THE IDENTIFICATION OF BIOMARKERS TO PREDICT RESPONSE TO TREATMENTS IN ASTHMA

Background: Asthma is a complex heterogeneous disease of the airways characterized by non-specific symptoms such as cough, wheeze and shortness of breath. Despite this known heterogeneity asthma patients are generally treated the same way. As such, patients are at risk of taking medications they either do not require or will not benefit from. The identification of biomarkers capable of aiding in disease phenotyping is essential to ensure patients receive treatments that will be of the most benefit to them. Aim: To personalize asthma treatments by identifying clinical and physiological characteristics that can reliably identify the patients who will and will not benefit from traditional corticosteroid and novel biologic treatments. Method: Three clinical studies were conducted to describe and characterize individual responses. Two studies evaluated responses to corticosteroids, while the third study investigated responses to treatment with mepolizumab, an anti-IL-5 monoclonal antibody. Clinical features as well as systemic cytokine levels were documented for each study. Results: The first study determined that a low level of fractional exhaled nitric oxide (≤27 ppb) excluded a clinical benefit from initiating treatment with an inhaled corticosteroid in steroid-naïve patients with suspected asthma in the short-term. The second study identified that patients with poorly controlled asthma have varying responses to increased doses of corticosteroid. This study failed to identify specific markers that were predictive of response with the exception that those on a low level of maintenance inhaled corticosteroid were most likely to benefit from an increased dose. The third study found that 61.5 % of patients responded to treatment with mepolizumab. The responders were significantly older at diagnosis, experienced fewer exacerbations in the previous year, were on a slightly higher daily maintenance dose of systemic corticosteroids and reported better controlled asthma than the non-responders. Conclusions: The work performed in this thesis demonstrated a high level of heterogeneity in response to asthma treatments which supports the need to personalize treatments in asthma by identifying biomarkers predictive of response so that the right treatments can be given to the right patients maximizing benefit and minimizing unnecessary treatment effects

A low exhaled nitric oxide level excludes a short-term benefit from inhaled corticosteroids in suspected asthma: A randomized placebo-controlled trial

Background and objective: Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker that reflects IL-4/IL-13 production and therefore represents T2 allergic inflammation. FeNO has previously been used to guide inhaled corticosteroid (ICS) treatment in asthma. The purpose of this study was to determine if a low FeNO (≤27 ppb) could be used to reliably identify patients with symptoms suggestive of asthma who would not benefit from initiating treatment with an ICS. Methods: A total of 180 steroid-naïve adults with healthcare professional suspected asthma and an FeNO of ≤27 ppb were randomized to receive either 400 mcg of budesonide or placebo daily for 3 months. The primary outcome was the difference in the Asthma Control Questionnaire 7 (ACQ7) between treatment groups and the study was powered to determine equivalence. Secondary outcomes were the difference in FEV , Medical Research Council and Leicester Cough Questionnaire scores. Results: One hundred and thirty-four patients (68 budesonide and 66 placebo) completed the study and were included in the analysis. The between-group mean difference in ACQ7 from baseline to the end of the study was −0.25 and the 95% CI around this difference was −0.004 to 0.495 confirming equivalence (p < 0.05). Differences in forced expiratory volume over 1 s and other secondary outcomes were also small and clinically unimportant. Conclusion: The results of this study suggest that steroid-naïve patients with symptoms suggestive of asthma and an FeNO ≤ 27 ppb are unlikely to benefit from initiating treatment with an ICS over 3 months. However, further research is recommended to confirm these findings before withholding ICS treatment.

THE IDENTIFICATION OF BIOMARKERS TO PREDICT RESPONSE TO TREATMENTS IN ASTHMA

Background: Asthma is a complex heterogeneous disease of the airways characterized by non-specific symptoms such as cough, wheeze and shortness of breath. Despite this known heterogeneity asthma patients are generally treated the same way. As such, patients are at risk of taking medications they either do not require or will not benefit from. The identification of biomarkers capable of aiding in disease phenotyping is essential to ensure patients receive treatments that will be of the most benefit to them. Aim: To personalize asthma treatments by identifying clinical and physiological characteristics that can reliably identify the patients who will and will not benefit from traditional corticosteroid and novel biologic treatments. Method: Three clinical studies were conducted to describe and characterize individual responses. Two studies evaluated responses to corticosteroids, while the third study investigated responses to treatment with mepolizumab, an anti-IL-5 monoclonal antibody. Clinical features as well as systemic cytokine levels were documented for each study. Results: The first study determined that a low level of fractional exhaled nitric oxide (≤27 ppb) excluded a clinical benefit from initiating treatment with an inhaled corticosteroid in steroid-naïve patients with suspected asthma in the short-term. The second study identified that patients with poorly controlled asthma have varying responses to increased doses of corticosteroid. This study failed to identify specific markers that were predictive of response with the exception that those on a low level of maintenance inhaled corticosteroid were most likely to benefit from an increased dose. The third study found that 61.5 % of patients responded to treatment with mepolizumab. The responders were significantly older at diagnosis, experienced fewer exacerbations in the previous year, were on a slightly higher daily maintenance dose of systemic corticosteroids and reported better controlled asthma than the non-responders. Conclusions: The work performed in this thesis demonstrated a high level of heterogeneity in response to asthma treatments which supports the need to personalize treatments in asthma by identifying biomarkers predictive of response so that the right treatments can be given to the right patients maximizing benefit and minimizing unnecessary treatment effects