Biologic Therapies for Severe Asthma

Biologic Therapies for Severe Asthma Patients with severe asthma are at increased risk for a decreased quality of life, fixed airway obstruction, hospitalization, and death. Biologics may be required to reduce the disease burden. This review discusses the mechanisms, efficacy, and safety of biologics for severe asthma

Beta(2)-adrenergic receptor (ADRB2) gene polymorphisms and risk of COPD exacerbations : the Rotterdam study

The role of the beta(2)-adrenergic receptor (ADRB2) gene in patients with chronic obstructive pulmonary disease (COPD) is unclear. We investigated the association between ADRB2 variants and the risk of exacerbations in COPD patients treated with inhaled beta(2)-agonists. Within the Rotterdam Study, a population-based cohort study, we followed 1053 COPD patients until the first COPD exacerbation or end of follow-up and extracted rs1042713 (16Arg > Gly) and rs1042714 (27Gln > Glu) in ADRB2. Exposure to inhaled beta(2)-agonists was categorized into current, past, or non-use on the index date (date of COPD exacerbation for cases and on the same day of follow-up for controls). COPD exacerbations were defined as acute episodes of worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate exacerbations), or hospitalization (severe exacerbations). The associations between ADRB2 variants and COPD exacerbations were assessed using Cox proportional hazards models, adjusting for age, sex, use of inhaled corticosteroids, daily dose of beta(2)-agonists, and smoking. In current users of beta(2)-agonists, the risk of COPD exacerbation decreased by 30% (hazard ratio (HR); 0.70, 95% CI: 0.59-0.84) for each copy of the Arg allele of rs1042713 and by 20% (HR; 0.80, 95% CI: 0.69-0.94) for each copy of the Gln allele of rs1042714. Furthermore, current users carrying the Arg16/Gln27 haplotype had a significantly lower risk (HR; 0.70, 95% CI: 0.59-0.85) of COPD exacerbation compared to the Gly16/Glu27 haplotype. In conclusion, we observed that the Arg16/Gln27 haplotype in ADRB2 was associated with a reduced risk of COPD exacerbation in current users of inhaled beta(2)-agonists

Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR).

The Belgian severe asthma registry is a web-based registry encompassing demographic, clinical, functional and inflammatory data of severe asthmatics (SA), aiming at improving awareness, knowledge on its natural history and subphenotypes, and offering tools to optimize care of this asthma population. METHODS: The cross-sectional analyses of this registry included 350 SA as defined by the ATS (2000) from 9 Belgian centres, with at least one year follow up. RESULTS: Mean age was 55 +/- 14 yrs. SA were more frequently female (57%) and atopic (70%). Late-onset asthma (>/=40 yr) was observed in 31% of SA. Current smokers represented 12% while 31% were ex-smokers. In addition to high doses ICS + LABA, 65% of patients were receiving LTRA, 27% anti-IgE and 24% maintenance oral corticosteroids (8 mg (Interquartile range-IQR:4-8) methylprednisolone). Despite impaired airflow (median FEV1:67%; IQR: 52-81) only 65% had a post-bronchodilator FEV1/FVC ratio /= 50 ppb. Induced sputum was successful in 86 patients. Eosinophilic asthma (sputum Eos >/= 3%) was the predominant phenotype (55%) while neutrophilic (sputum Neu >/= 76%) and paucigranulocytic asthma accounted for 22% and 17% respectively. Comorbidities included rhinitis and chronic rhinosinusitis (49%), nasal polyposis (19%), oesophageal reflux (36%), overweight and obesity (47%) and depression (19%). In addition, 8% had aspirin-induced asthma and 3% ABPA. Asthma was not well-controlled in 83% according to ACT 1.5. CONCLUSION: In this cohort of patients with severe asthma, the majority displayed indices of persistent airflow limitation and eosinophilic inflammation despite high-dose corticosteroids, suggesting potential for eosinophil-targeted biotherapies

Bone mineral density and chronic lung disease mortality: the Rotterdam study

Context: Low bone mineral density (BMD) has been associated with increased all-cause mortality. Cause-specific mortality studies have been controversial. Objective: The aim of the study was to investigate associations between BMD and all-cause mortality and in-depth cause-specific mortality. Design and Setting: We studied two cohorts from the prospective Rotterdam Study (RS), initiated in 1990 (RS-I) and 2000 (RS-II) with average follow-up of 17.1 (RS-I) and 10.2 (RS-II) years until January 2011. Baseline femoral neck BMD was analyzed in SD values. Deaths were classified according to International Classification of Diseases into seven groups: cardiovascular diseases, cancer, infections, external, dementia, chronic lung diseases, and other causes. Gender-stratified Cox and competing-risks models were adjusted for age, body mass index, and smoking. Participants: The study included 5779 subjects from RS-I and 2055 from RS-II. Main Outcome Measurements: We measured all-cause and cause-specific mortality. Results: A significant inverse association between BMD and all-cause mortality was found in males [expressed as hazard ratio (95% confidence interval)]: RS-I, 1.07 (1.01-1.13), P = .020; RS-II, 1.31 (1.12-1.55), P = .001); but it was not found in females: RS-I, 1.05 (0.99-1.11), P = .098; RS-II, 0.91 (0.74-1.12), P = .362. An inverse association with chronic lung disease mortality was found in males [RS-I, 1.75 (1.34-2.29), P < .001; RS-II, 2.15 (1.05-4.42), P = .037] and in RS-I in females [1.72 (1.16-2.57); P = .008], persisting after multiple adjustments and excluding prevalent chronic obstructive pulmonary disease. A positive association between BMD and cancer mortality was detected in females in RS-I [0.89 (0.80-0.99); P = .043]. No association was found with cardiovascular mortality. Conclusions: BMD is inversely associated with mortality. The strong association of BMD with chronic lung disease mortality is a novel finding that needs further analysis to clarify underlying mechanisms

Usage of inhalation devices in asthma and chronic obstructive pulmonary disease: a Delphi consensus statement.

peer reviewedOBJECTIVES: The study aimed to assess usage of inhalation devices in asthma and chronic obstructive pulmonary disease (COPD). METHODS: In this two-round Delphi survey, 50 experts in asthma and COPD completed a 13-item, Internet-based, self-administered questionnaire about choice of inhalation device, training and monitoring of inhalation techniques, the interchangeability and the role of costs in the selection of inhalation devices. For each item, the median (central tendency) and interquartile ranges (degree of consensus) were calculated. RESULTS: Experts considered that the choice of inhalation device was as important as that of active substance (very good consensus) and should be driven by ease of use (good to very good consensus) and teaching (very good consensus). Experts recommended giving oral and visual instructions (good consensus) and systematic monitoring inhalation techniques. Pulmonologists and paramedics have predominantly educational roles (very good consensus). Experts discouraged inhalation device interchangeability (good consensus) and switching for cost reasons (good to very good consensus) without medical consultation (good consensus). CONCLUSIONS: The results of this survey thus suggested that inhalation devices are as important as active substances and training and monitoring are essential in ensuring effective treatment of asthma and COPD. Inhalation device switching without medical consultation should be avoided

Altered Cigarette Smoke-Induced Lung Inflammation Due to Ablation of Grx1

Glutaredoxins (Grx) are redox enzymes that remove glutathione bound to protein thiols, know as S-glutathionylation (PSSG). PSSG is a reservoir of GSH and can affect the function of proteins. It inhibits the NF-κB pathway and LPS aspiration in Grx1 KO mice with decreased inflammatory cytokine levels. In this study we investigated whether absence of Grx1 similarly repressed cigarette smoke-induced inflammation in an exposure model in mice. Cigarette smoke exposure for four weeks decreased lung PSSG levels, but increased PSSG in lavaged cells and lavage fluid (BALF). Grx1 KO mice had increased levels of PSSG in lung tissue, BALF and BAL cells in response to smoke compared to wt mice. Importantly, levels of multiple inflammatory mediators in the BALF were decreased in Grx1 KO animals following cigarette smoke exposure compared to wt mice, as were levels of neutrophils, dendritic cells and lymphocytes. On the other hand, macrophage numbers were higher in Grx1 KO mice in response to smoke. Although cigarette smoke in vivo caused inverse effects in inflammatory and resident cells with respect to PSSG, primary macrophages and epithelial cells cultured from Grx1 KO mice both produced less KC compared to cells isolated from WT mice after smoke extract exposure. In this manuscript, we provide evidence that Grx1 has an important role in regulating cigarette smoke-induced lung inflammation which seems to diverge from its effects on total PSSG. Secondly, these data expose the differential effect of cigarette smoke on PSSG in inflammatory versus resident lung cells

MicroRNA profiling in lung tissue and bronchoalveolar lavage of cigarette smoke-exposed mice and in COPD patients: A translational approach

© 2017 The Author(s). Chronic obstructive pulmonary disease (COPD) is characterized by a progressive airflow limitation and is associated with a chronic inflammatory response in both airways and lungs. microRNAs (miRNAs) are often highly conserved between species and have an intricate role within homeostatic conditions and immune responses. Also, miRNAs are dysregulated in smoking-associated diseases. We investigated the miRNA profile of 523 miRNAs by stem-loop RT-qPCR in lung tissue and cell-free bronchoalveolar lavage (BAL) supernatant of mice exposed to air or cigarette smoke (CS) for 4 or 24 weeks. After 24 weeks of CS exposure, 31 miRNAs were differentially expressed in lung tissue and 78 in BAL supernatant. Next, we correlated the miRNA profiling data to inflammation in BAL and lung, obtained by flow cytometry or ELISA. In addition, we surveyed for overlap with newly assessed miRNA profiles in bronchial biopsies and with previously assessed miRNA profiles in lung tissue and induced sputum supernatant of smokers with COPD. Several miRNAs showed concordant differential expression between both species including miR-31, miR-155, miR-218 and let-7c. Thus, investigating miRNA profiling data in different compartments and both species provided accumulating insights in miRNAs that may be relevant in CS-induced inflammation and the pathogenesis of COPD

Parasitic infections related to anti-type 2 immunity monoclonal antibodies: a disproportionality analysis in the food and drug administration’s adverse event reporting system (FAERS)

Introduction: Monoclonal antibodies (mAbs) targeting immunoglobulin E (IgE) [omalizumab], type 2 (T2) cytokine interleukin (IL) 5 [mepolizumab, reslizumab], IL-4 Receptor (R) α [dupilumab], and IL-5R [benralizumab]), improve quality of life in patients with T2-driven inflammatory diseases. However, there is a concern for an increased risk of helminth infections. The aim was to explore safety signals of parasitic infections for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab.Methods: Spontaneous reports were used from the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database from 2004 to 2021. Parasitic infections were defined as any type of parasitic infection term obtained from the Standardised Medical Dictionary for Regulatory Activities® (MedDRA®). Safety signal strength was assessed by the Reporting Odds Ratio (ROR).Results: 15,502,908 reports were eligible for analysis. Amongst 175,888 reports for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab, there were 79 reports on parasitic infections. Median age was 55 years (interquartile range 24–63 years) and 59.5% were female. Indications were known in 26 (32.9%) reports; 14 (53.8%) biologicals were reportedly prescribed for asthma, 8 (30.7%) for various types of dermatitis, and 2 (7.6%) for urticaria. A safety signal was observed for each biological, except for reslizumab (due to lack of power), with the strongest signal attributed to benralizumab (ROR = 15.7, 95% Confidence Interval: 8.4–29.3).Conclusion: Parasitic infections were disproportionately reported for mAbs targeting IgE, T2 cytokines, or T2 cytokine receptors. While the number of adverse event reports on parasitic infections in the database was relatively low, resulting safety signals were disproportionate and warrant further investigation