Management of airway disease

Lung analysisBankart, Beardsmore, Bradding, Brightling, Coats, Gaillard, Green, Morgan, Pandya, Siddiqui, Singh, Steiner, Thompson, Wardlaw

We are fully committed to a translational approach to our research and are keen to take our insights on pathogenesis of airway disease through to clinical trials of new drugs.

Highlights:

  1. We are particularly proud of our role in the development of the anti-eosinophil biological drug mepolizumab. We had identified some years ago that eosinophilic inflammation is closely associated with exacerbations of asthma but not with standard measures of asthma control such as symptoms and FEV1. A blocking antibody against the major eosinophil growth factor IL-5 (mepolizumab) had been shown to reduce eosinophil numbers in the blood and sputum but did not have clinical efficacy against the outcome measures chosen for the clinical trials (symptoms and FEV1) and so the company GSK were on the point of stopping the development of the drug. We persuaded them to allow us to do an investigator led study using exacerbations as an outcome and demonstrated a greater than 40% reduction in severe exacerbations in the treatment group. This study revived the development of this drug and our results have been confirmed in Phase II and Phase III studies.

    Mepolizumab and exacerbations of refractory eosinophilic asthma. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall R, Bradding P, Green RH, Wardlaw AJ and Pavord ID. N Engl J Med. 2009;360:973-984. (IF 47.05)
  2. Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. Our research found that Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma.

    Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Lancet. 2012 Aug 18;380(9842):651-9.
  3. Eosinophilic airway inflammation measured by using induced sputum is an important treatment stratification tool in patients with severe asthma. In addition, sputum eosinophilia has been shown to be associated with severe exacerbations and airflow limitation. We sought to identify whether eosinophilic inflammation in sputum is associated with FEV1 decrease in patients with severe asthma and whether we could identify subgroups of decrease behavior based on the variation of eosinophilic airway inflammation over time. The amplitude of sputum eosinophilia was associated with postbronchodilator FEV1 in asthmatic patients. In contrast, high variability rather than the amplitude at baseline or over time of sputum eosinophils was associated with accelerated FEV1 decrease.

    Lung function decline and variable airway inflammatory pattern: Longitudinal analysis of severe asthma. Newby C, Agbetile J, Hargadon B, Monteiro W, Green R, Pavord I, Brightling C, Siddiqui S. J Allergy Clin Immunol. 2014 Aug;134(2):287-294.e5.
  4. IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit from antifungal treatment. We sought to determine whether a 3-month course of voriconazole improved asthma-related outcomes in patients with asthma who are IgE sensitized to A fumigatus. We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control.

    Effectiveness of voriconazole in the treatment of Aspergillus fumigatus-associated asthma (EVITA3 study). Agbetile J, Bourne M, Fairs A, Hargadon B, Desai D, Broad C, Morley J, Bradding P, Brightling CE, Green RH, Haldar P, Pashley CH, Pavord ID, Wardlaw AJ. J Allergy Clin Immunol. 2014 Jul;134(1):33-9.
  5. Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous. We investigated the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations. We concluded that The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.

    Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE.
    Am J Respir Crit Care Med. 2012 Jul 1;186(1):48-55.
  6. We investigated whether an early rehabilitation intervention initiated during acute admission for exacerbations of chronic respiratory disease reduces the risk of readmission over 12 months and ameliorates the negative effects of the episode on physical performance and health status. We found that early rehabilitation during hospital admission for chronic respiratory disease did not reduce the risk of subsequent readmission or enhance recovery of physical function following the event over 12 months. Mortality at 12 months was higher in the intervention group. The results suggest that beyond current standard physiotherapy practice, progressive exercise rehabilitation should not be started during the early stages of the acute illness.

    An early rehabilitation intervention to enhance recovery during hospital admission for an exacerbation of chronic respiratory disease: randomised controlled trial. Greening NJ, Williams JE, Hussain SF, Harvey-Dunstan TC, Bankart MJ, Chaplin EJ, Vincent EE, Chimera R, Morgan MD, Singh SJ, Steiner MC. BMJ. 2014 Jul 8;349:g4315.
  7. Patients with severe asthma have marked airway inflammation and many have a degree of COPD like fixed airflow obstruction the cause of which is unknown. We have demonstrated that both the inflammation and the airway remodelling may be due to colonisation of the airways with filamentous fungi particularly Aspergillus fumigatus which opens up the possibility that treatment with anti-fungals will prevent this currently untreatable aspect of the disease.

    IgE Sensitisation to Aspergillus fumigatus is Associated with Reduced Lung Function in Asthma. Fairs A, Agbetile J, Hargadon B, Bourne M, Monteiro WR, Brightling CE, Bradding P, Green RH, Mutalithas K, Desai D, Pavord ID, Wardlaw AJ, Pashley CH. Am J Respir Crit Care Med. 2010.
  8. Bronchiectasis is a feature common to several airway diseases and it is important to routinely screen for cilial defects in the airway epithelium. We are fortunate in having a national centre in Leicester run by Chris O’Callaghan and he has recently demonstrated the success of the techniques he uses in identifying cilial deficiency.

    Diagnostic testing of patients suspected of primary ciliary dyskinesia. Stannard WA, Chilvers MA, Rutman AR, Williams CD, O'Callaghan C. Am J Respir Crit Care Med. 2010;181:307-314. (IF 10.69)
  9. Dr Steiner and Professor Singh lead the rehabilitation theme of the NIHR LNR CLAHRC (Collaboration for Leadership in Health Research and Care) for LNR which is conducting applied research exploring the delivery and effectiveness of novel rehabilitation strategies in chronic cardiopulmonary diseases.
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