Search

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

BackgroundIn infants, distinct nasopharyngeal bacterial microbiotas differentially associate with the incidence and severity of acute respiratory tract infection and childhood asthma development.ObjectiveWe hypothesized that distinct nasal airway microbiota structures also exist in children with asthma and relate to clinical outcomes.MethodsNasal secretion samples (n = 3122) collected after randomization during the fall season from children with asthma (6-17 years, n = 413) enrolled in a trial of omalizumab (anti-IgE) underwent 16S rRNA profiling. Statistical analyses with exacerbation as the primary outcome and rhinovirus infection and respiratory illnesses as secondary outcomes were performed. Using A549 epithelial cells, we assessed nasal isolates of Moraxella, Staphylococcus, and Corynebacterium species for their capacity to induce epithelial damage and inflammatory responses.ResultsSix nasal airway microbiota assemblages, each dominated by Moraxella, Staphylococcus, Corynebacterium, Streptococcus, Alloiococcus, or Haemophilus species, were observed. Moraxella and Staphylococcus species-dominated microbiotas were most frequently detected and exhibited temporal stability. Nasal microbiotas dominated by Moraxella species were associated with increased exacerbation risk and eosinophil activation. Staphylococcus or Corynebacterium species-dominated microbiotas were associated with reduced respiratory illness and exacerbation events, whereas Streptococcus species-dominated assemblages increased the risk of rhinovirus infection. Nasal microbiota composition remained relatively stable despite viral infection or exacerbation; only a few taxa belonging to the dominant genera exhibited relative abundance fluctuations during these events. In vitro, Moraxella catarrhalis induced significantly greater epithelial damage and inflammatory cytokine expression (IL-33 and IL-8) compared with other dominant nasal bacterial isolates tested.ConclusionDistinct nasal airway microbiotas of children with asthma relate to the likelihood of exacerbation, rhinovirus infection, and respiratory illnesses during the fall season.

In our recent article [1], it has come to our attention that the sample labels are not consistent between Table 1, the data labels deposited in the Sequence Read Archive, and Additional file 1: Table S2. We are therefore providing an updated Additional file 1: Table S2 so identical samples now have the same label.

BackgroundRespiratory illness caused by viral infection is associated with the development and exacerbation of childhood asthma. Little is known about the effects of respiratory viral infections in the absence of illness. Using quantitative PCR (qPCR) for common respiratory viruses and for two genes known to be highly upregulated in viral infections (CCL8/CXCL11), we screened 92 asthmatic and 69 healthy children without illness for respiratory virus infections.ResultsWe found 21 viral qPCR-positive and 2 suspected virus-infected subjects with high expression of CCL8/CXCL11. We applied a dual RNA-seq workflow to these subjects, together with 25 viral qPCR-negative subjects, to compare qPCR with sequencing-based virus detection and to generate the airway transcriptome for analysis. RNA-seq virus detection achieved 86% sensitivity when compared to qPCR-based screening. We detected additional respiratory viruses in the two CCL8/CXCL11-high subjects and in two of the qPCR-negative subjects. Viral read counts varied widely and were used to stratify subjects into Virus-High and Virus-Low groups. Examination of the host airway transcriptome found that the Virus-High group was characterized by immune cell airway infiltration, downregulation of cilia genes, and dampening of type 2 inflammation. Even the Virus-Low group was differentiated from the No-Virus group by 100 genes, some involved in eIF2 signaling.ConclusionsRespiratory virus infection without illness is not innocuous but may determine the airway function of these subjects by driving immune cell airway infiltration, cellular remodeling, and alteration of asthmogenic gene expression.

BackgroundBronchial airway expression profiling has identified inflammatory subphenotypes of asthma, but the invasiveness of this technique has limited its application to childhood asthma.ObjectivesWe sought to determine whether the nasal transcriptome can proxy expression changes in the lung airway transcriptome in asthmatic patients. We also sought to determine whether the nasal transcriptome can distinguish subphenotypes of asthma.MethodsWhole-transcriptome RNA sequencing was performed on nasal airway brushings from 10 control subjects and 10 asthmatic subjects, which were compared with established bronchial and small-airway transcriptomes. Targeted RNA sequencing nasal expression analysis was used to profile 105 genes in 50 asthmatic subjects and 50 control subjects for differential expression and clustering analyses.ResultsWe found 90.2% overlap in expressed genes and strong correlation in gene expression (ρ = .87) between the nasal and bronchial transcriptomes. Previously observed asthmatic bronchial differential expression was strongly correlated with asthmatic nasal differential expression (ρ = 0.77, P = 5.6 × 10(-9)). Clustering analysis identified TH2-high and TH2-low subjects differentiated by expression of 70 genes, including IL13, IL5, periostin (POSTN), calcium-activated chloride channel regulator 1 (CLCA1), and serpin peptidase inhibitor, clade B (SERPINB2). TH2-high subjects were more likely to have atopy (odds ratio, 10.3; P = 3.5 × 10(-6)), atopic asthma (odds ratio, 32.6; P = 6.9 × 10(-7)), high blood eosinophil counts (odds ratio, 9.1; P = 2.6 × 10(-6)), and rhinitis (odds ratio, 8.3; P = 4.1 × 10(-6)) compared with TH2-low subjects. Nasal IL13 expression levels were 3.9-fold higher in asthmatic participants who experienced an asthma exacerbation in the past year (P = .01). Several differentially expressed nasal genes were specific to asthma and independent of atopic status.ConclusionNasal airway gene expression profiles largely recapitulate expression profiles in the lung airways. Nasal expression profiling can be used to identify subjects with IL13-driven asthma and a TH2-skewed systemic immune response.

Objectives. We describe the prevalence of asthma risk factors within racial/ethnic and language groups of infants participating in an intervention study for reducing chronic asthma. Methods. Low-income children aged 9 to 24 months with 3 or more episodes of wheezing illness were enrolled. Baseline information included family and medical histories, allergic status, environmental exposures, emotional environment, and caregiver psychosocial resources. Results. Racial/ethnic and language groups--European Americans, African Americans, high-acculturated Hispanics, and low-acculturated Hispanics--showed different patterns of risk factors for childhood asthma, with low-acculturated Hispanics showing the most distinctive pattern. Conclusions. Patterns of covariation of biological and psychosocial risk factors for childhood asthma were associated with racial/ethnic and language status among urban, low-income children.

The seismic demand on potentially liquefiable soils can be approximated by a series of uniform shear stress cycles. Procedures are reviewed for converting an arbitrary acceleration time history to a series of uniform cycles with amplitude = 0.65 of the peak. The number of cycles (N) at this amplitude is evaluated so as to represent a seismic demand for liquefaction triggering equivalent to that of the accelerogram. An assumed relationship between N and magnitude (m) underlies so-called magnitude scaling factors used to adjust the liquefaction resistance of soil for the effects of duration/magnitude. Scaling factors can alternatively be related directly to N, which enables the effects of factors other than m (for example, site-source distance r) to be quantified. We develop empirical models for N that are applicable to active tectonic regions and find a strong dependence on m and r and a weaker dependence on site condition and near-fault rupture directivity effects. The model for N is used to develop new scaling factors for soil liquefaction resistance that are distance-dependent and have a defined level of uncertainty.

Background: Characterization of allergic responses to cockroach (CR), a common aeroallergen associated with asthma, has focused mainly on IgE reactivity, but little is known about T cell responses, particularly in children. We conducted a functional evaluation of CR allergen‐specific T cell reactivity in a cohort of CR allergic children with asthma. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 71 children, with mild‐to‐moderate asthma who were enrolled in a CR immunotherapy (IT) clinical trial, prior to treatment initiation. PBMC were stimulated with peptide pools derived from 11 CR allergens, and CD4+ T cell responses assessed by intracellular cytokine staining. Results: Highly heterogeneous responses in T cell reactivity were observed among participants, both in terms of the magnitude of cytokine response and allergen immunodominance. Reactivity against Bla g 9 and Bla g 5 was most frequent. The phenotype of the T cell response was dominated by IL‐4 production and a Th2 polarized profile in 54.9% of participants, but IFNγ production and Th1 polarization was observed in 25.3% of the participants. The numbers of regulatory CD4+ T cells were also highly variable and the magnitude of effector responses and Th2 polarization were positively correlated with serum IgE levels specific to a clinical CR extract. Conclusions: Our results demonstrate that in children with mild‐to‐moderate asthma, CR‐specific T cell responses display a wide range of magnitude, allergen dominance, and polarization. These results will enable examination of whether any of the variables measured are affected by IT and/or are predictive of clinical outcomes. [ABSTRACT FROM AUTHOR]

We report the availability of a digitized Chinese male and a digitzed Chinese female typical of the population and with no obvious abnormalities. The embalming and milling procedures incorporate three technical improvements over earlier digitized cadavers. Vascular perfusion with coloured gelatin was performed to facilitate blood vessel identification. Embalmed cadavers were embedded in gelatin and cryosectioned whole so as to avoid section loss resulting from cutting the body into smaller pieces. Milling performed at −25 °C prevented small structures (e.g. teeth, concha nasalis and articular cartilage) from falling off from the milling surface. The male image set (.tiff images each of 36 Mb) has a section resolution of 3072 × 2048 pixels (∼170 µm, the accompanying magnetic resonance imaging and computer tomography data have a resolution of 512 × 512, i.e. ∼440 µm). The Chinese Visible Human male and female datasets are available at . (The male is 90.65 Gb and female 131.04 Gb). MPEG videos of direct records of real-time volume rendering are at: [ABSTRACT FROM AUTHOR]

Background and Objectives: Programs designed to enhance the diagnosis and management of asthma and chronic obstructive pulmonary disease (COPD) in primary care settings have had variable success and have not been broadly implemented. The Respiratory Toolkit was created to bridge this gap.Methods: The 2-year program providing primary care training in both asthma and COPD was conducted in an urban federally qualified health center with 13 clinics and 87 staff. The program included interactive training with multidisciplinary teams, in-clinic follow-up trainings, electronic medical record (EMR) tools, and patient-centered educational resources.Results: For asthma patients, use of spirometry increased from 7% of visits before to 43% after training, severity assessment from 13% to 29%, asthma action plans from 2% to 8%, and prescription of inhaled corticosteroids from 33% to 42%. For COPD patients, spirometry use increased from 21% to 35% of visits, and long-acting beta2-agonists from 19% to 26%. Among undiagnosed smokers, use of the COPD screener increased from 0 to 11% of visits, of spirometry from 4% to 36%, and of advice to quit from 74% to 79%.Conclusions: The Respiratory Toolkit produced significant changes in guideline-based care for patients with asthma or COPD; however, time constraints and other barriers prevented full adoption. [ABSTRACT FROM AUTHOR]

To study the control of hematopoietic cell differentiation, a human negative differentiation regulator (NDR) gene was identified by the comparative analysis of differentially expressed genes in hemato-lymphoid tissues. NDR is expressed preferentially in the adult bone marrow, fetal liver and testis. Immunocytochemistry with anti-NDR antiserum showed the presence of NDR in human erythroleukemia K562 cell line and CD34[sup +] cells sorted from the umbilical cord blood. When fused to the green fluorescent protein (GFP), NDR was directed to the nucleus of mouse 3T3 and K562 cells. Fusion protein with a deletion from residues 7 to 87 was detected in the cytoplasm. NDR appeared not to affect the proliferation of K562 cells when overly expressed. However, its expression was down-regulated during megakaryocytic differentiation of K562 cells induced by 12-O -tetradecanoylphorbol-13-acetate (TPA). Down-regulation of NDR correlated well with up-regulation of megakaryocytic markers, CD41 and CD61. Overexpression of the nuclear NDR-GFP in K562 cells inhibited the expression of CD41 and CD61 in megakaryocytic differentiation. Treatment of K562 cells with GF-109203X (GFX), an antagonist of the protein kinase C (PKC), blocked NDR down-regulation, up-regulated expression of CD41/CD61 and TPA-induced megakaryocytic differentiation. These results suggest a novel function of nuclear NDR protein in regulating hematopoietic cell development. Copyright © 2004 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives. We describe the prevalence of asthma risk factors within racial/ethnic and language groups of infants participating in an intervention study for reducing chronic asthma. Methods. Low-income children aged 9 to 24 months with 3 or more episodes of wheezing illness were enrolled. Baseline information included family and medical histories, allergic status, environmental exposures, emotional environment, and caregiver psychosocial resources. Results. Racial/ethnic and language groups--European Americans, African Americans, high-acculturated Hispanics, and low-acculturated Hispanics--showed different patterns of risk factors for childhood asthma, with low-acculturated Hispanics showing the most distinctive pattern. Conclusions. Patterns of covariation of biological and psychosocial risk factors for childhood asthma were associated with racial/ethnic and language status among urban, low-income children. (Am J Public Health. 2002;92:792-798) [ABSTRACT FROM AUTHOR]