The assessment of quality of life in acute cough with the Leicester Cough Questionnaire (LCQ-acute)

Acute cough has a significant impact on physical and psychosocial health and is associated with an impaired quality of life (QOL). The Leicester Cough Questionnaire (LCQ) is a validated cough-related health status questionnaire designed for patients with chronic cough. The purpose of this study was to validate the LCQ for the assessment of health related QOL in patients with acute cough and determine the clinical minimal important difference (MID).Methods: 10 subjects with cough due to acute upper respiratory tract infection underwent focused interviews to investigate the face validity of the LCQ. The LCQ was also evaluated by a multidisciplinary team. 30 subjects completed the revised LCQ-acute and a cough visual analogue score (VAS: 0-100 mm) within one week of onset of cough and again <2 weeks later and at resolution of cough. The concurrent validity, internal reliability, repeatability and responsiveness of the LCQ-acute were also assessed. Patients also completed a Global Rating of Change Questionnaire that assessed the change in cough severity between visits. The MID was calculated as the change in LCQ-acute score for patients responding to GRCQ category representing the smallest change in health status that patients found worthwhile.Results: Health status was severely impaired at baseline affecting all domains; median (interquartile range) total LCQ-acute score 13.0 (3.4). All subjects found the LCQ-acute questionnaire acceptable for assessing their cough. Internal reliability of the LCQ-acute was good for all domains and total score, Cronbach's α coefficients >0.9. There was a significant correlation between LCQ-acute and VAS (ρ = -0.48, p = 0.007). The LCQ-acute and its domains were highly responsive to change; effect sizes 1.7-2.3. The MID for total LCQ and VAS were 2.5 and 13 mm respectively.Conclusion: The LCQ-acute is a brief, simple and valid instrument to assess cough specific health related QOL in patients with acute cough. It is a highly responsive tool suggesting that it will be particularly useful to assess the effect of antitussive therapy

Rebuttal From Dr Pavord

I find myself agreeing with almost all of Professor Chalmer’s comments. I accept that this is not in the spirit of a pro-con debate, but suggest it represents much more important and exciting development: an emerging consensus on the use of inhaled corticosteroids (ICS) in patients with COPD. We both recommend that treatment is initiated in patients who have evidence of involvement the relevant biological pathway rather than those who possess an arbitrary label. We agree that in the blood eosinophil count we have a convenient and reasonably robust biomarker of corticosteroid responsive eosinophilic airway inflammation. As the main impact of treatment is to reduce the frequency of exacerbations (particularly those requiring treatment with oral corticosteroids) and as prior exacerbations are the most important predictor of future events, we also agree that ICS should be applied in a secondary prevention type fashion

Counterpoint: Should an attempt be made to withdraw inhaled corticosteroids in all patients with stable GOLD 3 (30% ≤ FEV1 < 50% predicted) COPD? No.

Inhaled corticosteroids (ICS) have been accepted by successive GOLD documents as being effective agents for the prevention of COPD exacerbations and decline in health status. The combination of an ICS and a long-acting beta-agonist (LABA) is superior to the LABA alone in achieving these positive benefits. As the major effect of adding ICS is to reduce exacerbations, conventional guidance suggests this treatment in patients with a history of prior exacerbations. However, there has been a reappraisal of the use of ICS mainly driven by two factors: the recognition that treatment is associated with important adverse events, best documented in clinical trials as an approximately doubling of the risk of pneumonia; and the demonstration in a large and influential clinical trial that combined LABA and long acting antimuscarinic (LAMA) treatment has a larger positive impact on exacerbations, symptoms and lung function and is less likely to be associated with pneumonia than treatment with LABA/ICS. As a result GOLD 2017 recommends LABA/LAMA as a primary exacerbation reduction strategy and a more restricted role for ICS

Biologics and chronic obstructive pulmonary diseases

The presence of airway inflammation in patients with chronic obstructive pulmonary disease (COPD) provides a rationale for biological agents targeting specific inflammatory pathways. This approach has been strikingly effective in patients with other chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and asthma. However, there are important and unresolved challenges in COPD, including our incomplete understanding of heterogeneity of the lower airway inflammatory response and how these contribute to the clinical expression of disease. As a result, progress has been slow, and there have been many failures. One notable exception is the targeting of eosinophilic airway inflammation with anti-IL-5, which has an acknowledged and important role in the treatment of severe eosinophilic asthma. Recent phase III studies have shown a reduction in exacerbations of around 20% in patients with COPD and clear evidence of a blood eosinophil count-dependent beneficial effect. The demonstration of clinical efficacy linked to a clinically accessible biomarker raises the possibility of precision biomarker-directed use of biological agents in patients with COPD. The hope is that this will be an exemplar for the future development of biological agents in patients with COPD

Type 2 inflammation and biological therapies in asthma: targeted medicine taking flight

The field of asthma has undergone a dramatic change in recent years. Advances in our understanding of type 2 airway inflammation have driven the discovery of monoclonal antibodies targeting specific aspects of the immune pathway. In landmark trials, these drugs have shown efficacy in reducing asthma attacks and exposure to oral corticosteroids, important causes of morbidity in people with asthma. Our review explores the key features of type 2 inflammation in asthma and summarizes the clinical trial evidence of the novel monoclonal antibody treatments and future avenues for treatment

Lung epithelial cell inhibition of cytokine production by peripheral blood mononuclear cells and lung lymphocytes

Type 2 cytokines such as IL-5, IL-13 and IL-4 produced by primed type 2 T cells have been shown to be important in the pathogenesis of eosinophilic airway inflammation. They . Factors regulating the state of activation of these cells are incompletely understood. We and others have shown that release of IL-13 by stimulated T cells can be inhibited by epithelial cells. In this studyto used a PBMC based bulk culture system to: 1) determine whether production of other type-2 cytokines is inhibited by co-culture with epithelial cells; 2) compare inhibition of activated PBMC and human lung lymphocytes; and 3) investigate whether specific soluble mediators modified inhibition of IL-13 release. PBMC isolated from blood and lymphocytes isolated from lung tissue were cultured with IL-2 for five days in the absence and presence of A549 and BEAS2B epithelial cells. The cytokines IL-13, IL-5, IL-9 and TNFa were measured in the supernatant of these cells. We also did similar co-culture experiments in the presence of different inhibitors or blocking cytokine antibodies

Defining severe obstructive lung disease in the biologic era: an endotype-based approach.

Severe obstructive lung disease, which encompasses patients with asthma, chronic obstructive pulmonary disease (COPD) or features of both, remains a considerable global health problem and burden on healthcare resources. However, the clinical definitions of severe asthma and COPD do not reflect the heterogeneity within these diagnoses or the potential for overlap between them, which may lead to inappropriate treatment decisions. Furthermore, most studies exclude patients with diagnoses of both asthma and COPD. Clinical definitions can influence clinical trial design and are both influenced by, and influence, regulatory indications and treatment recommendations. Therefore, to ensure its relevance in the era of targeted biologic therapies, the definition of severe obstructive lung disease must be updated so that it includes all patients who could benefit from novel treatments and for whom associated costs are justified. Here, we review evolving clinical definitions of severe obstructive lung disease and evaluate how these have influenced trial design by summarising eligibility criteria and primary outcomes of phase III randomised controlled trials of biologic therapies. Based on our findings, we discuss the advantages of a phenotype- and endotype-based approach to select appropriate populations for future trials that may influence regulatory approvals and clinical practice, allowing targeted biologic therapies to benefit a greater proportion and range of patients. This calls for co-ordinated efforts between investigators, pharmaceutical developers and regulators to ensure biologic therapies reach their full potential in the management of severe obstructive lung disease

The association between blood eosinophils and risk and treatment outcome in COPD is not dichotomised

We would like to congratulate Bafadhel et al on their excellent paper examining the response to Budesonide and blood eosinophils counts (on line version 10th Jan) in COPD. In clearly demonstrating the continuous nature of the relationship between blood eosinophil count and the risk of exacerbations as well the benefit of inhaled corticosteroids in COPD, they have helped clarify a point that we alluded to in our original paper1 that the nature of the response is “graded” dependent on the eosinophil count. The use of a cutoff point in our paper has frequently been misunderstood, and has prompted much irrelevant debate about the relevance of the cut off for allocating treatment and the stability of the biomarker over time. We would like to clarify the choice of the cut point in our original paper was intended to allow comparison with previously published work and did not and does not reflect or infer any belief that at the 2% blood eosinophil count, or any other specific eosinophil level, there is a sudden step wise change in the relationship between blood eosinophils with either risk or benefit, as would be seen with a dichotomized variable