Transcriptomic gene signatures associated with persistent airflow limitation in patients with severe asthma

A proportion of severe asthma patients suffers from persistent airflow limitation (PAL), often associated with more symptoms and exacerbations. Little is known about the underlying mechanisms. Here, our aim was to discover unexplored potential mechanisms using Gene Set Variation Analysis (GSVA), a sensitive technique that can detect underlying pathways in heterogeneous samples. Severe asthma patients from the U-BIOPRED cohort with PAL (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio below the lower limit of normal) were compared with those without PAL. Gene expression was assessed on the total RNA of sputum cells, nasal brushings, and endobronchial brushings and biopsies. GSVA was applied to identify differentially enriched predefined gene signatures based on all available gene expression publications and data on airways disease. Differentially enriched gene signatures were identified in nasal brushings (n=1), sputum (n=9), bronchial brushings (n=1) and bronchial biopsies (n=4) that were associated with response to inhaled steroids, eosinophils, interleukin-13, interferon-α, specific CD4+ T-cells and airway remodelling. PAL in severe asthma has distinguishable underlying gene networks that are associated with treatment, inflammatory pathways and airway remodelling. These findings point towards targets for the therapy of PAL in severe asthma

Treatable traits in the European U-BIOPRED adult asthma cohorts

Letter to the edito

Developing and emerging clinical asthma phenotypes

For more than a century, clinicians have attempted to subdivide asthma into different phenotypes based on triggers that cause asthma attacks, the course of the disease, or the prognosis. The first phenotypes that were described included allergic asthma, intrinsic or nonallergic asthma, infectious asthma, and aspirin-exacerbated asthma. These phenotypes are being reviewed elsewhere in this issue of the journal. The present article focuses on developing and emerging clinical asthma phenotypes. First, asthma phenotypes that are associated with environmental exposures (occupational agents, cigarette smoke, air pollution, cold dry air); second, asthma phenotypes that are associated with specific symptoms or clinical characteristics (cough, obesity, adult onset of disease); and third, asthma phenotypes that are based on biomarkers. This latter approach is the most promising because it attempts to identify asthma phenotypes with different underlying mechanisms so that therapies can be better targeted toward disease-specific features and disease outcomes can be improve

Comorbidities in Difficult-to-Control Asthma

Difficult-to-control asthma is associated with significant medical and financial burden. Comorbidities are known to contribute to uncontrolled asthma. Better insight into the prevalence, nature, and risk factors of comorbidities may optimize treatment strategies in patients with difficult-to-control asthma and decrease disease burden. The objectives of this study were to assess the prevalence, number, and type of comorbidities in difficult-to-control asthma compared with not-difficult-to-control asthma, and to investigate whether specific patient characteristics are associated with particular comorbidities. A total of 5,002 adult patients with a prescription for high-dose (>1,000 μg) fluticasone or oral corticosteroids, extracted from 65 Dutch pharmacy databases, were sent questionnaires about patient characteristics. Of the 2,312 patients who returned the questionnaires, 914 were diagnosed with difficult-to-control asthma. Diagnoses of comorbidities (gastroesophageal reflux, nasal polyps, cardiovascular disease, anxiety/depression, obesity, and diabetes) were based on treatment prescriptions or questionnaires. Associations were assessed using multivariable logistic regression analyses. A total of 92% of patients with difficult-to-control asthma had ≥1 comorbidity. Patients with difficult-to-control asthma had more comorbidities (mean ± SD comorbidities 2.22 ± 1.27 vs 1.69 ± 1.32; P < .01), and a significantly higher prevalence of each comorbidity, compared with patients with not-difficult-to-control asthma, except for diabetes and nasal polyposis. Comorbidities were associated with specific patient characteristics, including older age, female gender, smoking history, and chronic prednisone use. Almost all patients with difficult-to-control asthma have comorbidities, in particular asthmatic women of older age, former smokers, and asthmatics who are prednisone dependent. Recognition of these typical characteristics can help physicians in the diagnostic workup, so that adequate preventive measures can be take

The prevalence of severe refractory asthma

BACKGROUND: Severe asthma is characterized by difficulty to achieve disease control despite high-intensity treatment. However, prevalence figures of severe asthma are lacking, whereas longstanding estimates vary between 5% and 10% of all asthmatic patients. Knowing the exact prevalence of severe refractory asthma as opposed to difficult-to-control asthma is important for clinical decision making, drug development, and reimbursement policies by health authorities. OBJECTIVE: We sought to estimate the prevalence of severe refractory asthma as defined by the Innovative Medicine Initiative consensus. METHODS: Adult patients with a prescription for high-intensity treatment (high-dose inhaled corticosteroids and long-acting β2-agonists or medium- to high-dose inhaled corticosteroids combined with oral corticosteroids and long-acting β2-agonists) were extracted from 65 Dutch pharmacy databases, representing 3% of the population (500,500 inhabitants). Questionnaires were sent to 5,002 patients, of which 2,312 were analyzed. The diagnosis of asthma and degree of asthma control were derived from questionnaires to identify patients with difficult-to-control asthma. Inhalation technique was assessed in a random sample of 60 adherent patients (prescription filling, ≥80%). Patients with difficult-to-control asthma, adherence to treatment, and a correct inhalation technique were qualified as having severe refractory asthma. Results were mirrored to the Dutch population. RESULTS: Of asthmatic adults, 3.6% (95% CI, 3.0% to 4.1%) qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants. CONCLUSION: The prevalence of severe refractory asthma might be lower than estimated by expert opinion. This implies that currently recognized severe asthma subphenotypes could meet the criteria of rare diseases

The prevalence of severe refractory asthma

Severe asthma is characterized by difficulty to achieve disease control despite high-intensity treatment. However, prevalence figures of severe asthma are lacking, whereas longstanding estimates vary between 5% and 10% of all asthmatic patients. Knowing the exact prevalence of severe refractory asthma as opposed to difficult-to-control asthma is important for clinical decision making, drug development, and reimbursement policies by health authorities. We sought to estimate the prevalence of severe refractory asthma as defined by the Innovative Medicine Initiative consensus. Adult patients with a prescription for high-intensity treatment (high-dose inhaled corticosteroids and long-acting β2-agonists or medium- to high-dose inhaled corticosteroids combined with oral corticosteroids and long-acting β2-agonists) were extracted from 65 Dutch pharmacy databases, representing 3% of the population (500,500 inhabitants). Questionnaires were sent to 5,002 patients, of which 2,312 were analyzed. The diagnosis of asthma and degree of asthma control were derived from questionnaires to identify patients with difficult-to-control asthma. Inhalation technique was assessed in a random sample of 60 adherent patients (prescription filling, ≥80%). Patients with difficult-to-control asthma, adherence to treatment, and a correct inhalation technique were qualified as having severe refractory asthma. Results were mirrored to the Dutch population. Of asthmatic adults, 3.6% (95% CI, 3.0% to 4.1%) qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants. The prevalence of severe refractory asthma might be lower than estimated by expert opinion. This implies that currently recognized severe asthma subphenotypes could meet the criteria of rare disease

Peripheral infiltration of remdesivir in 3 patients with COVID-19: Case series and discussion

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic resulted in accelerated market access to remdesivir worldwide. Therefore, data about complications experienced during use of the drug are limited. This is the first published case series (1 case report exists) to describe remdesivir infiltration in 3 patients with COVID-19. SUMMARY: In the first case, a 91-year-old woman experienced remdesivir infiltration resulting in edema, hematoma at the area of infiltration; on palpation, the affected area felt cooler than the surrounding areas. Swelling was still present after 6 weeks. In the second case, remdesivir infiltration occurred in a 72-year-old male, resulting in edema, hematoma, and pain at the area of infiltration. The hematoma lasted for 7 days. The third case concerned a 67-year-old woman, in whom remdesivir infiltration led to edema and a small hematoma. The hematoma regressed to a negligible size within 3 days. However, a week after infiltration, redness had reappeared. In 2 cases, the patient was immediately treated with hyaluronidase injections, but no specific treatments were provided in the other case. CONCLUSION: Based on the product information provided by remdesivir's manufacturer, we believe symptoms and signs observed in the 3 cases may have resulted from the low pH (~4) of the nonbuffered remdesivir solution, although the patients were not formally assessed for caustic injury. Previous experience with other noncytotoxic medications suggests that infusion-specific factors (eg, volume of leaked fluid) and patient-specific factors (eg, advanced age) may have a role in the outcome of remdesivir infiltration. The possibility of symptoms caused by cyclodextrins in the formulation or by intrinsic toxicity of remdesivir warrants exploration

Identification and prospective stability of electronic nose (eNose)–derived inflammatory phenotypes in patients with severe asthma

Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes. Objectives: We aimed (1)to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses)and (2)to assess the stability of eNose-derived phenotypes in relation to within-patient clinical and inflammatory changes. Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability. Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNose-driven clusters (n = 26/33/19)were revealed, showing differences in circulating eosinophil (P =.045)and neutrophil (P =.017)percentages and ratios of patients using oral corticosteroids (P =.035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P =.045). Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma

Pathway discovery using transcriptomic profiles in adult-onset severe asthma

Background: Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous samples. Objective: We sought to identify gene profiles associated with adult-onset severe asthma. Methods: This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age >18 years) as compared with childhood-onset severe asthma (<18 years) were selected from the U-BIOPRED cohort. Gene expression was assessed on the total RNA of induced sputum (n 5 83), nasal brushings (n 5 41), and endobronchial brushings (n 5 65) and biopsies (n 5 47) (Affymetrix HT HG-U1331 PM). Gene set variation analysis was used to identify differentially enriched predefined gene signatures of leukocyte lineage, inflammatory and induced lung injury pathways. Results: Significant differentially enriched gene signatures in patients with adult-onset as compared with childhood-onset severe asthma were identified in nasal brushings (5 signatures), sputum (3 signatures), and endobronchial brushings (6 signatures). Signatures associated with eosinophilic airway inflammation, mast cells, and group 3 innate lymphoid cells were more enriched in adult-onset severe asthma, whereas signatures associated with induced lung injury were less enriched in adult-onset severe asthma. Conclusions: Adult-onset severe asthma is characterized by inflammatory pathways involving eosinophils, mast cells, and group 3 innate lymphoid cells. These pathways could represent useful targets for the treatment of adult-onset severe asthma