Severe Asthma Cohort Research Articles

Characteristics of Severe Asthma Clinic Patients With Eosinophilic Granulomatosis With Polyangiitis

BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis associated with varying clinical presentations and overlapping multiorgan involvement. Asthma is a predominant feature of EGPA, typically in its prodromal phase, often severe and precedes vasculitic complications. However, there is paucity of studies describing the prevalence and characteristics of EGPA in the asthma population. ObjectiveWe aim to describe the clinical and serological characteristics and longitudinal therapeutic outcomes of patients with EGPA in the severe asthma (SA) cohort. MethodsRetrospective study of patients with EGPA attending the multidisciplinary SA clinic in a tertiary hospital from 2011 to 2023 was conducted. Baseline demographics, organ manifestations, biological markers, lung function and therapeutic outcomes were assessed. Results23 out of 596 patients in the SA registry were identified to have EGPA. Median time interval between asthma and EGPA diagnosis was 10 years (range 2.5 to 32 years). Almost all patients (95.7%) had peak blood eosinophil count of >1.0 x 109/L (range 0.47 – 14.08 x 109/L). Upper airway involvement was the most detected manifestation in addition to asthma, followed by neuropathy and renal involvement. Patients who were treated with biologic therapy were significantly younger, had more upper airway, renal, pulmonary involvement and lower five factor score (FFS). ConclusionThe prevalence of EGPA in the SA population was 3.9% in our cohort. Its diagnosis requires high clinical suspicion in patients with SA and blood eosinophilia, prompting stringent evaluation for extrapulmonary manifestations and multidisciplinary involvement.

Species-level, metagenomic and proteomic analysis of microbe-immune interactions in severe asthma.

The airway microbiome in severe asthma has not been characterised at species-level by metagenomic sequencing, nor have the relationships between specific species and mucosal immune responses in 'type-2 low', neutrophilic asthma been defined. We performed an integrated species-level metagenomic data with inflammatory mediators to characterise prevalence of dominant potentially pathogenic organisms and host immune responses. Sputum and nasal lavage samples were analysed using long-read metagenomic sequencing with Nanopore and qPCR in two cross-sectional adult severe asthma cohorts, Wessex (n = 66) and Oxford (n = 30). We integrated species-level data with clinical parameters and 39 selected airway proteins measured by immunoassay and O-link. The sputum microbiome in health and mild asthma displayed comparable microbial diversity. By contrast, 23% (19/81) of severe asthma microbiomes were dominated by a single respiratory pathogen, namely H. influenzae (n = 10), M. catarrhalis (n = 4), S. pneumoniae (n = 4) and P. aeruginosa (n = 1). Neutrophilic asthma was associated with H. influenzae, M. catarrhalis, S. pneumoniae and T. whipplei with elevated type-1 cytokines and proteases; eosinophilic asthma with higher M. catarrhalis, but lower H. influenzae, and S. pneumoniae abundance. H. influenzae load correlated with Eosinophil Cationic Protein, elastase and IL-10. R. mucilaginosa associated positively with IL-6 and negatively with FGF. Bayesian network analysis also revealed close and distinct relationships of H. influenzae and M. catarrhalis with type-1 airway inflammation. The microbiomes and cytokine milieu were distinct between upper and lower airways. This species-level integrated analysis reveals central, but distinct associations between potentially pathogenic bacteria and airways inflammation in severe asthma.

Overcoming Barriers to Remission in Severe Eosinophilic Asthma: Two-Year Real-World Data With Benralizumab.

Benralizumab has been reported to lead to clinical remission of severe eosinophilic asthma (SEA) at 1 year in some patients. However, whether this is maintained over a longer term remains unclear. Additionally, the impact of pulmonary and extrapulmonary comorbidities on the ability to meet remission is poorly understood. Clinical outcomes including remission of SEA with benralizumab at 1 and 2 years were assessed retrospectively in a real-world UK multi-centre severe asthma cohort. The presence of clinically relevant pulmonary and extrapulmonary comorbidities associated with respiratory symptoms was recorded. Analyses to identify factors associated with the ability to meet remission were performed. In total, 276 patients with SEA treated with benralizumab including 113 patients who had switched from a previous biologic to benralizumab were included. Overall, clinical remission was met in 17% (n = 31/186) and 32% (n = 43/133) of patients at 1 and 2 years, respectively. This increased to 28% at 1 year and 49% at 2 years once patients with pulmonary and/or extrapulmonary comorbidities were excluded. Body mass index (BMI) and maintenance OCS (mOCS) use demonstrated a negative association with clinical remission at 1 (BMI: OR: 0.89, 95% CI: 0.82-0.96, p < 0.01; mOCS: OR: 0.94, 95% CI: 0.89-0.99, p < 0.05) and 2 years (BMI: OR: 0.93, 95% CI: 0.87-0.99, p < 0.05; mOCS: OR: 0.95, 95% CI: 0.89-0.99, p < 0.05). In this long-term, real-world study, patients with SEA demonstrated the ability to meet and sustain clinical remission when treated with benralizumab. The presence of comorbidities including obesity, which are known to be independently associated with respiratory symptoms, reduced the likelihood of meeting clinical remission.

Comparison of Asthma Phenotypes in Severe Asthma Cohorts (SARP, U-BIOPRED, ProAR and COREA) From 4 Continents.

Asthma is a clinical syndrome with various underlying pathomechanisms and clinical phenotypes. Genetic, ethnic, and geographic factors may influence the differences in clinical presentation, severity, and prognosis. We compared the characteristics of asthma based on the geographical background by analyzing representative cohorts from the United States, Europe, South America, and Asia using the Severe Asthma Research Program (SARP), Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED), Program for Control of Asthma in Bahia (ProAR), and Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), respectively. The clinical characteristics and medications for the SARP (n = 669), U-BIOPRED (n = 509), ProAR (n = 996), and COREA (n = 3,748) were analyzed. Subgroup analysis was performed for severe asthma. The mean age was highest and lowest in the COREA and SARP, respectively. The asthma onset age was lowest in the ProAR. The mean body mass index was highest and lowest in the SARP and COREA, respectively. Baseline pulmonary function was lowest and highest in the U-BIOPRED and COREA, respectively. The number of patients with acute exacerbation in the previous year was highest in U-BIOPRED. The mean blood eosinophil count was highest in COREA. The total immunoglobulin E was highest in the ProAR. The frequency of atopy was highest in the SARP. The principal component analysis plot revealed differences among all cohorts. The cohorts from 4 different continents exhibited different clinical and physiological characteristics, probably resulting from the interplay between genetic susceptibility and geographical factors.

Increased adiposity-to-muscle ratio and severity of sinusitis affect quality of life in asthma: Computed tomographic analysis

BackgroundDeteriorated sinusitis and increased adiposity relative to muscle mass may affect the quality of life(QoL) in patients with asthma. However, whether these effects are observed regardless of intra-pulmonary pathology is unknown. ObjectivesTo evaluate the correlation of the cross-sectional ratio of abdominal visceral fat (VF) to erector spinae muscle (ESM) and sinus findings based on Lund-Mackey scoring system (LMS) on computed tomography (CT) with the impaired score of the Asthma Quality of Life Questionnaire (AQLQ), regardless of airway and parenchymal disease, in patients with asthma. MethodsParticipants from the Hokkaido-based severe asthma cohort who had completed AQLQ and CT examination at the entry. The participants were divided into high (highest) and low (other quartiles) groups based on the extra-pulmonary indices. The multivariate analysis examined the association of VF/ESM for the adiposity-to-muscle ratio, LMS with AQLQ, after adjusting for the airway fractal dimension for airway index, %low attenuation volume for parenchymal index. ResultsNo significant differences were observed in VF/ESM and LMS in terms of sex. The AQLQ score in the high VF/ESM group and high LMS group was lower than those in low VF/ESM group and low LMS group (N:Male/Female, 63/100). High VF/ESM (estimate [95% confidence interval], (-0.43[-0.61,-0.25]) and high LMS scores (-0.22(-0.41, -0.03)) were associated with low AQLQ scores, adjusted for age, body mass index, smoking status, blood eosinophil counts, and intra pulmonary CT indices. ConclusionsIncreased VF relative to ESM mass and high LMS may deteriorate asthma related QoL, regardless of intra-pulmonary disease.

Predictors of persistent poor control and validation of ASSESS score: Longitudinal 5-year follow-up of severe asthma cohort

BackgroundLongitudinal predictors of persistent poor asthma control in severe asthma (SA) cohort remain scarce. The predictive value of the asthma severity scoring system (ASSESS) and their validation in the SA cohort outside the original study and in the Asian population is unknown. ObjectiveTo determine the 5-year longitudinal outcome of SA patients and validate the use of ASSESS score in predicting future outcomes in SA. MethodsProspective longitudinal observational study of patients with severe asthma (SA) attending the multidisciplinary specialist SA clinic from 2011 to 2021. The number of exacerbations and asthma control tests (ACT) were recorded yearly for 5 consecutive years. ASSESS score was computed at baseline, and the area under the receiving operating characteristics curve (AUC) for predicting persistent poor asthma control was generated. ResultsOf the 489 patients recruited into the study, 306 patients with 5-year follow-up data were analyzed. Seventy-three percent had Type-2 inflammation (T2) with increased overall exacerbations over 5 years (rate ratio (RR) 2.55, 95% CI 1.31-4.96, p=0.006) relative to non-T2 SA. In the multivariate model, bronchiectasis, gastroesophageal reflux disease (GERD) and ACT<20, were significantly associated with persistent poor asthma control over 5 -years. ASSESS scores were good at predicting persistent poor asthma control with an AUC of 0.71 (95% CI 0.57-0.84). ConclusionBronchiectasis and GERD are predictors for persistent poor asthma control and targeted traits for precision medicine in SA. The ASSESS score has a good prediction for persistent poor asthma control over 5 years.

Clinical remission in severe asthma with biologic therapy: an analysis from the UK Severe Asthma Registry.

Novel biologic therapies have revolutionised the management of severe asthma with more ambitious treatment aims. Here we analyse the definition of clinical remission as a suggested treatment goal and consider the characteristics associated with clinical remission in a large, real-world severe asthma cohort. This was a retrospective analysis of severe asthma patients registered in the UK Severe Asthma Registry (UKSAR) who met strict national access criteria for biologics. Patients had a pre-biologics baseline assessment and annual review. The primary definition of clinical remission applied included Asthma Control Questionnaire (ACQ)-5 <1.5 and no oral corticosteroids for disease control and forced expiratory volume in 1 s above lower limit of normal or no more than 100 mL less than baseline. 18.3% of patients achieved the primary definition of remission. The adjusted odds of remission on biologic therapy were 7.44 (95% CI 1.73-31.95)-fold higher in patients with type 2 (T2)-high biomarkers. The adjusted odds of remission were lower in patients who were female (OR 0.61, 95% CI 0.45-0.93), obese (OR 0.49, 95% CI 0.24-0.65) or had ACQ-5 ≥1.5 (OR 0.19, 95% CI 0.12-0.31) pre-biologic therapy. The likelihood of remission reduced by 14% (95% CI 0.76-0.97) for every 10-year increase in disease duration. 12-21% of the cohort attained clinical remission depending on the definition applied; most of those who did not achieve remission failed to meet multiple criteria. 18.3% of patients achieved the primary definition of clinical remission. Remission was more likely in T2-high biomarker patients with shorter duration of disease and less comorbidity. Further research on the optimum time to commence biologics in severe asthma is required.

Real-world super-response to biologics in severe asthma: A French monocentric retrospective cohort study

BackgroundBiologics have dramatically improved outcomes in severe T2-high asthma. Although the identification of patients with the best response is key to understand the efficacy of these agents and select the best target populations, the definition and predictors of super-response are not fully established yet. MethodsThis study aimed to describe super-response and to identify predictors of super-response to biologics in a French severe eosinophilic asthma cohort followed in a severe asthma tertiary care center between January 2005 and December 2020. Super-response was defined a priori as no oral corticosteroids intake and no exacerbations over 12 months. Collected data at baseline and after 12 months included asthma history, comorbidities, clinical characteristics, lung function, T2-biomarkers, baseline asthma-related treatments, and asthma control. ResultsAmong 157 patients assessed for eligibility, 108 were included, corresponding to 166 treatments with biologics. Overall response rate was 63.2 % (105/166) and super-response rate was 39.7 % (66/166). In omalizumab group (n = 67), lower dose of oral corticosteroids in maintenance was the only factor associated with super-response (p = 0.008). In the anti-IL-5/anti-IL-5R group (n = 99), absence or lower dose of oral corticosteroids in maintenance and absence of eosinophilic granulomatosis with polyangiitis were statistically associated with super-response (p = 0.009, p = 0.001 and p = 0.02 respectively). ConclusionIn this real-life study in severe T2-high asthma patients, a lower dose or absence of daily oral corticosteroids and absence of eosinophilic granulomatosis with polyangiitis were the only identifiable predictors of super-response to biologics. Physicians should not wait for maintenance oral corticosteroids to be required before considering the initiation of a biologic in severe asthma.

CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma

Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation. CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1high murine severe asthma model. Sputum CCL5 expression strongly correlated with T1 chemokines (P< .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5high participants had greater fractional exhaled nitric oxide (P= .009), blood eosinophils (P<.001), and sputum eosinophils (P= .001) in addition to sputum neutrophils (P= .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1high/T2variable/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P= .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. Arole for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation. CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.

Patient Characteristics Associated with Adequacy of Inhaler Technique in a Severe Asthma Cohort in the Bronx

To date, most studies addressing predictive characteristics of adequate inhaler technique have been in adolescents. However, there is evidence to suggest older age correlates with poor inhaler technique. This study aimed to further investigate this association and correlate other patient characteristics with adequacy of inhaler technique in an adult asthma cohort in the Bronx.

Heterogeneity of asthma-chronic obstructive pulmonary disease (COPD) overlap from a cohort of patients with severe asthma and COPD.

A considerable proportion of patients have features of both asthma and chronic obstructive pulmonary disease (COPD) simultaneously, called asthma-COPD overlap (ACO). The aim of this study was to identify heterogeneity of ACO from a cohort of patients with severe asthma and COPD using the same diagnostic criteria. We used the International Severe Asthma Registry (ISAR) and the Korean COPD Subgroup Study (KOCOSS) to evaluate clinical characteristics of ACO from each cohort. We classified subjects into four groups: (1) pure severe asthma, (2) ACO from the severe asthma cohort, (3) ACO from the COPD cohort, and (4) pure COPD. ACO was defined by satisfying extreme bronchodilator response (BDR) >15% and 400 ml and/or blood eosinophil count ⩾300 /µL in patients aged 40 years or older and post-BD forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7. The ACO group had 25 (23%) of 111 in the ISAR cohort and 403 (23%) of 1781 in the KOCOSS cohort. The ACO from the COPD cohort was older with more males and more smokers, but had similar degree of airflow limitation compared with the ACO from the severe asthma cohort. ICS-containing inhaler treatment was prescribed for all severe asthma subjects, but only for 43.9% of ACO subjects from the COPD cohort. Compared with patients having pure severe asthma, the risk for exacerbation was comparable in ACO either from severe asthma or COPD cohort [adjusted odds ratio (aOR): 1.54, 95% CI: 0.22-10.95 or aOR: 2.15, 95% CI: 0.59-7.85]. The prevalence of ACO was similar in severe asthma and COPD cohorts applying identical diagnostic criteria. ACO from the severe asthma cohort was similar to ACO from the COPD cohort in terms of lung function and exacerbation risk.

Blood eosinophil count variability in chronic obstructive pulmonary disease and severe asthma

BackgroundBlood eosinophils are essential biomarkers that vary substantially over time in patients with COPD and asthma. However, no study has identified the changes and effects in the changes of the blood eosinophil counts over time in both diseases. This study aimed to demonstrate blood eosinophil variability in patients with COPD and severe asthma based on these backgrounds. MethodsA total of 172 patients with COPD from the Hokkaido COPD cohort study and 96 patients with severe asthma from the Hokkaido Severe Asthma Cohort Study, whose blood eosinophil counts were measured annually over a 3-year period, were analyzed. The factors contributing to consistently high or low blood eosinophil counts were examined in each cohort. The stability of the eosinophil classification (<150, 150–299, ≥300 cells/μL) was compared based on the number of asthma-like features in patients with COPD and the smoking status in patients with severe asthma. ResultsAmong all the patients, the most stable range of baseline blood eosinophil counts differed between the two diseases, with <150 cells/μL in COPD and ≥300 cells/μL in severe asthma. In COPD, the number of asthma-like features (bronchodilator reversibility, blood eosinophilia, and atopy) affects the blood eosinophil count variation patterns. In severe asthma, smoking status did not affect the blood eosinophil count variation patterns. ConclusionsWe identified variations in the blood eosinophil counts and their contributing factors in patients with COPD and severe asthma.

NOVEL INSIGHTS GAINED FROM AN INTEGRATED ELECTRONIC INHALER IN PATIENTS WITH SEVERE ASTHMA TREATED WITH BIOLOGICS

NOVEL INSIGHTS GAINED FROM AN INTEGRATED ELECTRONIC INHALER IN PATIENTS WITH SEVERE ASTHMA TREATED WITH BIOLOGICS

Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts.

Background and objectiveSevere asthma (SA) is a heterogeneous disease. Transcriptomic analysis contributes to the understanding of pathogenesis necessary for developing new therapies. We sought to identify and validate mechanistic pathways of SA across two independent cohorts.MethodsTranscriptomic profiles from U‐BIOPRED and Australian NOVocastrian Asthma cohorts were examined and grouped into SA, mild/moderate asthma (MMA) and healthy controls (HCs). Differentially expressed genes (DEGs), canonical pathways and gene sets were identified as central to SA mechanisms if they were significant across both cohorts in either endobronchial biopsies or induced sputum.ResultsThirty‐six DEGs and four pathways were shared across cohorts linking to tissue remodelling/repair in biopsies of SA patients, including SUMOylation, NRF2 pathway and oxidative stress pathways. MMA presented a similar profile to HCs. Induced sputum demonstrated IL18R1 as a shared DEG in SA compared with healthy subjects. We identified enrichment of gene sets related to corticosteroid treatment; immune‐related mechanisms; activation of CD4+ T cells, mast cells and IL18R1; and airway remodelling in SA.ConclusionOur results identified differentially expressed pathways that highlight the role of CD4+ T cells, mast cells and pathways linked to ongoing airway remodelling, such as IL18R1, SUMOylation and NRF2 pathways, as likely active mechanisms in the pathogenesis of SA.

Exacerbation Profile and Risk Factors in a Type-2-Low Enriched Severe Asthma Cohort: A Clinical Trial to Assess Asthma Exacerbation Phenotypes.

Rationale: The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. Objectives: The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2HIGH and T2LOW at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation. Methods: Exacerbation assessment was a prespecified secondary analysis of data from a 48-week, multicenter, randomized controlled clinical study comparing the use of biomarkers and symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort. Participants were phenotyped as T2LOW (fractional exhaled nitric oxide ⩽ 20 ppb and blood eosinophil count ⩽ 150 cells/µl) or T2HIGH (fractional exhaled nitric oxide > 20 or blood eosinophil count > 150) at study enrollment and at each exacerbation. Here, we report the findings of the exacerbation analyses, including comparison of exacerbators and nonexacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation. Measurements and Main Results: Of the 301 participants, 60.8% (183) had one or more self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher body mass index, and have more exacerbations requiring oral corticosteroid and unscheduled primary care attendances for exacerbations. At enrollment, 23.6% (71) were T2LOW and 76.4% (230) T2HIGH. The T2LOW group had more asthma primary care attendances, were more likely to have a previous admission to HDU (high dependency unit)/ICU and to be receiving maintenance oral corticosteroids. At exacerbation, the T2LOW events were indistinguishable from T2HIGH exacerbations in terms of lung function (mean fall in T2LOW FEV1, 200 [400] ml vs. T2HIGH 200 [300] ml; P = 0.93) and symptom increase (ACQ5: T2LOW, 1.4 [0.8] vs. T2HIGH, 1.3 [0.8]; P = 0.72), with no increase in T2 biomarkers from stable to exacerbation state in the T2LOW exacerbations. The inflammatory phenotype within individual patients was dynamic; inflammatory phenotype at study entry did not have a significant association with exacerbation phenotype. Conclusions: Asthma exacerbations demonstrating a T2LOW phenotype were physiologically and symptomatically similar to T2HIGH exacerbations. T2LOW asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlight the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma. Clinical trial registered with www.clinicaltrials.gov (NCT02717689).

Further evidence for association of YKL-40 with severe asthma airway remodeling

BackgroundThe chitinase-like protein YKL-40 is associated with airflow limitation on spirometry and airway remodeling in patients with asthma. It remains unclear whether YKL-40 is associated with morphologic changes in the airways and parenchyma or with future progression of airflow limitation in severe asthma. ObjectiveTo evaluate the association of circulating YKL-40 levels with morphologic changes in the airways and parenchyma and with longitudinal progression of airflow limitation. MethodsThe patients were participants in the Hokkaido Severe Asthma Cohort Study (n = 127), including smokers. This study consisted of 2 parts. In analysis 1, we analyzed associations between circulating YKL-40 levels and several asthma-related indices, including computed tomography–derived indices of proximal wall area percentage, the complexity of the airways (airway fractal dimension), and the parenchyma (exponent D) cross-sectionally (n = 97). In analysis 2, we evaluated the impact of circulating YKL-40 levels on forced expiratory volume in 1 second (FEV1) decline longitudinally for a 5-year follow-up (n = 103). ResultsCirculating YKL-40 levels were significantly associated with proximal wall area percentage and airway fractal dimension (r = 0.25, P = .01; r = −0.22, P = .04, respectively), but not with exponent D. The mean annual change in FEV1 was −33.7 (± 23.3) mL/y, and the circulating YKL-40 level was a significant independent factor associated with annual FEV1 decline (β = −0.24, P = .02), even after controlling for exponent D (β = −0.26, P = .01). ConclusionThese results provide further evidence for the association of YKL-40 with the pathogenesis of airway remodeling in severe asthma.

Phenotype of Asthma-COPD Overlap in COPD and Severe Asthma Cohorts.

BackgroundAsthma and chronic obstructive pulmonary disease (COPD) are airway diseases with similar clinical manifestations, despite differences in pathophysiology. Asthma-COPD overlap (ACO) is a condition characterized by overlapping clinical features of both diseases. There have been few reports regarding the prevalence of ACO in COPD and severe asthma cohorts. ACO is heterogeneous; patients can be classified on the basis of phenotype differences. This study was performed to analyze the prevalence of ACO in COPD and severe asthma cohorts. In addition, this study compared baseline characteristics among ACO patients according to phenotype.MethodsPatients with COPD were prospectively enrolled into the Korean COPD subgroup study (KOCOSS) cohort. Patients with severe asthma were prospectively enrolled into the Korean Severe Asthma Registry (KoSAR). ACO was defined in accordance with the updated Spanish criteria. In the COPD cohort, ACO was defined as bronchodilator response (BDR) ≥ 15% and ≥ 400 mL from baseline or blood eosinophil count (BEC) ≥ 300 cells/μL. In the severe asthma cohort, ACO was defined as age ≥ 35 years, smoking ≥ 10 pack-years, and post-bronchodilator forced expiratory volume in 1 s/forced vital capacity < 0.7. Patients with ACO were divided into four groups according to smoking history (threshold: 20 pack-years) and BEC (threshold: 300 cells/μL).ResultsThe prevalence of ACO significantly differed between the COPD and severe asthma cohorts (19.8% [365/1,839] vs. 12.5% [104/832], respectively; P < 0.001). The percentage of patients in each group was as follows: group A (light smoker with high BEC) – 9.1%; group B (light smoker with low BEC) – 3.7%; group C (moderate to heavy smoker with high BEC) – 73.8%; and group D (moderate to heavy smoker with low BEC) – 13.4%. Moderate to heavy smoker with high BEC group was oldest, and showed weak BDR response. Age, sex, BDR, comorbidities, and medications significantly differed among the four groups.ConclusionThe prevalence of ACO differed between COPD and severe asthma cohorts. ACO patients can be classified into four phenotype groups, such that each phenotype exhibits distinct characteristics.

Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

BackgroundInterleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2. MethodsWe used house dust mite (HDM) or interleukin-1β in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1β and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database. ResultsAblation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1β-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1β-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. 13C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma. ConclusionsGSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease.

β-Agonist exposure preferentially impacts lung macrophage cyclic AMP-related gene expression in asthma and asthma COPD overlap syndrome.

Bronchoalveolar lavage (BAL) samples from Severe Asthma Research Program (SARP) patients display suppression of a module of genes involved in cAMP-signaling pathways (BALcAMP) correlating with severity, therapy, and macrophage constituency. We sought to establish if gene expression changes were specific to macrophages and compared gene expression trends from multiple sources. Datasets included single-cell RNA sequencing (scRNA-seq) from lung specimens including a fatal exacerbation of severe Asthma COPD Overlap Syndrome (ACOS) after intense therapy and controls without lung disease, bulk RNA sequencing from cultured macrophage (THP-1) cells after acute or prolonged β-agonist exposure, SARP datasets, and data from the Immune Modulators of Severe Asthma (IMSA) cohort. THP monocytes suppressed BALcAMP network gene expression after prolonged relative to acute β-agonist exposure, corroborating SARP observations. scRNA-seq from healthy and diseased lung tissue revealed 13 cell populations enriched for macrophages. In severe ACOS, BALcAMP gene network expression scores were decreased in many cell populations, most significantly for macrophage populations (P < 3.9e-111). Natural killer (NK) cells and type II alveolar epithelial cells displayed less robust network suppression (P < 9.2e-8). Alveolar macrophages displayed the most numerous individual genes affected and the highest amplitude of modulation. Key BALcAMP genes demonstrate significantly decreased expression in severe asthmatics in the IMSA cohort. We conclude that suppression of the BALcAMP gene module identified from SARP BAL samples is validated in the IMSA patient cohort with physiological parallels observed in a monocytic cell line and in a severe ACOS patient sample with effects preferentially localizing to macrophages.

Asthma Phenotyping in Primary Care: Applying the International Severe Asthma Registry Eosinophil Phenotype Algorithm Across All Asthma Severities

We developed an eosinophil phenotype gradient algorithm and applied it to a large severe asthma cohort (International Severe Asthma Registry). We sought to reapply this algorithm in a UK primary care asthma cohort, quantify the eosinophilic phenotype, and assess the relationship between the likelihood of an eosinophilic phenotype and asthma severity/health care resource use (HCRU). Patients age 13 years and older with active asthmaand blood eosinophil count or 1 or greater, who were included from the Optimum Patient Care Research Databaseand the Clinical Practice Research Datalink, were categorized according to the likelihood of eosinophilic phenotype using the International Severe Asthma Registry gradient eosinophilic algorithm. Patient demographic, clinicaland HCRU characteristics were described for each phenotype. Of 241,006 patients, 50.3%, 22.2%, and 21.9% most likely (grade 3), likely (grade 2), and least likely (grade 1), respectively, had an eosinophilic phenotype, and 5.6% had a noneosinophilic phenotype (grade 0). Compared with patients with noneosinophilic asthma, those most likely to have an eosinophilic phenotype tended to have more comorbidities (percentage with Charlson comorbidity index of ≥2: 28.2% vs 6.9%) and experienced more asthma attacks (percentage with one or more attack: 24.8% vs 15.3%). These patients were also more likely to have asthma that was difficult to treat (31.1% vs 18.3%), to receive more intensive treatment (percentage on Global Initiative for Asthma 2020 step 4 or 5: 44.2% vs 27.5%), and greater HCRU (eg, 10.8 vs 7.9 general practitioner all-cause consultations per year). The eosinophilic asthma phenotype predominates in primary care and is associated with greater asthma severity and HCRU. These patients may benefit from earlier and targeted asthma therapy.