Clinical practice guidelines are by their nature general recommendations aimed for broad applicability in the clinical setting. Applicability, however, is limited by several factors. One of the challenges to the daily use of current asthma guidelines by physicians is that these guidelines tend to be disease-oriented, not patient-oriented. Guidelines are written not from the perspective of the patient who comes to the physician's office with symptoms, but rather from the perspective of the patient with a clear-cut asthma diagnosis. Symptom-based guidelines are needed [
2]. In addition, there are patients who do not fit within many current guideline definitions; for example, children with intermittent wheezing that does not appear to be the classical asthmatic phenotype [
18]. Moreover, guideline recommendations tend to be based on disease severity without accounting for concomitant conditions, such as allergic rhinitis, or the time course of disease – factors used by clinicians to individualize the diagnosis and the treatment plan.
In addition, clinical practice guidelines for asthma tend not to consider the heterogeneity of asthma or to accommodate individual patient variations in response to treatment or their needs, differences in practice settings, or local differences in availability and cost of therapies. Guideline recommendations are generally made on the basis of grouped mean data, and fail to recognize individual heterogeneity. For instance, a recent crossover trial comparing an inhaled corticosteroid with a leukotriene receptor antagonist for the treatment of persistent childhood asthma found that, while both treatments were effective, on average the effect was greater in those treated with inhaled corticosteroid. When individual patient responses on each treatment were compared, however, 29% of children had better asthma control (asthma control days/week) on the leukotriene receptor antagonist, indicating that for this subgroup the leukotriene receptor antagonist would be the ideal monotherapy [
19].
Asthma is most commonly managed in the community in general practice settings, and the organization of medical care will affect how asthma care can be delivered. Differential diagnoses vary according to location, with infectious disease being more common in less developed countries. Moreover, currently available guidelines are based on the assumption that the recommended drugs are available and affordable [
2], an assumption that is not true in many parts of the world. There is therefore a pressing need for local guidelines [
8]. To be useful to primary care physicians, these guidelines must be in the local language as well as physically available, whether by Internet or in print.
Limitations of the evidence-based approach
The results of well-designed randomized controlled trials (RCTs) and meta-analyses of RCTs are awarded the highest level of evidence in hierarchies of evidence-based data collection used to formulate clinical practice guidelines [
6,
8]. RCTs, however, are designed to maximize internal validity and to minimize confounding factors by studying a tightly defined population in a controlled setting, and therefore to establish the
efficacy of treatment; namely, the benefit of the treatment under ideal conditions. RCTs are not primarily concerned with the external validity or generalizability of the findings to whole populations, and differences between the homogeneity of the trial population and the heterogeneity of the general population labeled as having asthma may limit the generalizability of RCT findings [
20]. These trials generally enroll a carefully selected patient population meeting strict inclusion criteria and exclusion criteria, involve frequent clinical and laboratory monitoring, and measure objective parameters of efficacy. In 'real-world' clinical practice, however, patients are unselected, monitoring tends to be less frequent and less complete, and
effectiveness – the benefit that treatment produces in routine clinical practice [
21] – is the most relevant outcome.
Herland and coworkers [
22] found that only 5.4% of outpatients with asthma recruited at 12 centers in their study would have qualified for enrollment in a classical RCT. If patients with symptoms or patients who regularly used inhaled corticosteroids were also excluded, as they are in some RCTs, the percentage fell to 3.3% of asthma outpatients. The patients entering RCTs are therefore not representative of asthma patients in primary care [
22]. Moreover, the frequent clinical care and monitoring of patients in RCTs is not typical of 'real-world' clinical situations and thus the outcomes of the RCTs may not be attainable in 'real-world' clinical situations. Finally, measures of airway obstruction do not correlate with patient-reported measures, and it is therefore important to assess at least one endpoint from each of these categories in clinical trials [
20,
23,
24].
Information gained from pragmatic trials and observational studies can be a valuable adjunct to that gained by RCTs. Pragmatic trials, which may be blinded or open label, are designed to more closely replicate conditions in clinical practice, including variability in patient characteristics and the use of a management protocol rather than a predetermined assigned treatment [
21]. Observational studies are valuable to examine large groups of patients, to examine long-term outcomes, to examine rare but important outcomes such as mortality, and to examine outcomes that may not be easily assessed in RCTs, such as pharmacoeconomic data. Recent comparisons of results obtained by RCTs and by observational studies found that effects of treatment determined in observational studies were not systematically greater or qualitatively different from those of RCTs comparing the same treatments [
25,
26]. The reliance on RCTs as the highest level of evidence is therefore being challenged [
27]; even regulatory agencies are now beginning to review evidence from well-designed observational research when making labeling evaluations. On the contrary, the quality of design and reporting of many observational studies has been questioned [
28]. The same attention to design, the control of confounding factors, and complete reporting are clearly as necessary for observational studies as for RCTs.
Evidence-based guidelines are further limited by the time lag involved in the process, typically entailing 1–2 years, of reviewing the literature, arriving at a consensus, and actually writing and publishing the guidelines. This allows for potentially relevant studies to be published but not assessed. One mechanism for acknowledging more recent papers might be to provide electronic links to them from the guidelines, noting that the information they contain may be relevant but will not be commented on in the present guidelines.
Lack of accounting for comorbid conditions and confounding factors
Most guidelines see asthma in isolation rather than considering other factors that may impact on asthma and the response to asthma therapy, particularly allergic rhinitis, cigarette smoking, adherence to therapy, and genetic factors.
The association between the upper airways and the lower airways has been recognized for two millennia: as long ago as 200 AD, Galen recommended purging the nostrils of secretions in order to relieve the lungs. In the late nineteenth century, Charles Blackley linked hay fever and asthma [
29]. Current evidence for the many pathophysiological and epidemiological links between asthma and allergic rhinitis is discussed in other papers in the present supplement [
30,
31]. In recent clinical guidelines, however, with the exception of the ARIA guidelines [
32], these links between allergic rhinitis and asthma are not fully addressed.
The GINA guidelines note that 'special considerations are required in managing asthma in relation to ... rhinitis'; however, there is no further guidance – such as a recommendation to examine the nose or to ask the patient whether or how allergic rhinitis worsens their asthma [
10]. Moreover, the guidelines note that treatment of rhinitis may improve asthma symptoms, citing results of an observational study and a review [
33,
34]. They do not, however, cover the concept that asthma and allergic rhinitis are related conditions linked by one common airway. Therefore, while the GINA guidelines mention the association between asthma and allergic rhinitis, they fall short of describing practical recommendations for concomitant treatment. The British asthma guidelines and the Canadian asthma guidelines cited earlier are similarly lacking in providing advice on concomitant treatment.
The ARIA guidelines [
32] were the first to stress the connection between allergic rhinitis and asthma. Since their publication in 2001 new data have been published that support these recommendations, as summarized in another paper in the present supplement [
30]. The ARIA guidelines note that allergic rhinitis should be considered one of the risk factors for asthma [
32]. Moreover, these guidelines recommend evaluating patients with persistent allergic rhinitis for asthma and evaluating patients with asthma for rhinitis. A 'combined strategy' to treat the upper airways and the lower airways is recommended [
32].
The early evidence indicates that treating allergic rhinitis may help to control asthma symptoms. A recent post-hoc evaluation of the Clinical Observation of Montelukast as a Partner Agent for Complementary Therapy study showed the benefit of montelukast, a potent leukotriene receptor antagonist, for patients with coexisting asthma and rhinitis [
35]. Cysteinyl leukotrienes are key mediators of both allergy and allergic rhinitis [
32,
36,
37]; montelukast, which is approved to treat both asthma and allergic rhinitis in many parts of the world, has been shown to improve asthma and allergic rhinitis in patients with both these conditions [
38]. The study enrolled adult patients with asthma inadequately controlled by inhaled corticosteroids; adding montelukast to the therapy was compared with doubling the inhaled budesonide dose [
39]. In the group of patients receiving the doubled budesonide dose, patients with coexisting rhinitis did less well than those without rhinitis; whereas in the montelukast therapy group, patients with coexisting rhinitis performed as well as those without rhinitis [
35]. These results suggest that improvements in rhinitis produced by montelukast therapy may be associated with improvements in asthma.
Cigarette smoking is another factor that can adversely affect asthma control. The prevalence of active smoking among adults with asthma is similar to that among those without asthma, tending to be about 25% in developed countries [
40]. Cigarette smoking, both active and passive, can increase susceptibility to developing asthma in predisposed individuals [
10,
40,
41]. Moreover, for patients with asthma, active smoking is associated with more severe asthma symptoms and a more rapid decline in lung function than for nonsmokers. Of note, active smokers with asthma tend to be resistant to both oral and inhaled corticosteroid therapy [
40]. Smoking cessation is therefore an important component of asthma management. Recent evidence indicates that lung function improves and sputum neutrophil counts fall within several weeks among patients who quit smoking relative to those who do not quit [
42].
Adherence to therapy and compliance with physician recommendations are other important components of successful asthma management. Many factors contribute to level of adherence to controller therapy for asthma, including beliefs about the benefits of treatment, concerns about potential adverse effects of treatment, perceived asthma severity, and duration of asthma [
43,
44]. In addition, cultural factors may influence beliefs about medications [
45]. Reported factors influencing adherence among adolescents also include cognitive difficulties, lack of social support, lack of self-efficacy, denial or distrust, and peer and family issues [
46].
A complete understanding of the goals of asthma therapy could improve patient adherence to prescribed therapy. Both physicians and patients often overestimate asthma control relative to guideline definitions of control; moreover, patients tend to accept their asthma symptoms and may consider their asthma better controlled than their physicians do [
3,
4,
47]. A better awareness of guideline definitions should therefore be promoted: patients and their families need to understand the nature of asthma symptoms and, most importantly, the criteria defining asthma control.
Finally, as a better understanding is gained of the genetic factors controlling asthma phenotypes, this information should be included in asthma guidelines. Genetic factors are important in determining responders and nonresponders to specific treatments for asthma. For example, patients with aspirin-intolerant asthma show upregulation of leukotriene C
4 synthase and excess leukotriene production, with responsiveness to leukotriene receptor antagonist therapy [
48,
49]. A single nucleotide polymorphism (allelic variant C of leukotriene C
4 synthase) has been identified that shows moderate association with aspirin-intolerant asthma [
48]. Polymorphisms of the gene encoding the β
2-adrenergic receptor (
ADRB2) appear to play a role in bronchodilator responsiveness and constitute an area of active research [
50], the results of which should be reflected in future guidelines.