The relationship between asthma, atopy, and underlying type 2 (T2) airway inflammation is complex. Although the bacterial airway microbiota is known to differ in asthmatic patients, the fungal and ...bacterial markers that discriminate T2-high (eosinophilic) and T2-low (neutrophilic/mixed-inflammation) asthma and atopy are still incompletely identified.
The aim of this study was to demonstrate the fungal microbiota structure of airways in asthmatic patients associated with T2 inflammation, atopy, and key clinical parameters.
We collected endobronchial brush (EB) and bronchoalveolar lavage (BAL) samples from 39 asthmatic patients and 19 healthy subjects followed by 16S gene and internal transcribed spacer–based microbiota sequencing. The microbial sequences were classified into exact sequence variants. The T2 phenotype was defined by using a blood eosinophil count with a threshold of 300 cells/μL.
Fungal diversity was significantly lower in EB samples from patients with T2-high compared with T2-low inflammation; key fungal genera enriched in patients with T2-high inflammation included Trichoderma species, whereas Penicillium species was enriched in patients with atopy. In BAL fluid samples the dominant genera were Cladosporium, Fusarium, Aspergillus, and Alternaria. Using generalized linear models, we identified significant associations between specific fungal exact sequence variants and FEV1, fraction of exhaled nitric oxide values, BAL fluid cell counts, and corticosteroid use. Investigation of interkingdom (bacterial-fungal) co-occurrence patterns revealed different topologies between asthmatic patients and healthy control subjects. Random forest models with fungal classifiers predicted asthma status with 75% accuracy for BAL fluid samples and 80% accuracy for EB samples.
We demonstrate clear differences in bacterial and fungal microbiota in asthma-associated phenotypes. Our study provides additional support for considering microbial signatures in delineating asthma phenotypes.
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Non―Cystic Fibrosis Bronchiectasis MCSHANE, Pamela J; NAURECKAS, Edward T; TINO, Gregory ...
American journal of respiratory and critical care medicine,
09/2013, Letnik:
188, Številka:
6
Journal Article
Recenzirano
There is renewed interest in non-cystic fibrosis bronchiectasis, which is a cause of significant morbidity in adults and can be diagnosed by high-resolution chest computed tomography scan. No longer ...mainly a complication after pulmonary infection with Mycobacterium tuberculosis, diverse disease processes and mechanisms have been demonstrated to result in the chronic cough, purulent sputum production, and airway dilation that characterize this disease. Improved understanding of the role of mucus stasis in causing bacterial colonization has led to increased emphasis on the use of therapies that enhance airway clearance. Inhalational antibiotics reduce the bacterial burden associated with a worse outcome. Low-dose, chronic macrolide therapy has been shown to decrease exacerbation frequency and airway inflammation. For the first time, a number of therapies for non-cystic fibrosis bronchiectasis are undergoing testing in clinical research trials designed specifically for this population. This concise clinical review focuses on the major etiologies, diagnostic testing, microbiology, and management of patients with adult non-cystic fibrosis bronchiectasis. Systematic evaluation identifies a specific cause in the majority of patients and may affect subsequent treatment. We outline current therapies and review the data that support their use.
Cystic fibrosis (CF) is an autosomal recessive disease characterized by abnormal airways secretions, chronic endobronchial infection, and progressive airway obstruction. The use of medications to ...slow the progression of lung disease has led to significant improvement in survival. An evidence review of chronic medications for CF lung disease was performed in 2007 to provide guidance to clinicians in evaluating and selecting appropriate treatment for individuals with this disease. We have undertaken a new review of the literature to update the recommendations, including consideration of new medications and additional evidence on previously reviewed therapies. A multidisciplinary committee of experts in CF pulmonary care was established to review the evidence for use of chronic medications for CF lung disease and make treatment recommendations. Published evidence for chronic lung therapies was systematically reviewed and resulting treatment recommendations were graded based on the United States Preventive Services Task Force scheme. These guidelines provide up-to-date evidence of safety and efficacy of chronic treatments of CF lung disease, including the use of novel therapies that have not previously been included in CF pulmonary guidelines.
Background The lung has a diverse microbiome that is modest in biomass. This microbiome differs in asthmatic patients compared with control subjects, but the effects of clinical characteristics on ...the microbial community composition and structure are not clear. Objectives We examined whether the composition and structure of the lower airway microbiome correlated with clinical characteristics of chronic persistent asthma, including airflow obstruction, use of corticosteroid medications, and presence of airway eosinophilia. Methods DNA was extracted from endobronchial brushings and bronchoalveolar lavage fluid collected from 39 asthmatic patients and 19 control subjects, along with negative control samples. 16S rRNA V4 amplicon sequencing was used to compare the relative abundance of bacterial genera with clinical characteristics. Results Differential feature selection analysis revealed significant differences in microbial diversity between brush and lavage samples from asthmatic patients and control subjects. Lactobacillus , Pseudomonas , and Rickettsia species were significantly enriched in samples from asthmatic patients, whereas Prevotella , Streptococcus , and Veillonella species were enriched in brush samples from control subjects. Generalized linear models on brush samples demonstrated oral corticosteroid use as an important factor affecting the relative abundance of the taxa that were significantly enriched in asthmatic patients. In addition, bacterial α-diversity in brush samples from asthmatic patients was correlated with FEV1 and the proportion of lavage eosinophils. Conclusion The diversity and composition of the bronchial airway microbiome of asthmatic patients is distinct from that of nonasthmatic control subjects and influenced by worsening airflow obstruction and corticosteroid use.
Bronchial thermoplasty is an alternative treatment for patients with severe, uncontrolled asthma in which the airway smooth muscle is eliminated using radioablation. Although this emerging therapy ...shows promising outcomes, little is known about its effects on airway inflammation.
We examined the presence of bronchoalveolar lavage cytokines and expression of smooth muscle actin in patients with severe asthma before and in the weeks after bronchial thermoplasty.
Endobronchial biopsies and bronchoalveolar lavage samples from 11 patients with severe asthma were collected from the right lower lobe before and 3 and 6 weeks after initial bronchial thermoplasty. Samples were analyzed for cell proportions and cytokine concentrations in bronchoalveolar lavage and for the presence of α-SMA in endobronchial biopsies.
α-SMA expression was decreased in endobronchial biopsies of 7 of 11 subjects by Week 6. In bronchoalveolar lavage fluid, both transforming growth factor-β1 and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5 were substantially decreased 3 and 6 weeks post bronchial thermoplasty in all patients. The cytokine tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in several cell types, was increased in concentration both 3 and 6 weeks post bronchial thermoplasty.
Clinical improvement and reduction in α-SMA after bronchial thermoplasty in severe, uncontrolled asthma is associated with substantial changes in key mediators of inflammation. These data confirm the substantial elimination of airway smooth muscle post thermoplasty in the human asthmatic airway and represent the first characterization of significant changes in airway inflammation in the first weeks after thermoplasty.
Asthma is a heterogeneous, complex syndrome, and identifying asthma endotypes has been challenging. We hypothesize that distinct endotypes of asthma arise in disparate genetic variation and life-time ...environmental exposure backgrounds, and that disease comorbidity patterns serve as a surrogate for such genetic and exposure variations. Here, we computationally discover 22 distinct comorbid disease patterns among individuals with asthma (asthma comorbidity subgroups) using diagnosis records for >151 M US residents, and re-identify 11 of the 22 subgroups in the much smaller UK Biobank. GWASs to discern asthma risk loci for individuals within each subgroup and in all subgroups combined reveal 109 independent risk loci, of which 52 are replicated in multi-ancestry meta-analysis across different ethnicity subsamples in UK Biobank, US BioVU, and BioBank Japan. Fourteen loci confer asthma risk in multiple subgroups and in all subgroups combined. Importantly, another six loci confer asthma risk in only one subgroup. The strength of association between asthma and each of 44 health-related phenotypes also varies dramatically across subgroups. This work reveals subpopulations of asthma patients distinguished by comorbidity patterns, asthma risk loci, gene expression, and health-related phenotypes, and so reveals different asthma endotypes.
Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that ...acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma.
Importantly, the cohorts had a racial balance that was majority white (62% and 66%), with relatively few African Americans (11% and 23%). Because African Americans have a greater prevalence of ...diseases associated with low-grade systemic inflammation,6,7 the definition of an IL-6–high phenotype might differ based on race. Asthmatic patients met the criteria defined by the Expert Panel Report 3 guidelines on asthma.E9 Control subjects had no lifetime history of pulmonary disease, were in good health, did not use respiratory-related medication, and had a less than 16% reduction in FEV1 after inhalation of 25 mg/mL methacholine. Subjects with a smoking history of 10 pack years or greater or who were actively smoking within 6 months of potential recruitment; had a history of chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis, or Churg-Strauss syndrome; or had any medical contraindication to bronchoscopy were excluded.Statistical analysis Statistical analyses were conducted in STATA 14 software (StataCorp, College Station, Tex). Parameter Control subjects (n = 68) Asthmatic patients (n = 124) Age (y), median (IQR) 31 (21-48) 33.5 (25-48) Women, no. (%) 43 (63) 81 (65) Ancestry (EA/AA/other), no. 27/32/9 44/77/2 BMI (kg/m2), median (IQR) 26.1 (23.5-31.4) 28.7 (25.1-34.6) BMI >30 kg/m2, no. (%) 19 (28) 57 (46)∗ History of sinusitis, no. (%) 1 (1) 22 (18) History of GERD, no. (%) 2 (3) 22 (18) Serum IgE (IU/mL), median (IQR) 39 (17-157) 134 (39-383)† Inhaled corticosteroid use, no. (%) — 72 (58) Oral corticosteroid use, no. (%) — 21 (17) Blood eosinophil count/μL (mean ± SD) 123 ± 82 297 ± 77† Blood eosinophil count >300/μL, no. (%) 1 (1) 35 (28)† Blood neutrophil count/μL (mean ± SD) 3718 ± 1649 3818 ± 1984 Feno (ppb), median (IQR) 15 (12-22) 24 (14-42)† FEV1 (% predicted), mean ± SD 96.2 ± 12.2 79.2 ± 21.0† FEV1 ≥80% of predicted value, no. (%) — 65 (52) FEV1 60% to 80% of predicted value, no. (%) — 35 (28) FEV1 ≤60% of predicted value, no. (%) — 24 (19) Plasma IL-6 in all subjects (pg/mL mean ± SD) 1.77 ± 1.26 2.69 ± 3.19‡ Plasma IL-6 in subjects of EA ancestry (pg/mL mean ± SD) 1.58 ± 1.26 2.67 ± 4.20‡ Plasma IL-6 in subjects of AA ancestry (pg/mL mean ± SD) 2.15 ± 1.30§ 2.75 ± 2.52 Table I Baseline characteristics of the control subjects and asthmatic patients in this study Parameter (asthmatic patients only) IL-6−low group (n = 105) IL-6−high group (n = 16) Age (y), median (IQR) 32 (24-47) 44 (34.8-55.8)† Female sex, no. (%) 64 (61) 15 (94)‡ Ancestry (EA/AA/other), no. 36/69/0 8/8/0 Subjects of AA ancestry in phenotype, no. (%) 69 (90) 8 (10) Subjects of EA ancestry in phenotype, no. (%) 36 (82) 8 (18) BMI (kg/m2), median (IQR) 28.1 (24.9-34.0) 42.7 (27.5-50.3)† BMI >30 kg/m2, no. (%) 46 (44) 11 (69) Inhaled corticosteroid use, no. (%) 59 (56) 12 (75) Oral corticosteroid use, no. (%) 16 (15) 5 (31) Blood eosinophil count/μL, median (IQR) 200 (110-320) 155 (82-290) Blood neutrophil count/μL, median (IQR) 3200 (2490-4540) 3690 (2898-4920) Feno (ppb), median (IQR) 25 (14-44) 16 (7-33) Serum IgE (IU/mL), median (IQR) 141 (41-505) 101 (25-231) FEV1 (% predicted mean ± SD) 79.4 ± 21.9 75.1 ± 15.7 Table II Characteristics of patients with asthma in the IL-6−low and IL-6−high groups∗
The study sought to implement and assess the CommunityRx e-prescribing system to recruit research participants from a predominantly non-Hispanic Black community on Chicago's South Side.
CommunityRx ...integrates with electronic medical record systems to generate a personalized list of health-promoting community resources (HealtheRx). Between December 2015 and December 2016, HealtheRxs distributed at outpatient visits to adults with asthma or chronic obstructive pulmonary disease also incentivized participation in a pulmonary research registry. Usual practices for registry recruitment continued in parallel.
Focus groups established acceptability and appropriateness among the target population. Pulmonary research registry recruitment information was included on 13 437 HealtheRxs. Forty-one (90% non-Hispanic Black) patients responded with willingness to participate and 9 (8 non-Hispanic Black) returned a signed consent required to enroll. Usual recruitment practices enrolled 4 registrants (1 non-Hispanic Black).
Automating research recruitment using a community e-prescribing system is feasible.
Implementation of an electronic medical record-integrated, community resource referral tool promotes enrollment of eligible underrepresented research participants; however, enrollment was low.
Previous studies of patients with bronchiectasis have found that the cause is idiopathic in the majority of cases, but these studies were done in homogeneous populations. We hypothesized that the ...etiology of bronchiectasis can be determined in a higher percentage of patients in a diverse US population and will differ significantly based on ethnicity.
One hundred twelve patients with bronchiectasis confirmed by chest CT scan entered the study. Data from 106 patients were available for full evaluation. Clinical questionnaire, pulmonary function tests, sputum microbiology, laboratory data, and immune function testing were done. Results were analyzed by ethnicity and etiology.
Patients were 61.6% European American (EA), 26.8% African American (AA), 8.9% Hispanic American (HA), and 2.7% Asian American. A cause of bronchiectasis was determined in 93.3% of patients. In 63.2% of patients, bronchiectasis was caused by immune dysregulation, including deficiency (n = 18 17%), autoimmune disease (n = 33 31.1%), hematologic malignancy (n = 15 14.2%), and allergic bronchopulmonary aspergillosis (n = 1 0.9%). Rheumatoid arthritis was the cause of bronchiectasis in 28.6% of AA patients vs 6.2% of EA patients (P < .05). Hematologic malignancy was the etiology in 20.0% of the EA patients vs none of the AA patients (P = .02). A significantly higher percentage of HA patients had Pseudomonas aeruginosa in their sputum compared with AA and EA patients (P = .01).
The etiology of bronchiectasis can be determined in the majority of patients in a heterogeneous US population and is most often due to immune dysregulation. Rheumatoid arthritis is more likely in AA patients than EA patients. HA patients are more likely to have P aeruginosa in their sputum.