Measuring adherence to inhaled corticosteroids in asthma: getting closer!

Patients with difficult-to-treat severe asthma represent an asthma category in which poor response to treatment reflects the presence of factors other than asthma alone (1). An important factor to address in such cases includes poor adherence to medication. Nonadherence is a major reason for poor asthma control, asthma-related emergency visits and hospitalizations, persistent eosinophilic inflammation, and increased oral steroid use (2, 3). In consequence, guidelines and consensus statements on the diagnosis and assessment of patients with difficult-to-treat asthma unanimously stress the importance of identifying and addressing nonadherence in this population (1, 4). Adequate assessment of adherence allows practitioners to determine whether uncontrolled asthma symptoms are due to the intrinsic disease severity, the inadequacy of treatment, or a failure to follow prescribed recommendations. This is the more important given currently available and other imminent expensive biological therapies (5). It is not unexpected that adherence to inhaled corticosteroids is relatively poor (6), due to absence of perceived immediate relief. Measuring adherence to inhaled corticosteroids, however, is notoriously difficult. Serum levels cannot be measured, and canister weighing and patients’ and physicians’ reports are unreliable (7). Electronic monitoring giving the time and date of use is a good means of directly assessing medicine taking (8), but monitoring itself can change behavior. More recently, prescription data recorded in administrative health databases have been used to assess patients’ adherence to chronic medications. However, satisfactory prescription filling does not mean that the medication is actually taken (6). Thus, at present, there are no reliable tests for assessing this aspect of patient care. In this issue of the Journal, McNicholl and colleagues (pp. 1102– 1108) have developed a clinical test for objective assessment of adherence to inhaled corticosteroid therapy, using changes in exhaled nitric oxide during a trial of directly observed inhaled steroid treatment in patients attending a Difficult Asthma Clinic (9). The authors studied 213 new referrals and assessed adherence on the basis of prescription-filling records. Subsequently, the authors administered inhaled corticosteroid treatment for 7 days, observed directly by a research fellow at home visits or clinic attendance, and measured the fraction of exhaled nitric oxide (FENO) levels before and after the 7 days of treatment. FENO was chosen because it is rapidly responsive to inhaled corticosteroids (10). The authors calculated the change in FENO as a log ratio, and derived the optimum cut point for the ratio as a determinant of adherence/nonadherence. They then validated their findings by applying the optimum FENO cut point to a further 40 patients, out of 229 who were screened. These 40 had an elevated baseline FENO of more than 45 ppb at screening. In these patients, nonadherence was verified using a composite adherence measure including prescription records, adherence interview, blood testing, and inhaler technique. For practical purposes, a shortened 5-day directly observed test was chosen. The results of this study are novel and important. Previous reports have suggested that FENO measurements may be used to confirm nonadherence with inhaled corticosteroid therapy in children (11), but until now there have been no data to validate this claim in adults. The study by McNicholl and colleagues clearly demonstrates that the dynamic effect of inhaled corticosteroids on FENO may be used as an accurate discriminator of nonadherence to inhaled corticosteroids, and therefore addresses a very sizable gap in the evidence base. The strengths of the study include the way patients were recruited, the use of directly observed therapy with inhaled corticosteroids, and the study design combining a proof-of-concept study and a validation cohort. To limit the effect of study recruitment on adherence behavior, participants were informed that the study was examining the effect of inhaled steroids on inflammation without reference to adherence measurement. In the proof-of-concept study, patients received inhaled corticosteroids by directly observed therapy, which is considered the most accurate method to guarantee adherence (12). To validate the test, a “gold standard” composite adherence measure was used in a cohort of patients with difficult-to-treat asthma. Together, these strengths justify the introduction of this test in clinical practice. The question is how practical this test really is for use in dayto-day patient care. A FENO-guided assessment of adherence requires that patients with uncontrolled asthma who exhibit a FENO level of 45 ppb or more have directly observed therapy twice daily for at least 5 consecutive days. In the study setting, a research fellow was assigned to observe treatment administration at home visits or clinic attendance depending on patient preference. In real life, this is difficult to realize, even though it cannot be excluded that a shorter duration (3 d) of a FENO suppression test might be feasible (10). More importantly, the test will also raise questions by the patients. Explaining the reason for the test will obviously violate patients’ confidence in their health care professional, which is the least desirable outcome. There are, however, other situations in which the FENO suppression test as described by McNicholl and coworkers might be extremely useful in the management of adults with difficult-totreat asthma, for example, when invasive therapeutic interventions or expensive biologicals are being considered as a Global Initiative for Asthma step-5 add-on treatment (13). In this case, the test should not be applied to assess nonadherence as such, but rather to verify that there is no further room for improvement of asthma symptoms with high doses of correctly inhaled corticosteroids. Accurate indication for most of the novel biologicals requires the demonstration of an inhaled corticosteroid resistant inflammatory process (14), and this could be effectuated by the FENO suppression test. For the practicing physician, nonadherence should always be the prime suspect in causing loss of asthma control in every patient with difficult-to-treat asthma. With or without an accurate measurement of adherence, physicians should address the factors that might lead to nonadherence in their patients at every office visit. These factors may be multifactorial and complex, including fear of drug-related side effects, erroneous health beliefs, psychosocial elements, complexity of the regimen, insufficient knowledge about the disease, or just individual acceptance of suboptimal control. If these issues are being addressed in a concordance discussion in which patients share in making decisions about their treatment, there may be significant alteration in patient behavior with improved adherence and asthma outcome (15).