Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry

Objective: To determine the prevalence of systemic corticosteroid-induced morbidity in severe asthma.
Design: Cross-sectional observational study.Setting The primary care Optimum Patient Care Research Database and the British Thoracic Society Difficult Asthma Registry.
Participants: Optimum Patient Care Research Database (7195 subjects in three age- and gender-matched groups)—severe asthma (Global Initiative for Asthma (GINA) treatment step 5 with four or more prescriptions/year of oral corticosteroids, n=808), mild/moderate asthma (GINA treatment step 2/3, n=3975) and non-asthma controls (n=2412). 770 subjects with severe asthma from the British Thoracic Society Difficult Asthma Registry (442 receiving daily oral corticosteroids to maintain disease control).
Main outcome measures: Prevalence rates of morbidities associated with systemic steroid exposure were evaluated and reported separately for each group.
Results: 748/808 (93%) subjects with severe asthma had one or more condition linked to systemic corticosteroid exposure (mild/moderate asthma 3109/3975 (78%), non-asthma controls 1548/2412 (64%); p<0.001 for severe asthma versus non-asthma controls). Compared with mild/moderate asthma, morbidity rates for severe asthma were significantly higher for conditions associated with systemic steroid exposure (type II diabetes 10% vs 7%, OR=1.46 (95% CI 1.11 to 1.91), p<0.01; osteoporosis 16% vs 4%, OR=5.23, (95% CI 3.97 to 6.89), p<0.001; dyspeptic disorders (including gastric/duodenal ulceration) 65% vs 34%, OR=3.99, (95% CI 3.37 to 4.72), p<0.001; cataracts 9% vs 5%, OR=1.89, (95% CI 1.39 to 2.56), p<0.001). In the British Thoracic Society Difficult Asthma Registry similar prevalence rates were found, although, additionally, high rates of osteopenia (35%) and obstructive sleep apnoea (11%) were identified.

Conclusions: Oral corticosteroid-related adverse events are common in severe asthma. New treatments which reduce exposure to oral corticosteroids may reduce the prevalence of these conditions and this should be considered in cost-effectiveness analyses of these new treatments.

Asthma control and exacerbations: two different sides of the same coin.

Purpose of review: Optimal asthma management includes both the control of asthma symptoms and reducing the risk of future asthma exacerbations. Traditionally, treatment has been adjusted largely on the basis of symptoms and lung function and for many patients, this approach delivers both excellent symptom control and reduced risk. However, the relationship between these two key components of the disease may vary between different asthmatic phenotypes and disease severities and there is increasing recognition of the need for more individualized treatment approaches.

Recent findings: A number of factors which predict exacerbation risk have been identified including demographic and behavioural features and specific inflammatory biomarkers. Type-2 cytokine-driven eosinophilic airways inflammation predisposes to frequent exacerbations and predicts response to corticosteroids, and the usefulness of sputum eosinophilia as both a marker of exacerbation risk and biomarker for adjustment of corticosteroid treatment has been established for some time. However, attempts to develop surrogate markers, which would be more straightforward to deliver in the clinic, have been challenging.

Summary: Some patients with asthma have persistent symptoms in the absence of type-2 cytokine driven-eosinophilic airways inflammation due to noncorticosteroid responsive mechanisms (T2-low disease). Composite biomarker strategies using easily measured surrogate indicators of type-2 inflammation (such as fractional exhaled nitric oxide, blood eosinophil count and serum periostin levels) may predict exacerbation risk better but it is unclear if they can be used to adjust corticosteroid treatment. Biomarkers will be used to target novel biologic treatments but additionally may be used to optimize corticosteroid treatment dose and act as prognostics for exacerbation risk and potentially other important longer term asthma outcomes.

TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma

Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.

Dedicated severe asthma services improve health-care use and quality of life

Background: Systematic assessment of severe asthma can be used to confirm the diagnosis, identify comorbidities, and address adherence to therapy. However, the prospective usefulness of this approach is yet to be established. The objective of this study was to determine whether the systematic assessment of severe asthma is associated with improved quality of life (QoL) and health-care use and, using prospective data collection, to compare relevant outcomes in patients referred with severe asthma to specialist centers across the United Kingdom. Methods: Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics, and health-care use between initial assessment and a median follow-up of 286 days. Results: The study population consisted of 346 patients with severe asthma. At follow-up, there were significant reductions in health-care use in terms of primary care or ED visits (66.4% vs 87.8%, P < .0001) and hospital admissions (38% vs 48%, P = .0004). Although no difference was noted in terms of those requiring maintenance oral corticosteroids, there was a reduction in steroid dose (10 mg [8-20 mg] vs 15 mg [10-20 mg], P = .003), and fewer subjects required short-burst steroids (77.4% vs 90.8%, P = .01). Significant improvements were seen in QoL and control using the Asthma Quality of Life Questionnaire and the Asthma Control Questionnaire. Conclusions: To our knowledge, this is the first time that a prospective study has shown that a systematic assessment at a dedicated severe asthma center is associated with improved QoL and asthma control and a reduction in health-care use and oral steroid burden.

Drug therapies in severe asthma - the era of stratified medicine

Difficult-to-treat asthma affects up to 20% of patients with asthma and is associated with significant healthcare cost. It is an umbrella term that defines a heterogeneous clinical problem including incorrect diagnosis, comorbid conditions and treatment non-adherence; when these are effectively addressed, good symptom control is frequently achieved. However, in 3–5% of adults with difficult-to-treat asthma, the problem is severe disease that is unresponsive to currently available treatments. Current treatment guidelines advise the ‘stepwise’ increase of corticosteroids, but it is now recognised that many aspects of asthma are not corticosteroid responsive, and that this ‘one size fits all’ approach does not deliver clinical benefit in many patients and can also lead to side effects. The future of management of severe asthma will involve optimisation with currently available treatments, particularly corticosteroids, including addressing non-adherence and defining an ‘optimised’ corticosteroid dose, allied with the use of ‘add-on’ target-specific novel treatments. This review examines the current status of novel treatments and research efforts to identify novel targets in the era of stratified medicines in severe asthma.

Reduced risk of pancreatic cancer associated with asthma and nasal allergies

OBJECTIVE: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk.

DESIGN: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model.

RESULTS: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk.

CONCLUSIONS: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.

Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma

Severe asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high-dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the Janus kinase-signal transducers and activators of transcription pathway. We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.

Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, quantitative PCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating interleukin (IL)-13 signalling in vitro.

SOCS1 gene expression was significantly lower in the airways of severe asthmatics compared with mild/moderate asthmatics, and was inversely associated with airway eosinophilia and other measures of T-helper type 2 (Th2) inflammation. Immunohistochemistry demonstrated SOCS1 was predominantly localised to the bronchial epithelium. SOCS1 overexpression inhibited IL-13-mediated chemokine ligand (CCL) 26 (eotaxin-3) mRNA expression in bronchial epithelial cells.

Severe asthma patients with persistent airway eosinophilia and Th2 inflammation have reduced airway epithelial SOCS1 expression. SOCS1 inhibits epithelial IL-13 signalling, supporting its key role in regulating Th2-driven eosinophilia in severe asthma.

A comparison of different pre-lysis methods and extraction kits for recovery of Stretococcus agalacticae (Lancefield group B Streptococcus) DNA from whole blood

Sub-optimal recovery of bacterial DNA from whole blood samples can limit the sensitivity of molecular assays to detect pathogenic bacteria. We compared 3 different pre-lysis protocols (none, mechanical pre-lysis and achromopeptidasepre-lysis) and 5 commercially available DNA extraction platforms for direct detection of Group B Streptococcus (GBS) in spiked whole blood samples, without enrichment culture. DNA was extracted using the QIAamp Blood Mini kit (Qiagen), UCP Pathogen Mini kit (Qiagen), QuickGene DNA Whole Blood kit S (Fuji), Speed Xtract Nucleic Acid Kit 200 (Qiagen) and MagNA Pure Compact Nucleic Acid Isolation Kit I (Roche Diagnostics Corp). Mechanical pre-lysis increased yields of bacterial genomic DNA by 51.3 fold (95% confidence interval; 31.6–85.1, p < 0.001) and pre-lysis with achromopeptidase by 6.1 fold (95% CI; 4.2–8.9, p < 0.001), compared with no pre-lysis. Differences in yield dueto pre-lysis were 2–3 fold larger than differences in yield between extraction methods. Including a pre-lysis step can improve the limits of detection of GBS using PCR or other molecular methods without need for culture.

Human Papillomavirus (HPV): Making the case for “Immunisation for All”

Human Papillomavirus (HPV) contributes to the most common sexually transmitted infections, with repeated and persistent infection with particular types causing disease in both men and women. Infection with low-risk HPV types can lead to genital warts and benign lesions of the oral cavity, while high-risk types can cause various HPV-related malignancies. The incidence of head and neck cancer has been rising in the past number of decades mostly due to oropharyngeal cancer linked to HPV infection. HPV vaccination has been shown to be effective for cervical and other anogenital HPV-related cancers, and there is significant potential for HPV vaccination to prevent oropharyngeal cancers, given that the HPV types implicated in this disease can be protected against by the HPV vaccine. Few countries have implemented a universal HPV vaccination programme for males and females, with many countries arguing that female only vaccination programmes protect males via herd immunity, and that men-who-have-sex-with-men will be protected via targeted vaccination programmes. We argue these may be limited in their effectiveness. We propose that the most effective, practical, ethical and potentially cost effective solution is universal HPV vaccination that might lead to control of HPV-related diseases in men and women alike.

The epidemiology, healthcare and societal burden and costs of asthma in the UK and its member nations: analyses of standalone and linked national databases

Background: There are a lack of reliable data on the epidemiology and associated burden and costs of asthma. We sought to provide the first UK-wide estimates of the epidemiology, healthcare utilisation and costs of asthma. 

Methods: We obtained and analysed asthma-relevant data from 27 datasets: these comprised national health surveys for 2010-11, and routine administrative, health and social care datasets for 2011-12; 2011-12 costs were estimated in pounds sterling using economic modelling. 

Results: The prevalence of asthma depended on the definition and data source used. The UK lifetime prevalence of patient-reported symptoms suggestive of asthma was 29.5 % (95 % CI, 27.7-31.3; n = 18.5 million (m) people) and 15.6 % (14.3-16.9, n = 9.8 m) for patient-reported clinician-diagnosed asthma. The annual prevalence of patient-reported clinician-diagnosed-and-treated asthma was 9.6 % (8.9-10.3, n = 6.0 m) and of clinician-reported, diagnosed-and-treated asthma 5.7 % (5.7-5.7; n = 3.6 m). Asthma resulted in at least 6.3 m primary care consultations, 93,000 hospital in-patient episodes, 1800 intensive-care unit episodes and 36,800 disability living allowance claims. The costs of asthma were estimated at least £1.1 billion: 74 % of these costs were for provision of primary care services (60 % prescribing, 14 % consultations), 13 % for disability claims, and 12 % for hospital care. There were 1160 asthma deaths. 

Conclusions: Asthma is very common and is responsible for considerable morbidity, healthcare utilisation and financial costs to the UK public sector. Greater policy focus on primary care provision is needed to reduce the risk of asthma exacerbations, hospitalisations and deaths, and reduce costs.