Chronic obstructive pulmonary disease (COPD) is a leading but underrecognized cause of morbidity and mortality worldwide. No other disease that is responsible for a comparable burden worldwide is as neglected by health care providers as COPD. In 1996, the Institute of Medicine aimed to relate the amount of disease-specific research funding provided by the National Institutes of Health (NIH) with the burden of disease for society . Acquired immunodeficiency syndrome, breast cancer, diabetes mellitus, and dementia all received relatively generous funding, regardless of which measure was used as the basis for calculating support. Research on COPD, perinatal conditions, and peptic ulcer was relatively underfunded, and by far COPD was the condition that deserved less attention in comparison to its population burden (Figure 1). Disappointingly, the situation remains unchanged 10 years later .
| ||Figure 1. Relationship between disease burden and National Institutes of Health funding in 1996. |
(Reproduced from Gross CP, Anderson GF, Powe NR. The relation between funding by the National Institutes of Health and the burden of disease. N Engl J Med 1999;340:1881-1887. Copyright © 1999 Massachusetts Medical Society. All rights reserved.)
Fortunately, a number of initiatives are currently underway to change this discouraging state of affairs. A small but significant step forward was the agreement on spirometry thresholds of diagnosis and severity by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [3,4], and the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2004 guidelines on standards for the diagnosis and management of patients with COPD . Furthermore, the establishment of the Burden of Obstructive Lung Disease (BOLD) initiative to facilitate standardized burden studies at an international level is considered a major step and is briefly discussed later in this chapter.
The burden of COPD can be assessed in a number of ways including the following: mortality, morbidity, prevalence, disability-adjusted life-years, cost, and quality of life. A number of authors have comprehensively reviewed the historical data on the burden of COPD in detail elsewhere [6,7]. As the causes of COPD are comprehensively discussed in other chapters within this series , this chapter focuses on mortality, prevalence, and morbidity of COPD, ending with the burden caused by COPD exacerbations.
THE MAGNITUDE OF THE PROBLEM
Death rates from COPD have been rising steadily over the past few decades. This trend is particularly striking since the death rates for cardiovascular or other common chronic diseases have fallen. From 1965 to 1998, death rates from coronary heart disease in males in the United States dropped 59%, deaths from stroke decreased by 64%, and other cardiovascular diseases by 35%. Over the same period, deaths from COPD increased by 163% .
The Global Burden of Disease Study from the World Health Organization (WHO) has been systematically assessing worldwide statistics on specific causes of death and disability since 1990 . According to WHO, at least 2.9 million deaths are due to COPD every year, and their 30-year projections for the global increase in COPD are startling. COPD is projected to move from the sixth most common cause of death worldwide in 1990 to currently fourth, and by 2020 to third; it is also expected to rise from fourth to third in terms of morbidity within the same time frame [10,11]. This striking increase in COPD as a cause of death is projected to occur because of the worldwide epidemic of smoking and the changing global demographics, with more people in developing countries living longer and, therefore, at risk of COPD for a longer time. A United Nations report projected that the number of people worldwide aged >60 years will nearly double over the next 50 years and, by the mid twenty-first century, the population aged >100 years will be 15 times higher than it is today . Although more people smoke today than at any other time in human history, it is actually the changing demographics worldwide that is driving the COPD tidal wave even faster than the increase in smoking worldwide, as illustrated in the ERS European Lung White Book (Figure 2) .
| ||Figure 2. Standardized mortality rates of chronic obstructive pulmonary disease for males in 42 European countries. |
(Reproduced from World Health Organization Atlas of Mortality in Europe. Subnational Pattern, 1980/81 and 1990/91, 1997. WHO Regional Publications, European Series no. 75 Copenhagen. WHO Regional Office for Europe. With permission)
Males consistently have higher COPD death rates than do females in all countries, and COPD has traditionally been thought of as a disease of elderly males who smoke. It was, therefore, surprising to see that in 2000 there were more deaths in the United States from COPD among females than there were among males . Although the rates of death were still higher in males than they were in females, they reflected the different age structure of the United States population for both sexes, with females living longer and, therefore, being more at risk of developing COPD. This dramatic change in the sex distribution of mortality is likely to be seen in other countries that have been lagging behind the United States in smoking patterns among females, but have been catching up over the past few decades. It is worth noting that in all countries but three (Norway, Sweden, and New Zealand), and in these only since 2003, females have never smoked as much as have males .
Of all of the descriptive epidemiological data available for COPD, mortality data are the most readily accessible, but they have to be interpreted with caution. As a ballpark figure, mortality rates due to COPD are 50 per 100,000 for males and 20 per 100,000 for females . However, inconsistent use of terminology and the lack of widely accepted diagnostic standards for the diseases that are included in the coding within the COPD spectrum have contributed to the inaccuracy of mortality data for COPD. For example, the codes used for COPD in the International Classification of Diseases (ICD), ninth edition, include chronic bronchitis (ICD-9 491); emphysema (ICD-9 492); and chronic airway obstruction (ICD-9 496). Asthma (ICD-9 493) should not be included in the COPD definition. Using the single term COPD is being championed in global and national guidelines, with the expectation that this will improve awareness, simplify the coding, and, ultimately, lead to greater accuracy in death certification for COPD. For the next iteration of the ICD coding, the consolidation of emphysema, chronic bronchitis, and chronic airway obstruction will be an important step toward obtaining more accurate data on the distribution of COPD worldwide.
Whatever the disease, prevalence estimates depend on the definition that is used for diagnosis. For COPD, a number of different approaches have been used, including the following: doctor diagnosis, diagnosis based on the presence of respiratory symptoms, and a diagnosis based on the presence of airflow limitation (with or without a bronchodilator test as recommended by GOLD). These different approaches, not surprisingly, give very different estimates, with doctor diagnosis giving the lowest estimate of prevalence , diagnosis based on respiratory symptoms giving the highest estimate, and a diagnosis based on spirometry giving an intermediate estimate . The advantages and limitations of conducting population spirometry have been the subject of much debate . Many experts disagree on when and where case findings or true population screening should be applied, and even on whether they are appropriate tools to establish COPD prevalence at all.
Since the GOLD guidelines were published, the need for spirometry in diagnosing COPD has been generally accepted, and this has now become the "gold standard." However, even when using so-called objective measurements, estimates may vary widely depending on which spirometric criteria are used [18,19]. The ATS/ERS COPD guidelines recommend that post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70% confirms the diagnosis of COPD, and FEV1 provides a way to stage COPD. For example, mild COPD is described as post-bronchodilator FEV1/FVC ratio <70% together with an FEV1 >80% predicted, all based on predicted (or reference) values using gender, age, and height. Moderate COPD corresponds to values of predicted FEV1 of 50 to 80%, severe of 30 to 50%, and very severe <30%. The controversy remains, with some clinicians claiming that this physiological definition in the absence of a significant tobacco history is of little practical use.
Up to 2001, only 32 prevalence surveys of COPD had been reported . In 2006, the same clinicians updated these figures by systematically searching for populationbased prevalence estimates published up to 2004, and 62 prevalence surveys were identified . Although there have been many additions during the last 5 years (Figure 3), these two-digit numbers are remarkably low given the hundreds of prevalence surveys available in asthma, and the thousands of studies available on the distribution of cancer, cardiovascular, or other major diseases. Overall, the prevalence of COPD in the general population is estimated to be approximately 1% across all ages, rising steeply to 8 to 10% or higher among those aged ≥40 years.
| ||Figure 3. Distribution of population surveys of chronic obstructive pulmonary disease by year and country. |
COPD is underdiagnosed not only in its early stages, but even when lung function is severely impaired. This is perhaps surprising, since simple and inexpensive spi rometers that are suitable in clinical practice are now available, and lung function is a powerful predictor of all-cause mortality, regardless of smoking status. To date, few well-conducted population-based prevalence surveys have been carried out, and prevalence estimates have often relied on expert opinion or self-reported doctor diagnosis, a notoriously unreliable source of information for COPD. For example, in the Third National Health and Nutrition Examination Survey (NHANES III), 70% of those with airflow obstruction had never received the diagnosis of COPD . The Epidemiological study of COPD in Spain Estudio Epidemiológico de Epoc en España (IBERPOC) also reported that there was no previous diagnosis of COPD in 78% of identified cases and, even more worrisome, that only 49% of those with severe COPD were receiving some kind of treatment . The Nippon COPD Epidemiology (NICE) study in Japan reported a similar finding . During the 1990s, asthma surveys successfully identified huge variations in asthma prevalence, both in children and adults, as high as twentyfold. With currently available data, it appears that the geographical distribution of COPD is more homogeneous than asthma, at least in developed countries. It seems likely that the distribution of COPD follows the distribution of its risk factors very closely, of which smoking is undoubtedly the most important worldwide .
Noticeably, most population surveys have been conducted in developed countries, without the participation of entire world regions and having only indirect evidence of the distribution of COPD [26,27]. New results from the PLATINO study (Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar), an initiative of the Latin American Thoracic Society, and the pilot BOLD sites are just arriving, indicating a higher prevalence of COPD than previously anticipated [28,29].
Whenever available, new evidence of specific causes of COPD other than that of cigarette smoking, such as occupational respiratory factors, will be warmly welcomed .
Morbidity assessment includes physician visits, emergency department visits, and hospitalizations. COPD morbidity data are often less reliable than are those of mortality, since the various ways of measuring morbidity are more prone to external factors, such as the availability of hospital beds, local and regional use of filters from primary to secondary care, coding affected by reimbursement patterns, and other such potentially biasing factors. Despite these external factors, morbidity for COPD is important to track, since these data can provide an estimate of the need for future health services [12,31].
Hospital admissions due to COPD are enormous and, as a way of comparison, they usually double the rates due to asthma. Despite efforts to reduce the length of stay and affect an early discharge, in most countries mean length of stay has remained almost unchanged at about 7 to 10 days . Periodically, most Western health systems collapse during winter due to influenza outbreaks and other factors . The impact of exacerbations on primary care consultations cannot be underestimated. The median number of exacerbations seen in primary care by an average patient with COPD is 2 per year, with a third of patients suffering 3 or more exacerbations in 1 year .
BURDEN OF EXACERBATIONS OF COPD
Exacerbations of COPD are currently considered a landmark event in the natural history of COPD, as they are associated with single decreases in lung function, their number and severity increase with the progression of COPD, and they produce increasing costs to national health systems. Comprehensive reviews on the burden imposed by exacerbations of COPD are available elsewhere [35-38].
Much has been debated about how to define COPD exacerbations. Exacerbations have been defined using respiratory symptoms alone (symptom-based), or symptoms plus an event such as the prescription of medication by a general practitioner, or hospital admission for an acute exacerbation . All these approaches have advantages and disadvantages and, as yet, there is no consensus. The search for an objective COPD biomarker is active but not completed, and any candidate should combine good sensitivity and specificity, as well as identify either the presence or severity of an exacerbation .
There is a subgroup of patients with COPD who experience an above-normal number of exacerbations, the socalled frequent exacerbators. They are usually defined with a cut-off of 3 or more exacerbations per year. However, this cut-off point surely will depend on the definition and on the management strategies applied to different clinical series. Patients with frequent exacerbations are said to have a poor quality of life, high inflammatory markers when stable, and a fast decline in lung function. They are more likely to become housebound, to experience more colds, and to be chronic sputum producers than are those with few exacerbations. Furthermore, they are prone to hospital readmission . This propensity toward frequent exacerbation appears for the most part to be independent of disease severity . Finally, it is important to identify, stage, and treat all types of COPD exacerbations, as they are strongly and independently associated with death in COPD .
BURDEN OF OBSTRUCTIVE LUNG DISEASE
As previously discussed, the lack of accurate populationbased estimates of COPD prevalence in most countries prompted the formation of the BOLD initiative in 2002. BOLD is designed to provide strictly standardized, rigorous, and practical methods for estimating the prevalence and social and economic burden of COPD. Data obtained from BOLD should help to achieve a long-term goal of epidemiology as a discipline of public health by enabling governments and the private sector to make policy decisions on how to provide adequate and appropriate care for those suffering from COPD.
The primary objectives of BOLD are to measure the prevalence of COPD and its risk factors in various countries around the world; to estimate the burden of COPD in terms of its impact on quality of life, activity limitation, respiratory symptoms, and use of health care services; and to develop a validated model to project future burden of disease for COPD. BOLD also seeks to determine the extent to which variations in risk factors contribute to variations in the prevalence of COPD. Recognizing the importance of standardizing methods worldwide, BOLD worked collaboratively with PLATINO  to develop the methods. PLATINO subsequently used these methods to estimate COPD prevalence in five Latin American countries, that is, Brazil, Mexico, Uruguay, Chile, and Venezuela . The BOLD methods cookbook has been piloted in a number of countries, including China, Turkey, the United States, and Austria. BOLD is presently enrolling countries for implementation of the methods in 2006 and onward. Up-to-date information on BOLD can be found at http://www.boldcopd.org. Briefly, BOLD will obtain information from at least 300 men and 300 women aged 40 years or older from well-defined areas. In addition to spirometry, study participants will be administered a standardized questionnaire covering respiratory symptoms, health status, activity limitation, and exposure to potential risk factors, such as tobacco smoke, occupational risk factors, and biomass exposure.
All questionnaires are forward- and back-translated, again using standardized methods to ensure comparability of the questionnaires in all countries. An additional part of the BOLD initiative is the development of an interactive, web-based model to report country-specific estimates of the prevalence and economic burden of COPD.
COPD is and will be a huge and growing burden worldwide as a result of the changing demographics in developing countries and the tobacco epidemic. Currently, the prevalence of physiologically defined COPD, which is demonstrable, nonreversible airflow obstruction, in adults aged 40 years and older is approximately 9 to 10%. Better descriptive data on COPD mortality, prevalence, morbidity, and burden of COPD exacerbations are urgently needed in order to gain the attention of the health care community and planners on this growing problem. Attention must also be paid to the development and acceptance of standardized methods that can be used worldwide to accumulate these data.
Tobacco is and will remain the major enemy of COPD, all respiratory diseases, and, generally, of world health. Interventions that are appropriate for each country should be developed so that current COPD trends can be reversed.
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