPD. This is perhaps because patients with early COPD have no or mild symptoms and do not visit hospitals, making enrollment more difficult than that of patients with severe symptoms. Determining the effectiveness of treatment of severe COPD could be more useful. Recently, however, reports indicated the benefit of early treatment to patients with early COPD in terms of disease process, in comparison with no treatment. Patients who underwent appropriate treatment of early COPD had improved lung function19 and reduced acute exacerbation20; thereby, their medical expense was reduced21. In addition, the rates of lung function and mortality were more significantly reduced in patients with mild to moderate COPD who stopped smoking than in those who continued smoking2223. Subjects with early COPD who underwent respiratory rehabilitation had fewer hospital admissions and less medical costs24 and had better exercise capacity than the control group25. Even though none of the existing medications for COPD has been conclusively shown to modify the long-term decline in lung function, the GOLD document recommends that influenza and pneumococcal vaccinations should be offered depending on local guidelines3. Moreover, all COPD patients benefit from exercise training programs, showing improvements in exercise tolerance and symptoms of dyspnea and fatigue3. Overall, aggressive treatment should be considered for patients with early COPD.

Early COPD could be identified in two groups based on the COPD GOLD or Korean domestic guidelines1626. The two groups included subjects with slight deterioration in lung function (FEV1 >50% of the predicted normal value) with fewer symptoms16 (or FEV1 >60% of the predicted normal value, GOLD A, group "ga"26) and those with slight deterioration in lung function with more symptoms (GOLD B, group "na"), respectively. Although no immediate large-scale study has been conducted, screening is expected to provide beneficial results to patients, considering the above-mentioned reports. However, the 2008 U.S. Preventive Services Task Force (USPSTF) recommended against screening adults for COPD by using spirometry (USPSTF recommendation state grade D)18. For example, under the best-case assumptions about response to therapy, an estimated 455 adults between 60 and 69 years of age would need to be screened to defer one exacerbation27. Thus, taking into account the cost and effectiveness of screening, they suggest that diagnostic tests not be performed in patients without symptoms. However, the USPSTF recommendations were relatively old by the 2008 report. Since then, several recent studies have been reported about the pathophysiological mechanism and treatment of COPD, and the updated 2015 USPSTF was also released. Based on the recent literature, whether screening should be performed as the USPSTF recommended or not should be reconsidered because of the relatively higher prevalence of early COPD in Korea than in the United States, where lung function tests are low-cost.

U.S. Preventive Services Task Force Recommendation 2008 and 2015

1. The benefits of screening and smoking cessation

The 2008 USPSTF described that all individuals with COPD, including those with mild or moderate illness, would benefit from smoking cessation. However, fair evidence shows that providing smokers with spirometry results does not independently improve cessation rates. Thus, spirometric screening is not necessary for asymptomatic subjects27. However, one study showed that smoking cessation rates more than doubled when lung function tests were performed and spirometric test results with lung age were released for 561 smokers aged >35 years (p=0.01)2829. That is, providing subjects with spirometric test results with lung age and lung function test results might be effective for increasing smoking cessation rates. After that study, no trials were found that directly assessed if screening asymptomatic adults aged >40 years for COPD is useful in terms of improving health-related quality of life or reducing morbidity or mortality29. However, the 2015 USPSTF showed that in high-risk asymptomatic adults, screening for COPD using prescreening questionnaires such as the COPD diagnostic questionnaire, focusing mainly on primary care population, detected mild or moderate disease in most of the patients (83.8% to 94.7%)3031.

2. Benefits of early treatment

In the 2008 USPSTF, good evidence suggests that pharmacological therapy prevents exacerbations (worsening of symptoms and the need for medical care) but does not affect hospitalizations or all-cause mortality among symptomatic individuals who have been smokers in the past ("ever smokers") who are 40 years or older.

Since then, large-scale updated studies have been conducted. A post hoc analysis in a study that targeted 2,156 subjects with FEV1 >50% of the predicted normal value in the TORCH trial, which aimed to determine the effective treatment for decreasing mortality rate in COPD, suggested that drug management showed reduced mortality rate and number of acute exacerbations (p<0.05)20. The post hoc analysis of 2,739 subjects with early COPD in the UPLIFT study also showed that treatment of COPD with inhaler reduced the annual decline of lung function and the number of hospitalizations owing to acute exacerbation of approximately 20%32. Cases with FEV1 >60% also showed decreased mortality and acute exacerbation33. The 2015 USPSTF stated that they identified no trials that addressed the effectiveness of any treatment to improve health outcomes in patients with mild COPD. Nonetheless, even relatively weak data consistently support some reduction in exacerbations for each of the treatment classes, especially long acting beta-2 agonist (LABA) and tiotropium, in subjects with mild to moderate COPD. To sum up, recent large-scale studies suggested that symptomatic GOLD B group "na" subjects benefitted from medication.

3. The harms of detection and early treatment

In the 2008 USPSTF, fair evidence indicates that spirometry can lead to substantial over diagnosis of COPD in "never smokers" aged >70 years. Even though a comparison study was conducted to compare effectiveness between using a fixed ratio and using the lower limit of normal (LLN) for diagnosing COPD, no study has compared the two groups of subjects. Generally, using the LLN could reduce the prevalence of COPD, which means that the high-risk group who need hospitalization could be excluded. Thus, further research is needed to target multiple-risk groups. However, compared with using a fixed ratio, using the LLN for diagnosing COPD reduces the risk of over diagnosis34. The 2015 USPSTF found no evidence to estimate the long-term harms of these screening tests. The potential harms of treatment may include pneumonia with the use of LABA and inhaled corticosteroids, and decreased bone density and increased fractures with the use of inhaled corticosteroids. However, data were sparse, with few adverse events, and no differences were found between the intervention and control groups3. For all classes of medications, the one consistent finding was that treatment suppressed COPD exacerbation in persons with moderate COPD, without consistent effects on all-cause mortality, dyspnea, or quality of life and evidence on the effects of treatment on exercise capacity was insufficient. As all of the treatment trials were conducted in persons with mild to moderate COPD, how these results would apply to asymptomatic populations is unclear. Given the lack of potential benefits of treatment in asymptomatic persons and the non-trivial efforts of screening, the USPSTF determined that there is no net benefit of screening.

4. Cost effectiveness for screening of COPD

The 2008 USPSTF stated that the opportunity costs associated with screening for COPD using spirometry are high even in populations at higher risk. This means that its cost effectiveness is low. Recent guidelines from the GOLD 2015 recommend case finding in symptomatic patients but not screening in asymptomatic populations3.

However, in the tertiary US NHANES, the prevalence of COPD was 2.6% in subjects aged >50 years35. Korea showed a relatively higher prevalence (9.0% in women and 15.0% in men)1. In addition, the cost for lung function test using a bronchodilator in the United States was $100 or higher, but around $25 in Korea, which means that it is highly cost-effective in the domestic situation than in the United States. Whether early detection of COPD, education, and care are needed for subjects who do not recognize or report their symptoms should be studied at a national level. And health screening might be revised to include active lung function tests in order to detect early COPD.

Conclusion

Whereas the prevalence of early COPD is higher than that of severe or very severe COPD, the tendency of subjects to visit hospital is low. Taking into account the many recent studies, the benefit of treatment for group B or the Korean group "na," who had more complaints of symptoms with fair lung function, is thought to be considerably high. The GOLD document and domestic Korean guideline suggested active treatment for this group of patients. In reality, patients with early COPD with mild symptoms visit primary clinics first. Thus, a simple test method should be developed for effectively diagnosing early COPD in primary clinics. It is relatively difficult to implement the lung function test in primary healthcare clinics because of the need for medical technicians to conduct the lung function test and the difficulties of quality control. Currently, the Health Insurance Review and Assessment Service has implemented the COPD adequacy assessment. Considering the lung function test implementation rate contained in the evaluation of adequacy items, a simple test method needs to be developed for use in primary clinics, combined with research to evaluate the effectiveness and usefulness of the test. On the other hand, due to the relatively higher actual medical cost in the United states than in Korea for the detection of early COPD patients in GOLD A or group "ga," research studies are needed to verify the effectiveness of early diagnosis and intervention. Then, we can contemplate on a number of studies published in the last decades. Even though USPSTF 2015 recommendation again came out, there were no significant changes and the recommendation strength was D. So, the USPSTF 2008 and 2015 recommendation should be modified according to the current situation in Korea. As studies regarding early COPD are few, research for these patients is needed. Conducting studies regarding clinical characteristics, risk factors, and prognosis is top priority. Furthermore, clinical trials regarding treatment response to inhalers in early COPD patients are also needed. Whether early treatment of early COPD is effective should be validated in terms of not only clinical parameters but also economic parameters.