Upham discusses the study of house dust mite sublingual allergen immunotherapy (HDM-SLIT), by Woehlk et al, to determine if this intervention enhances bronchial epithelial cell (BEC) antiviral ...responses in allergic asthma. The study recruited 39 people with HDM sensitization and suboptimal asthma control despite maintenance inhaled corticosteroids, to which HDM-SLIT or placebo was added for 24 weeks. They interpret the findings as evidence that HDM-SLIT can improve innate airway epithelial responses to viral infection, thereby providing a mechanism by which HDM-SLIT might reduce asthma exacerbations and respiratory viral infections.
ABSTRACT
OCS play an important role in the management of asthma. However, steroid‐related AE are common and represent a leading cause of morbidity. Limited published studies suggest OCS usage varies ...across countries and recent registry data indicate that at least 25–60% of patients with severe asthma in developed countries may at some stage be prescribed OCS. Recent evidence indicate that many patients do not receive optimal therapy for asthma and are often prescribed maintenance OCS or repeated steroid bursts to treat exacerbations. Given the recent progress in adult severe asthma and new treatment options, judicious appraisal of steroid use is merited. A number of strategies and add‐on therapies are now available to treat severe asthma. These include increasing specialist referral for multidisciplinary assessments and implementing OCS‐sparing interventions, such as improving guideline adherence and add‐on tiotropium and macrolides. Biologics have recently become available for severe asthma; these agents reduce asthma exacerbations and lower OCS exposure. Further research, collaboration and consensus are necessary to develop a structured stewardship approach including realistic OCS‐weaning programmes for patients with severe asthma on regular OCS; education and public health campaigns to improve timely access to specialized severe asthma services for treatment optimization; and implementing targeted strategies to identify patients who warrant OCS use using objective biomarker‐based strategies.
Severe asthma is a high-burden disease. Real-world data on mepolizumab in patients with severe eosinophilic asthma is needed to assess whether the data from randomised controlled trials are ...applicable in a broader population.The Australian Mepolizumab Registry (AMR) was established with an aim to assess the use, effectiveness and safety of mepolizumab for severe eosinophilic asthma in Australia.Patients (n=309) with severe eosinophilic asthma (median age 60 years, 58% female) commenced mepolizumab. They had poor symptom control (median Asthma Control Questionnaire (ACQ)-5 score of 3.4), frequent exacerbations (median three courses of oral corticosteroids (OCS) in the previous 12 months), and 47% required daily OCS. Median baseline peripheral blood eosinophil level was 590 cells·µL
Comorbidities were common: allergic rhinitis 63%, gastro-oesophageal reflux disease 52%, obesity 46%, nasal polyps 34%.Mepolizumab treatment reduced exacerbations requiring OCS compared with the previous year (annualised rate ratio 0.34 (95% CI 0.29-0.41); p<0.001) and hospitalisations (rate ratio 0.46 (95% CI 0.33-0.63); p<0.001). Treatment improved symptom control (median ACQ-5 reduced by 2.0 at 6 months), quality of life and lung function. Higher blood eosinophil levels (p=0.003) and later age of asthma onset (p=0.028) predicted a better ACQ-5 response to mepolizumab, whilst being male (p=0.031) or having body mass index ≥30 (p=0.043) predicted a lesser response. Super-responders (upper 25% of ACQ-5 responders, n=61, 24%) had a higher T2 disease burden and fewer comorbidities at baseline.Mepolizumab therapy effectively reduces the significant and long-standing disease burden faced by patients with severe eosinophilic asthma in a real-world setting.
Background Asthma pathophysiology and treatment responsiveness are predicted by inflammatory phenotype. However, the relationship between airway microbiology and asthma phenotype is poorly ...understood. Objective We aimed to characterize the airway microbiota in patients with symptomatic stable asthma and relate composition to airway inflammatory phenotype and other phenotypic characteristics. Methods The microbial composition of induced sputum specimens collected from adult patients screened for a multicenter randomized controlled trial was determined by using 16S rRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined by using α- and β-diversity measures, and interphenotype differences were identified by using similarity of percentages, network analysis, and taxon fold change. Phenotypic predictors of airway microbiology were identified by using multivariate linear regression. Results Microbiota composition was determined in 167 participants and classified as eosinophilic (n = 84), neutrophilic (n = 14), paucigranulocytic (n = 60), or mixed neutrophilic-eosinophilic (n = 9) asthma phenotypes. Airway microbiology was significantly less diverse ( P = .022) and more dissimilar ( P = .005) in neutrophilic compared with eosinophilic participants. Sputum neutrophil proportions, but not eosinophil proportions, correlated significantly with these diversity measures (α-diversity: Spearman r = −0.374, P < .001; β-diversity: r = 0.238, P = .002). Interphenotype differences were characterized by a greater frequency of pathogenic taxa at high relative abundance and reduced Streptococcus , Gemella , and Porphyromonas taxa relative abundance in patients with neutrophilic asthma. Multivariate regression confirmed that sputum neutrophil proportion was the strongest predictor of microbiota composition. Conclusions Neutrophilic asthma is associated with airway microbiology that is significantly different from that seen in patients with other inflammatory phenotypes, particularly eosinophilic asthma. Differences in microbiota composition might influence the response to antimicrobial and steroid therapies and the risk of lung infection.
: Respiratory syncytial virus (RSV) bronchiolitis causes significant infant mortality. Bronchiolitis is characterized by airway epithelial cell (AEC) death; however, the mode of death remains ...unknown.
: To determine whether necroptosis contributes to RSV bronchiolitis pathogenesis via HMGB1 (high mobility group box 1) release.
: Nasopharyngeal samples were collected from children presenting to the hospital with acute respiratory infection. Primary human AECs and neonatal mice were inoculated with RSV and murine
, respectively. Necroptosis was determined via viability assays and immunohistochemistry for RIPK1 (receptor-interacting protein kinase-1), MLKL (mixed lineage kinase domain-like pseudokinase) protein, and caspase-3. Necroptosis was blocked using pharmacological inhibitors and RIPK1 kinase-dead knockin mice.
: HMGB1 levels were elevated in nasopharyngeal samples of children with acute RSV infection. RSV-induced epithelial cell death was associated with increased phosphorylated RIPK1 and phosphorylated MLKL but not active caspase-3 expression. Inhibition of RIPK1 or MLKL attenuated RSV-induced HMGB1 translocation and release, and lowered viral load. MLKL inhibition increased active caspase-3 expression in a caspase-8/9-dependent manner. In susceptible mice,
infection upregulated RIPK1 and MLKL expression in the airway epithelium at 8 to 10 days after infection, coinciding with AEC sloughing, HMGB1 release, and neutrophilic inflammation. Genetic or pharmacological inhibition of RIPK1 or MLKL attenuated these pathologies, lowered viral load, and prevented type 2 inflammation and airway remodeling. Necroptosis inhibition in early life ameliorated asthma progression induced by viral or allergen challenge in later life.
:
infection induces AEC necroptosis. Inhibition of necroptosis may be a viable strategy to limit the severity of viral bronchiolitis and break its nexus with asthma.
The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological ...consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy.
To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes.
16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.
Paired sputum samples were available from 61 patients (
= 34 placebo,
= 27 azithromycin). Azithromycin did not affect bacterial load (
= 0.37) but did significantly decrease Faith's phylogenetic diversity (
= 0.026) and
load (
< 0.0001). Azithromycin did not significantly affect levels of
,
,
, or
. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly.
In patients with persistent uncontrolled asthma, azithromycin reduced airway
load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.
Background
Several recent randomised controlled trials (RCT) have investigated the use of direct oral anticoagulants (DOAC) in the treatment of malignancy‐associated venous thromboembolism (VTE).
...Aims
This meta‐analysis combines all RCT data to determine the risks of recurrent VTE and bleeding with DOAC in patients with malignancy‐associated VTE compared with low‐molecular‐weight heparin (LMWH).
Methods
The study followed PRISMA guidelines. MEDLINE, EMBASE and CENTRAL were systematically searched from inception to 1 April 2020. References of reviews and relevant conference proceedings were searched by hand. Two authors independently evaluated study eligibility, extracted data and assessed risk of bias. Direct and indirect meta‐analyses were performed.
Results
In four RCT with low risk of bias (2907 patients), high certainty evidence suggested that DOAC had a 37% reduction in risk of recurrent VTE compared with LMWH (direct pooled risk ratio (RR) 0.63; 95% confidence interval (CI) 0.44–0.91; I2 = 28%). No significant difference was observed in the risk of major bleeding with DOAC compared with LMWH (RR 1.31; 95% CI 0.83–2.07; I2 = 22%; moderate certainty evidence), including in patients in gastrointestinal and genitourinary malignancy. An increased risk of combined major or clinically relevant non‐major bleeding was seen with DOAC (RR 1.52; 95% CI 1.09–2.12; I2 = 51%; low certainty evidence). Apixaban had the highest probability of being ranked the most effective and least bleeding risk among the DOAC.
Conclusion
DOAC are effective in treating malignancy associated VTE; however, caution is required in patients with high risk of bleeding. Apixaban had lower risk of bleeding compared to other DOAC in this population.
The treatment landscape in severe asthma is changing rapidly, with multiple new therapies emerging that promise to transform patient outcomes. In a patient who is not responding to conventional ...therapy with inhaled corticosteroids and long-acting β2-agonists, it is important to first consider if the diagnosis of asthma is correct and, second, to reflect on whether readily modifiable factors are contributing to poor asthma control. In selected patients it may be appropriate to consider a modified n-of-1 trial of add-on therapies such as long-acting anti-muscarinic agents, leukotriene blockers, theophylline or low dose macrolide antibiotics. A number of monoclonal antibodies are now available that target the molecular pathways that contribute to asthma pathogenesis, and more such agents are likely to emerge in the near future. These biologicals can be transformative in selected patients, markedly reducing the frequency of asthma exacerbations, and allowing many patients to reduce or eliminate their use of long term oral corticosteroids. If the promise of personalised treatment is to be fully realised, it is important that better methods are developed to target these new and expensive treatments to patients most likely to respond. The ultimate goal of inducing remission or cure of asthma is still some distance away.
Dendritic cells (DCs) are potent antigen-presenting cells. Because of their particular ability to initiate and regulate cell mediated and humoral immune responses, there is considerable interest in ...the role that DCs play in the pathogenesis of various lung diseases, especially those in which there is an excessive immune response to specific antigens (as in asthma) or a deficient immune response (as in lung cancer). A number of DC subpopulations have been defined in the lungs, including myeloid or conventional DCs that initiate T-cell immunity and antibody production and plasmacytoid DCs that have an important role in antiviral immunity and immune tolerance. Although an extensive body of literature has documented the role that DCs play in experimental models of lung disease, this review will highlight recent advances in our understanding of DC function in human disease, including asthma, COPD, antimicrobial immunity, and lung cancer. The future is likely to see new approaches whereby antigens and small molecules are targeted to receptors on particular DC subpopulations in order to modify pulmonary immune responses.
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