Novel biomarkers of inhaled corticosteroids adherence and response

Abstract

Backgrounds: Although steroid medications have proven effectiveness in controlling asthma and reducing the risk of exacerbation, poor adherence is common. Several methods have been investigated in assessing adherence; however, there is no validated gold standard. In this thesis, novel methods were tested to monitor adherence in serum and urine, and further candidate exhaled biomarkers were investigated. Aims: The main aim was to objectively determine whether the level of detection of inhaled or oral corticosteroids in serum or urine could be used as a potential marker of medication use. We also investigated the response of inhaled steroid by using exhaled nitric oxide (FeNO), volatile organic compounds (VOC), exhaled breath temperature (EBT) and particles in exhaled air (PExA). Methods: Firstly, we conducted a systematic review of the literature reporting biological methods; we included studies reporting direct measurement of exogenous corticosteroids in blood or the effect of adherence on exhaled nitric oxide. Next, we accessed data from the U-BIOPRED project and included severe asthma patients prescribed daily oral corticosteroids who completed the MARS adherence questionnaire and provided a urine sample for analysis of prednisolone and metabolites by liquid-chromatography mass spectrometry. Then, we assessed the feasibility of using liquid chromatography tandem mass spectrometry (LC-MS/MS) in detecting the most common ICS inhalers in serum blood over 8 hours post-dosing. Based on preliminary findings of these studies, we conducted a real-world study in severe asthma patients attending FeNO suppression clinic and compared their ICS levels in blood with adherence rate using an electronic monitoring device over one week. Lastly, the same FeNO suppression patients were tested for an early response of ICS (within 2 hours of ICS administration) and one-week response using exploratory exhaled markers. Results: We report poor adherence in around 40% of patients using oral steroids by using urinary prednisolone and MARS questionnaire. However, disagreement in adherence identification was identified between the methods in around 50% of cases. After 8hrs of post-inhalation, all patients using budesonide (n=10) and beclomethasone dipropionate (n=15), and all but one using fluticasone propionate (FP, 28) had detectable serum drug levels. While fluticasone furoate was detected in two patients (of four), ciclesonide in none (of seven). Blood ICS levels correlated negatively with exacerbation rate, and (for FP only) positively with FEV1 %predicted. There was a significant increase in ICS concentration after one week of FP inhaler use. The ICS serum concentration at the second visit correlated with the number of inhalations taken over the week, and the time since the last dose taken, but not to the level of FeNO suppression. As expected significant reduction in FeNO, was found following seven days of ICS treatment. This study also demonstrated for the first time, a rapid impact of ICS on EBT. For VOCs, we have shown that there was a clear variability in the pattern of some compounds following ICS use. In contrast, we do not observe any change any difference in all of the PExA parameters. Conclusion: Poor adherence is a common problem in severe asthma, whether measured directly or self-reported and associated with poor asthma outcomes. The adherence method we developed in this thesis is potentially suitable to be implemented in clinical asthma services. Furthermore, exhaled markers that are affected after ICS showed promising results and should be explored in other large clinical trials.

Date of Award	31 Dec 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Robert Niven (Supervisor), Stephen Fowler (Supervisor) & Brian Keevil (Supervisor)