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Harefield, United Kingdom

Simonds A.K.,NIHR Respiratory Biomedical Research Unit
European Respiratory Review | Year: 2013

While obstructive sleep apnoea syndrome dominates discussion of the prevalence of sleep disordered breathing, nocturnal hypoventilation remains extremely prevalent in those with chronic ventilatory disorders and in the natural history of these conditions pre-dates the development of daytime ventilatory failure. In this review the clinical management of chronic hypoventilation in neuromuscular disease will be considered and then compared with that in obesity hypoventilation syndrome. In simple terms these conditions illustrate the polar opposite ends of the spectrum, as in neuromuscular disease the reduced capacity of the respiratory system is unable to withstand a normal respiratory load, and in obesity hypoventilation syndrome the normal capacity of the respiratory system is unable to tolerate a substantially increased ventilatory load. © ERS 2013.

Cottin V.,University Claude Bernard Lyon 1 | Maher T.,Imperial College London | Maher T.,NIHR Respiratory Biomedical Research Unit
European Respiratory Review | Year: 2015

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, progressively destructive lung disease that culminates in respiratory failure and death. Randomised controlled trials have demonstrated that treatment of IPF patients with pirfenidone reduces lung function decline, improves progression-free survival and significantly reduces the risk of all-cause mortality at 1 year. Pirfenidone has been shown to have a favourable safety profile and was generally well tolerated over the long term in clinical trials and realworld experience. However, side-effect management is critical to help some patients remain on treatment over the long term. The primary treatment-related adverse events associated with pirfenidone therapy are gastrointestinal upset, rash and photosensitivity. Gastrointestinal events may be mitigated by ensuring that pirfenidone is taken with food, while skin symptoms may be reduced by avoiding sun exposure and frequent use of sunblock. Educating patients about the potential for these adverse events to occur and providing instructions prior to treatment to avoid adverse drug reactions are an important means of ensuring patients may derive the important benefits provided by long-term treatment with pirfenidone. ©ERS 2015.

Spagnolo P.,University of Basel | Tzouvelekis A.,Yale University | Maher T.M.,NIHR Respiratory Biomedical Research Unit
Current Opinion in Pulmonary Medicine | Year: 2015

Purpose of review In this article, we summarize and discuss the most recent literature on personalized medicine in idiopathic pulmonary fibrosis (IPF), a chronic progressive and almost invariably lethal disease of unknown cause. This review is timely as major advances in our understanding of disease pathobiology and improvements in molecular techniques have recently led to the identification of potential surrogates of diagnosis, prognosis and response to treatment. Recent findings The most promising and advanced candidate biomarkers are presented based on their proposed mechanistic pathways (e.g. alveolar epithelial cell dysfunction, immune dysregulation, microbiome, extracellular matrix remodeling and fibroproliferation, epigenetic markers and metabolomics). Recent data suggest that components of the immune system may contribute to the development of IPF. A potential role for infections as a cofactor in disease development and progression or as a trigger in disease exacerbation has also recently been proposed. Summary Clinical management of IPF is unsatisfactory because of limited availability of truly effective therapies, lack of accurate predictors of disease behavior and absence of simple short-term measures of therapeutic response. A number of putative biomarkers have been identified in patients with IPF, although none has been validated to the standard necessary for their use in either therapeutic trials or clinical practice. Currently, ongoing prospective longitudinal studies will hopefully permit such validation. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Kotecha S.,University of Cardiff | Davies P.L.,University of Cardiff | Clark H.W.,NIHR Respiratory Biomedical Research Unit | McGreal E.P.,University of Cardiff
Thorax | Year: 2013

Background: Surfactant protein D (SP-D) is a soluble oligomeric C-type lectin known to protect against lipopolysaccharide and ventilator-induced lung injury in preterm lambs. Here we assess the expression and functional status of SP-D in bronchoalveolar lavage fluid (BALF) from preterm infants at risk of chronic lung disease (CLD) of prematurity and term controls. This is the first systematic evaluation of SP-D function in any clinical cohort. Methods: SP-D was quantified in BALF from 28 ventilated preterm infants and five ventilated term infants. SP-D lectin activity was tested in a zymosan binding assay followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blot in BALF from the same infants. SP-D lectin activity was also tested towards maltose-agarose and mannan for selected BALF samples. Results: SP-D expression was lower on day 1 in those preterm infants who subsequently developed CLD but increased over the first 5 days of life in term and preterm neonates. The percentage of neonatal SP-D capable of binding zymosan rarely exceeded 50% in any BALF sample and was 3.5 times lower in preterm infants than term infants on day 1 of life. Similar binding defects were observed towards maltose-agarose and mannan. SDS-PAGE analysis revealed that zymosan-bound SP-D was more highly oligomerised (≥12-mers) than unbound SP-D, which was composed primarily of trimers and lower oligomeric forms. Conclusions: Substantial and functionally relevant variation in the expression and oligomeric distribution of SP-D exists between preterm and term neonatal lung secretions. This has implications for proposed SP-D replacement therapy in this population.

Woodcock H.V.,NIHR Respiratory Biomedical Research Unit | Woodcock H.V.,University College London | Maher T.M.,NIHR Respiratory Biomedical Research Unit | Maher T.M.,Imperial College London
F1000Prime Reports | Year: 2014

Idiopathic pulmonary fibrosis (IPF) is a progressive and invariably fatal disease with a median survival of less than three years from diagnosis. The last decade has seen an exponential increase in clinical trial activity in IPF and this in turn has led to important developments in the treatment of this terrible disease. Previous therapeutic approaches based around regimens including corticosteroids and azathioprine have, when tested in randomized clinical trials, been shown to be harmful in IPF. By contrast, compounds with anti-fibrotic actions have been shown to be beneficial. Subsequently, the novel anti-fibrotic agent pirfenidone has, in many parts of the world, become the first treatment ever to be licensed for use in IPF. This exciting development, coupled with ongoing clinical trials of a range of other novel compounds, is bringing hope to patients and their clinicians and raises the prospect that, in the future, it may become possible to successfully arrest the development of progressive scarring in IPF.

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