Randomised controlled trial for the titration of oral corticosteroids using markers of inflammation in severe asthma.

INTRODUCTION: Biomarkers are used to select biologic therapies for patients with severe asthma, but not to regularly adjust therapy, especially oral corticosteroids (OCS). OBJECTIVE: Our goal was to test the efficacy of an algorithm to guide the titration of OCS using blood eosinophil count and fraction of exhaled nitric oxide (FeNO) levels. DESIGN, PARTICIPANTS, INTERVENTIONS AND SETTING: This proof-of-concept prospective randomised controlled trial assigned adult participants with severe uncontrolled asthma (n=32) to biomarker-based management (BBM) where OCS dose was adjusted based on a composite biomarker score comprised of blood eosinophil count and FeNO, or a standard best practice (SBP) arm. The study was conducted at the Hunter Medical Research Institute, Newcastle, Australia. Participants were recruited from the local Severe Asthma Clinic and were blinded to their study allocation. MAIN OUTCOME: The coprimary outcomes were number of severe exacerbations and time to first severe exacerbation assessed over 12 months. RESULTS: There was a longer median time to first severe exacerbation with BBM, although not significant (295 vs 123 days, Adj. HR: 0.714; 95% CI: 0.25 to 2.06; p=0.533). The relative risk of a severe exacerbation in BBM (n=17) vs SBP (n=15) was 0.88 (Adj.; 95% CI: 0.47 to 1.62; p=0.675) with a mean exacerbation rate per year of 1.2 and 2.0, respectively. There was a significant reduction in the proportion of patients requiring an emergency department (ED) visit using BBM (OR 0.09, 95% CI: 0.01 to 0.91; p=0.041). There was no difference in the cumulative OCS dose used between the two groups. CONCLUSION: A treatment algorithm to adjust OCS using blood eosinophil count and FeNO is feasible in a clinical setting and resulted in a reduced odds of an ED visit. This warrants further study to optimise the use of OCS in the future. TRIAL REGISTRATION NUMBER: This trial was registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12616001015437).

Does prior mediastinal lymph node aspiration contribute to false-positive positron emission tomography-computed tomography?

BACKGROUND: Proper staging of the mediastinum is an essential component of lung cancer evaluation. Positron emission tomography-computed tomography (PETCT) and endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) are an integral part of this process. False-positive PETCT results can occur following surgical procedures but has not been demonstrated following EBUS-TBNA. We aimed to determine whether false-positive PETCT rates increase when EBUS-TBNA is performed prior to PETCT. STUDY DESIGN AND METHODS: A retrospective review was carried out of clinical cases that underwent both PETCT and EBUS-TBNA within 30 days for the suspected malignancy. The impact of test sequence on the PETCT false-positive rate (FPR) was determined using Generalised Estimating Equation logistic regression analysis. RESULTS: A total of 675 lymph node stations were sampled and imaged on PETCT. Overall, 332 (49.2%) nodes were sampled by EBUS-TBNA before PETCT, and 343 (50.8%) afterwards, with the interval between EBUS and subsequent PETCT being a mean±sd of 11.6±6.8 days (range 1-29). The FPR on qualitative PETCT for the EBUS first group was 41 (23.2%) out of 164, and for PETCT first it was 57 (29.0%) out of 193 for a difference of 5.8% (95% CI -3.4-14.7, p=0.22). In the regression model, EBUS as the first test was associated with a lower FPR when using the clinical PETCT interpretation. INTERPRETATION: The performance of EBUS-TBNA sampling did not influence the FPR of PETCT when bronchoscopy took place in the 30 days prior to testing. Test sequence should be selected based on other clinical considerations.

Serum prednisolone levels as a marker of oral corticosteroid adherence in severe asthma.

BACKGROUND: Severe asthma is a complex heterogeneous disease typically requiring advanced therapies. Underlying the treatment of all asthma, however, is the consistent recommendation across international guidelines to ensure that adherence to therapy is adequate. Currently, there is no consensus on an objective marker of adherence. METHODS: We performed a prospective observational study of 17 participants taking oral prednisolone using serum prednisolone levels as a marker of adherence, and sputum eosinophilia as a marker of control of type 2 airway inflammation. Based on these biomarkers, we classified participants into a non-adherent and an adherent cohort, and further stratified by the presence of ongoing sputum eosinophilia. RESULTS: We identified 3 non-adherent participants and 14 who were adherent, based on their serum prednisolone levels. Stratification using sputum eosinophil counts identified one participant as having ongoing sputum eosinophilia in the setting of non-adherence, while six were identified as steroid resistant with ongoing sputum eosinophilia despite adherence to oral prednisolone therapy. CONCLUSION: Serum prednisolone can be used an objective marker of adherence in those patients with severe asthma taking daily oral prednisolone. In combination with sputum eosinophil counts, a steroid resistant cohort can be distinguished from one with ongoing inflammation in the setting of non-adherence. This information can then be used by clinicians to differentiate the optimal next steps for treatment in these specific populations. TRIAL REGISTRATION: Participants were recruited as part of the Markers of Inflammation in the Management of Severe Asthma (MIMOSA) study, trial registration ACTRN12616001015437 , 02 August 2016.

A survey of specialist opinions on biomarker use in severe asthma in Australia: scepticism but hope?

Asthma specialists are interested in adopting biomarkers into clinical practice, but more work needs to be done to support resources towards their use and provide clearer direction on this. This concern is not limited to European specialists. https://bit.ly/2WWEQXb.

Mechanisms and Management of Asthma Exacerbations.

Acute asthma remains an important medical emergency, the most frequent cause of acute admissions in children and a major source of morbidity for adults with asthma. In all ages with asthma, the presence of exacerbations is an important defining characteristic of asthma severity. In this review, we assess the epidemiology of acute asthma, the triggers of acute exacerbations, and the mechanisms that underlie these exacerbations. We also assess current treatments that prevent exacerbations, with an emphasis on the role of type 2 airway inflammation in the context of acute exacerbations and the novel treatments that effectively target this. Finally we review current management strategies of the exacerbations themselves.

Appropriate use of oral corticosteroids for severe asthma.

Severe asthma represents a significant burden of disease, particularly in high income nations; oral corticosteroids (OCS) remain an important part of the management toolkit for these patients. Corticosteroids are effective at targeting numerous elements of the type 2/eosinophilic inflammatory pathway and lead to both rapid reduction in eosinophilic inflammation and longer term reduction in airway hyper-responsiveness. Resistance or insensitivity to corticosteroids is a feature of severe asthma, with persistent type 2 inflammation often occurring despite regular use of OCS. OCS remain the only accepted, effective treatment for acute asthma, and also continue to play an important role in the long term management of severe asthma, in spite of their significant side effect profile. Even with the availability of the new biological therapies against IgE and interleukin-5, it is likely that a large proportion of patients will continue to require OCS to control their asthma. Future work should focus on optimising the balance between OCS efficacy and safety, and continued development of agents that allow reduction, or ideally discontinuation of their use, is needed.