Wisia Wedzicha and Mike Pearson

The Big Asthma Lie

Alternative Ways to Treat Asthma

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Why is there a need for a variety of outcome measures in COPD?

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive decline in lung function that leads to dyspnoea on exertion and eventually to death. However, there is considerable variability in the rate of decline of forced expiratory volume in 1 second (FEVX) in different patients. A number of guidelines have been produced for the management of COPD, including those from the European Thoracic Society [1], American Thoracic Society [2], British Thoracic Society [3] and the Word Health Organization's Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [4]. All of these guidelines agree on the point that the most accurate way to diagnose the condition is with measurement of FEVj by spirometry and that the FEVj also gives an indication of the severity of the disease. However, FEVj is only part of the explanation for the symptoms. In addition to the effect on lung function, there are important effects on physical disability and psychological function that impact on the quality of life experienced by the patient. Examples include the systemic effect in more severe COPD, leading to muscle wasting, that may progress and have direct effects on exercise capacity.

The levels of disability for a particular level of FEV1 can therefore vary markedly; one patient with an FEVj of 40% predicted may be less breathless than a patient with an FEVj of 60% predicted. Studies of health status in patients with COPD have shown that there is variability in the relation between health status and FEVj [5,6] (Fig. 17.1). Two patients with the same degree of impairment of FEV1 may therefore have a different level of health status or quality of life. Clinical studies have also shown that some therapeutic agents, such as long-acting bronchodilators, may have a relatively small effect on FEVj but a greater effect on health status [7]. Evaluation of new therapeutic agents thus requires a wider range of outcome measures, including measures of health status, exercise capacity and daily activities.

Symptoms, health status, exercise capacity and the exacerbation rate have all been proposed as additional outcome measures to the FEV1, but because

FEV, (% pred)

Fig. 17.1 The St George's Respiratory Questionnaire (SGRQ) is related to the level of forced expiratory volume in 1s (FEVi), but the relationship is such that almost any level of SGRQ can be associated with almost any level of FEVi. From [6].

they may change differently with various interventions—e.g. exercise capacity changes by a much greater extent after a course of pulmonary rehabilitation [8] than after home ventilatory support [9]—the outcome must be specifically chosen in relation to the particular intervention being tested. But if a clinician is to interpret these different measures, it is essential to understand how the measurements relate to stable populations, how they behave in different types of COPD and how they vary over time. There is a further problem in that definitions for each of these vary between studies: 'acute exacerbation' has been defined in many ways, ranging from relatively mild exacerbations that may require a visit to the general practitioner to a severe attack that requires hospitalization.

Perhaps the most difficult aspect is that of time. Doctors treating asthma problems are used to observing dramatic changes in function within hours or days and are able to use these to make decisions about treatment that are understandable to the patient and more important are often confirmed to be correct in the longer term. By comparison, COPD is a chronic, slowly evolving disorder in which there are few short-term changes and even fewer that can be easily or reliably measured. This makes assessment and treatment planning difficult and has often been used as an excuse for negativism. However, the work that has been performed on outcomes in COPD in recent years would suggest that it is possible to record outcomes in COPD and that many changes are perceived favourably by patients and their relatives. This chapter addresses some of the outcomes in more detail.

What outcome measures are useful in COPD?

Symptoms

Symptoms are what the patient experiences and thus arguably are the most important effect of COPD. The commonest are dyspnoea on exertion, and cough (with or without sputum). Wheeze is often noted by the physician, but less commonly complained of by the patient. Symptoms are by definition subjective and therefore prone to interpretation. Many factors affect reporting, such as the ability to estimate distance; thus 'I can walk 100 m without stopping' is dependent on how far the individual thinks 100 m, is and few people are able to estimate distance reliably. Relating a symptom to a specific activity such as climbing stairs can help standardize the work requirement, but still leaves a subjective interpretation that relates to the person's ability to perceive 'load' and to their depression status. Depressed patients will report more symptoms than non-depressed ones, and sensitive 'wimps' may report more than more tolerant 'stoics', who are inclined to keep going and 'make the best of it'.

Thus, no one has yet derived a successful symptom score with which to evaluate all COPD patients. Some have attempted to produce scores. A Dutch group [10] used a modified Delphi process to ask a series of experts to derive a 10-question score of the most important symptoms. This remains under evaluation, but it is doubtful whether busy clinicians will find time to ask 10 questions at each clinic visit, and moreover the utility and reliability of the score have not yet been established. Most practical clinicians rely on recording a few basic symptoms from the patient, based on activities that the patient actually does. The same specific activities can then be asked about on subsequent visits —i.e. using the patient as his or her own control and assessing the change in a particular lifestyle.

Breathlessness

Validated research measures that have been used include the Borg score and visual analogue scores that require patients to estimate how breathless they are in relation to a prompt. These scores are of limited value in estimating individual experience at any point in time, because of the substantial interindividual variability mentioned above, and they do not have much utility in the clinical context. However, they do have value when applied to measuring short-term changes in breathlessness in the individual, or in assessing the overall effect in groups of patients. Such measures have been used to document improvement in breathlessness in response to a number of interventions in

COPD such as physical training, bronchodilators and ambulatory oxygen therapy [8,11,12].

While the limitations of interpreting breathlessness data for the individual are legion, the picture when studying groups is much more encouraging. The Medical Research Council (MRC) dyspnoea score [13] set out a scale for grading disability in populations in the 1960s that has stood the test of time. This scale runs from 1 (breathless only with strenuous exercise) to 5 (too breathless to leave the house). Studies have shown that with increasing MRC grade, there are reductions in exercise capacity, daily activities and health status, and thus this scale can be used to select patients for pulmonary rehabilitation [14]. There was much enthusiasm at the Royal College of Physicians Edinburgh Consensus COPD conference [15], suggesting that all doctors should record a simple measure like this as a marker case-mix variable to help evaluate responses to interventions such as rehabilitation. It has not been used in many studies, and there is concern that it may not be capable of responding to change. Few if any patients will respond to an intervention sufficient to move a whole point on the scale, and thus it is unlikely to be useful to evaluate the effects of interventions.

Cough and sputum

The next most important symptoms in COPD are cough and sputum production; these symptoms may occur in the early stages of COPD. Fletcher and Peto [16] suggested that cough and sputum did not relate to mortality or progression of COPD and that they therefore reflected a separate process in the lung. More recently, Vestbo et al. [17] have suggested that those with cough and sputum do have a worse outcome, but the predictive value in individuals is weak.

As with dyspnoea, there are many factors that affect the reporting and recording of cough and sputum. The recent GOLD guidelines have suggested an early stage (stage 0) of COPD, in which cough and sputum are present (bronchitis), but without any change in airflow obstruction [4]. Some may debate whether or not this stage is really a stage of COPD, since the 'O' in the acronym is not satisfied. If patients do not notice that a productive cough is abnormal, because they expect it as a 'smoker's cough' — a normal response to smoking—then they may not report it. And how should the symptoms be recorded with regard to the severity of COPD? Consider the smoker who has a regular cough during mild and moderate phases of COPD and who then develops severe disease and sufficient symptoms that he is persuaded to quit smoking. The productive cough will often abate or disappear with the smoking cessation, but the severity of the COPD remains high. It is therefore pos sible to record more symptoms in mild disease than in severe—making it hard to interpret either individual or group data.

Other symptoms

The same problems apply to wheeze, which is a common but variable symptom in COPD. Weight loss, which is an important symptom in severe COPD and predictive of early mortality, is only of value in the most severe cases [18].

Thus, the symptoms have so far proved to be of limited value in outcome assessments, because we have not yet developed ways in which to evaluate symptoms that are consistent enough across individuals to be incorporated easily into clinical assessments or into clinical trials. This is a factor in the move toward quality-of-life measures, or more accurately health-status tools, described below.

Physiological measurement

The accelerated decline in FEVj over many years is characteristic of COPD, and the measurement of FEVj is key to both diagnosis and the staging of severity [16]. It is effort-independent and thus a reproducible measure of airflow limitation, and many studies have shown that FEV1 (particularly the post-bronchodilator FEVj) is closely linked to the prognosis in COPD [19]. Theory would suggest that interventions should aim either to improve FEVj or at least to reduce the loss of function over time.

Improving FEV1

In groups of patients, it is possible to show improvements in FEV1 with a number of interventions, such as bronchodilators [20] and some antiinflammatory therapies [21]. The changes are often relatively small and difficult to distinguish from the natural variability of the FEVj measurement. When applied to individuals, there has been considerable debate about the use of FEVj short-term reversibility to bronchodilators. The day-to-day variation in reversibility test results and the difficulty of separating a real variation from chance mean that unless changes are large (i.e. of a level that indicates that the diagnosis is more likely to be asthma), there is little value in clinical practice. Short-term responses are not predictive of later responses to therapy [22].

It is also possible to have improvement in functioning without a change in the FEVj, for example in the response to physical interventions such as exercise training or oxygen therapy [8,12].

Measuring a reduced rate of decline of FEV1

Any intervention that purports to alter the eventual natural history of the disease must be associated with a change in the rate of loss of FEVj. Smoking cessation unequivocally produces a reduction in FEV1 decline [20,23]. But the problems of measurement are even more difficult than for short-term responses. The average rate of decline of FEV1 in healthy subjects is between 20 and 30mL/year, and the average rate of decline in smokers is approximately double this. The average covers a wide range, with a few individuals (almost all of them smokers) losing FEVj at a rate of more than 100mL/year. Distinguishing a difference between an average of 50 mL/year and 25 mL/year while using a measurement that has a natural variability between repeated measures of 170 mL [24] is clearly difficult. The slow change of FEV1 means that it is not possible to make realistic estimates of rate of decline in an individual unless there are repeated measures over 3-5years. In groups, it is possible to show change over shorter periods [20], and it will remain an important outcome goal of large-scale therapeutic and epidemiological studies.

However, day-to-day clinical practice demands outcomes that can be measured on a much shorter time scale, and FEV1 is of almost no value in measuring the effectiveness of daily clinical practice. It is probably worth recording in order to be able to record the mean rate of decline over time to inform the prognosis, but there are no published data to support such an assertion.

Measurements of peak expiratory flow rate (PEFR) have been used much less in COPD, as isolated measurements cannot distinguish COPD from other types of lung disease, whether obstructive or restrictive. PEFR is much less reproducible than FEV, but it too can be of value in large-scale group data. Recently, the Copenhagen City Lung Study suggested that PEFR may be valuable as a predictor of overall mortality in COPD [25]. One study of the long-acting anticholinergic bronchodilator tiotropium has also shown significant effects of tiotropium on peak flow, compared to placebo [26].

Exercise capacity

Measurement of exercise capacity provides an indication of the patient's functional limitation. Although generally there is a relation between FEV1 and exercise capacity, this is variable in the individual patient, and exercise capacity cannot be predicted from the level of the FEV1 [27]. The complex exercise tests—requiring specialized equipment, with measurement of ventilation and maximum oxygen consumption and with considerable physiological expertise being needed for interpretation — are usually kept as research tools. They have been replaced by much simpler walking tests, such as the 6-min walking test, which are probably as informative. Asking patients to walk at their own pace for 6 min is much more typical of daily living and does not require any complex equipment. Such tests, despite their simplicity, have been shown to be reproducible, as long as correct procedures are followed and practice walks are performed [28]. A variant is the shuttle walk test [29], which is an externally paced maximum walking test, requiring the patient to walk between two cones placed 10 m apart. Walking tests have been shown to be very useful for assessing the outcome after pulmonary rehabilitation, and physical training is one of the few interventions that has been shown to increase exercise capacity to date [30].

However, as with symptoms and FEV1, these are changes that can be detected in groups of patients, and the value of the measures in assessing the progress of an individual patient is less well documented.

Quality of life/health-status questionnaires

Health status is a concept that has grown in importance over the last 15years. It attempts to measure the overall effect of a disease on the individual and to make allowance for factors such as depression by estimating function in a series of domains, of which physical functioning is but one. There are generic health-status questionnaires, such as the SF36 or the Sickness Impact Profile (SIP), that can be applied in any condition, but which were found to be generally insensitive to change in patients with COPD. Two important disease specific questionnaires were introduced: the Chronic Respiratory Questionnaire (CRQ) [31] and the St George's Respiratory Questionnaire (SGRQ) [32]. Both of these questionnaires have been shown to be sensitive to interventions in COPD. The CRQ is based on the symptom of dyspnoea, while the SGRQ consists of three components — symptoms, activities and impacts — that are summed to provide a total score for health status.

These are now among the most important outcome measures in COPD and have been shown to be improved by a variety of measures, including pulmonary rehabilitation and pharmacological therapies such as bronchodila-tors and inhaled steroids. Health status has been shown to deteriorate with progressive COPD and is closely linked to exacerbation rates [33,34]. Their importance has been recognized by regulatory authorities, such as the Commission on the Safety of Medicines in the UK, for demonstrating efficacy—i.e. improved quality of life is a valid outcome. This might sound obvious, but until these instruments were devised, there was no way of demonstrating such effects.

Although the SGRQ provides a score for activities, there are other questionnaires that have been developed to assess daily activities. The Nottingham Extended Activities of Daily Living (NEADL) has been used in COPD [35], al though it is of more use in describing disability in a population and is not sensitive to change after an intervention such as rehabilitation. One reason for the lack of sensitivity is that daily activities are only affected significantly in more severe COPD, e.g. MRC dyspnoea scores 4 and 5 [14]. The London Chest Activity of Daily Living Questionnaire (LCADL) has been developed for use in this population with more severe disability, although experience with its use in interventions is limited to date [36].

A novel feature of these health-status scores is that they have made it possible to determine the magnitude of change that is likely to be noticeable by the individual patient. A change of four points on the SGRQ scale is likely to be observable by the individual patient [7], and changes that exceed this threshold in a group study can thus be inferred to be noticeable by more than half the group. This considerably helps those who have to interpret the various studies and is a major improvement on the long history of clinical studies demonstrating highly statistically significant, but very clinically insignificant, changes in function. With justification, clinicians have questioned the relevance of small changes that an individual would be unable to perceive and have asked whether the cost of the intervention could be justified. However, there is a significant caution that must be borne in mind before accepting these new measures as definitive—the fact that they are significantly influenced by non-COPD factors such as mood and depression [37].

The weakness of health-status questionnaires is their relative length and thus their impracticability for routine clinical use. However, as they provide information on the likely health needs of the patient group and on their likely future health costs, it seems probable that use will increase. The process of developing newer and simpler versions is likely to accelerate this process.

Exacerbations (see also Chapter 15)

Recently, exacerbations of COPD have been shown to be a major outcome measure in COPD. The frequency of exacerbations is directly related to health status, and has important health-economic implications [38]. It is also cited by patients as one of the features that concerns them most. There is also some recent evidence that exacerbations may have an effect on disease progression in COPD, and thus it is essential to define and detect exacerbations accurately [39,40]. Exacerbations are unusual in mild to moderate COPD and are too infrequent to be of value as an outcome indicator. In the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study [41], the population were divided up into tertiles and it was only in the tertile with the lowest FEV1 (< 1.25L) that there was a significant alteration in the exacerbation rate in response to drugs. This was in part because only in this group were exacerbations sufficiently frequent that there were enough numbers to achieve comparisons.

An exacerbation refers to a worsening of symptoms, especially of the major symptoms of dyspnoea, increased sputum volume and sputum purulence. Exacerbations are associated with physiological change and increased inflammatory markers in the sputum, although these measures are too variable to be of use in diagnosis [42]. The exacerbation frequency refers to the number of exacerbations per year, and in group studies, a number of pharmacological interventions have been shown to reduce exacerbation frequency [33]. However, to estimate exacerbation frequency, a whole year of data must be collected. Other exacerbation measures that can be used over shorter periods have therefore been devised, such as time to the first exacerbation [43]. But this is of limited value, as it is dependent on season and withdrawal of medication before the study.

Exacerbations are not easy to measure. Not only does the definition above include a subjective interpretation of 'worsening', but also a significant number of exacerbations are not reported to health-care professionals. Collecting complete data from patients in the community who have elected not to attend hospital is a challenge.

Other possible outcomes in COPD

A number of other outcomes have been proposed, although experience with them and with the effects of interventions is still limited.

• Changes in sputum inflammatory markers, e.g. the levels of leukotriene B4 (LTB4) can occur in response to treatment and resolution of an exacerbation [44], although the use of such markers in clinical practice to follow exacerbations has not been evaluated. Further work is required on the longer-term changes in sputum inflammatory markers and relationships to disease progression.

• There is relatively little information on the use of bronchial biopsies in COPD. A relationship has been shown between the number of CD8 lymphocytes in the biopsies and FEVX, but to date only patients with relatively mild COPD have been studied [45]. There is also little information on the relationship between sputum examination and changes in bronchial biopsies. Thus, the use of bronchial biopsies is currently limited to research studies in COPD.

• Other outcomes such as computed tomography (CT) scanning may have a role in the future, both to diagnose COPD and follow changes after interventions, although experience is limited to date.

So what is success?

Much of the discussion above has focused on the limitations of the various outcome measures, and this remains a major challenge for those who wish to treat COPD more aggressively and with more success. Much depends on what can realistically be expected.

Long-term epidemiology

The FEVi remains the best marker of the rate of long-term decline of FEVi, and any therapy for which a disease-modifying role can be claimed will need to show that it can slow the rate of decline. So far, only smoking cessation is known to alter the long-term outcome measured in this way. Therapies that can reduce exacerbation frequency also may affect disease progression.

Shorter-term clinical outcomes

Once COPD has become established, the damage cannot at present be repaired; improvements in lung function with therapy are small and are rarely of value in individuals.

In patients with more severe COPD, the reduction in the exacerbation frequency is probably the most sensitive measure of response and moreover is one that has clear economic benefits and that is instantly appreciated by patients.

The disease-specific health-status measures apply to both severe and moderate stages of disease and have been shown to be responsive to a range of supportive treatments, including long-acting bronchodilators and rehabilitation programs. Again, these can be quantified, and the proportion of patients experiencing noticeable changes can be calculated. Unfortunately, measurement often takes too long for busy clinicians to use any of these in routine practice.

Routine practice is still dependent on the subjective recording of symptoms and the very subjective 'Do you feel better?' approach — and a challenge for researchers is to improve on this weak armamentarium.

Success for the patient or success by the doctor?

In the modern world, physicians are expected not only to provide treatment, but also to demonstrate that their treatments work. In a condition in which little can be expected to change over a period of years in the individual, the patient outcomes discussed above are of little value when trying to determine whether a doctor is providing good or bad care. This is a problem common to many, if not all, chronic diseases and has led to attempts to examine the process of care rather than just the outcome. If the process measures are chosen to have some potential to predict outcome, then there is purpose to the exercise, and this has been shown to have merit in cardiology [46].

A recent audit of care provided in 46 UK hospitals collected data on 1400 acute admissions with an acute exacerbation and examined a series of standards derived from current COPD management guidelines, a number of severity indicators (to control for case mix) and the 3-month mortality. Care standards varied very widely between hospitals and so too did the 3-month mortality. For most factors measured, the care ranged from acceptable to appalling — few units scored consistently well. It is difficult to justify the management provided for many aspects of care. As an example, spirometry is recommended as essential for making the diagnosis by all national and international guidelines, and the audit accepted any measurement made either in the 5 years prior to or the 3 months after the index admission. Even with this latitude, only half the patients (51%) had their diagnosis confirmed [47]. There were three strong statistically significant predictors of death within 3 months —the performance score (as used in cancer studies), severe acidosis on admission and the presence of bilateral ankle oedema. Even after controlling for these three predictors, there was a more than twofold difference in deaths between large and small hospitals, which raises worrying questions about the service being offered [48].

The marked differences in the process of care between hospitals shown in the above study are mirrored in other national audits of other conditions as disparate as stroke [49], incontinence [50], and blood transfusions [51]. Professionals are often unwilling to admit that the care they provide is anything less than excellent — until faced with figures that tell a different story. Defining target outcomes for COPD is clearly an important step forward, but those targets are unlikely to be attained if the processes of care within our hospital units are so variable and so far below the optimal levels set out in management guidelines.

COPD has been a Cinderella condition for many years—that is, one in which the professions acknowledge the patients' existence, but take little interest in their problems and provide even less in the way of health-care resources. Part of this has been due to the feeling that in part COPD is the patient's fault — a self-inflicted disability due to their cigarette-smoking habit. But society does not impose similar criticism on those who develop heart disease following over-indulgence in fatty foods. And even if it were possible for cigarettes to be banned now, those with airflow limitation will still be with us for many years and will still require treatment.

The last decade has witnessed a marked change. Firstly, it has been recognized that even if the damage done cannot be reversed, the quality of life for COPD patients can be significantly improved and in some cases their life expectancy can be improved too. Secondly, the research world has woken up to the possibilities, and the burgeoning number of sessions allocated to COPD at international meetings is evidence of the amount of new effort being devoted to the disease. And thirdly, the pharmaceutical industry has developed a range of products that are now of proven benefit—with more on the way.

We hope that those who read this book will be left with an enthusiasm that COPD is not a 'no-hope' disorder. Much can and should be done that will benefit not only the patients directly, but also their families and thus society. But if we are to succeed, we need not only to recognize what can be done, but also to put into place systems that ensure it really is done.

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