FEV1 Reversibility Research Articles

Covert airflow obstruction dominates the overt ones in interstitial lung disease: An appraisal.

Background & objectives The co-presence of non-emphysematous airflow obstruction in interstitial Lung disease (ILD) is not elaborated. The present study aims the job with spirometry. Methods ILD affected individuals with or without airflow obstruction (FEV1/FVC<0.7 or >0.7) on spirometry were compared in terms of FEV1 and FEF25-75 derived variables [FEF25-75 (%-predicted), FEV1-FEF25-75 distance, reversibility of FEV1 and FEF25-75 to salbutamol and change in FEV1 and FEF25-75 in %-predicted values]. Those showing significant difference (P=0.0001) suggesting obstruction were selected to draw respective receiver operating curve (ROC) curves to identify the best cut-off value for individual parameters. The efficacy of each surrogate was tested to identify airflow obstruction in both the initial 'overlap' as well as the 'unmixed' ILD affected individual for the presence of airflow obstruction. Results FEV1/FVC identified 30 overlap from 235 ILDs. The FEF25-75 (%-predicted), FEV1-FEF25-75 distance, FEF25-75 reversibility (in ml) and FEV1 (%-predicted) were significantly (P<0.0001) different between the two groups. Of these, the FEF25-75 (%-predicted) had high specificity and sensitivity (93.33 and 79.47%) to identify airflow limitation in the initial unmixed ILD-group. The surrogates with their cut off values identified 92 extra individuals making it 122/235 (51.91%) of ILD having airflow obstruction. The 'unmixed' group showed higher frequency and degree of FEV1 reversibility. Interpretation & conclusions The findings of this study suggest that the airflow obstruction in ILD involves both the intrathoracic large and small airways. Although seemingly parallel, their relative status (qualitative and quantitative) needs research especially in light of the a etio pathology and the extent of involvement of ILD.

Genetic variants associated with SARS-CoV-2 infection also affect lung function and asthma severity

BackgroundHost genetic factors may be associated with COVID-19 unfavourable outcomes. The first genome-wide association study (GWAS) conducted in individuals with respiratory failure due to COVID-19 revealed susceptibility loci close to six genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1) and the ABO blood-group gene. We aimed to investigate how polymorphisms in those genes could relate to lung function and severe asthma in a Brazilian population. MethodsDNA samples of 784 individuals following the ProAR (Programa para Controle da Asma e Rinite Alérgica da Bahia) were genotyped by the Multi-Ethnic Global Array panel with ∼2 million polymorphisms (Illumina). Polymorphisms in SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1 and the ABO blood-group gene were evaluated. Logistic regression for severe asthma, airway obstruction and lack of FEV1 reversibility was performed using PLINK software 1.9, in the additive model and was adjusted for sex, age and PCA-1. Pairwise Linkage disequilibrium analyses were performed using Haploview 4.2. The haplotypes and gene score analyses were performed in the SNPstat tool. In silico functions of polymorphisms were analysed using rSNPbase and RegulomeDB plataforms. ResultsWe identified the rs8176733 (G allele) and rs8176725 (A allele) in the ABO blood-group gene as risk factors for severe asthma, lower pulmonary obstruction and lack of FEV1 reversibility. Polymorphisms in CCR9 are risk factors for both severe asthma (A allele of rs34338823) and airway obstruction (A allele of rs6806802). The markers rs13079478 (A allele) and rs75817942 (A allele) in FYCO1 are related to more severe asthma and a lack of FEV1 reversibility, respectively. We identified the A allele of both rs35731912 and rs34338823 in LZTFL1 as risk factors for severe asthma. The marker rs6806802 (C allele) was associated with airway obstruction and rs7614952 (A allele), rs7625839 (G allele) and rs112509260 (A allele) are related to a lack of FEV1 reversibility. The A allele of rs2531747 in the SLC6A20 gene is also associated with severe asthma. Conversely, polymorphisms in XCR1 play a protective role in relation to severe asthma (A allele of rs2036295) and airway obstruction (A allele of rs2036295). Additionally, we found that individuals with a higher number of risk alleles have a greater risk of severe asthma, airway obstruction and FEV1 reversibility. ConclusionOur study suggests that polymorphisms in genes associated with respiratory failure in SARS-CoV-2-infected individuals are associated with greater susceptibility to severe asthma and reduced lung function in subjects with asthma.

FEV1 (FORCED EXPIRATORY VOLUME IN THE 1ST SECOND) REVERSIBILITY AFTER NEBULISATION WITH SABA (SHORT ACTING BETA AGONIST) AS A MARKER OF CONTROL OF ASTHMA

INTRODUCTION: Variable expiratory airow due to bronchoconstriction, airway wall thickening and increased mucus is an obvious feature in asthma. Variable airow obstruction is evidenced by reversibility of FEV1 following a bronchodilator inhalation. PFT (Pulmonary Function Testing) using spirometry is often used for the estimation of FEV1. Reversibility is not uniform in all cases and vary with respect to severity and control of asthma. AIMS &amp; OBJECTIVES: 1) To determine the control of asthma in 5-15-year-old children using GINA checklist and estimate FEV1 before and after SABA nebulisation. 2) To nd out the association between FEV1 reversibility and control of asthma. MATERIALS &amp; METHODS: This cross-sectional study included 90 consecutive 5-15-year-old-children with a clinical diagnosis of asthma attending the Paediatric OPD of a teaching hospital from October-May 2021. The symptoms, signs, comorbidities, treatment, compliance and assessment of control of asthma into 2 subgroups: Well-controlled and Partly-controlled/Uncontrolled asthma, as per GINA 2020 were recorded. All were subjected to spirometry for assessment of FEV1 before and 20 minutes after nebulisation with SABA. Depending upon FEV1, they were grouped as those with &gt;12% reversibility and &lt;12% reversibility. Data analysed using SPSS 20.0, Paired t test for comparison of means, Chi-square test for statistical difference in proportion, and post hoc tests. The RESULTS: M:F ratio was 1.2:1, 52.2% were 10-15 years and 47.8% 5-10 years. 68.9% had partly/uncontrolled, the rest well-controlled asthma (38.1%). The difference between mean FEV1 before (67.9±10.6) and after nebulisation (80.6±9.7) was statistically signicant (p&lt;0.00*). Among those with &gt;12 reversibility, 64.5% were in partly/uncontrolled and 35.5% in well-controlled asthma and the difference was statistically signicant (p -0.013*). The CONCLUSION: nding in the study that 68.9% had partly/uncontrolled asthma is an eye-opener to optimise protocol-based treatment among children. The statistically signicant difference of &gt;12% before and after nebulisation a marker of poor control was observed in 64.5% of partly/uncontrolled asthma compared to 35.5% of well controlled asthma. Hence, the persistence of a signicant degree of bronchodilator response noted in those with partly/uncontrolled asthma is recommended as an objective surrogate of poor asthma control in children who can co-operate for a PFT in order to optimise protocol-based treatment.

Determinants of Severe Asthma - A Long-Term Cohort Study in Northern Sweden.

BackgroundRisk factors for severe asthma are not well described. The aim was to identify clinical characteristics and risk factors at study entry that are associated with severe asthma at follow-up in a long-term prospective population-based cohort study of adults with asthma.MethodsBetween 1986 and 2001, 2055 adults with asthma were identified by clinical examinations of population-based samples in northern Sweden. During 2012–2014, n = 1006 (71% of invited) were still alive, residing in the study area and participated in a follow-up, of which 40 were identified as having severe asthma according to ERS/ATS, 131 according to GINA, while 875 had other asthma. The mean follow-up time was 18.7 years.ResultsObesity at study entry and adult-onset asthma were associated with severe asthma at follow-up. While severe asthma was more common in those with adult-onset asthma in both men and women, the association with obesity was observed in women only. Sensitization to mites and moulds, but not to other allergens, as well as NSAID-related respiratory symptoms was more common in severe asthma than in other asthma. Participants with severe asthma at follow-up had lower FEV1, more pronounced FEV1 reversibility, and more wheeze, dyspnea and nighttime awakenings already at study entry than those with other asthma.ConclusionAdult-onset asthma is an important risk factor for development of severe asthma in adults, and obesity increased the risk among women. The high burden of respiratory symptoms already at study entry also indicate long-term associations with development of severe asthma.

Dupilumab efficacy in subgroups of type 2 asthma with high-dose inhaled corticosteroids at baseline

Background and objectiveDupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks reduced severe exacerbations, improved pre-bronchodilator forced expiratory volume in 1 s (FEV1), and was generally well tolerated in patients with uncontrolled moderate-to-severe asthma. This post hoc analysis assessed dupilumab efficacy in subpopulations of patients with type 2 asthma and high-dose inhaled corticosteroids (ICS). MethodsAdjusted annualized severe exacerbation rates over the treatment period, least squares (LS) mean change from baseline at Week 12 in pre-bronchodilator FEV1, and LS mean change from baseline at Week 24 in 5-item Asthma Control Questionnaire (ACQ-5) scores were analyzed in subgroups of patients receiving high-dose (>500 μg) ICS with baseline blood eosinophils ≥150 cells/μL and/or fractional exhaled nitric oxide ≥25 ppb. Subgroups included allergic phenotype (with/without), comorbid chronic rhinosinusitis and/or nasal polyposis (with/without), pre-bronchodilator FEV1/forced vital capacity (<70%/≥70%), blood eosinophil level, exacerbation history, median baseline pre-bronchodilator FEV1, age at asthma onset (≤40/>40 years), median FEV1 reversibility, body mass index (<30/≥30 kg/m2), and sex. ResultsDupilumab vs placebo reduced exacerbations and improved pre-bronchodilator FEV1 at Week 12 and ACQ-5 at Week 24 across subgroups of patients with type 2 asthma and high-dose ICS at baseline. Dupilumab was also effective in patients receiving medium-dose ICS. ConclusionDupilumab reduced severe exacerbations and improved lung function and asthma control in subgroups of patients with type 2 asthma and high-dose ICS at baseline. Clinical trial registration numberNCT02414854.

Identification of pyroptosis-related subtypes and establishment of prognostic model and immune characteristics in asthma.

BackgroundAlthough studies have shown that cell pyroptosis is involved in the progression of asthma, a systematic analysis of the clinical significance of pyroptosis-related genes (PRGs) cooperating with immune cells in asthma patients is still lacking.MethodsTranscriptome sequencing datasets from patients with different disease courses were used to screen pyroptosis-related differentially expressed genes and perform biological function analysis. Clustering based on K-means unsupervised clustering method is performed to identify pyroptosis-related subtypes in asthma and explore biological functional characteristics of poorly controlled subtypes. Diagnostic markers between subtypes were screened and validated using an asthma mouse model. The infiltration of immune cells in airway epithelium was evaluated based on CIBERSORT, and the correlation between diagnostic markers and immune cells was analyzed. Finally, a risk prediction model was established and experimentally verified using differentially expressed genes between pyroptosis subtypes in combination with asthma control. The cMAP database and molecular docking were utilized to predict potential therapeutic drugs.ResultsNineteen differentially expressed PRGs and two subtypes were identified between patients with mild-to-moderate and severe asthma conditions. Significant differences were observed in asthma control and FEV1 reversibility between the two subtypes. Poor control subtypes were closely related to glucocorticoid resistance and airway remodeling. BNIP3 was identified as a diagnostic marker and associated with immune cell infiltration such as, M2 macrophages. The risk prediction model containing four genes has accurate classification efficiency and prediction value. Small molecules obtained from the cMAP database that may have therapeutic effects on asthma are mainly DPP4 inhibitors.ConclusionPyroptosis and its mediated immune phenotype are crucial in the occurrence, development, and prognosis of asthma. The predictive models and drugs developed on the basis of PRGs may provide new solutions for the management of asthma.

Systemic vascular health is compromised in both confirmed and unconfirmed asthma

IntroductionAsthma is associated with increased risk of cardiovascular diseases. Despite many presenting with symptoms of asthma, asthma cannot always be confirmed by physiological assessment. It is thus far unknown if the heightened cardiovascular risk applies to this group. The purpose of this study was to examine markers of cardiovascular risk, including endothelial function, arterial stiffness, and systemic inflammation, in individuals with confirmed asthma, unconfirmed asthma, and healthy controls. As short-acting beta agonist (SABA) use is associated with increased cardiovascular risk, a secondary analysis was conducted to investigate the impact of regular SABA use on vascular outcomes. MethodsIndividuals with confirmed asthma (n = 26), unconfirmed asthma (n = 15), and healthy controls (n = 26) were recruited for this cross-sectional study. Asthma was confirmed by FEV1 reversibility, methacholine challenge, or exercise challenge. Endothelial function was assessed using flow-mediated dilation (FMD), arterial stiffness using pulse wave velocity (PWV), and systemic inflammation by C-reactive protein (CRP) levels. ResultsFMD was significantly lower in both asthma groups compared to controls (confirmed: 7.7 ± 3.6%, unconfirmed: 7.3 ± 3.5%, controls: 10.4 ± 3.6%, p = 0.02). No difference was found in PWV nor CRP. Asthma participants who used SABA had increased arterial stiffness compared to those without SABA (9.2 ± 2.7 m/s, 7.7 ± 1.1 m/s respectively, p = 0.03). No difference was seen in FMD or CRP between SABA groups. ConclusionIndividuals with a clinical history of asthma symptoms demonstrate vascular impairments regardless of physiological confirmation of disease. Regular SABA use increases arterial stiffness. Avoiding potentially inappropriate SABA use among people without physiologically confirmed asthma may thus be beneficial in curbing cardiovascular risk.

Autophagy-Related Genes Are Involved in the Progression and Prognosis of Asthma and Regulate the Immune Microenvironment.

BackgroundAutophagy has been proven to play an important role in the pathogenesis of asthma and the regulation of the airway epithelial immune microenvironment. However, a systematic analysis of the clinical importance of autophagy-related genes (ARGs) regulating the immune microenvironment in patients with asthma remains lacking.MethodsClustering based on the k-means unsupervised clustering method was performed to identify autophagy-related subtypes in asthma. ARG-related diagnostic markers in low-autophagy subtypes were screened, the infiltration of immune cells in the airway epithelium was evaluated by the CIBERSORT, and the correlation between diagnostic markers and infiltrating immune cells was analyzed. On the basis of the expression of ARGs and combined with asthma control, a risk prediction model was established and verified by experiments.ResultsA total of 66 differentially expressed ARGs and 2 subtypes were identified between mild to moderate and severe asthma. Significant differences were observed in asthma control and FEV1 reversibility between the two subtypes, and the low-autophagy subtype was closely associated with severe asthma, energy metabolism, and hormone metabolism. The autophagy gene SERPINB10 was identified as a diagnostic marker and was related to the infiltration of immune cells, such as activated mast cells and neutrophils. Combined with asthma control, a risk prediction model was constructed, the expression of five risk genes was supported by animal experiments, was established for ARGs related to the prediction model.ConclusionAutophagy plays a crucial role in the diversity and complexity of the asthma immune microenvironment and has clinical value in treatment response and prognosis.

Biomarkers to Predict Response to Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists in Adolescents and Adults with Mild Persistent Asthma.

Rationale: Whether biomarkers can be used to predict response to inhaled corticosteroids (ICS) or long-acting muscarinic antagonists (LAMA) in mild persistent asthma is unclear. Objectives: In a prespecified exploratory analysis of a randomized clinical trial of 295 participants 12 years of age or older with uncontrolled mild persistent asthma, we sought to identify biomarkers of treatment response after 12 weeks of ICS (mometasone, 200 μg or 220 μg twice/d), LAMA (tiotropium, 5 μg/d), or placebo in adults (⩾18 yr) and adolescents (12-17 yr) separately. Methods: The primary outcome was a composite outcome of asthma control (treatment failure, asthma control days, and forced expiratory volume in 1 second [FEV1]). Analyses examined type 2 inflammatory biomarkers and physiologic biomarkers. We assessed the area under the receiver operating characteristic curve (AUC) for response to ICS and LAMA (each versus placebo). An AUC of 0.5 suggests no discrimination, 0.7-0.8 is considered acceptable, more than 0.8-0.9 is considered excellent, and more than 0.9 is considered outstanding. Results: In 237 adults, sputum and blood eosinophil levels and fractional exhaled nitric oxide (FeNO) each predicted ICS response (AUCs: 0.61 [95% confidence interval (CI), 0.53-0.69], 0.64 [95% CI, 0.56-0.72], and 0.62 [95% CI, 0.54-0.70], respectively; all P < 0.01); the AUC for blood eosinophil levels and FeNO together was 0.66 (95% CI, 0.58-0.74; P < 0.001). In 58 adolescents, the number of positive aeroallergens and total serum immunoglobulin E each predicted ICS response (AUCs: 0.69 [95% CI, 0.52-0.85] and 0.73 [95% CI, 0.58-0.87], respectively; both P < 0.03); the AUC for both together was 0.73 (95% CI, 0.58-0.87; P = 0.003). After ipratropium bromide, FEV1 reversibility predicted LAMA response in adults (AUC: 0.61 [95% CI, 0.53-0.69], P = 0.007) but not in adolescents. Conclusions: The AUCs of the type 2 inflammatory biomarkers and physiological biomarkers we examined may not be high enough to confidently identify individuals with asthma who respond to ICS and LAMA. However, our findings indicate that the biomarkers that predict response to ICS or LAMA may differ in adults versus adolescents with uncontrolled mild persistent asthma. Prospective, biomarker-stratified clinical trials are needed to confirm these findings and to identify first-line controllers tailored for each population.

Paucigranulocytic asthma: Do sputum macrophages matter?

Background: Although paucigranulocytic asthma (PGA) is the most common phenotype of stable asthma, its features have not been adequately studied. In this study, we aimed to display the characteristics of PGA. Method: A total of 116 non-smoking adult patients with asthma (80% women; mean ± standard deviation age, 39 ± 12.9 years) admitted to three tertiary centers were included. Their demographic and clinical features, allergy status, biochemical results, scores of Asthma Control Test (ACT), spirometry, and exhaled nitric oxide (FeNO) measurements were obtained. Induced sputum cytometry was performed. Results: Four phenotypes, according to induced sputum cell counts, were detected: eosinophilic asthma (EA) (22.4%), mixed granulocytic asthma (MGA) (6.9%), neutrophilic (NA) (7.8%), and PGA (62.9%). In the sputum, macrophages were higher in the PGA group compared with the other groups (PGA versus NA and PGA versus MGA, p < 0.001; and PGA versus EA, p =0 .030). The atopy rate between phenotypes was the same. Although the forced expiratory volume in the first second of expiration (FEV1) was similar in four groups, the ratio of FEV1 to the forced vital capacity ratio was higher (p = 0.013) and FEV1 reversibility was lower in the patients with PGA than the corresponding values in other phenotypes (p = 0.015). Low reversibility was comparable both in patients with PGA who were inhaled corticosteroid (ICS) naive and in patients on ICS treatment. Although insignificant, the FeNO values and blood eosinophil counts were higher in the MGA and EA groups, whereas these were the lowest in the PGA group. The uncontrolled asthma ratio was low in PGA (16%), whereas it was 11% for NA, 25% for MG, and 23% in EA. Conclusion: Macrophages are predominant in sputum of patients with PGA. Besides a lower uncontrolled asthma ratio, lower FEV1 reversibility is a prominent characteristic of this phenotype.

A study of Spirometric parameters in non asthmatic allergic rhinitis

IntroductionAllergic rhinitis (AR) is a common IgE -mediated inflammatory condition characterised by sneezing, nasal congestion, itching and rhinorrhoea. Nasal allergy is a strong risk factor for the onset of asthma in adults. Bronchial hyper-responsiveness (BHR) is a distinct feature of pathophysiology in asthma. Spirometric parameters like Forced Expiratory Volume in first second [FEV1] and Forced Expiratory Flow [FEF 25–75%] are known to be impaired in patients with allergic rhinitis. We studied these parameters in subjects of AR who have never experienced any chest symptoms. It is well known that, subjects with allergic rhinitis are at greater risk of developing overt bronchial asthma in future. MethodsAll patients presented with symptoms of allergic rhinitis without history of bronchial asthma were included. Patients those who were clinically diagnosed with allergic rhinitis were evaluated with absolute eosinophilic count, serum IgE and Spirometric assessment. In spirometry, post bronchodilator FEV1 reversibility and post bronchodilator FEF 25–75% values were used to assess lower airway abnormalities. ResultsAmong 61 subjects, 32 were males and 29 were females. The maximum numbers [28] of patients were in 21–35 age group. Absolute eosinophil count was elevated in 38% of patients. 33% of patients showed elevated IgE values above 1000. 43% of patients showed FEV1 reversibility which is a sign of Bronchial hyperreactivity. 5% of patients showed impaired post bronchodilator FEF 25–75% which indicates presence of small airway disease. There was significant correlation between FEV1 reversibility and elevated IgE. ConclusionImpaired spirometric parameters indicate coexistence of bronchial impairment and hence predisposition to progression from allergic rhinitis alone to overt asthma in future. Thus careful evaluation of lower airway has to be done to rule out coexisting subclinical asthma.

Prevalence and clinical features of most frequent phenotypes in the Italian COPD population: the CLIMA Study.

BackgroundChronic obstructive pulmonary disease (COPD) is a complex, progressive respiratory condition characterized by heterogeneous clinical presentations (phenotypes). The aim of this study was to assess the prevalence of the main COPD phenotypes and match of each phenotype to the most fitting clinical and lung function profile.Methodsthe CLIMA (Clinical Phenotypes in Actual Clinical Practice) study was an observational, cross-sectional investigation involving twenty-four sites evenly distributed throughout Italy. Patients were tentatively grouped based on their history and claimed prevailing symptoms at recruitment: chronic cough (CB, suggesting chronic bronchitis); dyspnoea (possible emphysema components, E); recurrent wheezing (presuming asthma components, A). Variables collected were: anagraphics; smoking habit; history of asthma; claim of >1 exacerbations in the previous year; blood eosinophil count; total blood IgE and alpha1 anti-trypsin (α1-AT) levels; complete lung function, and the chest X-ray report. mMRC, CAT, BCS, EQ5d-5L were also used. The association between variables and phenotypes were checked by Chi-square test and multinomial logistic regression.ResultsThe CB phenotype was prevalent (48.3%), followed by the E and the A phenotypes (38.8% and 12.8%, respectively). When dyspnoea was the prevailing symptom, the probability of belonging to the COPD-E phenotype was 3.40 times higher. Recurrent wheezing was mostly related to the COPD-A phenotype. Lung function proved more preserved in the COPD-CB phenotype. Smoke; n. exacerbations/year; VR, and BODE index were positively correlated with the COPD-E phenotype, while SpO2, FEV1/FVC, FEV1/VC, and FEV1 reversibility were negatively correlated. Lower DLco values were highly probative for the COPD-E phenotype (p<0.001). Conversely, smoke, wheezing, plasma eosinophils, FEV1 reversibility, and DLco were positively correlated with the COPD-A phenotype. The probability of belonging to the COPD-A phenotype raised by 2.71 times for any increase of one unit in % plasma eosinophils (p<0.001). Also multiparametrical scores contributed to discriminate the three phenotypes.ConclusionThe recognition of the main phenotypes of COPD can be effectively pursued by means of a few clinical and instrumental parameters, easy to obtain also in current daily practice. The phenotypical approach is crucial in the management of COPD as it allows to individualize the therapeutic strategy and to obtain more effective clinical outcomes.

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.

Evaluation of Post-Bronchodilator Reversibility in Patient with Chronic Obstructive Pulmonary Disease and Asthma

Obstructive lung disease is a group of disorders comprising Chronic Obstructive Pulmonary Disease (COPD) and asthma. It is one of the most common causes of morbidity and mortality worldwide. COPD is a preventable and treatable disease characterized by persistent respiratory symptoms and airflow limitation, whereas asthma is reversible episodes of recurrent wheezing, cough, breathlessness, and chest tightness. It is sometimes difficult to distinguish COPD from asthma when COPD patients present with significant post-bronchodilator reversibility. Spirometry is the gold standard test to diagnose obstructive airway disease. We carried out a hospital-based cross-sectional study in Nepal Medical College Teaching Hospital from January 2018 to December 2018. One hundred and ninety eight patients who met the inclusion criteria underwent spirometry. Basal and post-bronchodilator FEV1, FVC, FEV1/FVC, and reversibility of FEV1 were measured. The majority of the patients enrolled in the study were males (n=100). The mean age of the patients was 49.3±17.0 years. Most of the patients were above 60 years of age (n=68). Clinical diagnosis of asthma was made in 113 (57%) and COPD in 85 (43%) patients. Post-bronchodilator reversibility was observed in 48 (42%) asthmatic and 19 (22%) COPD patients. Post-bronchodilator reversibility was statistically significant in asthmatic patients (p=0.032). Post-bronchodilator reversibility was observed in COPD patients as well. Therefore, post-bronchodilator reversibility alone may have a limited role in differentiating COPD from bronchial asthma. However, spirometry is mandatory to diagnose a patient with obstructive lung disease.

The processes of inflammation and fibrosis in patients with chronic obstructive pulmonary disease

The aim of the study was to determine the categories of COPD patients with a predominance of fibrotic or inflammatory processes. The study included 37 stable COPD patients (men – 33 (89.2%), women – 4 (10.8%), mean age – 63.5±1.18 years, the level of forced expiratory volume for the first second after the test with bronchodilators (FEV1post) – 46.7±5.81% of the proper value). To determine the categories of COPD patients with a predominance of inflammation or fibrosis, a cluster analysis was performed. For this purpose the most important indicators from a clinical point of view were selected: the number of exacerbations over the past year, dyspnea severity according to the mMRC scale, the level of FEV1 post and reversibility level in absolute values, systemic inflammation markers levels (CAA, C-RP) and profibrotic cytokine TGF-β1. Thus, according to the results of cluster analysis, two categories of patients were identified. The first category – COPD patients with a predominance of the inflammatory process with low dyspnea severity, high functional indicators (FEV1 &gt;50% of the proper value), high airway reversibility level, low level of profibrotic cytokine TGF-β1, high levels of systematic inflammation markers (C-RP and CAA). The second category – COPD patients with a predominance of the fibrosis process, with a high dyspnea severity, low functional indicators (FEV1 ≤50% of the proper value), low airway reversibility level, low levels of systematic inflammation markers (C-RP and CAA), and high profibrotic cytokine TGF-β1 levels. The prevalence of inflammatory processes was observed mainly in COPD patients, who belong to clinical group C; the prevalence of fibrotic processes – mainly in patients of clinical group B.

THE EFFECT OF TEZEPELUMAB ON EXACERBATIONS IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA ACCORDING TO BASELINE INHALED CORTICOSTEROID DOSE: RESULTS FROM THE PHASE 2B PATHWAY STUDY

SESSION TITLE: Updates in the Management of Severe Asthma SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine implicated in asthma pathogenesis. In the phase 2b PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAER) by up to 71% versus placebo in adults with severe, uncontrolled asthma. This post hoc analysis evaluated the effect of tezepelumab on AAER and forced expiratory volume in 1 second (FEV1) in patients from PATHWAY taking medium-dose (MD) or high-dose (HD) inhaled corticosteroids (ICS) at baseline. METHODS: Adults (18–75 years) with severe, uncontrolled asthma were randomized to receive subcutaneous tezepelumab (70mg every 4 weeks [Q4W], 210mg Q4W, 280mg every 2 weeks) or placebo for 52 weeks. AAER and FEV1 were determined in patients taking MD (250–500μg/day of fluticasone propionate [FP] or equivalent) or HD (>500μg/day FP or equivalent) ICS at baseline. Data are reported for tezepelumab 210mg and pooled tezepelumab doses. RESULTS: Overall, 550 patients were randomized to placebo (n=138) or tezepelumab 70mg (n=138), 210mg (n=137) or 280mg (n=137). Patients taking HD ICS (n=269) had more exacerbations in the prior year (mean: 2.6 vs 2.2), higher fractional exhaled nitric oxide levels (median: 24.3 vs 20.5 ppb) and lower post-bronchodilator FEV1 reversibility (median: 287.0 vs 340.0 mL) at baseline than those taking MD ICS (n=281), and higher occurrence of nasal polyps (18.6% vs 11.4%) and maintenance oral corticosteroid (OCS) use (18.6% vs 0.4%). Over 52 weeks, AAER in placebo-treated patients was higher in the HD ICS group than in the MD ICS group (1.12 [95% confidence interval (CI): 0.76–1.66] vs 0.38 [95% CI: 0.24–0.61], respectively). For tezepelumab 210mg, AAER was reduced by 77% (95% CI: 54–89) and 60% (95% CI: 8–83) versus placebo in the HD and MD ICS groups, respectively. Results were similar for pooled tezepelumab doses versus placebo (HD ICS, 74% [95% CI: 57–84]; MD ICS, 52% [95% CI: 12–73]). Compared with placebo, the least squares mean change from baseline in FEV1 at week 52 was 160mL (95% CI: 10–300) and 140mL (95% CI: 0–280) in patients taking HD and MD ICS, respectively, in the tezepelumab 210mg group, and 190mL (95% CI: 70–310) and 120mL (95% CI: 10–230), respectively, in the pooled tezepelumab dose group. CONCLUSIONS: Patients with severe, uncontrolled asthma taking HD ICS had more exacerbations in the prior year and higher baseline maintenance OCS use than those taking MD ICS, which is consistent with patients taking HD ICS having more severe disease. Treatment with tezepelumab reduced exacerbations and improved FEV1 versus placebo in both ICS dose groups, with a trend of greater effects in patients taking HD ICS. CLINICAL IMPLICATIONS: This study further supports the potential benefits of tezepelumab treatment in patients with severe, uncontrolled asthma, irrespective of pre-treatment maintenance ICS dose. 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Variation in spirometry parameters in children with and without recurrent respiratory problems

Background: Children having recurrent episodes of respiratory symptoms account for a major source of hospitalization. These children have increased morbidities and if not identified in time can have impaired lung function as adults. &#x0D; Objectives: The aim of our study was to compare the spirometry parameters and bronchodilator reversibility in children with and without recurrent respiratory problems.&#x0D; Methodology: This was a prospective observational study conducted in the Pediatric department of Manipal Teaching Hospital comparing 35 children with recurrent respiratory problems and 35 children with no history of recurrent respiratory problems. After thorough instructions, baseline spirometry was done in all children and recordings were noted. Thereafter they were given two puffs of salbutamol (100 µg) and repeat testing was done 20 minutes later. Bronchodilator reversibility was calculated according to standard formula. Various statistical tests were used to compare the findings between the two groups.&#x0D; Results: The recurrent respiratory problem group had 31 (88%) cases of bronchial asthma, two (5.7%) bronchiolitis obliterans, one (2.8%) pulmonary eosinophilia, and one (2.8%) common variable immunodeficiency syndrome. The median values of FEV1 (p=&lt;0.001), FVC (p=0.007), FEV1/FVC (p=0.005), PEF (p=0.042) and FEF25-75(p=0.026) were lower in the group with recurrent respiratory problems. Post-bronchodilator reversibility of FEV1 (p=0.001), FVC (p=&lt;0.001) and FEF25-75 (p=0.026) was higher in the groups with recurrent respiratory problems&#x0D; Conclusion: We found that lung function parameters in children with recurrent respiratory problems show features of obstructive defect. The post-bronchodilator response is higher in the group with recurrent respiratory problems as compared to normal children.

Histopathological Comparison of Endobronchial Biopsies from Different Pulmonary Lobes of Severe Asthmatic Patients

Histopathological Comparison of Endobronchial Biopsies from Different Pulmonary Lobes of Severe Asthmatic Patients

In patients with severe asthma with eosinophilia in reslizumab clinical trials, high peripheral blood eosinophil levels are associated with low FEV1 reversibility

BackgroundA post hoc analysis of two randomized, placebo–controlled, Phase 3 trials of intravenous reslizumab, an anti-interleukin-5 (IL-5) biologic for severe eosinophilic asthma.MethodsRelationships between baseline blood eosinophil levels (EOS), forced expiratory volume in 1 s (FEV1) reversibility to β2-agonists and treatment outcomes were assessed.ResultsMean baseline FEV1 reversibility was numerically lower among patients with high (≥ 400 cells/µL) versus low baseline EOS. Reslizumab produced clinically significant improvement in FEV1, exacerbation rates and patient-reported outcomes after 52 weeks, including in patients with high EOS and low FEV1 reversibility (≤ 14%) to β2-agonists at baseline.ConclusionsClinical trial eligibility criteria stipulating minimum FEV1 reversibility to β2-agonists of ≥ 12% might exclude patients who would benefit from treatment with anti-IL-5 biologics.

Updated Evaluation of Dupilumab in the Treatment of Asthma: Patient Selection and Reported Outcomes.

Uncontrolled asthma continues to be a problem for many patients with moderate-to-severe allergic asthma. Dupilumab, which blocks the receptors for interleukin-4 and interleukin-13, has been effective in reducing asthma exacerbations, improving forced expiratory volume in one second (FEV1), and reducing oral corticosteroid use. When selecting patients for dupilumab, it is important to consider entry criteria for the original studies, subgroups that have responded best, and the presence of comorbid diseases that may also respond to dupilumab. Factors that were considered when selecting patients likely to respond to dupilumab in asthma studies include: failure of moderate or high dose inhaled steroids in combination with an additional controller medication, baseline FEV1 reversibility of 12% or greater, and Asthma Control Questionnaire > 1.5. The baseline characteristics that predicted a better response to dupilumab included blood eosinophils > 150 cells/mm3 and fractional exhaled nitric oxide > 25 parts per billion. Comorbidities that may also respond to treatment with dupilumab include atopic dermatitis, chronic rhinosinusitis, and allergic rhinitis. A combination of these factors should be considered when selecting the patients most likely to benefit from dupilumab.