Does allergy explain why some children have severe asthma?

Asthma is a common disease in childhood with a minority of affected children having severe therapy-resistant asthma (STRA). Children with STRA can be differentiated from those with mild-moderate disease by greater allergic sensitization, increased eosinophilic airway inflammation, increased airway remodelling and reduced corticosteroid responsiveness. The aetiology of STRA in children is multifactorial but allergy seems to play a key role. Many children with asthma have coexisting allergic disease, and severe rhinitis seems to be an important driver of STRA in children. Allergies to foods, moulds, pollen and pets have also been associated with severe asthma exacerbations. Identifying allergens that are driving asthma symptoms in children with STRA may provide additional strategies for improving their disease control. Avoidance strategies may be possible. Additional monoclonal antibody therapy with Omalizumab or Mepolizumab may be helpful in children with clinically important polysensitization.

Prevalence of alopecia in gray seals Halichoerus grypus atlantica in Massachusetts, USA, 2004-2013.

There has been an increase in the presence of alopecia among gray seals Halichoerus grypus atlantica in Massachusetts, USA. To understand the prevalence and describe the presentation of this condition, data records and photographs of 10070 gray seals from 2004-2013 were reviewed; there were sufficient data to confidently assess the presence or absence of alopecia in 2134 seals. Mild hair loss presented in multifocal patches with minimal to no skin lesions or erythema. In severe cases, alopecia was concentrated over the dorsal head, neck, and shoulders and extended down the ventrum, affecting >50% of the body. Associated skin lesions and erythema were often present. Alopecia was documented in 7.1% of the surveyed seals, and was centered in Nantucket. Alopecia was more prevalent in stranded/sighted animals in spring and summer, with 81% of cases documented from April to July. There was no sex bias, and weanlings were the most affected age class (38%). The etiology for alopecia in Massachusetts gray seals is unknown. Possible causes of alopecia in wildlife are infectious disease, nutritional deficiencies, endocrinopathies, or chronic physiologic stress. High population density around Nantucket may escalate intraspecific competition for resources, which may indirectly lead to stress-induced immunosuppression or nutritional deficiencies. Crowded haul-out sites increase the opportunity for disease transmission. The weanling age class may be prone to alopecia due to naïve immune systems and inexperienced foraging capabilities. Diagnostic sample collection from gray seals will be required to characterize the etiology, pathogenesis, and significance of alopecia in this population.

Mast cell activation disrupts interactions between endothelial cells and pericytes during early life allergic asthma.

Allergic asthma generally starts during early life and is linked to substantial tissue remodeling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLSs), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MC) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-cadherin. Furthermore, spatial transcriptomics of pediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodeling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.

Distinct airway epithelial immune responses after infection with SARS-CoV-2 compared to H1N1.

Children are less likely than adults to suffer severe symptoms when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while influenza A H1N1 severity is comparable across ages except for the very young or elderly. Airway epithelial cells play a vital role in the early defence against viruses via their barrier and immune functions. We investigated viral replication and immune responses in SARS-CoV-2-infected bronchial epithelial cells from healthy paediatric (n = 6; 2.5-5.6 years old) and adult (n = 4; 47-63 years old) subjects and compared cellular responses following infection with SARS-CoV-2 or Influenza A H1N1. While infection with either virus triggered robust transcriptional interferon responses, including induction of type I (IFNB1) and type III (IFNL1) interferons, markedly lower levels of interferons and inflammatory proteins (IL-6, IL-8) were released following SARS-CoV-2 compared to H1N1 infection. Only H1N1 infection caused disruption of the epithelial layer. Interestingly, H1N1 infection resulted in sustained upregulation of SARS-CoV-2 entry factors FURIN and NRP1. We did not find any differences in the epithelial response to SARS-CoV-2 infection between paediatric and adult cells. Overall, SARS-CoV-2 had diminished potential to replicate, affect morphology and evoke immune responses in bronchial epithelial cells compared to H1N1.

Factors and mechanisms contributing to the development of preschool wheezing disorders.

INTRODUCTION: Half of all children will experience an episode of wheezing by their sixth birthday and acute episodes of wheezing in preschool children account for the majority of all childhood hospital admissions for wheeze. Recurrent preschool wheezing associates with early loss of lung function and a life-long impact on lung health. AREAS COVERED: We reviewed the literature on PubMed from August 2010-2020 focussing on factors associated with wheeze inception and persistence, paying specific attention to mechanistic studies that have investigated the impact of early life exposures in shaping immune responses in children with underlying susceptibility to wheezing. In particular, the role of early allergen sensitization, respiratory infections, and the impact of the environment on shaping the airway microbiome and resulting immune responses are discussed. EXPERT OPINION: There is an abundance of associative data showing the role of in utero and postnatal factors influencing wheeze onset and persistence. However, mechanistic and stratified, biomarker-based interventional studies that confirm these associations are now needed if we are to impact the significant healthcare burden resulting from preschool wheezing disorders.

Implementation of a Modified Neonatal Early-onset Sepsis Calculator in Well-baby Nursery: a Quality Improvement Study.

BACKGROUND: The use of sepsis risk scores (SRSs), calculated based on the neonatal early-onset sepsis (EOS) calculator, has been shown to limit the unwarranted sepsis evaluations and to reduce the empirical use of antibiotics in neonates.s. PURPOSE: To reduce both the sepsis evaluation rate (SER) and antibiotic initiation rate (AIR) by 25% from baseline by incorporating conservative SRS cutoff values into the routine sepsis risk assessment of well-appearing neonates born at 34 weeks and older gestation. METHODS: During a pre quality improvement (QI) period (June 2016-August 2016), a QI team calculated SRS on all newborn infants to determine safe SRS cutoff values. During the QI-study period (September 2016-November 2017), we implemented an EOS evaluation algorithm based on 2 SRS cutoff values, 0.05 (later increased to 0.1) for sepsis evaluation and 0.3 for the initiation of antibiotic therapy. Monthly SER and AIR were summarized and analyzed by using standard statistical tests and statistical process control charts. During the surveillance phase (January 2019-June 2019), we evaluated whether previously attained improvements in SER and AIR were sustained. RESULTS: During the pre-QI period, the mean (±SD) of monthly SER and monthly AIR were 23.8% (±5.7%) and 6.2% (±0.4%), respectively. During the QI-study period, the mean (±SD) of monthly SER and monthly AIR decreased to 15% (±4.7%), P = 0.01, and 3.2% (±1.5%), P = 0.005, respectively. During the surveillance period, both outcome measures were comparable with the QI-study period. CONCLUSION: The implementation of a modified EOS calculator-based EOS algorithm using a conservative approach was successful in reducing antibiotic exposure and the need for blood work in well-appearing neonates.

Dynamics of human monocytes and airway macrophages during healthy aging and after transplant.

The ontogeny of airway macrophages (AMs) in human lung and their contribution to disease are poorly mapped out. In mice, aging is associated with an increasing proportion of peripherally, as opposed to perinatally derived AMs. We sought to understand AM ontogeny in human lung during healthy aging and after transplant. We characterized monocyte/macrophage populations from the peripheral blood and airways of healthy volunteers across infancy/childhood (2-12 yr), maturity (20-50 yr), and older adulthood (>50 yr). Single-cell RNA sequencing (scRNA-seq) was performed on airway inflammatory cells isolated from sex-mismatched lung transplant recipients. During healthy aging, the proportions of blood bronchoalveolar lavage (BAL) classical monocytes peak in adulthood and decline in older adults. scRNA-seq of BAL cells from lung transplant recipients indicates that after transplant, the majority of AMs are recipient derived. These data show that during aging, the peripheral monocyte phenotype is consistent with that found in the airways and, furthermore, that the majority of human AMs after transplant are derived from circulating monocytes.