Asthma Exacerbations In Patients Research Articles

Patterns of Rescue and Maintenance Medication Claims Surrounding an Asthma Exacerbation in Patients Treated as Intermittent or Mild Persistent Asthma.

To examine patterns of short-acting ß2-agonist (SABA) and maintenance therapy claims surrounding the subset of severe asthma exacerbations associated with outpatient, urgent care, or emergency department visits or hospitalization (termed serious exacerbations) in patients treated as intermittent or mild persistent asthma. This was a retrospective study of 2010-2017 administrative claims from MerativeTM MarketScan® US databases for patients ≥12 years filling a SABA prescription for asthma (index). Patients had ≥12 months continuous insurance eligibility pre- and post-index and ≥1 additional SABA and/or maintenance medication fill appropriate for mild persistent asthma post-index. Prescription fills were assessed over 30 days before and after a serious exacerbation event. Of 323,443 patients (mean [standard deviation] age: 34.9 [18.2] years; 62.0% female) treated as intermittent or mild persistent asthma, 51,690 (16.0%) experienced ≥1 serious exacerbation post-index. During the 30 days pre-event, a greater proportion of patients filled a SABA versus maintenance therapy (24.6% vs 19.0%; odds ratio [OR]: 1.39, 95% confidence interval [CI]: 1.35-1.43; p < 0.001); during the 30 days post-event, patients were more likely to fill maintenance medication versus SABA (88.6% vs 67.0%; OR [95% CI]: 3.88 [3.75-4.01]; p < 0.001). The closer in time prior to the event, the greater the likelihood of filling a SABA versus maintenance prescription (OR [95% CI]; 1-7 days pre-event: 1.42 [1.36-1.48]; 8-14 days pre-event: 1.34 [1.27-1.41]; 15-30 days pre-event: 1.18 [1.12-1.24]; all p < 0.001). Over 4.5 times more patients filled a maintenance therapy within 7 days post-event (45,014) versus all 30 days pre-event (9835) (OR [95% CI]: 28.7 [27.7-29.7]; p < 0.001). These patterns of SABA rescue and maintenance fills suggest that a "window of opportunity" may exist to interrupt a serious exacerbation occurrence for patients treated as intermittent or mild persistent asthma if symptoms and inflammation are addressed concomitantly.

Terapi &lt;i&gt;Montelukast &lt;/i&gt;pada Asma

Asthma is a chronic inflammatory respiratory condition caused by various inflammatory mediators, including those from the arachidonic acid pathway, which serves as a precursor for leukotrienes and prostaglandins. Leukotriene receptor antagonists (LTRAs) have been approved since 1998 as a treatment for asthma. Montelukast is one of the LTRAs that is useful for asthma control, including cases that accompanied by allergic rhinitis. A daily dose of 5-10 mg is recommended for persistent asthma as the preferred controller. LTRAs are not recommended for acute asthma exacerbation due to their relatively slow onset, but they are beneficial in preventing exacerbations. They are also indicated for exercise-induced asthma (EIA), and can be taken 2 hours prior to exercise. Montelukast can be administered as monotherapy or added to LABA-ICS therapy. It is suitable for adults, children, and infants over 1 year of age, preferably taken at night to prevent symptoms in the early morning. Possible side effects include respiratory tract infections, abdominal pain, diarrhea, and neuropsychiatric disorders. Montelukast is considered safe for use during pregnancy and breastfeeding. Physicians should provide comprehensive education for patients regarding medication compliance and the potential risks of side effects. Regular daily use of montelukast is beneficial in preventing acute exacerbations in asthma patients.

An efficient machine learning framework to identify important clinical features associated with pulmonary embolism.

A misdiagnosis of pulmonary embolism (PE) can have severe consequences such as disability or death. It's crucial to accurately identify key clinical features of PE in clinical practice to promptly identify potential PE patients who may present asymptomatically, and to prevent misdiagnosing PE as asthma exacerbation in patients with symptoms like dyspnea or chest pain. However, reliably identifying these important features can be challenging due to many factors influencing the likelihood of PE development in complex fashions (e.g., the interactions among these factors). To address this difficulty, we presented an effective framework using the deep neural network (DNN) model and the permutation-based feature importance test (PermFIT) procedure, i.e., PermFIT-DNN. We applied the PermFIT-DNN framework to the analysis of data from a PE study for asthma exacerbation patients. Our analysis results show that the PermFIT-DNN framework can robustly identify key features for classifying PE status. The important features identified can also aid in accurately predicting the PE risk.

Myeloid-associated differentiation marker is associated with type 2 asthma and is upregulated by human rhinovirus infection.

Human rhinoviruses are known to predispose infants to asthma development during childhood and are often associated with exacerbations in asthma patients. MYADM epithelial expression has been shown to associate with asthma severity. The goal of this study was to determine if MYADM expression patterns were altered in asthma and/or rhinovirus infection and if increased MYADM expression is associated with increased asthma-associated factors. Utilizing H1HeLa cells and differentiated primary human airway epithelial cells (AECs), we measured the expression of MYADM and inflammatory genes by qRT-PCR in the presence or absence of RV-1B infection or poly I:C treatment and with siRNA knockdown of MYADM. Expression of MYADM in the asthmatic lung was determined in the ovalbumin (ova)-challenged murine model. MYADM expression was upregulated in the lungs from ova-treated mice and in particular on the subsurface vesicle membrane in airway epithelial cells. Upon infection with RV-1B, human AECs grown at an air-liquid interface had increased the MYADM expression predominantly detected in ciliated cells. We found that the presence of MYADM was required for expression of several inflammatory genes both in a resting state and after RV-1B or poly I:C treatments. Our studies show that in a mouse model of asthma and during RV-1B infection of primary human AECs, increased MYADM expression is observed. In the mouse model of asthma, MYADM expression was predominantly on the luminal side of airway epithelial cells. Additionally, MYADM expression was strongly associated with increases in inflammatory genes, which may contribute to more severe asthma and RV-linked asthma exacerbations.

The Role of Inflammatory Phenotype in Patients With Exacerbation-prone Asthma and Ongoing Therapy

IntroductionThe risk factors for having frequent exacerbations are not well documented in cohort studies of patients with asthma on existing therapy. The objective of the present study was to compare the clinical and inflammatory characteristics of patients with exacerbation-prone asthma (EPA) with a history of two or more exacerbations in the previous year with those who had presented just one or no exacerbation. MethodsAn ambispective observational study was conducted in a tertiary hospital. Patients diagnosed with moderate or severe asthma and ongoing therapy, whose inflammatory profile was determined by means of allergy and atopy status, blood eosinophilia and induced sputum were included. Patients were classified according to the number of asthma exacerbations in EPA (≥2 exacerbations in the previous year) vs. non-exacerbators (≤1 exacerbation in the previous year). Clinical, lung function and inflammatory characteristics of the two groups were compared. ResultsThree hundred ten patients were visited in the Asthma Unit in 2018 and the combination of atopy and allergy status, blood eosinophilia and induced sputum was obtained in 96 (31%) patients. Of this latter group, 46 patients (47%) presented EPA compared to 50 (53%) non-exacerbators. Airway and blood eosinophilic inflammation did not differ between EPA and non-exacerbators in patients with asthma and ongoing therapy, and it was not a risk factor for EPA in our cohort. ConclusionAirway or blood type 2 inflammation status is not a valid tool for recognizing EPA or predicting asthma exacerbations in asthma patients following controller therapy.

An overview of the preclinical discovery and development of tezepelumab for the treatment of asthma

ABSTRACT Introduction Tezepelumab is a human IgG2 monoclonal antibody (mAb) that binds to human thymic stromal lymphopoietin (TSLP), preventing its interaction with the receptor and inhibiting multiple downstream inflammatory pathways. TSLP is an alarmin relevant to the pathogenesis of asthma. Areas covered This article focuses on the significance of TSLP in developing asthma and how tezepelumab can target it, thus playing a potentially relevant role in the treatment of asthma. Expert opinion An extensive clinical development program has shown that tezepelumab can improve all key primary and secondary endpoints in patients with severe asthma, compared to placebo, when added to standard therapy. Of particular importance is the favorable impact of this biological drug on exacerbation rates and lung function in patients with uncontrolled severe asthma regardless of the type 2 endotype. Therefore, tezepelumab is likely the first biologic to treat asthma exacerbations in patients with low eosinophil levels successfully. Furthermore, it appears to be a safe drug and can be ‘self-administered’ using a pre-filled, disposable pen. Tezepelumab should be preferred over other currently available biologics because blocking upstream mediators may have a broader therapeutic impact than those that inhibit downstream cytokines and/or block their receptors.

Effect of Azithromycin on Exacerbations in Asthma Patients with Obesity: Protocol for a Multi-Center, Prospective, Single-Arm Intervention Study.

Obesity is associated with severe asthma, but no specific treatment has been established. The gut microbiome is increasingly recognized as a crucial factor, but specific treatments focused on the gut microbiome have not been established. Recently, azithromycin has been found to have the capacity to attenuate exacerbations, a characteristic of severe asthma. The effect of azithromycin on obesity-induced severe asthma is not understood. The purpose of the present study is to clarify the effect of azithromycin on exacerbations in asthmatic patients with obesity. To explore the mechanism, the gut microbiome, metabolites of microbes such as short-chain fatty acids, and blood inflammatory cytokines will be analyzed to evaluate the correlation with the effect of azithromycin on exacerbations in obesity-induced severe asthma. A multi-center, prospective, single-arm intervention study is planned. The present study will allow us to evaluate the effect of azithromycin on exacerbations, particularly in asthma patients with obesity, and explore biomarkers, targeting molecules including the gut microbiome, which are correlated with decreased exacerbations. The present results could contribute to identifying new therapeutic prospects and targeted microbes or molecules associated with severe clinical characteristics in asthmatic patients with obesity. This study has been registered as a prospective study with the University Hospital Medical Information Network (UMIN0000484389) and the Japan Registry of Clinical Trials (jRCTs071220023).

Reduced Skeletal Muscle Mass Is Associated with an Increased Risk of Asthma Control and Exacerbation.

Skeletal muscle mass (SMM) has been suggested to be associated with multiple health-related outcomes. However, the potential influence of SMM on asthma has not been largely explored. To study the association between SMM and clinical features of asthma, including asthma control and exacerbation, and to construct a model based on SMM to predict the risk of asthma exacerbation (AEx). In this prospective cohort study, we consecutively recruited patients with asthma (n = 334), classified as the SMM Normal group (n = 223), SMM Low group (n = 88), and SMM High group (n = 23). We investigated the association between SMM and clinical asthma characteristics and explored the association between SMM and asthma control and AEx within a 12-month follow-up period. Based on SMM, an exacerbation prediction model was developed, and the overall performance was externally validated in an independent cohort (n = 157). Compared with the SMM Normal group, SMM Low group exhibited more airway obstruction and worse asthma control, while SMM High group had a reduced eosinophil percentage in induced sputum. Furthermore, SMM Low group was at a significantly increased risk of moderate-to-severe exacerbation compared with the SMM Normal group (relative risk adjusted 2.02 [95% confidence interval (CI), 1.35-2.68]; p = 0.002). In addition, a model involving SMM was developed which predicted AEx (area under the curve: 0.750, 95% CI: 0.691-0.810). Low SMM was an independent risk factor for future AEx. Furthermore, a model involving SMM for predicting the risk of AEx in patients with asthma indicated that assessment of SMM has potential clinical implications for asthma management.

The Impact of Tezepelumab in Uncontrolled Severe Asthma: A Systematic Review of Randomized Controlled Trials.

Asthma, a chronic illness, is characterized by inflammation and airway constriction. Uncontrolled severe asthma is related to poor quality of life and increased utilization of health resources. Conventional treatments are associated with a significant amount of adverse effects. Recent years have seen the identification of various molecular effectors and signaling pathways as interesting targets for the biological therapy of severe asthma that is resistant to current therapies. Because they only target some downstream components of the inflammatory response in asthma, leaving other components unaffected, current biologic treatments only lower the exacerbation rate by 50%. If we focus on the upstream mediators of the inflammatory response in asthma, it might have a greater effect and be more efficient. Tezepelumab is a human monoclonal IgG2 antibody that specifically binds to thymic stromal lymphopoietin (TSLP) at the level of its TSLPR (thymic stromal lymphopoietin receptor) binding site, inhibiting the interaction between human TSLP and TSLPR. It is being used to treat the cytokines on the respiratory epithelial layer known as "alarmins." It is the only biologic drug available for treating severe uncontrolled asthma, despite limitations in biomarker and phenotype. In light of recent developments, the lack of knowledge on tezepelumab prompts us to publish a comprehensive systematic review. We discovered that regardless of blood eosinophil level and fractional exhaled nitric oxide levels, tezepelumab dramatically lowers asthma exacerbation in patients with severe uncontrolled asthma when compared to placebo. Tezepelumab also lessens patients' demand for healthcare resources while improving clinical indicators of lung function, health-related quality of life, and asthma management in patients. Tezepelumab plays a role in enhancing pre-bronchodilator FEV1 and lowering blood eosinophil count and fractional exhaled nitric oxide in patients with or without chronic allergies (FeNO). There have been no reports of fatalities or severe adverse events connected to tezepelumab.

No Specific Factors Associated with Risk of Readmission for Rebound Pain in Children with Sickle Cell Disease and Asthma Treated with Systemic Corticosteroids

Introduction: Asthma occurs in up to 28% of patients with sickle cell disease (SCD) and is associated with increased incidence of vaso-occlusive pain, acute chest syndrome (ACS), and mortality. Systemic steroids are the standard treatment for acute asthma and are often used in patients with SCD, especially as clinical symptoms of acute asthma exacerbations may often overlap with those of ACS. The risk of rebound pain following treatment with corticosteroids has been reported in other studies. However, the temporal association and the factors associated with the risk of rebound vaso-occlusive pain, specifically in those with co-morbid asthma diagnosis, have not been well described. Objective: To evaluate the temporal association between the use of systemic corticosteroids in patients with SCD and asthma and the factors associated with the risk of rebound vaso-occlusive pain. Methods: Patients with confirmed SCD and asthma, between ages 4-18 years of age, and admitted between 2006 and 2009, were eligible. Based on their associations with SCD and asthma, the co-variables of interest evaluated included hydroxyurea (HU) usage, age, sex, atopy, indication for hospitalization, and length of hospital admission. Participants were included if they received systemic glucocorticoids (dexamethasone, methylprednisolone, prednisone, prednisolone) during admission. Participants were excluded if they were receiving chronic blood transfusion therapies or participating in clinical trials involving blood transfusions. Our primary end-point was readmission for rebound vaso-occlusive pain within 14 days of the index admission. Continuous variables were analyzed with the mean (std. deviation) or median (inter-quartile range), based on the distribution, and compared by group with a t test or Somers'd statistic. Categorical variables were analyzed with counts (percent) and compared with a Chi-square statistic. All tests were adjusted for clustering by patients. Results: Fifteen distinct patients, 9 (60%) females, with a total of seventy-six admissions with administration of corticosteroids were included in the analysis (Table). Fifty-seven (75%) of admissions occurred in female patients with a median length of hospitalization of 3.0 days (IQR 2.0 - 4.8). Of the 76 episodes of corticosteroid use, 65 (85.5%) were due to a primary respiratory illness. There were twenty-eight (36.8%) readmissions for rebound vaso-occlusive pain with a median time to readmission of 3.0 (IQR 2.0 - 6.0) days. Amongst all patients, neither sex, history of atopy (>=2 positive skin sensitization tests), indication for hospitalization, or length of hospitalization were associated with the risk of readmission for rebound pain (p=0.425, p=0.540, p=0.721 respectively). Only 2 patients with 5 admissions were documented to be on HU and so we could not assess the relationship to rebound with HU usage. There was a trend for an association of history of early ACS and risk of rebound vaso-occlusive pain. Patients with ACS before the age of 4 were less likely to experience rebound vaso-occlusive pain compared to those without early ACS (P=0.051). Discussion: Our data shows that patients with sickle cell disease and asthma treated with corticosteroids are at risk for readmission due to rebound vaso-occlusive pain in more than one third of episodes (36.8%) following initial corticosteroid exposure. Our study did not identify any specific factors associated with risk of readmission for rebound pain following corticosteroid use. While corticosteroids are life-saving in status asthmaticus, the risk for rebound pain is significant and clinicians should work to optimize chronic asthma therapy to prevent the need for systemic corticosteroids in asthma exacerbations in patients with SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dupilumab Is Effective in Patients With Moderate-to-Severe Uncontrolled GINA-Defined Type 2 Asthma Irrespective of an Allergic Asthma Phenotype

The Global Initiative for Asthma report recommends consideration of add-on biologics for patients with type 2 inflammation (blood eosinophils ≥150 cells/μL, fractional exhaled nitric oxide [Feno] ≥20 parts per billion or allergic asthma) whose asthma cannot be controlled by high-dose inhaled corticosteroids. In QUEST (NCT02414854), add-on dupilumab versus placebo was efficacious in patients with uncontrolled, moderate to severe asthma, including those with eosinophils greater than or equal to 150 cells/μL and/or Feno greater than or equal to 25 parts per billion. To assess dupilumab efficacy in patients with a type 2 phenotype in the presence or absence of allergic asthma phenotype. Patients aged 12 years or older received add-on dupilumab 200/300 mg versus matched placebo every 2 weeks for 52 weeks. Allergic asthma phenotype was defined as baseline serum total IgE greater than or equal to 30 IU/mL and 1 or more perennial aeroallergen-specific IgE level greater than or equal to 0.35 kU/L. Annualized rate of severe asthma exacerbations and changes from study baseline in prebronchodilator and postbronchodilator FEV1 were evaluated in patients with allergic and nonallergic phenotype with baseline blood eosinophils greater than or equal to 150 cells/μL and/or Feno greater than or equal to 20 parts per billion. Of 1902 patients in QUEST, 83.3% had eosinophils and/or Feno above Global Initiative for Asthma thresholds; 56.9% had evidence for allergic asthma. Dupilumab significantly reduced the rate of severe asthma exacerbations in patients with (48.8%) and without (64.0%) evidence of allergic asthma and improved prebronchodilator and postbronchodilator FEV1 in patients with elevated type 2 biomarkers, irrespective of whether they showed evidence of an allergic asthma phenotype. In patients with type 2 biomarkers over Global Initiative for Asthma thresholds, dupilumab significantly reduced exacerbations and improved lung function. Efficacy was not impacted by allergic status.

Typical antipsychotics is associated with increased risk of severe exacerbation in asthma patients: a nationwide population-based cohort study

BackgroundSevere asthma exacerbation reduces patients’ quality of life, results in visits to the emergency department (ED) and hospitalization, and incurs additional medical costs. Antipsychotics block receptors with bronchodilation function; however, the association between antipsychotic use and severe asthma exacerbation is unknown. This study aimed to investigate the effects of antipsychotics on asthma-related ED visits and hospitalizations.MethodsA case-crossover design was used in this study. Using the 2003–2017 Taiwan National Health Insurance Reimbursement Database, we established a cohort of 18,657 adults with asthma exacerbation leading to ED visits or hospitalization. Univariate and multivariate conditional logistic regressions were conducted to explore the association between antipsychotic use and severe asthma exacerbation. Subgroup analyses of different classes, doses, receptor functions of antipsychotics, different psychiatric disease, and sensitivity analyses of excluding patients with schizophrenia were also performed.ResultsAntipsychotic use was associated with a higher risk of severe asthma exacerbation (adjusted odds ratio [OR]: 1.27; 95% confidence interval [CI] 1.05–1.54; P = 0.013) compared with no use of antipsychotics. The use of typical antipsychotics increased the risk of severe asthma exacerbation (adjusted OR: 1.40, 95% CI 1.10–1.79, P = 0.007), whereas the use of atypical antipsychotics did not. These results did not change after the exclusion of patients with schizophrenia. There was a dose-dependent effect of antipsychotics (trend test, P = 0.025). Antipsychotics that block the M2 muscarinic or D2 dopaminergic receptors were associated with an increased risk of severe asthma exacerbation (adjusted OR: 1.39, 95% CI 1.10–1.76, P = 0.007 and adjusted OR: 1.33, 95% CI 1.08–1.63, P = 0.008, respectively). However, use of antipsychotics did not increase risk of severe asthma exacerbation in patients with psychiatric disorder.ConclusionsThe use of typical antipsychotics is associated with a dose-dependent increased risk of severe asthma exacerbation, especially for patients without psychiatric disorders. Further research on the impact of typical antipsychotics on asthma exacerbation is warranted.

Efficacy of Dupilumab in the Prevention of Seasonal Exacerbations in Patients With and Without Evidence of an Allergic Asthma Phenotype

Asthma exacerbations are subject to seasonal variability. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases. The TRAVERSE open-label extension study (NCT02134028) evaluated long-term safety and tolerability of add-on dupilumab in patients with uncontrolled, moderate-to-severe asthma from the 52-week QUEST study (NCT02414854). This post-hoc analysis assessed long-term dupilumab efficacy in reducing seasonal asthma exacerbations in patients with/without evidence of an allergic phenotype.

REAL-WORLD STUDY ON THE USE OF AZITHROMYCIN IN ASTHMA: EXPERIENCE FROM A DISTRICT TEACHING HOSPITAL

TOPIC: Allergy and Airway TYPE: Original Investigations PURPOSE: Asthma affects approximately 300 million people world-wide with the global burden of disease estimated to be 15 million disability-adjusted life-years. Azithromycin exhibits anti-inflammatory effects in addition to antibiotic properties. The British Thoracic Society guidelines recommends long-term macrolides use in adult asthmatics to reduce exacerbation rate. Azithromycin has been associated with side effects like prolonged QTc, ventricular arrhythmias, hearing impairment and diarrhoea. Real world studies are important for clinical decision making. This study aimed to determine if there is an improvement in the number exacerbations in asthmatic patients on long-term azithromycin in addition to other aspects of prescription METHODS: An observational study looking at 34 asthmatic patients on azithromycin was done. The patient data sets were anonymised and analysed on an Excel 2010 Spread sheet. Asthmatic patients aged 18 and over were included. This study excluded patients with non-tuberculosis mycobacterium, overlap conditions such as COPD and bronchiectasis, and patients on nebulised antibiotics or monoclonal antibodies.Data collected included: age, sex, respiratory diagnosis, co-morbidities, and immune status, number of infections and hospitalisations prior to and after staring azithromycin, lung function, corrected QT intervals, hearing issues, liver function test and gastrointestinal symptoms. RESULTS: 34 asthmatic patients (9 male, 25 female) with a median age of 58 (Range: 23-81) years were commenced on prophylactic azithromycin at the dose of 250mg Three times a week. The average BMI was 31.66 (S.D. 7.83). There were 8 smokers, 9 ex-smokers and 17 non-smokers. 7 patients were immunosuppressed. The dose prescribed was 250 mg three times a week. Mean duration was 39.83 (S.D. 24.04). Treatment was stopped in 13 patients: 7/13 for ineffectiveness, 4/13 for side effects (gastrointestinal problems 2/13 and hearing issues in 2/13), and 2/13 for other reasons not documented. Approximately 5.8 % hearing impairment exclusively due to azithromycin. Additionally, 2/34 patients (1 male, 1 female) had prolonged QTc before starting and 5/34 patients (3 female, 2 male) had prolonged QTc after starting azithromycin. No statistical significance (p>0.05) in the FEV1: FVC ratio before and after starting azithromycin. The average number of infections in the pre-treatment group was 6.44 (S.D. 2.80) versus 1.52 (S.D. 2.20) in the post azithromycin phase. The reduction in the number of infections and hospitalisations over the 12 months following treatment was significant with p<0.001 and p<0.034, respectively. 12/34 patients experienced a 100% reduction in the number of infections. Information on number of infections pre and post treatment were based on patients recalling and may pose a recall bias CONCLUSIONS: Long-term prophylactic azithromycin has been shown to correlate with a significant reduction the number of infections and hospitalisations in asthmatic patients. Our study did not show any lung function improvements with azithromycin use and the adverse effect hearing loss similar to previous studies of 5% CLINICAL IMPLICATIONS: Azithromycin is a safe and effective prophylactic drug in reducing exacerbations in this cohort of asthma patients our real world experience is in keeping with studies done so far DISCLOSURES: No relevant relationships by Hanan Ajay, source=Web Response No relevant relationships by Tanya Gordon, source=Web Response No relevant relationships by Nargis Khatoon, source=Web Response No relevant relationships by Aravind Ponnuswamy, source=Web Response

ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta-analysis.

The polymorphism Arg16 in β2 -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β2 -agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. The study was undertaken using data from 10 independent studies (n=5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects. In subjects treated with ICS and LABA (n=832, age: 3-21years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I2 =0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I2 =0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71-1.39, I2 =0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting β2 -agonists (n=973), ICS monotherapy (n=2623), ICS plus leukotriene receptor antagonists (LTRA; n=338), or ICS plus LABA plus LTRA (n=686). The ADRB2 Arg16haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2genotype-guided treatment which might improve clinical outcomes in asthmatic patients.

Exacerbation of asthma and neutrophil-dominated airway inflammation in patients with cold-induced airway hyperresponsiveness

Background . Neutrophils can play a significant role in the formation of bronchial inflammation in asthma exacerbation in patients with cold-induced airway hyperresponsiveness (CIAHR). Aim. To evaluate the role of neutrophils in the dynamics of the inflammatory pattern of bronchi in the exacerbation of asthma in patients with CIAHR. Materials and methods. In 31 patients (average age (37.2 ± 2.7) years) with persistent bronchial asthma (BA) with moderate exacerbation and previously established cold-induced airway hyperresponsiveness during cold air isocapnic hyperventilation (– 20 ºC, 3 min) (CAIH), the level of asthma control (Asthma Control Test (ACT), score) and external respiration (forced expiratory volume in the first second (FEV 1 ), forced expiratory flow between 25% and 75% of the vital capacity (FEF 25–75 )) were assessed; induced sputum (IS) was examined initially and after 24 weeks of follow-up. At the time of the examination, the patients were additionally prescribed prednisone orally (at a maximum dose of 30 mg) for the first 10 days in order to stop the exacerbation, and then they continued treatment with a combination of budesonide / formoterol (640 / 18 μg per day) for 24 weeks. Results. At the time of the initial examination, the ACT score was 17.0 (13.0; 19.5), FEV 1 was 89.1 ± 3.9%, and the number of neutrophils in the sputum was 55.9 ± 5.6%. At the end of treatment, the ACT score was 22.0 (17.0; 24.5) ( p = 0.037), FEV 1 was 96.2 ± 2.9% ( p = 0.038), the number of neutrophils in IS decreased, but remained high enough (40.0 ± 5.5%; p = 0.048); and the number of eosinophils did not change. A linear regression equation was made reflecting the relationship between the initially high number of neutrophils in the sputum, other cellular elements in the sputum, the level of asthma control, and the degree of severity of the bronchial response after a bronchoprovocation test with CAIH. Conclusion . Asthma exacerbation in patients with CIAHR is associated with an increase in the neutrophil pool of the bronchial inflammatory infiltrate and correlates with the degree of severity of the airway reaction to cold bronchoprovocation and the level of asthma control.

Increasing utility of FeNO as a biomarker of type-2 inflammation in severe asthma

Since the discovery that nitric oxide (NO) can be measured in the exhaled breath and that the fractional exhaled NO (FeNO) is increased in asthma, FeNO has been recognised as a biomarker of type 2 inflammation in the airways, reflecting the effect of type 2-associated cytokines, interleukin (IL)-4 and IL-13, that play an important role in bronchial hyperresponsiveness, mucus secretion and goblet cell hyperplasia, and T-helper type 2 polarisation, and also in allergic and eosinophilic inflammation. Since 2011, FeNO, which remains a convenient measurement for patients as young as 5 years, has been recommended for use in the diagnosis of eosinophilic airway inflammation as a supportive adjunct towards the diagnosis of asthma and in assessing corticosteroid responsiveness. 1 Dweik RA Sorkness RL Wenzel S et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med. 2010; 181: 1033-1041 Crossref PubMed Scopus (220) Google Scholar Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysisIn uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations. Full-Text PDF The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational studyExacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. Full-Text PDF

Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysis

Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations. In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEV1 percent predicted 40-80%; FEV1 reversibility of 12% or higher and 200 mL; Asthma Control Questionnaire (ACQ-5) score of 1·5 or higher; and complete data on baseline type 2 biomarkers (FeNO, eosinophils, and total IgE) with no baseline minimum requirement. Annualised severe exacerbation rate was assessed by baseline FeNO (<25 ppb, ≥25 to <50 ppb, ≥50 ppb; negative binomial model) and cross-classified by baseline blood eosinophils (<150 cells per μL, ≥150 to <300 cells per μL, ≥300 cells per μL) and prior exacerbations (one, two or more), all adjusted for baseline ACQ-5, postbronchodilator FEV1, and other clinical characteristics. Post-hoc analyses were done in the intention-to-treat population. The LIBERTY ASTHMA QUEST STUDY is registered on ClinicalTrials.gov, NCT02414854, and is complete. Patients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to <50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per μL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per μL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011). In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations. Sanofi and Regeneron Pharmaceuticals.

Safety of biological treatment of severe asthma during the COVID-19 pandemic

COVID-19 is an infectious disease that rapidly spread around the world and therefore is a challenge for treating chronic diseases, such as severe asthma. According to the guidelines of various health organizations, biological treatment in patients with severe asthma should be continued. The aim of this study was to evaluate the information we have gathered so far about safety of biological treatment of severe asthma during the COVID-19 pandemic. We analyzed data involving omalizumab, reslizumab, mepolizumab, benralizumab and dupilumab coming from case studies, surveys, single-center and multicenter studies, and review articles as well. The study focuses on risks of asthmatic patients' deterioration during COVID-19 and the severity of the infection itself. As a result, we learned that there is no strong evidence for asthma exacerbations in patients infected with COVID-19 while on their biological treatment course. Biological therapy can be safely used in patients with severe asthma, as long as all the precautions and the individual evaluation are provided.

Effectiveness of fevipiprant in reducing exacerbations in patients with severe asthma (LUSTER-1 and LUSTER-2): two phase 3 randomised controlled trials

Fevipiprant, an oral antagonist of the prostaglandin D2 receptor 2, reduced sputum eosinophils and improved lung function in phase 2 trials of patients with asthma. We aimed to investigate whether fevipiprant reduces asthma exacerbations in patients with severe asthma. LUSTER-1 and LUSTER-2 were two phase 3 randomised, double-blind, placebo-controlled, parallel-group, replicate 52-week studies; LUSTER-1 took place at 174 clinical sites in 25 countries and LUSTER 2 took place at 169 clinical sites in 19 countries. Fevipiprant or placebo was added to Global Initiative for Asthma Steps 4 and 5 therapy in adolescents and adults with severe asthma. Patients aged 12 years or older with uncontrolled asthma on dual or triple asthma therapy were randomly assigned by use of interactive response technology to one of three treatment groups (once-daily fevipiprant 150 mg, fevipiprant 450 mg, or placebo) in a 1:1:1 ratio within each of the randomisation strata: peripheral blood eosinophil counts (<250 cells per μL or ≥250 cells per μL), patient age (<18 years or ≥18 years), and use or non-use of oral corticosteroids as part of their standard of care asthma therapy. The primary efficacy endpoint was the annualised rate of moderate to severe asthma exacerbations with 150 mg or 450 mg doses of fevipiprant once daily compared with placebo over 52 weeks, in patients with high blood eosinophil counts (≥250 cells per μL) and in the overall study population. All patients who underwent randomisation and received at least one dose of study medication were included in efficacy and safety analyses. These trials are registered with ClinicalTrials.gov, NCT02555683 (LUSTER-1) and NCT02563067 (LUSTER-2), and are complete and no longer recruiting. Between Dec 11, 2015, and Oct 25, 2018, 894 patients were randomly assigned to fevipiprant 150 mg (n=301), fevipiprant 450 mg (n=295), or placebo (n=298) in LUSTER-1. Between Dec 3, 2015, and July 10, 2018, 877 patients were randomly assigned to fevipiprant 150 mg (n=296), fevipiprant 450 mg (n=294), or placebo (n=287) in LUSTER-2. In the high eosinophil population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 1·04 (95% CI 0·77-1·41) for fevipiprant 150 mg and 0·83 (0·61-1·14) for fevipiprant 450 mg, and in LUSTER-2 it was 0·69 (0·50-0·96) for fevipiprant 150 mg and 0·72 (0·52-1·01) for fevipiprant 450 mg. In the overall population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 0·96 (95% CI 0·75-1·22) for fevipiprant 150 mg and 0·78 (0·61-1·01) for fevipiprant 450 mg and in LUSTER-2 it was 0·82 (0·62-1·07) for fevipiprant 150 mg and 0·76 (0·58-1·00) for fevipiprant 450 mg. In the overall pooled population of both studies, serious adverse events occurred in 53 (9%) patients in the fevipiprant 150 mg group, 50 (9%) in the fevipiprant 450 mg group, and 50 (9%) in the placebo group. Adverse events leading to death occurred in two (<1%) patients in the fevipiprant 450 mg group and three (<1%) in the placebo group. Although neither trial showed a statistically significant reduction in asthma exacerbations after adjusting for multiple testing, consistent and modest reductions in exacerbations rates were observed in both studies with the 450 mg dose of fevipiprant. Novartis.