Serum Prednisolone Levels as a Marker of Oral Corticosteroid Adherence in Severe Asthma

J. Michael Ramsahai; Emily King; Robert Niven; Gael Tavernier; Peter A. B. Wark; Jodie L. Simpson

Disclosures

BMC Pulm Med. 2020;20(228) 

In This Article

Methods

Participants were recruited as part of the Markers of Inflammation in the Management of Severe Asthma (MIMOSA) study. (ACTRN 12616001015437) Participants were adults with severe asthma, on GINA Step 4 or 5 therapy, who continued to have uncontrolled asthma. This was defined as those patients with Asthma Control Questionnaire score (ACQ-6) > 1.5,[2,7–9] or who required two or more courses of oral corticosteroids (OCS) for exacerbations in the past 12 months, or who required hospitalization in the past 12 months. All participants were either ex-smokers for at least 6 months, or had never smoked. In the MIMOSA study, a participant's oral prednisolone dose was adjusted monthly based on their blood eosinophil count, fraction of exhaled nitric oxide (FeNO), or ACQ-6 score, however, no specific interventions towards adherence were applied. Participants were included in this particular sub-study if they were on a regular daily dose of prednisolone at the time of enrolment. All participants who met this criteria were included.

On their first visit peripheral blood and induced sputum samples were obtained, and the dose and time of last administration of their prednisolone was recorded (Figure 1). At the end of the one-year follow-up period, these measurements were repeated. A descriptive analysis of participants who had measurements taken at both visits was performed with respect to the trends of their monthly measured values or ACQ-6 scores, blood eosinophil counts, and FeNO.

Figure 1.

Flow chart of assessments over the course of the study

Spirometry, FeNO, and Blood Eosinophil Measurements

FeNO measurements were performed using a NIOX VERO (Aerocrine, Sweden) device, as per manufacturer's suggestions and prior to spirometry. Spirometry was performed as per ATS criteria[10] using a MedGraphics CPFS/D USB-Ascensia spirometer and BreezeSuite software (Minneapolis, USA). Blood eosinophil counts were measured from samples obtained at each in-person visit through the MIMOSA study and processed at either Pathology North (NSW, Australia) laboratories, or the Hunter Medical Research Institute.

Sputum and Laboratory Processing

Sputum induction and processing were performed as previously described by Gibson et al.[11] Serum samples were shipped to the University Hospital of South Manchester for analysis of serum prednisolone and cortisol levels. Serum prednisolone levels were measured using high pressure liquid chromatography tandem mass spectroscopy, as previously described,[12] while cortisol measurement was performed as described by Gamble et al..[13]

A Participant was categorised as adherent if prednisolone was detectable in the serum sample. Those patients with a serum prednisolone level below the level of detection of the assay (low) were defined as non-adherent. Sputum cell count was performed as previously described.[11] Persistent eosinophilic asthma was defined as a sputum eosinophil proportion of equal to or greater than 3%.[14–17] The population of participants who were adherent with elevated sputum eosinophils, were defined as steroid resistant eosinophilic asthma.[18]

Serum cortisol levels were deemed suppressed if they were less than 50 nmol/L.[19] This level has also been found to account for the effects of a short course of high dose steroids, where median cortisol is suppressed to 112 nmol/L (in a chronic obstructive pulmonary disease (COPD) population treated for 14 days).[20]

Comparisons between groups were performed using medians, interquartile ranges and Wilcoxon tests, given the small observed sample sizes. Serum cortisol, prednisolone levels over time, and proportions were compared using means, 95% confidence intervals and Student t-tests and binomial distributions. Correlations were analyzed using Pearson's correlations.

Ethics approval was obtained from the Hunter New England Human Research Ethics (16/05/18/3.03) and University of Newcastle Human Research Ethics Committees (H-2016-0261). Written informed consent was obtained from all participants.

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