35. Respiratory Diseases of Adults

Chronic Respiratory Diseases: Nature, Causes, and Burden

COPD and asthma have very different diagnoses and causes; hence, they are discussed in separate sections. However, the treatments for these different chronic respiratory diseases share similarities, and that discussion is therefore combined. One of the difficulties in defining COPD on a worldwide basis is that three distinct levels are used, depending on the sophistication of the health care system in the country where the patient is being evaluated:

• Chronic bronchitis with and without obstruction, which may be part of the COPD diagnosis, is defined by the presence of chronic cough and phlegm for three months per year for two or more years and is generally assessed by standardized questionnaires.

• Obstructive airways disease is often assessed by reduced pulmonary function as measured by simple spirometry and the presence of a reduced ratio of the forced expiratory volume in one second (FEV₁) divided by the vital capacity (VC).

• For emphysema, which is also part of the syndrome of COPD, pulmonary function (changes in lung volume and reduced diffusion capacity), x-ray evidence of bullae formation, hyperinflation of the chest, and (with the use of high-resolution CT scanning) the presence of characteristic changes in lung architecture all may contribute to the diagnosis.

What is apparent is that not all these diagnostic procedures are applied equally, particularly in the developing world; thus, COPD may be seriously underreported. The 1998 Workshop Report by the WHO and the National Institutes of Health (NIH) on "Global Strategy for the Diagnosis, Management, and Prevention of COPD," developed as part of the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2001), uses an international standard for defining the level of obstruction from COPD. This strategy should improve worldwide estimates. This standard definition will still require the use of equipment that measures pulmonary function (Buist 2002). Over the next several years, as the price and distribution of this equipment becomes more favorable and as more groups undertake the training in its use and in the interpretation of results from the tests, diagnostic uniformity will improve. Unfortunately, as pointed out by Ait-Khaled, Enarson, and Bousquet (2001), the applicability of these guidelines has not been effectively tested in developing countries.

In adults, COPD dominates all other chronic respiratory diseases in accounting for 2 percent to more than 10 percent of lost disability-adjusted life years (DALYs) on a worldwide basis. Its incidence increases dramatically with age (figures 35.1a and 35.1b). Of note, mortality from COPD is low before age 45. Over age 45, death rates increase from 50 to 200 per 10,000 individuals and are consistent across age groups in men and women, with the exception of death rates in women over age 80, which exceed those in men in that age group (figure 35.2).
[Figure 35.1]

[Figure 35.2]

Much of COPD in the developed world is related to cigarette smoking, and there is no question that progression of the disease is related to the number of cigarettes smoked and the years of smoking. Smoking cessation has been associated with reduced mortality from COPD, presumably through a mechanism that results in a modest improvement in pulmonary function that appears to be related primarily to the extent of chronic bronchitis and mucus hypersecretion (Scanlon and others 2000; Speizer and others 1989). Within a few years of stopping smoking, smokers' rate of decline of pulmonary function (that is, FEV₁) returns to the rate found in nonsmokers, although little of the lost pulmonary function is regained (Fletcher and others 1976). Similar effects are seen in the developing world. However, because smoking is far less prevalent in developing countries, especially among women, other exposures are related to the development of disease (see also chapter 46). One of the most important exposures, particularly for women, is to unvented coal-fired cooking stoves, starting during childhood and continuing into adult life (see chapter 42).

Because the interventions and treatments for COPD overlap with those for asthma, they will be treated together.

The diagnosis of asthma has been debated for centuries. Health care providers can generally agree on the diagnosis in the individual patient who is wheezing and in whom other etiologic factors are ruled out. They would also agree on the definition of the disease as an inflammatory response in the airways that results in variable and generally reversible airflow obstruction with or without treatment. However, depending on the training of health care providers, the nature of surveillance, the characteristics of a given community, and the particular environment of the community, the accuracy of the estimate of the prevalence of asthma in a community may vary much more. The reported prevalence of the disease may be based on no more than an answer to this question: "Has a provider ever told you that you (or your child) has had asthma?" The response to this question has been validated in a number of studies. In contrast, the diagnosis may depend on examination of the patient's chest, physiological testing, responsiveness to provocative stimuli to the airways, and specific response to therapy. Thus, estimates of community burden from asthma may depend on the threshold used in making the diagnosis.

Despite variations in diagnostic criteria, worldwide estimates of the asthma burden among adults have generally come from surveys within selected communities. In contrast to other adult respiratory diseases, the prevalence of asthma is relatively low (figures 35.1a and 35.1b). In adults, the DALYs for asthma are at a peak of about 2 percent of the total worldwide in people age 15 to 29, and they decline in each older age group. This pattern is also reflected in mortality rates, with the highest rates occurring in young people and equal rates in men and women about age 60. After age 60, reported rates of death caused by asthma in men begin to exceed those in women, and both become substantial. That shift reflects primarily either increasingly questionable diagnostic accuracy or misclassification of other obstructive respiratory diseases such as COPD.

Economic Impact of Asthma and COPD in the Developed World

In the United Kingdom (where asthma rates are particularly high), respiratory disease accounts for 6.5 percent of hospital admissions. Fifteen percent of the working population report work-limiting health problems caused by respiratory disease, and 18.3 million workdays were lost to asthma problems in 1995-96 (Chung and others 2002).

In the Netherlands, annual costs associated with asthma and COPD (direct and indirect) were estimated to exceed US$500 million for a population of about 14 million (data for the 1980s). Asthma or COPD was responsible for 3 percent of absenteeism caused by illness, and asthma was also the main reason for absence from school among children age 4 to 12 (Rutten-van Molken and others 1992).

In the United States in the early 1990s, health care costs attributable to respiratory disease were US$11 billion (about 2 percent of total health care costs), and an estimated 3 million workdays and 10 million schooldays were lost to respiratory disease (Stoloff, Poinsett-Holmes, and Dorinsky 2002).

Another survey (Weiss and Sullivan 2001) estimated the costs of asthma in 1991 US dollars for four developed countries (Australia, Sweden, the United Kingdom, and the United States) and one state (New South Wales in Australia). Per patient costs of asthma ranged from US$326 (Australia) to US$1,315 (Sweden) annually, with direct costs accounting, in most cases, for more than half of total costs.

Economic Impact of Asthma in the Developing World

Data for developing countries are much scarcer. For Estonia, Kiivet and others (2001, cited in Lee and Weiss 2002) estimated the direct annual costs of asthma to be US$104 per year per asthma patient, equivalent to 1.4 percent of direct health care costs. In Singapore, medical costs for asthma constitute 1.3 percent of total health care costs (Chew, Goh, and Lee 1999, cited in WHO 2001).

One study (Ait-Khaled, Enarson, and Bousquet 2001, cited in Weiss and Sullivan 2001) found that asthma drugs cost between 3.8 and 25 percent of the patient's monthly income in 24 developing countries in Asia and Africa. K. R. Smith (2000) estimates the burden of respiratory disease in India that is attributable to indoor air pollution (only a fraction of all respiratory disease) as 1.6 billion to 2 billion sick days per year. Of that total, asthma is responsible for about one-third, acute respiratory infection is responsible for about one-third, and the remainder is attributable to COPD, tuberculosis, and ischemic heart disease. Asthma and COPD combined account for 44 percent of the burden.

Cost-Effectiveness of Interventions for COPD and Asthma in Developed Countries

Five recent overviews of the economics of chronic respiratory disease, COPD, and asthma (Friedmann and Hilleman 2001; Lee and Weiss 2002; Ruchlin and Dasbach 2001; Sullivan and Weiss 2001; Weiss and Sullivan 2001), in addition to many individual studies, focus on developed countries.¹ Only a limited number of studies use cost- or quality-adjusted life years (QALYs) saved as the outcome (others use life years saved). (Studies focusing on intermediate health outcomes and on cost minimization are not discussed here.) In general, costs in developing countries would be about 20 percent of those reported here, according to detailed unit cost data by region from WHO-CHOICE (Choosing Interventions That Are Cost-Effective) and on comparisons of respiratory drug prices from online pharmacies in the United States and from the International Drug Price Indicator Guide (http://erc.msh.org). The exceptions are interventions involving nondiscounted drugs that are still under strictly enforced patents, for which the costs in developing countries would be closer to those in the United States. Table 35.2 summarizes the results.

Inhaled salbutamol (short-acting beta-2 agonist) is the first line of treatment for both intermittent asthma (daytime symptoms less than once per week, nocturnal symptoms less than twice per month, and normal spirometry between episodes) and COPD (mild to severe) in both developed and developing countries. This treatment became standard practice beginning in the 1970s, so there are no cost-effectiveness studies of salbutamol compared with placebo. This medical intervention is likely the most cost-effective one, but it is still likely to cost some thousands of dollars per life year saved in the United States.

The next line of treatment currently recommended for developing countries is inhaled corticosteroids (for example, beclomethasone) for mild to severe persistent asthma (disease ranging from daytime symptoms greater than once per week, nocturnal symptoms more than twice a month, and normal spirometry between episodes to daily frequent symptoms associated with severe obstruction) and inhaled ipratropium bromide for COPD. Both first-generation corticosteroids and ipratropium bromide are off patent. However, as pointed out by Chan-Yeung and others (2004), the use of corticosteroids either intermittently or chronically is commonly recommended in developed countries, where the background level of tuberculosis among patients is considerably lower. In developing countries with higher tuberculosis rates, corticosteroids must be used with greater caution.

Inhaled steroids cost about US$13,900 per QALY for mild to moderate asthma or when used in early treatment of COPD. The cost per QALY is likely to be lower for severe asthma, but ethical considerations render random controlled trials unfeasible.

No cost-effectiveness study could be found for ipratropium bromide compared with placebo. We estimate that the cost per QALY saved would be between one-half and two-thirds of that for a new-generation inhaled steroid such as fluticasone propionate. This estimate, which is based on the relative cost of the two drugs in the United States and assumes similar effectiveness of the two drugs, would put the cost of ipratropium bromide between US$6,700 and US$8,900 per QALY.

Most of the other interventions summarized in table 35.2 have a higher cost per QALY. For individuals who develop COPD related to a severe deficiency in alpha-1 antitrypsin, alpha-1 antitrypsin therapy is sometimes considered, at a cost of between US$45,000 and US$215,000 per life year.² The use of long-acting beta-2 agonists and leukotriene modifiers is now an accepted and integrated component of the treatment of moderate to severe asthma in the developed world. However, the cost savings for the developing world are difficult to demonstrate because the endpoints of studies using those drugs are often changes in spirometric testing, improved quality-of-life measures, steroid-sparing effects, or altered hospital admission rates.

Likewise, oral or intravenous steroids play a crucial role in the treatment of acute exacerbations in both asthma and COPD, but endpoint assessments in studies typically address decreases in the duration of hospital stays and increases in the use of emergency department facilities, which result in decreases in health costs in the developed world. Oral steroids are inexpensive, even by standards in developing countries, and in the short term might appear to be cost-effective, but they are associated with major medium- to long-term consequences and are not recommended as standard therapy.

Educational programs tend to be cost saving in developed countries, where uncontrolled exacerbations are extremely costly in terms of hospital care (six such programs are surveyed in Van Molken and others 1992 and one in Ruchlin and Dasbach 2001). Similarly, exercise rehabilitation programs (six surveyed in Ruchlin and Dasbach 2001) can also be cost saving. WHO (2001) has commented on cost savings achieved by education programs for asthma from four different U.S. studies. Only one of these studies addressed cost per well year, which was estimated at US$71,500 in 2001 (Toevs, Kaplan, and Atkins 1984, cited in Ruchlin and Dasbach 2001). However, there are likely to be monetary savings from fewer workdays lost, which are not factored into this analysis.

WHO (2001) surveyed one self-management training program for chronic asthma in India (Ghosh and others 1998), which resulted in improvements in health status, reduced use of emergency departments and hospitals, and savings on health costs. Sudre and others (1999) pointed out that studies of education programs tend not to provide a good description of the actual program content and that a more systematic description of these interventions needs to be promoted to replicate best practice.

Long-term oxygen therapy is a life-prolonging intervention in advanced stages of COPD. Recent studies do not quantify the cost per QALY but instead compare different methods of oxygen delivery (cylinder or concentrator). These authors' crude estimate for long-term oxygen use is US$19,000 per life year saved.³ If the quality-of-life scores of patients on long-term oxygen were 0.8 or 0.6, the cost per QALY would be US$22,750 or US$31,700, respectively. (K. J. Smith and Pesce 1994, cited in the Harvard Catalogue of Preference Scores, assign a median score of 0.4 to quality of life for patients with severe COPD with high supportive care needs and poor functional status.)

In hospitals, mechanical ventilation in the intensive care unit has been estimated to cost US$35,000 to US$60,700 per QALY in 2001 (Anon and others 1999, cited in Ruchlin and Dasbach 2001). Studies suggest that noninvasive positive pressure ventilation, where it is feasible, is less costly than invasive mechanical ventilation for specific indications. Finally, costs of lung transplants are at a level scarcely affordable even in developed countries; Al and others (1998, cited in Ruchlin and Dasbach 2001) estimated costs at US$464,000 per QALY, and Ramsey and others (1995, cited in Ruchlin and Dasbach 2001) estimated costs at US$238,000 per QALY (in 2000 U.S. dollars).

All those interventions compare unfavorably with the cost-effectiveness of smoking prevention for preventing COPD (discussed in chapter 46). Smoking prevention is one of the most cost-effective health interventions that exists, and there is a strong case for moving resources from expensive curative interventions to that intervention. Likewise, prevention of COPD by switching the cooking source from unventilated stoves that burn biomass to either improved stoves or kerosene stoves is more cost-effective than treatment (see chapter 42).

Cost-Effectiveness of Interventions for COPD and Asthma in Developing Countries

It is difficult to transfer the costs per QALY saved in developed countries to developing countries. The cost of patented drugs in developing countries should be the same as that in developed countries, whereas the costs of education and of the time of medical personnel should be substantially lower (on the order of 20 percent of U.S. levels). In practice, the costs of off-patent drugs also vary considerably. Beclomethasone dipropionate (one of the older, off-patent inhaled steroids) is available for about US$15 per 200-dose inhaler in Canada in online pharmacies but is quoted at US$1 to US$3 by agencies and suppliers on the International Drug Price Indicator Guide (http://erc.msh.org). A similar price difference exists for salbutamol inhalers. Hence, the most cost-effective therapies in developed countries (inhaled salbutamol and first-generation corticosteroids for asthma and ipratropium bromide for COPD) are also likely to be cost-effective in the wealthier developing countries—or more broadly if inexpensive drug supplies are available. Those drugs are likely to be particularly cost-effective for those with severe and moderately severe asthma or COPD but less cost-effective for those with mild disease. Recent practice suggests that a combination of long-acting beta agonists and inhaled corticosteroids can control moderate to severe disease more rapidly. However, to make this form of therapy cost-effective, the patient needs to be reevaluated to determine whether one or the other drug can be removed. Because of cost considerations, that may not be feasible in the developing world.

Once control has been obtained, education alone appears to be ineffective when only respiratory outcomes are considered (although education on the benefits of exercise has other health benefits: see chapter 44 on lifestyles). However, education addressing the appropriate use of medication is extremely important, particularly in developing countries, where timely emergency care for severe exacerbations may not be readily available. Although the cost of educational efforts would be expected to be considerably lower in developing countries, this area requires more systematic research.

Long-term oxygen is also an option for high-income households in middle-income developing countries. The costs are likely to be lower than in developed countries. In Brazil the monthly cost for supplemental home oxygen therapy is close to US$150 (Sant'Anna and others 2003), compared with US$400 per month paid by Medicare, which would bring the cost-effectiveness to US$7,000 per life year by these authors' crude estimates, or between US$8,750 and US$11,700 per QALY. Publicly funded systems are unlikely to be able to pay this rate, although private insurers and wealthy households might pay because such therapy prolongs life.

The other interventions in table 35.2 are likely to be too expensive for most developing countries to use at present.