Drugs Aging 2008; 25 (9): 717-728 1170-229X/08/0009-0717/$48.00/0
CURRENT OPINION
© 2008 Adis Data Information BV. All rights reserved.
What Defines Abnormal Lung Function in Older Adults with Chronic Obstructive Pulmonary Disease? Nitin Y. Bhatt and Karen L. Wood Ohio State University, Columbus, Ohio, USA
Abstract
Chronic obstructive pulmonary disease (COPD) is a very common lung disease most often related to a history of smoking. It becomes more prevalent with increasing age but remains under-diagnosed and under-treated in the elderly population. The Global Initiative for Obstructive Lung Disease (GOLD) programme has been instrumental in providing standard diagnostic criteria as well as recommendations for prevention and management of COPD. GOLD recommendations define COPD as a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of <70%, with the severity based on the value of FEV1. This recommendation is different from that of many previous reports that have recommended diagnosing obstruction using the statistically derived lower limit of normal (LLN), which varies for each person according to age, height, ethnicity and gender. While the use of a 70% ratio may be simpler, it may result in under-diagnosis of airflow obstruction in younger people and overdiagnosis in the elderly. This is particularly important as the elderly may be most sensitive to many of the adverse effects of medications used in the treatment of COPD, including corticosteroids and anticholinergic bronchodilators. Most of the studies comparing the LLN and a fixed ratio of 70% have not been performed with post-bronchodilator testing as recommended by GOLD. Generation of post-bronchodilator reference sets and studies comparing the LLN with the post-bronchodilator FEV1/FVC ratio of <70% will help resolve this issue. One recent study examined patients admitted to hospitals who had an FEV1/FVC ratio of <70% but above the LLN, and found they were at increased risk of death and COPD complications. This would support the use of GOLD criteria. Further studies examining this population are needed. In addition to the uncertainties about what diagnostic criteria should be utilized for diagnosis of airflow obstruction, different organizations make different recommendations on screening spirometry. A conservative recommendation is to perform spirometry in symptomatic individuals. It is important to remember that while COPD is under-diagnosed in the elderly, this group is also at a higher risk of being falsely classified as having airflow obstruction using the 70% ratio recommended by GOLD. This can result in unnecessary use of medications and increased risk of adverse effects to which the elderly are more prone.
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Chronic obstructive pulmonary disease (COPD) has traditionally been considered a diagnosis that includes individuals that have either emphysema or chronic bronchitis or some overlap of the two.[1] Emphysema is a pathological diagnosis based on destruction and permanent enlargement of the air spaces distal to the terminal bronchioles. Chronic bronchitis is a clinical diagnosis defined by the presence of cough and sputum production for ≥3 months of 2 consecutive years. While these are very descriptive of many features of COPD, there is much overlap between the two disorders, which has led most to combine them into the broader classification of COPD. Recently, guidelines have attempted to standardize the definition of COPD using the finding of incompletely reversible airflow obstruction (AFO) on spirometry.[2-4] Smoking remains the greatest risk factor for the development of COPD; however, other factors such as environmental and inhalational exposures to gases, dust and pollution also contribute to disease pathogenesis in susceptible individuals. The most common symptoms of COPD are dyspnoea and cough. Radiographically, the lungs demonstrate hyperinflation, and often have emphysematous changes such as bullae and blebs. Pulmonary function testing reveals AFO on spirometry that manifests as a reduced forced expiratory flow in 1 second (FEV1)/forced vital capacity (FVC) ratio. The severity of COPD is based on the decline in FEV1. Plethysmography demonstrates elevated lung volumes or hyperinflation as well as air trapping. Many patients have reduced diffusion of carbon monoxide. This article summarizes the literature regarding diagnostic thresholds for airflow obstruction and discusses recommendations for screening with spirometry and implications in the elderly. 1. Prevalence of Chronic Obstructive Pulmonary Disease The overall prevalence of COPD is usually quoted to be between 3% and 10%, but this varies widely depending on the diagnostic criteria.[5,6] According to the US National Institutes of Health (NIH), in the year 2000, an estimated 10 million Americans had self-reported doctor-diagnosed COPD, but the NIH also noted that data from the National Health and © 2008 Adis Data Information BV. All rights reserved.
Nutrition Examination Survey III (NHANES III) estimate that 24 million American adults have evidence of AFO.[7] COPD accounts for a significant number of healthcare visits each year and is a major source of morbidity and mortality. In patients aged >65 years, COPD was listed as a primary or secondary diagnosis for 11.3–15.1% of all hospital admissions.[8] The annual direct costs attributed to COPD in 2007 amounted to $US24.7 billion.[9] Interestingly, studies have shown that COPD may be under-diagnosed and under-treated in older patients. One study by Waterer et al.[10] evaluated spirometry and clinical data in 2485 well functioning patients aged 70–79 years who were participants in the Health ABC (Health, Aging and Body Composition) study. AFO was defined as an FEV1/FVC ratio below the lower limit of normal (LLN) [see section 3], based on NHANES III reference equations, and the severity of obstruction was based on percentage predicted FEV1 values. These investigators reported that 10.5% of patients had AFO. Only 37% of these patients with AFO recalled any diagnosis of respiratory disease and 74.8% of patients with AFO were not receiving treatment for lung disease. This is in agreement with data obtained from NHANES III in the US population. Examining spirometric criteria and questionnaires from 5743 participants aged ≥45 years, Coultas et al.[11] described a 12% rate of undiagnosed AFO, although many of these patients had mild AFO. Using an FEV1/FVC ratio
Defining Abnormal Lung Function in Older Adults with COPD
office spirometry.[12] The key phrase of this programme is “test your lungs – know your numbers”. The other major programme designed to increase awareness of COPD and standardize diagnosis and treatment is the Global Initiative for Obstructive Lung Disease (GOLD) programme (see section 2). 2. Gold Programme In 1998, the GOLD programme, sponsored by the NIH and WHO, was formed to increase awareness of COPD. The GOLD committee published its first consensus statement in 2001,[2] and this was most recently updated in 2006.[3] This consensus statement has provided a globally recognized guideline to standardize the diagnosis and management of COPD. The GOLD criteria recognize obstruction if the post-bronchodilator FEV1/FVC ratio is <70% and classify the severity of the disease by postbronchodilator FEV1. Severity is defined as: • stage I (mild): FEV1 ≥80% predicted; • stage II (moderate): FEV1 between 50% and 80% predicted; stage III (severe): FEV1 between 30% and 50% • predicted; and • stage IV (very severe): FEV1 ≤30% predicted. The 2001 document also defined a stage 0 or “at risk” group, consisting of individuals with normal spirometry but symptoms of chronic cough and sputum production. That category was removed because it was unclear if symptoms increased the likelihood of progression to abnormal spirometry. These diagnostic criteria proposed by GOLD were adopted by the American Thoracic Society (ATS) and European Respiratory Society (ERS) and published in a 2004 joint consensus statement.[4] In addition to diagnostic criteria, the GOLD guidelines discuss monitoring disease, reducing risk factors and treating both stable and exacerbated COPD. These guidelines have standardized the nomenclature for diagnosis, research and clinical purposes and will hopefully improve patient care with the risk factor modification and treatment recommendations. While the guidelines have been enormously helpful, two controversies remain after their publication. (i) What threshold should be used to diagnose obstruction from spirometry? Should a fixed © 2008 Adis Data Information BV. All rights reserved.
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FEV1/FVC ratio such as 70% be utilized or should the LLN be used? (ii) Who should be screened with spirometry? Should this include all smokers, or only people with symptoms? 3. What is the Lower Limit of Normal (LLN)? The LLN can be defined as a statistically derived level below which a value is considered abnormal. Many factors, most notably age, height, gender and ethnicity, influence spirometric values such as FEV1 and the FEV1/FVC ratio. The FEV1/FVC ratio is inversely proportional to age and height. As a result, using a fixed percentage would be expected to overdiagnose obstruction in the very old and tall and under-diagnose obstruction in the young and very short. Reference datasets usually provide the method for calculating LLN, which is typically based on confidence intervals or the fifth percentile. If this is not provided, it can be estimated by the standard error of the estimate. These reference equations are often incorporated into the software algorithms of current spirometry equipment. Using this method of pulmonary function test interpretation, software would give the actual test result values, a predicted value for a patient as well as the LLN, below which an interpretation of obstruction can be made. Use of LLN is not a new concept, but it is one that has been slow to gain acceptance in the medical community. For more than 40 years, concerns have been aired in respiratory journals over the practice of using a fixed percentage of predicted to define abnormal values instead of a statistical approach such as the 95% confidence intervals or LLN.[13] It has long been known that spirometric measures vary with gender, height and age. Measurement of both expiratory volumes and flows has been shown to be homoscedastic with respect to age and height. That is, the variance in the measured variable around the regression line is uniform throughout the range of measured height and age. Furthermore, the regression values for spirometric measures are also a function of height and age. Thus, taking a fixed percentage of the regression line (percentage predicted) as defining the ‘normal’ population either incorrectly includes or excludes a significant portion of this uniform variance at the extremes of height and age (figure 1).[13-15] It has long been suggested that a Drugs Aging 2008; 25 (9)
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a 80
African American Caucasian Mexican American
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below the LLN, and that the practice of using 70% as the LLN results in false positives in men aged >40 years and in women aged >50 years. In contrast to the ATS guidelines published for nearly 2 decades that have urged use of LLN to define abnormality, the GOLD recommendations use a fixed, post-bronchodilator FEV1/FVC ratio of <70% to declare abnormal lung function. The GOLD committee discussed this issue and stated that a fixed ratio of 70% was chosen for the level below which lung function is considered abnormal because of its simplicity; however, this has remained very controversial. The GOLD committee also agreed that this method may overestimate the diagnosis of COPD, especially in mild cases.[3] 4. How Does Aging Affect Lung Function and the LLN?
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Fig. 1. Predicted lower 95% confidence limits (lower limit of normal) for forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) [%] for (a) men and (b) women by race/ethnicity, based on National Health and Nutrition Examination Survey III data[16] (reprinted from Hnizdo et al.,[17] with permission from Taylor & Francis publishers).
more statistically sound approach is to use the LLN instead of a fixed-percentage cut-off, especially in the extremes of a population (very old or young, and very tall or short). There have been many published guidelines and recommendations relating to diagnosis of AFO, specifically the FEV1/FVC ratio. The ATS 1986 guidelines on Evaluation of Impairment/Disability Secondary to Respiratory Disorders used an FEV1/FVC ratio of <75% as diagnostic of AFO.[18] Because of concerns over using a fixed ratio of FEV1/FVC for diagnosis of AFO, the ATS, in 1991, proposed guidelines on lung function testing that recommended using a statistically derived LLN in lieu of a fixed ratio for diagnosing AFO.[19] This was reiterated in the 2005 joint ATS/ERS guidelines on lung function testing.[20] The guidelines specifically state that AFO is diagnosed when the FEV1/FVC is © 2008 Adis Data Information BV. All rights reserved.
Several recent reviews have addressed the effects of aging on the respiratory system.[21-23] Lung growth and development continue throughout childhood and the lungs reach their maximum size and function in the third decade of life. After this time, however, there is a progressive decline in lung function that is associated with changes in the lung parenchyma, chest wall compliance and respiratory muscle strength. Age-related alterations in lung parenchyma include alterations in collagen and elastic fibre arrangement. The end result is reduced lung elastic recoil.[24] This results in a shift of the normal lung pressure-volume curve to the left and upwards. These parenchymal changes also include alterations in the size and shape of alveoli, dilation of the alveolar ducts and development of enlarged air spaces.[25,26] There is also a reduction in the alveolar surface area.[22] The chest wall is also affected by aging.[22] Changes in the intercostal muscles, calcification of the rib-vertebral joints and age-related osteoporosis combine to increase kyphosis and the anteroposterior diameter of the chest.[27] This alters chest geometry and reduces chest wall compliance.[28] Inspiratory muscle function also changes with age. The changes in chest wall geometry result in alteration of the normal diaphragm curvature, leading to a mechanical disadvantage that decreases the maximal transdiaphragmatic pressure. Several studies have shown a decrease in respiratory muscle Drugs Aging 2008; 25 (9)
Defining Abnormal Lung Function in Older Adults with COPD
strength as measured by maximal inspiratory and expiratory pressures with age.[29-33] Many factors are thought to be involved, including age-related changes in muscle composition, mitochondrial dysfunction, reduced nutritional status and the presence of co-morbid conditions. Airflow is also altered with aging.[34,35] Small airway diameter is reduced and this, in combination with the decrease in elastic recoil, results in an increased propensity for small airway collapse. These changes in pulmonary mechanics combine to alter pulmonary physiology, as measured by pulmonary function testing. Spirometry reveals a decline in FEV1, FVC and the FEV1/FVC ratio with aging.[21,22] Cross-sectional studies estimate the beginning of the decline as occurring in the mid-20s,[36,37] while longitudinal studies have reported that FEV1 does not begin to decline until the mid-30s.[38] Lung volumes are determined by the balance between the elastic recoil forces of the lung parenchyma and the chest wall. This balance is relatively maintained with aging and, as a result, the total lung capacity (TLC) is generally unchanged with aging. Given the decrease in lung parenchyma recoil and the reduction in chest wall compliance, the equilibrium between these forces is shifted towards an increased functional residual capacity (FRC). Similarly, given the loss of lung parenchymal elastic recoil and the tendency towards small airway collapse, residual volume (RV) also increases with age.[24,39] This results in an RV/TLC ratio that increases from 25% at age 20 years to 40% by age 70 years. The closing volume similarly increases with age and exceeds the supine FRC at approximately age 45 years and the upright FRC at age 65 years.[40,41] In addition, studies have also shown expiratory flow limitation increasing with age in those with normal pulmonary function. These combined effects on expiratory flow and lung volumes can also be seen on expiratory flow-volume curves.[34,42-44] Studies of the effects of age on bronchodilator responsiveness have yielded mixed results. Aging has been reported to be associated with a decreased responsiveness to bronchodilators in some studies.[45,46] Other investigators have reported no changes in elderly asthmatic patients.[47] In a study © 2008 Adis Data Information BV. All rights reserved.
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of healthy subjects, those aged 60–76 years showed a reduced response to the bronchodilator effects of salbutamol (albuterol) after methacholine-induced bronchoconstriction.[46] It has been suggested that the response to β-adrenoceptor agonists and ipratropium bromide differs with age.[48,49] Several studies have examined spirometric data specifically obtained from healthy, non-smoking, elderly populations.[33,50-52] These studies found that, on average, FEV1 and FVC decline by approximately 30 mL/year and the decline in FEV1 is greater than the decline in FVC. Thus, as FEV1 and FVC decline with age, so do the predicted values and the LLN. Using data from the Cardiovascular Health Study, a subgroup of healthy, never-smokers aged 65–85 years was used to develop reference equations for spirometry.[52] The investigators reported a predicted FEV1/FVC ratio that ranged from 75% to 67% with advancing age and an LLN for an FEV1/ FVC ratio that ranged from 64% to 56% predicted for persons aged 65–85 years.[29] In another study, a group of healthy, elderly non-smokers from a crosssectional population-based study of over 4100 persons from Norway were evaluated.[53] Spirometry without bronchodilators showed that 7% of subjects aged 60–69 years had an FEV1/FVC ratio of <70% predicted, compared with 16% of men and 18% of women aged >70 years. Several studies have also reported spirometric reference equations for Europeans obtained from populations of healthy, never-smokers in Spain and England. One of these studies showed that for a given height, as age increased from 65 to 85 years, the LLN of FEV1/FVC decreased from 71% to 68% in women and from 70% to 64% in men.[54] Similarly, for a man 170 cm in height, the LLN of the FEV1/FVC ratio was 63% at age 70 years, 59% at age 80 years and 55% at age 90 years.[55] Together, these data show that healthy elderly people can be expected to undergo physiological changes that in many ways resemble AFO or COPD. Many asymptomatic, healthy non-smokers may have an FEV1/FVC ratio of <70%. Therefore, using a fixed cut-off of 70% to define COPD may result in over-classification of disease in the aging population. Drugs Aging 2008; 25 (9)
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5. Is There a Difference between the LLN and a Fixed Ratio? Recently, several studies have examined how these different diagnostic criteria affect the numbers of patients classified as obstructed (or with COPD) using a fixed 70% method versus LLN. In 1997, Margolis et al.[56] reported an overall discordance rate of 7.2% when comparing the fixed 70% method with LLN in a retrospective Veterans Affairs hospital cohort of 664 patients. In 2002, Hardie et al.,[57] reported that 35% of 71 healthy never-smoking participants aged 70–96 years from Norway had an FEV1/FVC ratio of <70%. This represented about 50% of patients in the >80 years group (28 patients). Additionally, in this study of asymptomatic, healthy non-smokers, 25% of those aged >70 years met GOLD criteria for stage I COPD and 10% met stage II criteria. For those aged >80 years, 32% would be classified as stage I COPD and 18% as stage II COPD. We reported a discordance rate of 7.5% using LLN versus the fixed 70% method of diagnosing AFO in a retrospective evaluation of 1503 pulmonary function tests from two academic medical centres.[58] The discordance was highest at the extremes of age and height. Sixteen percent of patients aged >74 years would have been diagnosed as obstructed using a 70% cut-off, but not by use of the LLN. Interestingly, when comparing different proposed criteria for diagnosing obstruction, the ERS criteria of using an FEV1/FVC ratio predicted of <88% for men and 89% for women had the lowest discordance. Similar results were obtained in a study by Lau et al.,[59] who examined the prevalence of AFO in Hong Kong using an LLN-based reference equation recently derived by the investigators versus fixed 70% as the diagnostic threshold of obstruction. They found a prevalence of AFO in the 60- to 80-year age group of 17.8% using the LLN and 45.4% using the fixed 70% method. In their study, use of the ERS criteria was also closer to the LLN than using a fixed percentage to predict obstruction. The NHANES III database of more than 9000 patients has been used to compare the 70% fixed method as utilized in the GOLD criteria with use of the LLN.[60] Significantly different rates of AFO were obtained with these different methods in this © 2008 Adis Data Information BV. All rights reserved.
study, which was performed without bronchodilators. The lowest rates of AFO were found using GOLD stage IIA (FEV1/FVC ratio of <70% and FEV1 of <80% predicted), while the fixed ratio of 70% resulted in the highest rates of AFO. Another study using NHANES III criteria concluded that using a fixed method of diagnosis compared with the LLN resulted in a significant misclassification of older never-smoking patients as obstructed.[61] A third study also examined NHANES III data and in combination with US population size estimates concluded that in patients aged 50–80 years, use of a fixed ratio overestimates AFO by 37% (of more than 4 million individuals).[17] These investigators also reported underestimation of AFO in younger patients aged 20–48 years by 31%, with many of these patients being symptomatic and undiagnosed. 6. Post-Bronchodilator Studies One important point to mention is that the GOLD criteria recommend diagnosing obstruction based on an FEV1/FVC ratio of <70% after the administration of a bronchodilator. This is an important difference in that post-bronchodilator studies may reveal an increase in the FEV1/FVC ratio and therefore may not over-diagnose COPD to the degree that has been predicted. In the GOLD criteria, as well as in the recent ATS/ERS pulmonary function testing guidelines, recommendations on the drug, dose or method of delivery of a specific bronchodilator are not given. In general, short-acting β2-adrenoceptor agonists are recommended.[20] In addition, there is no clear consensus on what constitutes reversibility in patients with AFO. The most widely accepted definition of a positive bronchodilator response is a 12% change from baseline and an absolute change of 200 mL in FEV1 and/or FVC. Previously published reference equations have utilized pre-bronchodilator values, and the last update to the GOLD criteria addressed this issue by stating that there was an urgent need for postbronchodilator studies.[3] In one study that applied post-bronchodilator GOLD criteria to a community population from Norway, 2235 subjects aged 25–82 years, including approximately 60% current or exsmokers, underwent pre- and post-bronchodilator spirometric testing.[62] The prevalence of COPD based on strict GOLD criteria was 7%. This was Drugs Aging 2008; 25 (9)
Defining Abnormal Lung Function in Older Adults with COPD
27% lower than the prevalence of COPD defined without bronchodilation. Ninety percent of the population maintained an FEV1/FVC ratio of >70% preand post-bronchodilation. 6.5% were <70% in both pre- and post-bronchodilation, while 3% were initially below but increased to >70% post-bronchodilation, and 0.5% were initially above but then fell to <70% post-bronchodilation. The effect of age on the diagnosis of COPD was also significant. The prevalence of COPD as measured by post-bronchodilation spirometry was 2.4% for those aged 26–44 years, 4.1% for those aged 45–59 years, 15.3% for those aged 60–74 years and 24.3% for those aged 75–82 years. All subjects aged >75 years diagnosed as having COPD by post-bronchodilator spirometry also had associated pulmonary symptoms. Similarly, the reduction in COPD prevalence postbronchodilator also varied with age. The reduction in COPD prevalence post-bronchodilator was 50% for those aged 26–44 years, 29% for those aged 45–59 years, 19% for those aged 60–74 years and 17% for those aged 75–82 years.[62] Recently, the same investigators utilized data from 515 healthy never-smoking patients with an age range of 26–82 years to determine post-bronchodilator reference equations in adults.[63] The investigators found that the post-bronchodilator FEV1/FVC ratio was never below 71%. This would substantiate the GOLD criteria for diagnosing COPD based on a postbronchodilator FEV1/FVC ratio of <70%. However, one drawback to this study was that there were only 13 men and 46 women in the 70- to 82-year-old age range, and no patient was aged >82 years. Recently, another study was published that used post-bronchodilator spirometry to evaluate the prevalence of COPD in New Zealand comparing GOLD criteria with the LLN technique.[64] These investigators found a prevalence of 14.2% using GOLD criteria versus 9% using the LLN. Their discordance rate was 5.2%. This study included 749 patients, of whom 104 were aged >70 years. In the cohort of patients investigated, the LLN for the FEV1/FVC ratio in patients aged 70 years would have been 65% and for those aged 75 years was 63%. However, it should be noted that more than half of the study population were ex- or current smokers. A population survey of several Latin American cities (the PLATINO [Latin American Project for © 2008 Adis Data Information BV. All rights reserved.
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the Investigation of Obstructive Lung Disease] study) sampled a representative population aged ≥40 years from five metropolitan areas.[65] Postbronchodilator spirometry reference values were developed from a population of healthy non-smokers. Inhalation of a bronchodilator, namely salbutamol 200 μg, resulted in an approximate 3% increase in FEV1, FEV1/FVC ratio and FEV1/FEV in 6 seconds (FEV6) ratio, with a minimum increase in FEV6 and a non-significant increase in FVC. Post-bronchodilator increases were shown to be relatively uniform over the age ranges studied for FEV1, but not for FVC. Thus, the FEV1/FVC ratio increased after administration of the bronchodilator. This caused an upward shift in the fifth percentile LLN of the predicted values. Similarly, bronchodilator testing reduced the overall prevalence of the FEV1/FVC ratio of <70% from 21.7% to 14% in a study of over 5100 patients from five Latin American cities.[66] Of those with an FEV1/FVC ratio of <70% after bronchodilator use, 21% were asymptomatic and lacked exposure risk for COPD. Fewer patients fell below the fifth percentile for the FEV1/FVC ratio of
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was 3.7%. Most cases (90.3%) were mild COPD (stage I), 9.7% of cases were moderate (stage II) and there were no severe (stage III) or very severe (stage IV) cases. In addition, 7.3% were categorized as stage 0. Increasing age was significantly associated with COPD based on post-bronchodilator spirometry. For the age groups 40–49, 50–59 and 60–69 years, the percentages with the diagnosis of COPD were 1.3%, 4.4% and 10.9%, respectively. The odds ratios for these age groups after adjustment for gender, smoking, income, body mass index and respiratory symptoms were 1, 2.56 and 8.95, respectively. 7. What Threshold Should Be Used to Diagnose Obstruction from Spirometry? Data summarized to this point illustrate that although much has been published on the differences between the LLN and the use of a fixed percentage to diagnose obstruction, the results remain controversial. The LLN is more statistically sound, while use of 70% will likely result in more false-positive or -negative tests and this becomes especially problematic at extremes of age. Younger people will often be under-diagnosed with use of 70% as the threshold, while the elderly are prone to over-diagnosis. The GOLD criteria recommend the use of post-bronchodilator spirometry, and many of the studies that have compared 70% versus the LLN have used only pre-bronchodilator values. Studies that have compared pre- and post-bronchodilator testing have reported a lower rate of classifying participants as obstructed with use of postbronchodilator expiratory volumes. The impact of this will be highest in people with borderline or mild AFO and in those with an overlap of asthma and COPD. While this may reduce the false-positive reporting rate in the elderly, generation of postbronchodilator reference equations and further studies comparing LLN versus the GOLD criteria of post-bronchodilator FEV1/FVC ratio of <70% would help resolve this issue. One interesting recent study used data from the Cardiovascular Health Study to evaluate the risk of death or COPD-related hospital admissions based on GOLD criteria in a group of 5201 men and women.[68] As expected, higher risks of both complications were seen with increased severity of lung dysfunction (higher GOLD stage). This study also © 2008 Adis Data Information BV. All rights reserved.
identified a group of people that had an FEV1/FVC ratio of <70% but higher than the LLN. Fifty-four percent of subjects (1134 of 2090) comprising this group were diagnosed with COPD using GOLD criteria (pre-bronchodilator) but not by the LLN. Interestingly, these people, who could be considered “over-diagnosed” by proponents of the LLN model, were also at increased risk of death and COPD hospitalizations. This group had an overall adjusted risk of death of 1.3 and COPD-related hospitalizations of 2.6. This study raises the question of whether 70% is possibly a better definition of AFO using long-term outcomes and highlights the remaining uncertainties. 8. Who Should Be Screened with Spirometry? In addition to the debate regarding the interpretation of spirometry, there is no consensus regarding the use of screening spirometry. Results of the Lung Health Study were published in 1994 and showed that healthy middle-aged smokers who were found to have mild AFO on screening spirometry and who underwent an intensive smoking cessation programme reduced their rate of FEV1 decline over 5 years.[69,70] Subsequently, the National Lung Health Education Program (NLHEP) was formed by the National Heart Lung, and Blood Institute (NHLBI).[71] In 2000, a NLHEP consensus statement recommended office spirometry to detect COPD in patients aged ≥45 years who have a smoking history.[72] This group cited the probable benefits of spirometry in influencing smoking cessation rates and the benefits of early treatment in preventing development of more severe disease. The recommendations of the NLHEP are supported by the results of a recent randomized controlled trial of 561 current smokers aged >35 years from England in which the effect on smoking cessation of patient education about their “lung age” based on spirometric measures was evaluated.[73] “Lung age” was defined as the age of the average healthy individual who would perform similarly to the patient undergoing spirometry. The control group received a raw figure for FEV1. Both groups were advised to quit smoking and offered referral to their local National Health Service smoking cessation services. Eighty-nine percent of the patients were followed up Drugs Aging 2008; 25 (9)
Defining Abnormal Lung Function in Older Adults with COPD
at 12 months and 13.6% of those in the intervention group were independently verified as having quit at 12 months compared with 6.4% in the control group. This difference was statistically significant (p = 0.005) and the number needed to treat was 14. Those with a worse spirometric lung age were not more likely to have quit than those with a normal lung age in either group, suggesting that the process of undergoing screening spirometry coupled with educating patients about their “lung age” affected smoking cessation rates. Other societies and initiatives recommend using spirometry only for diagnostic purposes in patients with clinical symptoms. The ATS recommends that the diagnosis of COPD be considered in any patient who has symptoms of cough, sputum production, dyspnoea or a history of exposure to risk factors for the disease.[4] This society also suggests that the diagnosis requires spirometry and that a postbronchodilator FEV1/FVC ratio of <70% be used to confirm the presence of airflow limitation that is not fully reversible. The ATS advises that spirometry should be obtained in all persons with the following history: exposure to cigarettes; and/or environmental or occupational pollutants; and/or presence of cough, sputum production or dyspnoea. Similar recommendations are proposed in the GOLD guidelines.[74] According to the GOLD committee, an initial diagnosis of COPD should be considered in those with dyspnoea that is progressive, worse with exercise, persistent or described by the patient as an ‘‘increased effort to breathe, heaviness, air hunger, or gasping”. Those with a chronic cough that may be intermittent, unproductive or associated with chronic sputum production should also be considered. Other risk factors include a history of exposure to tobacco smoke, occupational dusts and chemicals, smoke from home cooking and heating fuels. In patients meeting these criteria, the diagnosis of COPD should be considered and spirometry should be performed. The GOLD guidelines caution that these indicators are not diagnostic in themselves, but the presence of multiple key indicators increases the probability of a diagnosis of COPD. The GOLD committee also recommends that spirometry is needed to establish a diagnosis of COPD. Recent guidelines from the American College of Physicians (ACP) state that spirometry should not © 2008 Adis Data Information BV. All rights reserved.
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be used to screen for AFO in asymptomatic individuals.[75] Use of spirometry for diagnosis of AFO is recommended as beneficial when targeted towards individuals with respiratory symptoms, particularly dyspnoea. The ACP did not find evidence supporting use of spirometry to screen for AFO in asymptomatic individuals, including those who have risk factors for COPD. The ACP also cited the lack of high-quality evidence for obtaining and providing spirometry results to improve smoking cessation, identify and treat asymptomatic individuals to prevent future respiratory symptoms or reduce spirometric decline in lung function.[75] Use of spirometry as a tool to improve smoking cessation rates was recently reviewed.[76] This study evaluated trials that enrolled at least 25 smokers, assessed spirometry with counselling or in combination with other smoking cessation therapies, followed patients for ≥6 months and reported smoking abstinence rates. The reviewers concluded that the available evidence is insufficient to determine whether spirometry results improve smoking cessation compared with other methods. The US Preventative Services Task Force also recently recommended against screening asymptomatic adults for COPD using spirometry.[77] This group noted that spirometry can be used as a screening measure for those with a family history of α1antitrypsin deficiency and for those with symptoms of chronic cough, increased sputum production, wheezing or dyspnoea. In addition, this panel noted that no controlled studies have compared clinical outcomes between screened and non-screened populations. Whether the study populations and results of clinical trials of pharmacological therapies would apply to spirometric screening-detected COPD populations is also unclear. Patients identified through screening do not recognize or report symptoms, and on the basis of prevalence studies, most would be expected to have mild or moderate COPD. Aside from smoking cessation and preventative vaccinations, COPD therapies produce modest benefits in this population. In addition, the risks include the additional cost of screening as well as for the treatment of adverse effects, which generally are minor but can be more severe, such as fracture, delirium, incontinence or urinary retention. These are all problems to which the older patient population is Drugs Aging 2008; 25 (9)
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more susceptible. The task force also concluded that as the vast majority of cases of COPD result from tobacco use, an early intervention strategy aimed at increasing smoking cessation and smoking abstinence would likely be more effective than an early detection strategy based on performing spirometry in patients who do not note or report respiratory symptoms. Using data from NHANES III, the US Preventative Services Task Force also developed a hypothetical spirometry screening programme based on the assumptions that the true prevalence of FEV1 <50% predicted of the general primary care population is that measured in NHANES III; inhaled therapies benefit only patients with FEV1 of <50% of predicted; treatment consists of the combination of an inhaled β-adrenoceptor agonist and an inhaled corticosteroid; patients who do not recognize or report symptoms have similar benefits as symptomatic patients; treatment produces a 6% absolute risk reduction in patients having one or more COPD exacerbation over 6–36 months; and, as a COPD exacerbation causes a patient to seek medical care, leading to a clinical diagnosis, the incremental benefit of screening over clinical detection is limited to avoidance of a single exacerbation.[77] This resulted in a number needed to screen (NNS) to prevent one COPD exacerbation over a period of 6–36 months ranging from 833 for current smokers to 2000 for never-smokers. Based on age, the NNS ranged between 2500 (age 40–49 years), 667 (age 50–59 years), 455 (age 60–69 years) and 400 (age 70–74 years). Thus, while differences are presented in the various screening recommendations, in general, it is recommended that those with increased risk factors and/or the presence of symptoms as already outlined undergo spirometry to evaluate the possibility of a diagnosis of COPD. It is important to remember that the elderly population, while often under-diagnosed, is also very susceptible to false-positive test results and therefore screening of asymptomatic elderly individuals would likely lead to too many people being diagnosed as having COPD, especially if using GOLD diagnostic criteria. As a consequence, these individuals would be exposed to the risks of potentially unnecessary therapy. Given that the elderly are typically taking multiple medications, they © 2008 Adis Data Information BV. All rights reserved.
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are also more susceptible to drug adverse effects and interactions. While generally considered safe, possible adverse effects of COPD therapies can be significant and include tachycardia, hypokalaemia, urinary retention with bronchodilators and hyperglycaemia or adverse psychiatric effects with corticosteroids.[78] 9. Conclusion COPD is a disease with a significant population burden and individual risk for morbidity and mortality. No consensus exists regarding the definition of COPD or the diagnostic criteria. This is complicated by age-related changes in the respiratory system that mimic obstructive pulmonary physiology. The GOLD criteria were developed with the proposed advantages of being easier to use and applicable for widespread use, particularly in areas that may not have established reference equations. The disadvantages of these criteria, however, are not insignificant. Use of the FEV1/FVC ratio of <70% fixed cutoff does not have an established statistical basis. With increasing age, the risk of over-diagnosis of COPD also increases in those that may lack evidence of disease by other measures. Thus, the elderly may experience adverse effects from pharmacological therapy when they do not have COPD, but rather normal age-related decline in the FEV1/FVC ratio. Similarly, the younger population may have disease by other measures, but may be falsely excluded as normal. Larger scale population studies may better define the true differences between the diagnosis of COPD based on the strict postbronchodilator GOLD criteria and the LLN based on currently used reference equations, as well as the outcomes of those at risk for both over- and underdiagnosis. Acknowledgements No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this article.
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Correspondence: Dr Karen L. Wood, 201 DHLRI, 473 West 12th Avenue, Columbus, OH 43210, USA. E-mail:
[email protected]
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