ACE: A BIOMARKER-BASED APPROACH TO IMPROVING ASTHMA CONTROL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the past two decades, the prevalence of asthma has dramatically increased in many parts of the world. There is convincing evidence that children living in the inner cities of the United States, and living under economic disadvantages, constitute a unique and special at-risk population for asthma, which is characterized by increased morbidity and morality (Akinbami et al, 2002; Cloutier et al, 2002). Given this information and the unique needs of this inner-city population, the overall objectives of the National Institutes of Allergy and Infectious Diseases Inner City Asthma Consortium (ICAC) are (1) to identify forms of immune-based therapy that are most likely to promote control and prevention of asthma, (2) to design protocols that will evaluate immune-based therapies in the treatment of asthma in low-income inner-city adolescents, and (3) to determine both the mechanisms of immune-based therapies and the potential unique mechanisms associated with the pathogenesis of asthma in low-income inner-city adolescents by the conduct of parallel mechanistic investigations with the therapeutic protocols. The recent update to the National Asthma Education and Prevention Program (NAEPP) asthma guidelines identified inhaled corticosteroid (ICS) as the preferred long-term control therapy for all forms of persistent asthma (National Asthma Education and Prevention Program Report, 2002). However, there are still a significant proportion of patients with persistent asthma who are not receiving ICS therapy or do not adhere to the treatment plan (Bauman et al, 2002). The advantages of the treatment plan profiled in the NAEPP guidelines are that it is directed to preventative therapy, is standardized, simple, and provides an algorithmic approach to management. The reluctance to embrace the concepts of anti-inflammatory therapy may be related to under-recognition of asthma severity, apprehension related to the potential adverse effects of long-term ICS, and the difficulty in applying the guidelines due to all of the reasons mentioned previously. The guidelines will continue to change with further understanding of the pathogenesis of asthma, the introduction of new medications including immunomodulators, such as anti-IgE, and the potential application of biomarkers and pharmacogenetics in the clinical management of asthma. The application of additional measures that may be specific to subpopulations of patients would theoretically create the opportunity to individualized management, especially in patients who remain refractory to the conventional approach to asthma management. One of the additional measures proposed in this study is the use of biomarkers, specifically the measurement of exhaled nitric oxide (eNO) using the Aerocrine NIOX device. It is anticipated that the application of eNO measurements in addition to using the NAEPP guidelines will enhance the level of assessment of asthma and guide medication regimens and improve overall asthma control. It is well known that exhaled nitric oxide is increased during periods of uncontrolled asthma and is decreased during treatment with inhaled corticosteroids and leukotriene modifiers (Kharitonov and Barnes, 2001; Hunt and Gaston, 2000; Silkoff et al, 2000; Kharitonov et al, 1996). Bates and Silkoff, 2003, recently reviewed the evidence citing the applicability of exhaled NO in diagnosing asthma, monitoring the response to therapy, evaluating current symptom control, and predicting exacerbations of asthma. These studies support the role of eNO in the treatment of asthma in the clinical arena, as an added approach to improve asthma control. Exhaled nitric oxide is easy to measure and can obtained in less than 15 minutes and can be performed during the same patient visit. Futhermore, the Aerocrine NIOX device was given Food and Drug Administration (FDA) approval as a medical device and this has generated increased interest in its appropriate application. It is difficult to obtain sputum eosinophils and airway hyperresponsiveness, especially in adolescents. Therefore, we propose to use exhaled nitric oxide as an additional guide to the management strategy of asthma. It could serve as a monitor of poor asthma control that could be due to poor symptom recognition, poor medication adherence, and persistent inflammation. The ICAC therefore will conduct a randomized, prospective, double blind, parallel group trial involving inner city adolescents, ages 12-20 years of age, with persistent asthma requiring or eligible for inhaled coritcosteroid therapy. The planned sample size is 500 participants randomized into one of two treatment groups: 1) NAEPP Guidelines alone (the Reference Strategy group) or 2) the NAEPP guidelines plus eNO measurements (the Biomarker Strategy group). Participants will be screened and enrolled over a 6 month period and treated for 12 months. The protocol can be viewed as consisting of two phases: run-in characterization period of 3 weeks treatment with an initial controller regimen (based on presenting asthma severity, long-term asthma history, and pulmonary function tests) and a double-blind treatment strategy period of 46 weeks. The purpose of the run-in period is to observe the participant, to standardize the baseline treatment, to assess adherence, and to train the participant in the study procedures. The study results may change the paradigm of management for persistent asthma, with the addition of a biomarker-based approach to management, that could be particularly beneficial for inner city asthma adolescents where there appear to be unique characteristics, such as allergen exposure and poor adherence to therapy that could result in persistent inflammation.