Neuroimmune interactions in atopic and allergic contact dermatitis.

The skin is a barrier organ populated by many types of skin-resident immune cells and sensory neurons. It has become increasingly appreciated that neuroimmune interactions are an important component of inflammatory diseases such as atopic dermatitis and allergic contact dermatitis. Neuropeptides secreted from nerve terminals play an important role in mediating cutaneous immune cell function, and soluble mediators derived from immune cells interact with neurons to induce itch. In this review article, we will explore emerging research describing neuronal effector functions on skin immune cells in mouse models of atopic and contact dermatitis. We will also discuss the contributions of both specific neuronal subsets and secreted immune factors to itch induction and the associated inflammatory processes. Finally, we will explore how treatment strategies have emerged around these findings and discuss the relationship between scratching and dermatitis.

Assessment of Validity of a Blood-Based 3-Gene Signature Score for Progression and Diagnosis of Tuberculosis, Disease Severity, and Treatment Response.

Importance: The World Health Organization identified the need for a non-sputum-based triage test to identify those in need of further tuberculosis (TB) testing. Objective: To determine whether the 3-gene TB score can be a diagnostic tool throughout the course of TB disease, from latency to diagnosis to treatment response, and posttreatment residual inflammation. Design, Setting, and Participants: This nested case-control study analyzed the 3-gene TB score in 3 cohorts, each focusing on a different stage of TB disease: (1) the Adolescent Cohort Study profiled whole-blood samples from adolescents with latent Mycobacterium tuberculosis infection, some of which progressed to active TB (ATB), using RNA sequencing; (2) the Brazil Active Screen Study collected whole blood from an actively screened case-control cohort of adult inmates from 2 prisons in Mato Grosso do Sul, Brazil, for ATB from January 2016 to February 2016; and (3) the Catalysis Treatment Response Cohort (CTRC) identified culture-positive adults in primary health care clinics in Cape Town, South Africa, from 2005 to 2007 and collected whole blood for RNA sequencing from patients with ATB at diagnosis and weeks 1, 4, and 24. The CTRC patients also had positron emission tomography-computed tomography scans at diagnosis, week 4, and week 24. Analyses were performed from September 2017 to June 2018. Main Outcomes and Measures: A 3-gene messenger RNA expression score, measured by quantitative polymerase chain reaction or RNA sequencing, was evaluated for distinguishing the following: individuals who progressed to ATB from those who did not, individuals with ATB from those without, and individuals with slower treatment response during TB therapy. Results: Patients evaluated in this study included 144 adolescents from the Adolescent Cohort Study (aged 12-18 years; 96 female and 48 male), 81 adult prison inmates from the Brazil Active Screen Study (aged 20-72 years; 81 male), and 138 adult community members from the CTRC (aged 17-64 years; 81 female and 57 male). The 3-gene TB score identified progression from latent M tuberculosis infection to ATB 6 months prior to sputum conversion with 86% sensitivity and 84% specificity (area under the curve [AUC], 0.86; 95% CI, 0.77-0.96) and patients with ATB in the Brazil Active Screen Study cohort (AUC, 0.87; 95% CI, 0.78-0.95) and CTRC (AUC, 0.94; 95% CI, 0.88-0.99). It also identified CTRC patients with failed treatment at the end of treatment (AUC, 0.93; 95% CI, 0.83-1.00). Collectively, across all cohorts, the 3-gene TB score identified patients with ATB with 90% sensitivity, 70% specificity, and 99.3% negative predictive value at 4% prevalence. Conclusions and Relevance: Across 3 independent prospective cohorts, the 3-gene TB score approaches the World Health Organization target product profile benchmarks for non-sputum-based triage test with high negative predictive value. This gene expression diagnostic approach should be considered for further validation and future implementation.

Respiratory Care Training for Safety-Net Primary Care Practices.

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.

Stress and Bronchodilator Response in Children with Asthma.

RATIONALE: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR). OBJECTIVES: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma. METHODS: This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids. MEASUREMENTS AND MAIN RESULTS: High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the ß2-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety). CONCLUSIONS: High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children.

Predictors for asthma at age 7 years for low-income children enrolled in the Childhood Asthma Prevention Study.

OBJECTIVE: To identify the predictive factors of early childhood wheezing in children of low socioeconomic status. STUDY DESIGN: The Childhood Asthma Prevention Study enrolled 177 low-income children (9-24 months old) with frequent wheezing. At age 7 years, presence of asthma was assessed through caregiver reports of physician diagnosis of asthma (CRPDA) and corroborated by assessment of bronchial hyperresponsiveness (BHR). Lung function, inflammatory markers, and asthma symptom severity were compared for children with ±CRPDA, ±BHR, and asthma. Baseline predictors for CRPDA, BHR, and asthma at 7 years of age were examined. RESULTS: Maternal symptom report strongly differentiated children with +CRPDA (49%) despite comparable airflow measurements (P < .0001), and spirometric lung function measurements were different for +BHR (65%) versus -BHR (P < .005). Univariate analyses revealed different baseline predictors of +CRPDA and +BHR for children at age 7 years. Higher levels of maternal psychological resources were associated with +CRPDA, but not +BHR. Only 39% of children with a history of frequent wheezing met the conservative definition of asthma at age 7 years, with the following significant predictors found: low birth weight, baseline symptom severity, and maternal psychological resources. CONCLUSIONS: This low-income, multi-ethnic group of wheezing infants represents a unique population of children with distinct characteristics and risks for persistent asthma. Determination of asthma status at 7 years of age required objective measurement of BHR in addition to CRPDA. The association of maternal psychological resources with +CRPDA may represent a previously unrecognized factor in the determination of asthma status among low-income groups.

Status of asthma control in pediatric primary care: results from the pediatric Asthma Control Characteristics and Prevalence Survey Study (ACCESS).

OBJECTIVE: To estimate the prevalence of uncontrolled asthma in pediatric patients with asthma visiting their primary care provider for any medical reason. STUDY DESIGN: This was a cross-sectional survey conducted at 29 pediatric care sites across the United States. Children age 4-17 years with self- or caregiver-reported asthma completed the Childhood Asthma Control Test (C-ACT) or the Asthma Control Test (ACT) and responded to demographic and health-related questions. Uncontrolled asthma was defined as a C-ACT or ACT score

Immunopathology of chronic rhinosinusitis in young children.

OBJECTIVE: Previous investigation demonstrated predominantly lymphocytic inflammation in sinus mucosa of young children with chronic rhinosinusitis (CRS) rather than eosinophilic inflammation typical of adult CRS. Immunohistopathological study was undertaken to define further the cellular response in pediatric CRS. STUDY DESIGN: Maxillary mucosal biopsies from children and adults with CRS were stained for CD3 (T lymphocytes), CD4 (helper T lymphocytes), CD8 (cytotoxic T lymphocytes), CD20 (B lymphocytes), CD68 (monocytes/macrophages), CD56 (natural killer cells), kappa and lambda (plasma cells), and myeloperoxidase (MPO; neutrophils). RESULTS: Nineteen children with CRS (median age, 3.0 years; range, 1.4-8.2 years) had more CD8+, MPO+, and CD68+ cells (P < or = .03) and a trend toward more CD3+ and CD4+ cells (P = .06) in their epithelium and more CD20+, kappa+ and lambda+, MPO+, and CD68+ cells (P < or = .05) and a trend toward more CD4+ cells (P = .06) in their submucosa compared with adult control subjects. Immunostains from children with positive sinus cultures were similar to those with negative cultures except for more MPO+ cells in the submucosa (P = .04). CONCLUSION: The inflammatory response of young children with CRS is characterized by a mixed lymphocyte population, macrophages, and neutrophils. Differences between pediatric and adult CRS suggest differing pathogenic mechanisms or progression in the inflammatory response with protracted disease.

Chronic rhinosinusitis in young children differs from adults: a histopathology study.

OBJECTIVE: A histopathologic study of children with chronic rhinosinusitis (CRS) was undertaken to compare the sinus mucosa in pediatric and adult CRS. STUDY DESIGN: CRS has been defined as persistent or recurrent sinusitis symptoms for >or=12 weeks despite conventional medical therapy, with abnormal computed tomography of the maxillary sinuses. Maxillary mucosal biopsies were obtained from pediatric CRS subjects for inflammatory cell and morphologic studies. Archival sinus mucosal tissues from adults with CRS were used as histologic controls. Sinus lavages were performed on children with and without CRS for microbiologic studies. RESULTS: Sinus mucosal biopsies were obtained from 19 children with CRS (median age, 3.0 years; range 1.4-8.2 years). Pediatric CRS biopsies, as compared with adult CRS controls, had a higher density of submucosal lymphocytes (median 469 versus 294 cells/mm(2) per 5 high-power fields [HPF]; P=.02), lower density of submucosal eosinophils (medians 13 versus 82 cells/mm(2) per 5 HPF; P=.01), thinner and more intact epithelium (P=.01 and.07, respectively), thinner basement membranes (P=.002), and fewer submucosal mucous glands (P=.004). CONCLUSION: The sinus mucosa of young children with CRS has less eosinophilic inflammation, basement membrane thickening, and mucus gland hyperplasia characteristic of adult CRS.