Phenotypic and functional translation of IL33 genetics in asthma.

BACKGROUND: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. CONCLUSIONS: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

A real-life comparative effectiveness study into the addition of antibiotics to the management of asthma exacerbations in primary care.

BACKGROUND: Asthma exacerbations are major contributors to asthma morbidity and mortality. They are usually managed with bronchodilators and oral corticosteroids (OCS), but clinical trial evidence suggests that antibiotics could be beneficial. We aimed to assess whether treatment of asthma exacerbations with antibiotics in addition to OCS improved outcomes in larger, more representative routine-care populations. METHOD: A retrospective comparative effectiveness study into managing asthma exacerbations with OCS alone versus OCS plus antibiotics was conducted using the Optimum Patient Care Research Database. The dataset included 28 637 patients; following propensity score matching 20 024 adults and 4184 children were analysed. RESULTS: Antibiotics in addition to OCS were prescribed for the treatment of asthma exacerbations in 45% of adults and 32% of children. Compared to OCS alone, OCS plus antibiotics was associated with reduced risk of having an asthma/wheeze consultation in the following 2 weeks (children hazard ratio (HR) 0.84 (95% CI 0.73-0.96), p=0.012; adults HR 0.86 (95% CI 0.81-0.91), p<0.001), but an increase in risk of a further OCS prescription for a new/ongoing exacerbation within 6 weeks in adults (HR 1.11 (95% CI 1.01-1.21), p=0.030), but not children. Penicillins, but not macrolides, were associated with a reduction in the odds of a subsequent asthma/wheeze consultation compared to OCS alone, in both adults and children. CONCLUSION: Antibiotics were frequently prescribed in relation to asthma exacerbations, contrary to guideline recommendations. Overall, the routine addition of antibiotics to OCS in the management of asthma exacerbations appeared to confer little clinical benefit, especially when considering the risks of antibiotic overuse.

Oral corticosteroids stewardship for asthma in adults and adolescents: A position paper from the Thoracic Society of Australia and New Zealand.

Oral corticosteroids (OCS) are frequently used for asthma treatment. This medication is highly effective for both acute and chronic diseases, but evidence indicates that indiscriminate OCS use is common, posing a risk of serious side effects and irreversible harm. There is now an urgent need to introduce OCS stewardship approaches, akin to successful initiatives that optimized appropriate antibiotic usage. The aim of this TSANZ (Thoracic Society of Australia and New Zealand) position paper is to review current knowledge pertaining to OCS use in asthma and then delineate principles of OCS stewardship. Recent evidence indicates overuse and over-reliance on OCS for asthma and that doses >1000 mg prednisolone-equivalent cumulatively are likely to have serious side effects and adverse outcomes. Patient perspectives emphasize the detrimental impacts of OCS-related side effects such as weight gain, insomnia, mood disturbances and skin changes. Improvements in asthma control and prevention of exacerbations can be achieved by improved inhaler technique, adherence to therapy, asthma education, smoking cessation, multidisciplinary review, optimized medications and other strategies. Recently, add-on therapies including novel biological agents and macrolide antibiotics have demonstrated reductions in OCS requirements. Harm reduction may also be achieved through identification and mitigation of predictable adverse effects. OCS stewardship should entail greater awareness of appropriate indications for OCS prescription, risk-benefits of OCS medications, side effects, effective add-on therapies and multidisciplinary review. If implemented, OCS stewardship can ensure that clinicians and patients with asthma are aware that OCS should not be used lightly, while providing reassurance that asthma can be controlled in most people without frequent use of OCS.

A systematic review of methodology used in the development of prediction models for future asthma exacerbation.

BACKGROUND: Clinical prediction models are widely used to guide medical advice and therapeutic interventions. Asthma is one of the most common chronic diseases globally and is characterised by acute deteriorations. These exacerbations are largely preventable, so there is interest in using clinical prediction models in this area. The objective of this review was to identify studies which have developed such models, determine whether consistent and appropriate methodology was used and whether statistically reliable prognostic models exist. METHODS: We searched online databases MEDLINE (1948 onwards), CINAHL Plus (1937 onwards), The Cochrane Library, Web of Science (1898 onwards) and ClinicalTrials.gov, using index terms relating to asthma and prognosis. Data was extracted and assessment of quality was based on GRADE and an early version of PROBAST (Prediction study Risk of Bias Assessment Tool). A meta-analysis of the discrimination and calibration measures was carried out to determine overall performance across models. RESULTS: Ten unique prognostic models were identified. GRADE identified moderate risk of bias in two of the studies, but more detailed quality assessment via PROBAST highlighted that most models were developed using highly selected and small datasets, incompletely recorded predictors and outcomes, and incomplete methodology. None of the identified models modelled recurrent exacerbations, instead favouring either presence/absence of an event, or time to first or specified event. Preferred methodologies were logistic regression and Cox proportional hazards regression. The overall pooled c-statistic was 0.77 (95% confidence interval 0.73 to 0.80), though individually some models performed no better than chance. The meta-analysis had an I2 value of 99.75% indicating a high amount of heterogeneity between studies. The majority of studies were small and did not include internal or external validation, therefore the individual performance measures are likely to be optimistic. CONCLUSIONS: Current prognostic models for asthma exacerbations are heterogeneous in methodology, but reported c-statistics suggest a clinically useful model could be created. Studies were consistent in lacking robust validation and in not modelling serial events. Further research is required with respect to incorporating recurrent events, and to externally validate tools in large representative populations to demonstrate the generalizability of published results.

Predictors of severe asthma attack re-attendance in Ecuadorian children: a cohort study.

Asthma is a common cause of emergency care attendance in low- and middle-income countries (LMICs). While few prospective studies of predictors for emergency care attendance have been undertaken in high-income countries, none have been performed in a LMIC.We followed a cohort of 5-15-year-old children treated for asthma attacks in emergency rooms of public health facilities in Esmeraldas City, Ecuador. We collected blood and nasal wash samples, and performed spirometry and exhaled nitric oxide fraction measurements. We explored potential predictors for recurrence of severe asthma attacks requiring emergency care over 6 months' follow-up.We recruited 283 children of whom 264 (93%) were followed-up for ≥6 months or until their next asthma attack. Almost half (46%) had a subsequent severe asthma attack requiring emergency care. Predictors of recurrence in adjusted analyses were (adjusted OR, 95% CI) younger age (0.87, 0.79-0.96 per year), previous asthma diagnosis (2.2, 1.2-3.9), number of parenteral corticosteroid courses in previous year (1.3, 1.1-1.5), food triggers (2.0, 1.1-3.6) and eczema diagnosis (4.2, 1.02-17.6). A parsimonious Cox regression model included the first three predictors plus urban residence as a protective factor (adjusted hazard ratio 0.69, 95% CI 0.50-0.95). Laboratory and lung function tests did not predict recurrence.Factors independently associated with recurrent emergency attendance for asthma attacks were identified in a low-resource LMIC setting. This study suggests that a simple risk-assessment tool could potentially be created for emergency rooms in similar settings to identify higher-risk children on whom limited resources might be better focused.

Why are people with asthma susceptible to pneumonia? A review of factors related to upper airway bacteria.

Asthma and pneumonia are common respiratory conditions globally, affecting individuals of all ages. Streptococcus pneumoniae is the predominant bacterial cause of pneumonia, with nasopharyngeal carriage an important step towards invasive and pulmonary disease. Vaccines provide individual protection, and also prevent nasopharyngeal carriage, providing herd immunity. Asthma is associated with an increased risk of pneumonia, but there is limited information on the underlying mechanism of this predisposition. Both asthma and its treatment may conceivably alter propensity to, and density of, carriage through an altered epithelial microenvironment driven by disease-related inflammation or treatment-related immunomodulation, for example with inhaled corticosteroids. The relative importance of these factors could impact the efficacy of vaccines in this vulnerable patient population. In this review, we summarize the evidence for an increased risk of pneumonia in asthma, and discuss factors affecting nasopharyngeal carriage in the context of current guidelines for pneumococcal vaccination.

Digital technologies and adherence in respiratory diseases: the road ahead.

Outcomes for patients with chronic respiratory diseases remain poor despite the development of novel therapies. In part, this reflects the fact that adherence to therapy is low and clinicians lack accurate methods to assess this issue. Digital technologies hold promise to overcome these barriers to care. For example, algorithmic analysis of large amounts of information collected on health status and treatment use, along with other disease relevant information such as environmental data, can be used to help guide personalised interventions that may have a positive health impact, such as establishing habitual and correct inhaler use. Novel approaches to data analysis also offer the possibility of statistical algorithms that are better able to predict exacerbations, thereby creating opportunities for preventive interventions that may adapt therapy as disease activity changes. To realise these possibilities, digital approaches to disease management should be supported by strong evidence, have a solid infrastructure, be designed collaboratively as clinically effective and cost-effective systems, and reflect the needs of patients and healthcare providers. Regulatory standards for digital interventions and strategies to handle the large amounts of data generated are also needed. This review highlights the opportunities provided by digital technologies for managing patients with respiratory diseases.

Does antibiotic treatment duration affect the outcomes of exacerbations of asthma and COPD? A systematic review.

Asthma and chronic obstructive pulmonary disease (COPD) cause significant morbidity and mortality worldwide, primarily through exacerbations. Exacerbations are often treated with antibiotics but their optimal course duration is uncertain. Reducing antibiotic duration may influence antimicrobial resistance but risks treatment failure. The objective of this article is to review published literature to investigate whether shorter antibiotic therapy duration affects clinical outcomes in the treatment of asthma and COPD exacerbations. We systematically searched electronic databases (MEDLINE, EMBASE, CINAHL, World Health Organisation International Clinical Trial Registry Platform, the Cochrane library, and ISRCTN) with no language, location, or time restrictions. We retrieved observational and controlled trials comparing different durations of the same oral antibiotic therapy in the treatment of acute exacerbations of asthma or COPD in adults. We found no applicable studies for asthma exacerbations. We included 10 randomized, placebo-controlled trials for COPD patients, all from high-income countries. The commonest studied antibiotic class was fluoroquinolones. Antibiotic courses shorter than 6 days were associated with significantly fewer overall adverse events (risk ratio (RR): 0.84, 95% confidence interval (CI): 0.75-0.93, p = 0.001) when compared with those of 7 or more days. There was no statistically significant difference for clinical success or bacteriological eradication in sputum (RR: 1.00, 95% CI: 0.88-1.13 and RR: 1.06, 95% CI: 0.79-1.44, respectively). Shorter durations of antibiotics for COPD exacerbations do not seem to confer a higher risk of treatment failure but are associated with fewer adverse events. This is in keeping with previous studies in community acquired pneumonia, but studies were heterogeneous and differed from usual clinical practice. Further observational and prospective work is needed to explore the significance of antibiotic duration in the treatment of asthma and COPD exacerbations.

Socioeconomic deprivation and the outcome of pulmonary rehabilitation in England and Wales.

BACKGROUND: Pulmonary rehabilitation (PR) improves exercise capacity and health status in patients with COPD, but many patients assessed for PR do not complete therapy. It is unknown whether socioeconomic deprivation associates with rates of completion of PR or the magnitude of clinical benefits bequeathed by PR. METHODS: PR services across England and Wales enrolled patients to the National PR audit in 2015. Deprivation was assessed using Index of Multiple Deprivation (IMD) derived from postcodes. Study outcomes were completion of therapy and change in measures of exercise performance and health status. Univariate and multivariate analyses investigated associations between IMD and these outcomes. RESULTS: 210 PR programmes enrolled 7413 patients. Compared with the general population, the PR sample lived in relatively deprived neighbourhoods. There was a statistically significant association between rates of completion of PR and quintile of deprivation (70% in the least and 50% in the most deprived quintiles). After baseline adjustments, the risk ratio (95% CI) for patients in the most deprived relative to the least deprived quintile was 0.79 (0.73 to 0.85), p<0.001. After baseline adjustments, IMD was not significantly associated with improvements in exercise performance and health status. CONCLUSIONS: In a large national dataset, we have shown that patients living in more deprived areas are less likely to complete PR. However, deprivation was not associated with clinical outcomes in patients who complete therapy. Interventions targeted at enhancing referral, uptake and completion of PR among patients living in deprived areas could reduce morbidity and healthcare costs in such hard-to-reach populations.

PRO: confronting resistance to rule-based medicine is essential to improving outcomes.

The past 20 years have seen two great changes in the practice of medicine: the widespread adoption of evidence-based medicine, and the increasing challenge of managing complex multimorbid patients. Both these developments have resulted in clinical rules and protocols becoming ever more abundant and increasingly critical to delivering safe and effective patient care. These evidence-based clinical rules perform at least as well as expert opinion, and the increasing volume and quality of available clinical data suggests their performance could continue to improve. This article considers why clinicians deviate from effective rules, highlighting key issues such as the persisting culture of heroism, institutional inertia, deference to authority and personal heuristics. We argue that better rules can be created, and that clinical improvements will follow if there is a 'common knowledge' of these rules. Furthermore, we argue that there is a ceiling to the effectiveness of any rule, even one as simple as ensuring hand hygiene, unless individuals are held accountable for transgressions.

Case series: the application of "third wave" cognitive behavioural therapies in difficult to treat asthma.

OBJECTIVE: This paper provides for the first time cases of individual psychological therapy undertaken in tertiary, difficult to treat asthma services using "third wave" cognitive behavioural therapy (CBT) approaches. METHODS: These cases were selected to represent common psychological presentations in difficult to treat asthma clinics, namely denial of severity and over-identification with asthma. Assessment, formulation, intervention and results are outlined. RESULTS: Case 1 demonstrated change from severe to mild depression and anxiety, reduction in shame and improved well-being. Case 2 demonstrated improvements in well-being and psychological symptoms. Both interventions were experienced by the patients as highly satisfactory. CONCLUSIONS: It is concluded that a psychological understanding of patients' presentations can open up new avenues for intervention. Further research into the potential utility of third wave cognitive therapies in difficult to treat asthma is warranted.

Untangling asthma, inducible laryngeal obstruction, and dysfunctional breathing in a competitive sportsperson.

A young woman with historically mild asthma experienced worsening breathlessness and cough with competitive ice skating. Despite optimizing and escalating treatment for her eosinophilic asthma, and addressing known exacerbating factors, her symptoms remained uncontrolled and refractory to bronchodilators and oral corticosteroids. Objective testing suggested her presentation was out of keeping with asthma alone, and she was suspected to have comorbid dysfunctional breathing and/or inducible laryngeal obstruction. Evidence was required to confirm the diagnoses, assess each condition's contribution to her symptom burden, and guide therapy. As exercise was a predominant trigger, she proceeded to cardiopulmonary exercise test with continuous laryngoscopy during exercise (CPET-CLE). Testing confirmed the presence of two forms of inducible laryngeal obstruction and evidence of hyperventilation predominant dysfunctional breathing. This case highlights the importance of identifying coexisting conditions in difficult-to-treat asthma, and the value of structured multidisciplinary assessment in referral centres for such individuals.

Home spirometry appears accurate and feasible for monitoring chronic respiratory disease.

Spirometry is underutilised and can be difficult to access. This study assessed the accuracy and feasibility of home spirometry compared to gold standard. Findings suggest home spirometry is accurate and feasible across many respiratory disease groups. https://bit.ly/42TLoYd.

Acid suppression does not reduce symptoms from vocal cord dysfunction, where gastro-laryngeal reflux is a known trigger.

Vocal cord dysfunction (VCD) is characterized by paradoxical inspiratory abduction of the vocal cords. Gastro-oesophageal reflux disease (GORD) is a known trigger. We studied 77 patients referred to a tertiary VCD clinic. VCD was diagnosed in 62, of which 83.9% had proven GORD. Following 8 weeks of acid suppression, 24.2% reported improvement in the severity and frequency of VCD attacks. This study suggests that empirical treatment of GORD in VCD marginally improves symptom control.

Assessing the risk of attack in the management of asthma: a review and proposal for revision of the current control-centred paradigm.

Asthma guidelines focus on day-to-day control of symptoms. However, asthma attacks remain common. They continue to cause mortality and considerable morbidity, and are a major financial burden to the UK National Health Service (NHS) and the wider community. Asthma attacks have chronic consequences, being associated with loss of lung function and significant psychological morbidity. In this article we argue that addressing daily symptom control is only one aspect of asthma treatment, and that there should be a more explicit focus on reducing the risk of asthma attacks. Management of future risk by general practitioners is already central to other conditions such as ischaemic heart disease and chronic renal impairment. We therefore propose a revised approach that separately considers the related domains of daily control and future risk of asthma attack. We believe this approach will have advantages over the current 'stepwise' approach to asthma management. It should encourage individualised treatment, including non-pharmacological measures, and thus may lead to more efficacious and less harmful management strategies. We speculate that this type of approach has the potential to reduce morbidity and healthcare costs related to asthma attacks.

Asthma control conundrum in clinical practice - Data from a two-stage Delphi survey and literature review.

Definitions and measures of asthma control used in clinical trials and practice often vary, as highlighted in the manuscript, "Is asthma control more than just an absence of symptoms? An expert consensus statement". Furthermore, the authors discussed differences between patients and healthcare professionals (HCPs) in terms of understanding and managing asthma. Given these disparities, there is a need for consensus regarding what constitutes well-controlled asthma and, especially, how best it can be measured and recorded. In the current work, we describe our data and provide more detail on the methodology from a two-stage Delphi survey and a structured literature review, which were designed to reach a consensus definition of asthma control and alleviate misalignments between patients and HCPs. Survey data were collected using a two-stage Delphi technique; a method used to collate expert opinions over a series of sequential questionnaires to reach a consensus. The collated Delphi survey data were compared with results from a comprehensive, structured literature review of 216 publications, to assess if there was a correlation between existing guidance and measures of asthma control used in clinical trials and standard clinical practice. In order to collate and interpret findings from the Delphi survey, responses from 82 panelists (73 HCPs and 9 authors) were qualitatively analyzed, quantitatively categorized, and presented as percentages or counts in Excel databases, which are detailed in the current work. Searches conducted using PubMed and Cochrane identified 664 manuscripts, and Embase was used to identify 89 congress abstracts. After applying a stringent screening method using predefined key words, the structured literature review consisted of 185 peer-reviewed manuscripts and 31 congress abstracts, and assessed existing guidance and measures of asthma control used in clinical trials. In this publication, we provide further insight into the predefined keywords, search strings, and strategy applied to identify manuscripts and congress abstracts for inclusion/exclusion, and detail methods for data extraction. Together, the data from the Delphi survey and structured literature review aimed to provide greater insights into challenges and approaches in achieving asthma control in clinical practice, with the potential for results to be used to guide a universally accepted definition and measure of asthma control that can be used and understood by patients, HCPs, and researchers. Qualitative and quantitative methodology and analysis from the Delphi survey and literature review search strategy can potentially be used to identify disparities and explore expert opinion and relevant literature in other therapeutic areas to guide a consensus where disparities exist.

Clinical utility of diagnostic guidelines and putative biomarkers in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis is a rare disease occurring almost exclusively in women. Diagnosis often requires surgical biopsy and the clinical course varies between patients with no predictors of progression. We evaluated recent diagnostic guidelines, clinical features and serum biomarkers as diagnostic and prognostic tools. METHODS: Serum vascular endothelial growth factor-D (VEGF-D), angiotensin converting enzyme (ACE), matrix metalloproteinases (MMP) -2 and -9, clinical phenotype, thoracic and abdominal computerised tomography, lung function and quality of life were examined in a cohort of 58 patients. 32 healthy female controls had serum biomarkers measured. RESULTS: Serum VEGF-D, ACE and total MMP-2 levels were elevated in patients. VEGF-D was the strongest discriminator between patients and controls (median = 1174 vs. 332 pg/ml p < 0.0001 with an area under the receiver operating characteristic curve of 0.967, 95% CI 0.93-1.01). Application of European Respiratory Society criteria allowed a definite diagnosis without biopsy in 69%. Adding VEGF-D measurement to ERS criteria further reduced the need for biopsy by 10%. VEGF-D was associated with lymphatic involvement (p = 0.017) but not the presence of angiomyolipomas. CONCLUSIONS: Combining ERS criteria and serum VEGF-D reduces the need for lung biopsy in LAM. VEGF-D was associated with lymphatic disease but not lung function.

Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function.

RATIONALE: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. OBJECTIVES: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. METHODS: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. MEASUREMENTS AND MAIN RESULTS: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (ß = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (ß = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)). CONCLUSIONS: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.