Precision Medicine Intervention in Severe Asthma (PRISM) study: molecular phenotyping of patients with severe asthma and response to biologics.

Severe asthma represents an important clinical unmet need despite the introduction of biologic agents. Although advanced omics technologies have aided researchers in identifying clinically relevant molecular pathways, there is a lack of an integrated omics approach in severe asthma particularly in terms of its evolution over time. The collaborative Korea-UK research project Precision Medicine Intervention in Severe Asthma (PRISM) was launched in 2020 with the aim of identifying molecular phenotypes of severe asthma by analysing multi-omics data encompassing genomics, epigenomics, transcriptomics, proteomics, metagenomics and metabolomics. PRISM is a prospective, observational, multicentre study involving patients with severe asthma attending severe asthma clinics in Korea and the UK. Data including patient demographics, inflammatory phenotype, medication, lung function and control status of asthma will be collected along with biological samples (blood, sputum, urine, nasal epithelial cells and exhaled breath condensate) for omics analyses. Follow-up evaluations will be performed at baseline, 1 month, 4-6 months and 10-12 months to assess the stability of phenotype and treatment responses for those patients who have newly begun biologic therapy. Standalone and integrated omics data will be generated from the patient samples at each visit, paired with clinical information. By analysing these data, we will identify the molecular pathways that drive lung function, asthma control status, acute exacerbations and the requirement for daily oral corticosteroids, and that are involved in the therapeutic response to biological therapy. PRISM will establish a large multi-omics dataset of severe asthma to identify potential key pathophysiological pathways of severe asthma.

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA).

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

Characteristics, phenotypes, mechanisms and management of severe asthma.

ABSTRACT: Severe asthma is "asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy." The state of control was defined by symptoms, exacerbations and the degree of airflow obstruction. Therefore, for the diagnosis of severe asthma, it is important to have evidence for a diagnosis of asthma with an assessment of its severity, followed by a review of comorbidities, risk factors, triggers and an assessment of whether treatment is commensurate with severity, whether the prescribed treatments have been adhered to and whether inhaled therapy has been properly administered. Phenotyping of severe asthma has been introduced with the definition of a severe eosinophilic asthma phenotype characterized by recurrent exacerbations despite being on high dose ICS and sometimes oral corticosteroids, with a high blood eosinophil count and a raised level of nitric oxide in exhaled breath. This phenotype has been associated with a Type-2 (T2) inflammatory profile with expression of interleukin (IL)-4, IL-5, and IL-13. Molecular phenotyping has also revealed non-T2 inflammatory phenotypes such as Type-1 or Type-17 driven phenotypes. Antibody treatments targeted at the T2 targets such as anti-IL5, anti-IL5Rα, and anti-IL4Rα antibodies are now available for treating severe eosinophilic asthma, in addition to anti-immunoglobulin E antibody for severe allergic asthma. No targeted treatments are currently available for non-T2 inflammatory phenotypes. Long-term azithromycin and bronchial thermoplasty may be considered. The future lies with molecular phenotyping of the airway inflammatory process to refine asthma endotypes for precision medicine.

Molecular mechanisms of oxidative stress in asthma.

The lungs are exposed to reactive oxygen species oxygen (ROS) produced as a result of inhalation of oxygen, as well as smoke and other air pollutants. Cell metabolism and the NADPH oxidases (Nox) generate low levels of intracellular ROS that act as signal transduction mediators by inducing oxidative modifications of histones, enzymes and transcription factors. Redox signalling is also regulated by localised production and sensing of ROS in mitochondria, the endoplasmic reticulum (ER) and inside the nucleus. Intracellular ROS are maintained at low levels through the action of a battery of enzymatic and non-enzymatic antioxidants. Asthma is a heterogeneous airway inflammatory disease with different immune endotypes; these include atopic or non-atopic Th2 type immune response associated with eosinophilia, or a non-Th2 response associated with neutrophilia. Airway remodelling and hyperresponsiveness accompany the inflammatory response in asthma. Over-production of ROS resulting from infiltrating immune cells, particularly eosinophils and neutrophils, and a concomitant impairment of antioxidant responses lead to development of oxidative stress in asthma. Oxidative stress is augmented in severe asthma and during exacerbations, as well as by air pollution and obesity, and causes oxidative damage of tissues promoting airway inflammation and hyperresponsiveness. Furthermore, deregulated Nox activity, mitochondrial dysfunction, ER stress and/or oxidative DNA damage, resulting from exposure to irritants, inflammatory mediators or obesity, may lead to redox-dependent changes in cell signalling. ROS play a central role in airway epithelium-mediated sensing, development of innate and adaptive immune responses, and airway remodelling and hyperresponsiveness. Nonetheless, antioxidant compounds have proven clinically ineffective as therapeutic agents for asthma, partly due to issues with stability and in vivo metabolism of these compounds. The compartmentalised nature of ROS production and sensing, and the role of ROS in homeostatic responses and in the action of corticosteroids and ß2-adrenergic receptor agonists, adds another layer of complexity to antioxidant therapy development. Nox inhibitors and mitochondrial-targeted antioxidants are in clinical development for a number of diseases but they have not yet been investigated in asthma. A better understanding of the complex role of ROS in the pathogenesis of asthma will highlight new opportunities for more targeted and effective redox therapies.

Visual rating assessment of cerebral atrophy and its relationship with cognitive function in chronic obstructive pulmonary disease.

INTRODUCTION: Widespread white matter damage and cognitive impairment have been demonstrated in chronic obstructive pulmonary disease (COPD). However, it remains unclear if brain atrophy is a global phenomenon or if specific subregions are differentially affected. The aims of this study are, first, to test a simple, validated visual analogue grading technique. Second, we hypothesised that frontal regions of the brains of patients with COPD will show greater signs of atrophy compared with control subjects. Third, any localised regions of atrophy would correlate with components of cognitive performance. Finally, the severity of cerebral atrophy would be associated with measures of respiratory disease severity. METHODS: We used a simple, validated visual analogue grading technique to assess the degree of regional atrophy in multiple brain regions from cerebral MR images in patients with stable non-hypoxaemic COPD (n=25) and age-matched control subjects (n=25). We also explored correlations between regional brain atrophy with demographics, cognitive performance measures and disease severity. Measures of cognitive performance focused on executive function, working memory, verbal memory, overall memory and processing speed. Measures of disease severity include lung function, gas exchange, health status and breathlessness questionnaires. RESULTS: The visual grading scale found that patients with COPD had significantly greater frontal atrophy than control subjects (p=0.02), independent of smoking history, comorbid depression or anxiety. Cognitive function was significantly worse in the COPD group for executive function (p<0.001), working memory (p=0.02), verbal memory (p=0.03) and processing speed (p=0.001). Group differences in atrophy did not appear to account for differences in cognitive function. We were unable to identify meaningful correlations between regional atrophy and disease severity or cognitive function. CONCLUSION: Further work is needed to identify causative mechanisms behind unexplained structural brain changes in COPD.