Clair Barber

Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1.

Background Disease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood. Objective We aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients. Methods One hundred ninety-four asthmatic patients and 21 control subjects recruited from 2 separate centers underwent detailed clinical assessment, sputum induction, and phlebotomy. One hundred three clinical, physiologic, and inflammatory parameters were analyzed by using topological data analysis and Bayesian network analysis. Results Severe asthma was associated with anxiety and depression, obesity, sinonasal symptoms, decreased quality of life, and inflammatory changes, including increased sputum chitinase 3–like protein 1 (YKL-40) and matrix metalloproteinase (MMP) 1, 3, 8, and 12 levels. Topological data analysis identified 6 clinicopathobiologic clusters replicated in both geographic cohorts: young, mild paucigranulocytic; older, sinonasal disease; obese, high MMP levels; steroid resistant TH2 mediated, eosinophilic; mixed granulocytic with severe obstruction; and neutrophilic, low periostin levels, severe obstruction. Sputum IL-5 levels were increased in patients with severe particularly eosinophilic forms, whereas IL-13 was suppressed and IL-17 levels did not differ between clusters. Bayesian network analysis separated clinical features from intricately connected inflammatory pathways. YKL-40 levels strongly correlated with neutrophilic asthma and levels of myeloperoxidase, IL-8, IL-6, and IL-6 soluble receptor. MMP1, MMP3, MMP8, and MMP12 levels were associated with severe asthma and were correlated positively with sputum IL-5 levels but negatively with IL-13 levels. Conclusion In 2 distinct cohorts we have identified and replicated 6 clinicopathobiologic clusters based on blood and induced sputum measures. Our data underline a disconnect between clinical features and underlying inflammation, suggest IL-5 production is relatively steroid insensitive, and highlight the expression of YKL-40 in patients with neutrophilic inflammation and the expression of MMPs in patients with severe asthma.

CD48 on blood leukocytes and in serum of asthma patients varies with severity

CD48 is a membrane receptor (mCD48) on eosinophils and mast cells and exists in a soluble form (sCD48). CD48 has a pivotal role in murine asthma and in the proinflammatory interactions of mast cells with eosinophils via its ligand CD244. Thus, CD48 might be important in human asthma.

Randomised Controlled Trials in Severe Asthma: Selection by Phenotype or Stereotype

Previous publications have highlighted the disparity between research trial populations and those in clinical practice, but it has not been established how this relates to randomised controlled trials (RCTs) of phenotype-targeted biological therapies in severe asthma. Detailed characterisation data for 342 severe asthma patients within the Wessex Severe Asthma Cohort (WSAC) was compared against comprehensive trial eligibility criteria for published phase IIB and phase III RCTs evaluating biological therapies in severe asthma since 2000. 37 RCTs evaluating 20 biological therapies were identified. Only a median of 9.8% (range 3.5–17.5%) of severe asthma patients were found to be eligible for enrolment in the phase III trials. Stipulations for airflow obstruction, bronchodilator reversibility and smoking history excluded significant numbers of patients. A median of 78.9% (range 73.2–86.6%) of patients with severe eosinophilic asthma would have been excluded from participation in the phase III licensing trials of interleukin (IL)-5/IL-5R targeted therapies. Despite including only well characterised and optimally treated severe asthmatics under specialist care within the WSAC study, the vast majority were excluded from trial participation by criteria designed to re-confirm diagnostic labels rather than by biomarker criteria that predict the characteristic addressed by the treatment. RCTs of biological therapies in severe asthma are poorly generalisable with most patients excluded by outmoded disease concepts despite possessing the targetable trait addressed by the treatment http://ow.ly/iog930md0J3

The Wessex AsThma CoHort (WATCH) difficult asthma study; integrating research into the clinic

The WATCH Study is a longitudinal study of patients under the Difficult Asthma Clinic at University Hospital Southampton, UK. To create a better real life understanding of difficult asthma (British Thoracic Society (BTS) step 4/5), a process of clinical dataset compilation, meeting clinical and research needs, was adopted. One objective was to trial feasibility of longitudinal data collection in a large outpatient clinic cohort. Other aims included; a) Merging research and clinical objectives; meeting needs of the BTS Difficult Asthma registry plus data collation needed for research purposes b) Ensuring all eligible patients have the opportunity to participate in research, current and future. c) Gathering all relevant clinical data to support clinical phenotyping d) Ensuring data was collected in a time efficient manner Number of patients recruited to date (175). Recruitment rate (18.2 per month). Total recruitment failures; due to lack of asthma severity (10). Number declining participation (8). Number withdrawn (1) (no reason given). Using a method combining clinical and research services to collect longitudinal data from this large cohort of patients attending the Difficult Asthma clinic was feasible and successful. The majority of patients approached were consented, participated and stayed in the study.