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Papers by Patrick Mitchell

Journal of Allergy and Clinical Immunology, 2019

This study was funded by the British Medical Association James Trust Award. I.S. is funded by a f... more This study was funded by the British Medical Association James Trust Award. I.S. is funded by a fellowship from the European Respiratory Society/European Union Marie Curie Award. Disclosure of potential conflict of interest: I. Satia reports grant from the BMA James Trust Award and the North West Lung Centre Grant; personal fees from Educational Talks for GPs; and sponsorship to attend conference meetings outside the submitted work. P. D. Mitchell reports grants from the Irish Asthma Society and Teva and personal fees from Educational Talks for GPs and specialists outside the submitted work. P. M. O'Byrne reports personal fees from the Oversight Committee for LABA Safety study; consulting fees from AstraZenca, GlaxoSmithKline, Merck, and Boehringer; and grants from AstraZeneca and Genentech outside the submitted work. J. A. Smith reports grants from the British Medical Association James Trust during the conduct of the study and grants and personal fees from Ario Pharma, GlaxoS-mithKline, NeRRe Pharmaceuticals, Menlo, and Bayer; personal fees from Boehringer Ingleheim, Genentech, and Neomed; grants and personal fees from Merck; nonfinancial support from Vitalograph; personal fees from Cheisi; and grants and personal fees from Afferent outside the submitted work. In addition, J. A. Smith has a patent A method for generating output data licensed. The rest of the authors declare that they have no relevant conflicts of interest. Clinical Trial Registration: www.controlled-trials.com ISRCTN79930571.

Current Respiratory Medicine Reviews, 2018

Asthma is a heterogeneous chronic inflammatory airways disease that affects more than 325 million... more Asthma is a heterogeneous chronic inflammatory airways disease that affects more than 325 million people worldwide. Of these, approximately 10% have severe asthma that is refractory to commonly available treatments. In the past 15 years, there have been substantial advances in the understanding of asthma pathophysiology that have allowed for the development of targeted biological treatments such as omalizumab and mepolizumab in patients with severe asthma. On the horizon, several new classes of asthma treatments, specifically biological modulators of interleukin-4 (IL)-4, IL-5, IL-13, IL-33, and thymic stromal lymphopoietin (TSLP), are in both early and late phases of development or going through regulatory approval. Successes have also been met with failures, namely in targeting IL-17 and neutrophil-high asthma. This likely reflects knowledge gaps in the pathophysiology of non-eosinophilic and corticosteroid insensitive asthma. New treatment options are vital to patients with severe asthma who fall outside the indications for new biologic therapies or for those that have failed to respond. This review article shall be limited to a discussion on available and emerging biological treatment options in severe asthma and bronchial thermoplasty.

The World Allergy Organization journal, 2016

The present paper addresses severe asthma which is limited to 5-10% of the overall population of ... more The present paper addresses severe asthma which is limited to 5-10% of the overall population of asthmatics. However, it accounts for 50% or more of socials costs of the disease, as it is responsible for hospitalizations and Emergency Department accesses as well as expensive treatments. The recent identification of different endotypes of asthma, based on the inflammatory pattern, has led to the development of tailored treatments that target different inflammatory mediators. These are major achievements in the perspective of Precision Medicine: a leading approach to the modern treatment strategy. Omalizumab, an anti-IgE antibody, has been the only biologic treatment available on the market for severe asthma during the last decade. It prevents the linkage of the IgE and the receptors, thereby inhibiting mast cell degranulation. In clinical practice omalizumab significantly reduced the asthma exacerbations as well as the concomitant use of oral glucocorticoids. In the "Th2-high as...

International archives of allergy and immunology, Jan 30, 2016

Interleukin (IL)-25 plays a pivotal role in type 2 immune responses. In a baseline cross-sectiona... more Interleukin (IL)-25 plays a pivotal role in type 2 immune responses. In a baseline cross-sectional study, we previously showed that IL-25 plasma levels and IL-25 receptor (IL-25R: IL-17RA, IL-17RB, and IL-17RA/RB) expression on mature blood eosinophils are increased in atopic asthmatics compared to normal nonatopic controls. This study investigated allergen-induced changes in IL-25 and IL-25R expression in eosinophils from asthmatics. Dual responder atopic asthmatics (n = 14) were enrolled in this randomized diluent-controlled crossover allergen challenge study. Blood was collected before and 24 h after the challenge. The surface expression of IL-25R was evaluated by flow cytometry on eosinophils and Th2 memory cells. In addition, plasma levels of IL-25 were measured by ELISA, and functional responses to IL-25 including type 2 cytokine expression, degranulation, and the migrational responsiveness of eosinophils were evaluated in vitro. Following the allergen but not the diluent inha...

Respiratory research, Jan 14, 2016

The alarmin cytokines IL-25 and IL-33 are key promoters of type 2 inflammation. Basophils respond... more The alarmin cytokines IL-25 and IL-33 are key promoters of type 2 inflammation. Basophils respond to alarmin cytokines, however the relationship of these cytokines with basophil activation and recruitment in human studies of allergic asthma has not been well characterized. This study investigated the effect of IL-25 and IL-33 on basophils in a model of allergic asthma. 10 mild allergic asthmatics underwent allergen and diluent inhalation challenges. Bone marrow aspirates were collected at pre-challenge and 24 h (h) post challenge. Peripheral blood and sputum samples were collected at pre-challenge, 7 h, and 24 h post-challenge to measure basophil expression of IL-17RB, ST2, and intracellular IL-25. Freshly isolated peripheral blood basophils from allergic donors were incubated overnight with IL-25 and IL-33, or sputum supernatant collected post-allergen to assess pro-inflammatory effects of mediators released in the airways. There were increased percentage of basophils expressing IL...

European respiratory review : an official journal of the European Respiratory Society, 2014

A 65-year-old female presented to the emergency department with a 3-day history of dyspnoea and r... more A 65-year-old female presented to the emergency department with a 3-day history of dyspnoea and rightsided chest discomfort. She had been an inpatient 6 weeks earlier with right-sided pneumothorax treated with a computed tomography-guided chest drain. On this admission her chest radiograph demonstrated a recurrence of the pneumothorax (fig. 1). She was a life long nonsmoker.

Respiratory care, 2015

Emphysema and fibrosis, typically the idiopathic pulmonary fibrosis (IPF) form of usual interstit... more Emphysema and fibrosis, typically the idiopathic pulmonary fibrosis (IPF) form of usual interstitial pneumonia (UIP), can co-exist as combined pulmonary fibrosis emphysema (CPFE). It is unknown whether there is a pathobiologic basis for CPFE beyond the coexistence of fibrosis and emphysema. The aim of this study was to ascertain radiologic differences in severity of fibrosis and emphysema in smokers with IPF versus other forms of UIP. Computed tomography thorax images were prospectively rescored in retrospectively identified smokers (minimum 5-pack-year history) with radiologic UIP (any etiology). Radiologic severity (emphysema/fibrosis/reticulation) was scored in consensus by two radiologists, blinded to clinical details, across 5 lung regional levels, and then correlated with clinical data. For the whole cohort (IPF, n = 102; non-IPF UIP [mainly rheumatoid arthritis/asbestosis/scleroderma], n = 30), IPF and non-IPF UIP smokers were similar regarding pack-year, age, gender, and lun...

Respiratory care, Jan 20, 2015

Pneumomediastinum has been described in patients with asthma. In this case report, we describe a ... more Pneumomediastinum has been described in patients with asthma. In this case report, we describe a young patient who presented to our medical assessment unit with an asthma exacerbation and progressive dyspnea. The patient developed pneumomediastinum, a rare complication of an asthma exacerbation. Pneumomediastinum is usually characterized by chest pain, dyspnea, and neck swelling caused by subcutaneous emphysema. Although the condition is usually benign and treatment is primarily supportive, surgical intervention may be needed if the patient develops hemodynamic compromise or respiratory failure through mechanisms similar to those seen in a tension pneumothorax.

Open Journal of Respiratory Diseases, 2013

Diffuse Idiopathic Neuroendocrine Cell Hyperplasia (DIPNECH) is a rare pulmonary disease. It was ... more Diffuse Idiopathic Neuroendocrine Cell Hyperplasia (DIPNECH) is a rare pulmonary disease. It was first described by Aguayo et al. in 1992, and recognised by the World Health Organisation in 2004 as a precursor lesion to the development of pulmonary carcinoid tumour. DIPNECH has been described in several isolated case reports and series. This article describes a case of DIPNECH and summaries the recent literature in an attempt to raise awareness of this disease and management options.

British Journal of Clinical Pharmacology, 2002

Aims To compare the lipid-regulating effects and steady-state pharmacokinetics of rosuvastatin, a... more Aims To compare the lipid-regulating effects and steady-state pharmacokinetics of rosuvastatin, a new synthetic hydroxy methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, following repeated morning and evening administration in volunteers with fasting serum low-density lipoprotein cholesterol (LDL-C) concentrations < 4.14 mmol l-1. Methods In this open-label two-way crossover trial 24 healthy adult volunteers were randomized to receive rosuvastatin 10 mg orally each morning (07.00 h) or evening (18.00 h) for 14 days. After a 4 week washout period, volunteers received the alternative regimen for 14 days. Rosuvastatin was administered in the absence of food. Results Reductions from baseline in serum concentrations of LDL-C (-41.3% [morning] vs-44.2% [evening]), total cholesterol (-30.9% vs-31.8%), triglycerides (-17.1% vs-22.7%), and apolipoprotein B (-32.4% vs-35.3%) were similar following morning and evening administration. AUC(0,24 h) for plasma mevalonic acid (MVA), an in vivo marker of HMG-CoA reductase activity, decreased by-29.9% (morning) vs-32.6% (evening). Urinary excretion of MVA declined by-33.6% (morning) vs-29.2% (evening). The steady-state pharmacokinetics of rosuvastatin were very similar following the morning and evening dosing regimens. The C max values were 4.58 vs 4.54 ng ml-1 , and AUC(0,24 h) values were 40.1 vs 42.7 ng ml-1 h, following morning and evening administration, respectively. There were no serious adverse events during the trial, and rosuvastatin was well tolerated after morning and evening administration. Conclusions The pharmacodynamic effects and pharmacokinetics of rosuvastatin are not dependent on time of dosing. Morning or evening administration is equally effective in lowering LDL-C .

Advances in Therapy, 2014

Approximately one-third of patients with lung cancer will develop airway obstruction and many can... more Approximately one-third of patients with lung cancer will develop airway obstruction and many cancers lead to airway obstruction through metastases. The treatment of malignant airway obstruction is often a multimodality approach and is usually performed for palliation of symptoms in advanced lung cancer. Removal of airway obstruction is associated with improvement in symptoms, quality of life, and lung function. Patient selection should exclude patients with short life expectancy, limited symptoms, and an inability to visualize beyond the obstruction. This review outlines both the immediate and delayed bronchoscopic effect options for the removal of airway obstruction and preservation of airway patency with endobronchial stenting.

BACKGROUND: Emphysema and fibrosis, typically the idiopathic pulmonary fibrosis (IPF) form of usu... more BACKGROUND: Emphysema and fibrosis, typically the idiopathic pulmonary fibrosis (IPF) form of usual interstitial pneumonia (UIP), can co-exist as combined pulmonary fibrosis emphysema (CPFE). It is unknown whether there is a pathobiologic basis for CPFE beyond the coexistence of fibrosis and emphysema. The aim of this study was to ascertain radiologic differences in severity of fibrosis and emphysema in smokers with IPF versus other forms of UIP. METHODS: Computed tomography thorax images were prospectively rescored in retrospectively identified smokers (minimum 5-pack-year history) with radiologic UIP (any etiology). Radiologic severity (emphysema/fibrosis/reticulation) was scored in consensus by two radiologists, blinded to clinical details, across 5 lung regional levels, and then correlated with clinical data. RESULTS: For the whole cohort (IPF, n ‫؍‬ 102; non-IPF UIP [mainly rheumatoid arthritis/asbestosis/scleroderma], n ‫؍‬ 30), IPF and non-IPF UIP smokers were similar regarding pack-year, age, gender, and lung function (P > .1). IPF smokers had greater whole lung fibrosis and reticulation scores (P < .04 in all cases). CPFE was present in n ‫؍‬ 61 (IPF, n ‫؍‬ 49; non-IPF UIP, n ‫؍‬ 12). Compared with smokers with non-IPF CPFE, smokers with IPF and emphysema (IPFE) were similar regarding confounders (P > .1). There were significantly greater regional reticulation severity (P ‫؍‬ .009), cumulative emphysema severity (P ‫؍‬ .04), and cumulative reticulation severity (P < .001) scores in IPFE versus non-IPF CPFE. CONCLUSIONS: When controlled for confounders, smokers with IPFE have worse radiologic CPFE than other smokers with non-IPF UIP and emphysema, suggesting an interactive synergy among IPF, emphysema, and smoking, with more extensive emphysema due to either inherent susceptibility and/or traction effects. IPFE should be considered separately from other CPFE in future work. It is currently unknown whether CPFE is a distinct pathobiologic entity; therefore, we identified subjects with radiologic UIP (any etiology) who had been similarly exposed to smoke, and asked whether there are differences in the extent/severity of radiologic fibrosis and/or emphysema in those with IPF versus individuals with non-IPF UIP. Although relevant confounders were similar, IPF smokers had greater whole lung fibrosis and reticulation scores than smokers with secondary forms of UIP, and in the CPFE subgroup, smokers with IPF/emphysema had worse radiologic CPFE findings than smokers with non-IPF UIP/emphysema. It is shown for the first time that relevant confounding variables do not explain the observed excess radiologic severity of emphysema and fibrosis in smokers with IPF compared with smokers with non-IPF UIP, lending support to the hypothesis that there is a pathobiologic mechanism or synergy involved in IPF with emphysema that is distinct from the mere coexistence of UIP and emphysematous processes.