Identifying a Neurophenotype in Severe Asthma.
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ABSTRACT:
SUBMITTER: Satia I
PROVIDER: S-EPMC7193849 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Publications
Identifying a Neurophenotype in Severe Asthma.
Satia Imran I O'Byrne Paul M PM
American journal of respiratory and critical care medicine 20200501 9
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Project description:Previous metagenomic studies in asthma have been limited by inadequate sequencing depth for species-level bacterial identification and by heterogeneity in clinical phenotyping. We hypothesize that chronic bacterial airways infection is a key "treatable trait" whose prevalence, clinical phenotype and reliable biomarkers need definition. In this study, we have applied a method for Oxford Nanopore sequencing for the unbiased metagenomic characterization of severe asthma. We optimized methods to compare performance of Illumina MiSeq, Nanopore sequencing, and RT-qPCR on total sputum DNA extracts against culture/MALDI-TOF for analysis of induced sputum samples from highly phenotyped severe asthma during clinical stability. In participants with severe asthma (n = 23) H. influenzae was commonly cultured (n = 8) and identified as the dominant bacterial species by metagenomic sequencing using an optimized method for Illumina MiSeq and Oxford Nanopore. Alongside superior operational characteristics, Oxford Nanopore achieved near complete genome coverage of H. influenzae and demonstrated a high level of agreement with Illumina MiSeq data. Clinically significant infection was confirmed with validated H. influenzae plasmid-based quantitative PCR assay. H. influenzae positive patients were found to have sputum neutrophilia and lower FeNO. In conclusion, using an optimized method of direct sequencing of induced sputum samples, H. influenzae was identified as a clinically relevant pathogen in severe asthma and was identified reliably using metagenomic sequencing. Application of these protocols in ongoing analysis of large patient cohorts will allow full characterization of this clinical phenotype. IMPORTANCE The human airways were once thought sterile in health. Now metagenomic techniques suggest bacteria may be present, but their role in asthma is not understood. Traditional culture lacks sensitivity and current sequencing techniques are limited by operational problems and limited ability to identify pathogens at species level. We optimized a new sequencing technique-Oxford Nanopore technologies (ONT)-for use on human sputum samples and compared it with existing methods. We found ONT was effective for rapidly analyzing samples and could identify bacteria at the species level. We used this to show Haemophilus influenzae was a dominant bacterium in the airways in people with severe asthma. The presence of Haemophilus was associated with a "neutrophilic" form of asthma - a subgroup for which we currently lack specific treatments. Therefore, this technique could be used to target chronic antibiotic therapy and in research to characterize the full breadth of bacteria in the airways.
| S-EPMC9045196 | biostudies-literature
Project description:Airway microbiota in severe asthma and relationship to asthma clusters and severity
| PRJEB11495 | ENA
Project description:Severe asthma is a complex and heterogeneous phenotype where management can be challenging. While many patients with severe asthma respond to high-dose inhaled corticosteroids in combination with a long-acting beta-agonist, there remains a significant subset of patients that require oral corticosteroids to control symptoms. Alternative therapies are needed to help reduce the need for continuous oral corticosteroids; however, there are currently very few effective options. Several new alternatives to oral corticosteroids have been evaluated in severe asthma as add-on to conventional therapy. These include macrolide antibiotics, omalizumab, tumor necrosis factor-alpha inhibitors, cytokine receptor antagonists, and bronchial thermoplasty. The challenge with these entities is determining the appropriate phenotype of severe asthma where effectiveness is demonstrated, given the significant heterogeneity of the disease. Therefore, there is a crucial need to better understand the mechanisms and pathophysiology of severe asthma so more effective immunomodulators and biologic therapies can emerge.
| S-EPMC4390052 | biostudies-other
Project description:BackgroundBronchiolitis is the leading cause of infants hospitalization in the U.S. and Europe. Additionally, bronchiolitis is a major risk factor for the development of childhood asthma. Growing evidence suggests heterogeneity within bronchiolitis. We sought to identify distinct, reproducible bronchiolitis subgroups (profiles) and to develop a decision rule accurately predicting the profile at the highest risk for developing asthma.MethodsIn three multicenter prospective cohorts of infants (age < 12 months) hospitalized for bronchiolitis in the U.S. and Finland (combined n = 3081) in 2007-2014, we identified clinically distinct bronchiolitis profiles by using latent class analysis. We examined the association of the profiles with the risk for developing asthma by age 6-7 years. By performing recursive partitioning analyses, we developed a decision rule predicting the profile at highest risk for asthma, and measured its predictive performance in two separate cohorts.FindingsWe identified four bronchiolitis profiles (profiles A-D). Profile A (n = 388; 13%) was characterized by a history of breathing problems/eczema and non-respiratory syncytial virus (non-RSV) infection. In contrast, profile B (n = 1064; 34%) resembled classic RSV-induced bronchiolitis. Profile C (n = 993; 32%) was comprised of the most severely ill group. Profile D (n = 636; 21%) was the least-ill group. Profile A infants had a significantly higher risk for asthma, compared to profile B infants (38% vs. 23%, adjusted odds ratio [adjOR] 2⋅57, 95%confidence interval [CI] 1⋅63-4⋅06). The derived 4-predictor (RSV infection, history of breathing problems, history of eczema, and parental history of asthma) decision rule strongly predicted profile A-e.g., area under the curve [AUC] of 0⋅98 (95%CI 0⋅97-0⋅99), sensitivity of 1⋅00 (95%CI 0⋅96-1⋅00), and specificity of 0⋅90 (95%CI 0⋅89-0⋅93) in a validation cohort.InterpretationIn three prospective cohorts of infants with bronchiolitis, we identified clinically distinct profiles and their longitudinal relationship with asthma risk. We also derived and validated an accurate prediction rule to determine the profile at highest risk. The current results should advance research into the development of profile-specific preventive strategies for asthma.
| S-EPMC8741473 | biostudies-literature
Project description:Severe asthma constitutes a serious health burden with significant morbidity and socioeconomic costs. The development and introduction of new biologics targeting type 2 inflammation changed the paradigm for management of severe asthma and initiated a biological era. These changes impose a challenge to clinicians in managing difficult-to-treat and severe asthma. To understand the characteristics and heterogeneity of severe asthma and to develop a better strategy to manage it, the Korean Academy of Asthma, Allergy and Clinical Immunology, Working Group on Severe Asthma, has organized the Korean Severe Asthma Registry (KoSAR). In this review, we describe the challenges of severe asthma management regarding diagnosis, disease burden, heterogeneity, guidelines, and organization of severe asthma clinics. This review also examines the current global activities of national and regional registries and study groups. In addition, we present the KoSAR vision and organization and describe the findings of KoSAR in comparison with those of other countries.
| S-EPMC8925953 | biostudies-literature
Project description:Mouse lung samples from mice challenged with OVA or PBS control. Wildtype (B6) mice were tested, as well as mast cell deficient mice with engraftment of normal mast cells and mast cells deficient in IgE or Ifn-gamma signaling. Treatment/Control
2014-02-02 | E-GEOD-27066 | biostudies-arrayexpress
Project description:Mouse lung samples from mice challenged with OVA or PBS control. Wildtype (B6) mice were tested, as well as mast cell deficient mice with engraftment of normal mast cells and mast cells deficient in IgE or Ifn-gamma signaling.
2014-02-02 | GSE27066 | GEO
Project description: Not available
| S-EPMC8858615 | biostudies-literature
Project description:ObjectivesPsychological comorbidities have been associated with asthma in adults and children, but have not been studied in a population of children with severe asthma. The aim of this study was to test the hypothesis that symptoms of anxiety or depression are highly prevalent in pediatric severe asthma and negatively effects asthma control.MethodsLongitudinal assessments of anxiety or depression symptoms (Patient Health Questionnaire-4 [PHQ-4]), asthma control (Asthma Control Test [ACT]), and lung function were performed in a single-center pediatric severe asthma clinic. Participant data were collected during routine clinical care. Primary outcomes were ACT and forced expiratory volume in 1 s per forced vital capacity (FEV1/FVC).ResultsAmong 43 subjects (with total 93 observations), 58.1% reported at least one anxious or depressive symptom and 18.6% had a PHQ-4 more than 2, the threshold for an abnormal test result. After adjusting for age, sex, race, and asthma medication step, there was a significant reduction in ACT for girls with PHQ-4 more than 2 (adjusted mean [SE] ACT for PHQ-4 > 2: 13.64 [0.59], ACT for PHQ-4 ≤ 2: 20.64 [1.25], p = .02) but not boys. Moreover, there was a significant differential effect of mental health impairment for girls than boys. ACT for girls with PHQ more than 2: 13.64 (0.59) compared with boys with PHQ-4 more than 2: 17.82 (0.95), adjusted mean difference ACT by sex = 4.18 points; 95% confidence interval, 0.63-7.73; p = .033. In adjusted models, there was no association between PHQ-4 more than 2 and FEV1/FVC.ConclusionsSymptoms of anxiety and depression are common. In children with severe asthma, a PHQ-4 score more than 2 is associated with worse asthma symptom control in girls, but not boys.
| S-EPMC7736198 | biostudies-literature
Project description:Asthma is a heterogeneous disease in which adequate asthma control cannot be achieved in a substantial proportion despite currently available treatment possibilities. This subgroup has been defined as "severe refractory" asthma. Over the past years considerable progress has been made regarding a more exact definition of severe refractory asthma. A systematic approach to evaluate the asthma patient has been postulated. Further detailed classification into distinct phenotypes is ongoing to target the right treatment to the right patient. And, new therapeutic targeted treatment options are currently in development to provide possible new targets to improve disease state, symptoms and quality of life. This review will provide an update on the latest advancements with regard to all these domains.
| S-EPMC9487365 | biostudies-literature