Immunohistology and remodeling in fatal pediatric and adolescent asthma

Background: Thickening of reticular basement membrane, increased airway smooth muscle mass and eosinophilic inflammation are found in adult fatal asthma. At the present study the histopathology of fatal paediatric and adolescent asthma is evaluated. Methods: Post-mortem lung autopsies from 12 fatal asthma cases and 8 non-asthmatic control subjects were examined. Thickness of reticular basement membrane (RBM) and percentage of airway smooth muscle (ASM%) mass area were measured and inflammatory cells were counted. Patient records were reviewed for clinical history. Results: The age range of the cases was from 0.9 to 19.5 years, eight were males and five had received inhaled corticosteroids. Thickened RBM was detected in majority of the cases without any correlation to treatment delay, age at onset of symptoms or diagnosis. In the large airways ASM was clearly increased in one third of the cases whereas the median ASM% did not differ from that in healthy controls (14.0% vs. 14.0%). In small airways no increase of ASM was found, instead mucous plugs were seen in fatal asthma. The number of eosinophils, plasmacytoid dendritic cells, macrophages, and B-cells were significantly increased in fatal asthma cases compared with controls and the two latter correlated with the length of the fatal exacerbation. Conclusions: The findings highlight the strong presence of eosinophils and mucous plugs even in small airways in children and adolescents with fatal asthma. Thickened RBM was obvious in majority of the patients. Contrary to our hypothesis, increased ASM% was detected in only one third of the patients.Peer reviewe

Vitamin D, high-sensitivity C-reactive protein, and airway hyperresponsiveness in infants with recurrent respiratory symptoms

Background: Vitamin D insufficiency might be associated with biased T-cell responses resulting in inflammatory conditions such as atopy and asthma. Little is known about the role of vitamin D in low-grade systemic inflammation and airway hyperresponsiveness (AHR) in young children. Objective: To evaluate whether vitamin D insufficiency and increased serum high-sensitivity C-reactive protein (hs-CRP) are linked to AHR in symptomatic infants. Methods: Seventy-nine infants with recurrent or persistent lower respiratory tract symptoms underwent comprehensive lung function testing and a bronchial methacholine challenge test. In addition, skin prick tests were performed and serum 25-hydroxyvitamin D (S-25-OHD), hs-CRP, total immunoglobulin E, and blood eosinophil levels were determined. Results: S-25-OHD was lowest in infants with blood eosinophilia and AHR (n = 10) compared with those with eosinophilia only (n = 6) or AHR only (n = 50) or those with neither (n = 13; P = .035). Moreover, vitamin D insufficiency (S-25-OHD <50 nmol/L) was most common in infants with blood eosinophilia and AHR (P = .041). Serum hs-CRP was lower in infants with recurrent physician-diagnosed wheezing (P = .048) and in those with blood eosinophilia (P = .015) than in infants without these characteristics and was not associated with S-25-OHD or AHR. S-25-OHD levels were significantly lower (median 54 nmol/L) during the autumn-winter season than in the spring-summer season (median 63 nmol/L; P = .026). Conclusion: Vitamin D insufficiency could underlie eosinophilia and AHR in infants with troublesome lung symptoms, whereas hs-CRPemediated low-grade systemic inflammation is rare in early childhood wheezing. (C) 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.Peer reviewe

Expiratory variability index is associated with asthma risk, wheeze and lung function in infants with recurrent respiratory symptoms

Non peer reviewe

Monocytes accumulate in the airways of children with fatal asthma

Background: Activated T helper type 2 (Th2) cells are believed to play a pivotal role in allergic airway inflammation, but which cells attract and activate Th2 cells locally have not been fully determined. Recently, it was shown in an experimental human model of allergic rhinitis (AR) that activated monocytes rapidly accumulate in the nasal mucosa after local allergen challenge, where they promote recruitment of Th2 cells and eosinophils. Objective: To investigate whether monocytes are recruited to the lungs in paediatric asthma. Methods: Tissue samples obtained from children and adolescents with fatal asthma attack (n = 12), age-matched non-atopic controls (n = 9) and allergen-challenged AR patients (n = 8) were subjected to in situ immunostaining. Results: Monocytes, identified as CD68+S100A8/A9+ cells, were significantly increased in the lower airway mucosa and in the alveoli of fatal asthma patients compared with control individuals. Interestingly, cellular aggregates containing CD68+S100A8/A9+ monocytes obstructing the lumen of bronchioles were found in asthmatics (8 out of 12) but not in controls. Analysing tissue specimens from challenged AR patients, we confirmed that co-staining with CD68 and S100A8/A9 was a valid method to identify recently recruited monocytes. We also showed that the vast majority of accumulating monocytes both in the lungs and in the nasal mucosa expressed matrix metalloproteinase 10, suggesting that this protein may be involved in their migration within the tissue. Conclusions and clinical relevance: Monocytes accumulated in the lungs of children and adolescents with fatal asthma attack. This finding strongly suggests that monocytes are directly involved in the immunopathology of asthma and that these pro-inflammatory cells are potential targets for therapy.Peer reviewe

Determinants of expression of SARS-CoV-2 entry-related genes in upper and lower airways.

Funder: Dutch Research Council (NWO)Funder: Cancer Research UK Cambridge CentreFunder: ATS Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research FellowshipFunder: The Netherlands Ministry of Spatial Planning, Housing, and the EnvironmentFunder: Chan Zuckerberg InitiativeFunder: The Netherlands Ministry of Health, Welfare, and SportFunder: Longfonds Junior FellowshipFunder: Cambridge BioresourceFunder: The Netherlands Organization for Health Research and DevelopmentFunder: Cambridge NIHR Biomedical Research CentreFunder: Parker B. Francis FellowshipFunder: China Scholarship Counci

Genomic subtypes of breast cancer identified by array comparative genomic hybridization display distinct molecular and clinical characteristics

Abstract Introduction Breast cancer is a profoundly heterogeneous disease with respect to biologic and clinical behavior. Gene-expression profiling has been used to dissect this complexity and to stratify tumors into intrinsic gene-expression subtypes, associated with distinct biology, patient outcome, and genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. Methods We applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer. Results We identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene-expression subtypes, the former being enriched for 8p12-amplified cases, whereas the mixed subtype included many tumors with predominantly DNA copy-number losses and poor prognosis. Conclusions Global DNA copy-number analysis integrated with gene-expression data can be used to dissect the complexity of breast cancer. This revealed six genomic subtypes with different clinical behavior and a striking concordance to the intrinsic subtypes. These genomic subtypes may prove useful for understanding the mechanisms of tumor development and for prognostic and treatment prediction purposes

Early bronchial inflammation and remodeling and airway hyperresponsiveness at school age

Non peer reviewe