A theoretical risk of "rebound" worsening of eosinophilic airway inflammation associated with negative outcomes has been suggested3 on the basis of in vitro observations that anti-IL-5 therapy is ...associated with upregulation of IL-5 synthesis by TH2 cells, upregulation of IL-5R expression by eosinophils, and persistence of preformed IL-5 in complex with the drug for a variable period of time after cessation of therapy.4 As part of a follow-up analysis, subjects completing a 12-month study of mepolizumab in refractory asthma1 were observed for 12 months with assessments every 3 months. The rise in exacerbations at 3 to 6 months after stopping mepolizumab was preceded by a rise in sputum and blood eosinophils, supporting suggestions that these events are related but have different time courses.5-8 The finding of increased asthma symptoms following cessation of mepolizumab was unexpected because symptoms were not modified significantly during the treatment period.1 However, mean symptom scores for subjects receiving mepolizumab were lower than for subjects in the placebo group at the end of the treatment phase of the study.
Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. ...There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations.
We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum.
Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval CI, 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma.
Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)
Background Eosinophilic airway inflammation measured by using induced sputum is an important treatment stratification tool in patients with severe asthma. In addition, sputum eosinophilia has been ...shown to be associated with severe exacerbations and airflow limitation. Objectives We sought to identify whether eosinophilic inflammation in sputum is associated with FEV1 decrease in patients with severe asthma and whether we could identify subgroups of decrease behavior based on the variation of eosinophilic airway inflammation over time. Methods Ninety-seven patients with severe asthma from the Glenfield Asthma Cohort were followed up with scheduled 3-month visits; the median duration of follow-up and number of visits was 6 years (interquartile range, 5.6-7.6 years) and 2.7 visits per year. Induced sputum was analyzed for eosinophilic inflammation at scheduled visits. Linear mixed-effects models were used to identify variables associated with lung function and overall decrease. In addition, using individual patients' mean and SD sputum eosinophil percentages over time, a 2-step cluster analysis was performed to identify patient clusters with different rates of decrease. Results FEV1 decrease was −25.7 mL/y in the overall population. Postbronchodilator FEV1 was also dependent on exacerbations, age of onset, height, age, sex, and log10 sputum eosinophil percentages ( P < .001). Three decrease patient clusters were identified: (1) noneosinophilic with low variation (mean decrease, −14.0 mL/y), (2) eosinophilic with high variation (mean decrease, −40.9 mL/y), and (3) hypereosinophilic with low variation (mean decrease in lung function, −19.2 mL/y). Conclusion The amplitude of sputum eosinophilia was associated with postbronchodilator FEV1 in asthmatic patients. In contrast, high variability rather than the amplitude at baseline or over time of sputum eosinophils was associated with accelerated FEV1 decrease.
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial ...tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Background Thymic stromal lymphopoietin (TSLP) is a cytokine implicated in the pathophysiology of asthma through 2 distinct pathways: a TSLP–OX40 ligand (OX40L)–T cell axis and a TSLP–mast cell axis. ...Whether these pathways are active in human asthma is unknown. Objective We sought to investigate whether mucosal TSLP protein expression relates to asthma severity and distinct immunologic pathways. Methods In healthy subjects and patients with mild-to-severe asthma, we immunostained bronchial biopsy specimens for TSLP, OX40, OX40L, TH 2 cytokines, and inflammatory cell markers. We examined gene expression using RNA microarrays and quantitative RT-PCR. Results There was considerable heterogeneity in the levels of TSLP, IL-13, and IL-4 immunostaining across the cohort of asthmatic patients examined. Overall, TSLP protein expression was significantly increased in airway epithelium and lamina propria of asthmatic patients, particularly in patients with severe asthma. TSLP immunostaining in both compartments correlated with the severity of airflow obstruction. The majority of leukocytes expressing IL-13 were possibly nuocytes. Accounting for intersubject variability, the 55% of asthmatic patients with increased IL-13 immunostaining in the lamina propria also had increased IL-4 and TSLP expression. This was further substantiated by significant correlations between TSLP gene expression, a TH 2 gene expression signature, and eosinophilic inflammation in bronchial biopsy specimens. Immunostaining for OX40, OX40L, and CD83 was sparse, with no difference between asthmatic patients and healthy subjects. Conclusion TSLP expression is increased in a subset of patients with severe asthma in spite of high-dose inhaled or oral corticosteroid therapy. Targeting TSLP might only be efficacious in the subset of asthma characterized by increased TSLP expression and TH 2 inflammation.
Background IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit ...from antifungal treatment. Objectives We sought to determine whether a 3-month course of voriconazole improved asthma-related outcomes in patients with asthma who are IgE sensitized to A fumigatus. Methods Asthmatic patients who were IgE sensitized to A fumigatus with a history of at least 2 severe exacerbations in the previous 12 months were treated for 3 months with 200 mg of voriconazole twice daily, followed by observation for 9 months, in a double-blind, placebo-controlled, randomized design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the 12 months of the study. Results Sixty-five patients were randomized. Fifty-nine patients started treatment (32 receiving voriconazole and 27 receiving placebo) and were included in an intention-to-treat analysis. Fifty-six patients took the full 3 months of medication. Between the voriconazole and placebo groups, there were no significant differences in the number of severe exacerbations (1.16 vs 1.41 per patient per year, respectively; mean difference, 0.25; 95% CI, 0.19-0.31), quality of life (change in Asthma Quality of Life Questionnaire score, 0.68 vs 0.88; mean difference between groups, 0.2; 95% CI, −0.05 to −0.11), or any of our secondary outcome measures. Conclusion We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control.
Severe asthma represents a major unmet clinical need; understanding the pathophysiology is essential for the development of new therapies. Using microarray analysis, we previously found three ...immunological clusters in asthma: Th2-high, Th17-high, and Th2/17-low. Although new therapies are emerging for Th2-high disease, identifying molecular pathways in Th2-low disease remains an important goal. Further interrogation of our previously described microarray dataset revealed upregulation of gene expression for carcinoembryonic Ag cell adhesion molecule (CEACAM) family members in the bronchi of patients with severe asthma. Our aim was therefore to explore the distribution and cellular localization of CEACAM6 using immunohistochemistry on bronchial biopsy tissue obtained from patients with mild-to-severe asthma and healthy control subjects. Human bronchial epithelial cells were used to investigate cytokine and corticosteroid in vitro regulation of CEACAM6 gene expression. CEACAM6 protein expression in bronchial biopsies was increased in airway epithelial cells and lamina propria inflammatory cells in severe asthma compared with healthy control subjects. CEACAM6 in the lamina propria was localized to neutrophils predominantly. Neutrophil density in the bronchial mucosa was similar across health and the spectrum of asthma severity, but the percentage of neutrophils expressing CEACAM6 was significantly increased in severe asthma, suggesting the presence of an altered neutrophil phenotype. CEACAM6 gene expression in cultured epithelial cells was upregulated by wounding and neutrophil elastase. In summary, CEACAM6 expression is increased in severe asthma and primarily associated with airway epithelial cells and tissue neutrophils. CEACAM6 may contribute to the pathology of treatment-resistant asthma via neutrophil and airway epithelial cell-dependent pathways.
The ongoing coronavirus disease 2019 (COVID-19) pandemic has claimed over two and a half million lives worldwide so far. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is ...perceived to be seasonally recurrent, and a rapid noninvasive biomarker to accurately diagnose patients early on in their disease course will be necessary to meet the operational demands for COVID-19 control in the coming years.
The aim of this study was to evaluate the role of exhaled breath volatile biomarkers in identifying patients with suspected or confirmed COVID-19 infection, based on their underlying PCR status and clinical probability.
A prospective, real-world, observational study was carried out, recruiting adult patients with suspected or confirmed COVID-19 infection. Breath samples were collected using a standard breath collection bag, modified with appropriate filters to comply with local infection control recommendations, and samples were analysed using gas chromatography-mass spectrometry (TD-GC-MS).
81 patients were recruited between April 29 and July 10, 2020, of whom 52 out of 81 (64%) tested positive for COVID-19 by reverse transcription-polymerase chain reaction (RT-PCR). A regression analysis identified a set of seven exhaled breath features (benzaldehyde, 1-propanol, 3,6-methylundecane, camphene, beta-cubebene, iodobenzene and an unidentified compound) that separated PCR-positive patients with an area under the curve (AUC): 0.836, sensitivity: 68%, specificity: 85%.
GC-MS-detected exhaled breath biomarkers were able to identify PCR-positive COVID-19 patients. External replication of these compounds is warranted to validate these results.
Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in ...moderate-to-severe asthma during stable disease and exacerbation events.
We recruited 102 adults and 34 children with asthma. The adults were assessed at baseline, 3, 6, and 12-month follow-up visits. Thirty-seven subjects were assessed at onset of severe exacerbation. Forty sputum mediators and 43 serum mediators were measured. Receiver-operator characteristic (ROC) curves were constructed to identify mediators that distinguish between stable disease and exacerbation events. The strongest discriminating sputum mediators in the adults were validated in the children.
The mediators that were significantly increased at exacerbations versus stable disease and by ≥1.5-fold were sputum IL-1β, IL-6, IL-6R, IL-18, CXCL9, CXCL10, CCL5, TNFα, TNF-R1, TNF-R2, and CHTR and serum CXCL11. No mediators decreased ≥1.5-fold at exacerbation. The strongest discriminators of an exacerbation in adults (ROC area under the curve AUC) were sputum TNF-R2 0.69 (95% CI: 0.60 to 0.78) and IL-6R 0.68 (95% CI: 0.58 to 0.78). Sputum TNF-R2 and IL-6R were also discriminatory in children (ROC AUC 0.85 95% CI: 0.71 to 0.99 and 0.80 0.64 to 0.96 respectively).
Severe asthma exacerbations are associated with increased pro-inflammatory and Type 1 (T1) immune mediators. In adults, sputum TNF-R2 and IL-6R were the strongest discriminators of an exacerbation, which were verified in children.
Most patients with asthma are managed exclusively in primary care. Little is known about the patterns of airway dysfunction in these patients and how these relate to other aspects of the disease.
We ...set out to assess this in a cross-sectional study of 262 patients.
Symptoms, spirometry, airway responsiveness, reversibility, and airway inflammation were all assessed. Exacerbations requiring oral corticosteroids in the preceding year were enumerated.
Patients had heterogeneous patterns of airway dysfunction. Those with a post-bronchodilator forced expiratory volume in 1 sec/ forced vital capacity ratio of <0.7 had more exacerbations in the previous year (2.2 vs. 0.8; mean difference 1.4; 95% CI 0.4 to 2.4; p=0.007). Patients with normal results had less inflammation (proportion with a sputum eosinophil count of >1.9%, 20% vs. 48%, χ²=14.8, df=3; p<0.001) and fewer exacerbations (0.5 vs. 1.4; mean difference -0.9; 95% CI -1.4 to -0.4; p=0.001) but similar symptom scores (6.2 vs. 6.9; p=0.2) compared with patients with any abnormality.
Patients with a diagnosis of asthma have mixed patterns of physiological impairment; many have no airflow obstruction or airway hyper-responsiveness. The physiological characterisation of asthma is not related to symptoms and is of little value in predicting exacerbations or eosinophilic airway inflammation.
PDF
