Asthma is the most common chronic pediatric lung disease that has traditionally been defined as a syndrome of airway inflammation characterized by clinical symptoms of cough and wheeze. Highlighting ...the complex and heterogeneous nature of asthma, this review summarizes recent advances in asthma classification that are based on pathobiology, and thereby directly addresses limitations of existent definitions of asthma. By reviewing and contrasting clinical and mechanistic features of adult and childhood asthma, the review summarizes key biomarkers that distinguish childhood asthma subtypes. While atopy and its severity are important features of childhood asthma, there is evidence to support the existence of a childhood asthma endotype distinct from the atopic endotype. Although biomarkers of non-atopic asthma are an area of future research, we summarize a clinical approach that includes existing measures of airway-specific and systemic measures of atopy, co-existing morbidities, and disease severity and control, in the definition of childhood asthma, to empower health care providers to better characterize asthma disease burden in children. Identification of biomarkers of non-atopic asthma and the contribution of genetics and epigenetics to pediatric asthma burden remains a research need, which can potentially allow delivery of precision medicine to pediatric asthma. IMPACT: This review highlights asthma as a complex and heterogeneous disease and discusses recent advances in the understanding of the pathobiology of asthma to demonstrate the need for a more nuanced definitions of asthma. We review current knowledge of asthma phenotypes and endotypes and put forth an approach to endotyping asthma that may be useful for defining asthma for clinical care as well as for future research studies in the realm of personalized medicine for asthma.
The burden of obesity-related asthma among children, particularly among ethnic minorities, necessitates an improved understanding of the underlying disease mechanisms. Although obesity is an ...independent risk factor for asthma, not all obese children develop asthma. Several recent studies have elucidated mechanisms, including the role of diet, sedentary lifestyle, mechanical fat load, and adiposity-mediated inflammation that may underlie the obese asthma pathophysiology. Here, we review these recent studies and emerging scientific evidence that suggest metabolic dysregulation may play a role in pediatric obesity-related asthma. We also review the genetic and epigenetic factors that may underlie susceptibility to metabolic dysregulation and associated pulmonary morbidity among children. Lastly, we identify knowledge gaps that need further exploration to better define pathways that will allow development of primary preventive strategies for obesity-related asthma in children.
Obesity has reached pandemic proportions in the last few decades. The global increase in obesity has contributed to an increase in the number of pregnant women with pre-pregnancy obesity or with ...excessive gestational weight gain. Obesity during pregnancy is associated with higher incidence of maternal co-morbidities such as gestational diabetes and hypertension. Both obesity during pregnancy and its associated complications are not only associated with immediate adverse outcomes for the mother and their newborns during the perinatal period but, more importantly, are linked with long-term morbidities in the offsprings. Neonates born to women with obesity are at higher risk for cardiac complications including cardiac malformations, and non-structural cardiac issues such as changes in the microvasculature, e.g., elevated systolic blood pressure, and overt systemic hypertension. Pulmonary diseases associated with maternal obesity include respiratory distress syndrome, asthma during childhood and adolescence, and adulthood diseases, such as chronic obstructive pulmonary disease. Sequelae of short-term complications compound long-term outcomes such as long-term obesity, hypertension later in life, and metabolic complications including insulin resistance and dyslipidemia. Multiple mechanisms have been proposed to explain these adverse outcomes and are related to the emerging knowledge of pathophysiology of obesity in adults. The best investigated ones include the role of obesity-mediated metabolic alterations and systemic inflammation. There is emerging evidence linking metabolic and immune derangements to altered biome, and alteration in epigenetics as one of the intermediary mechanisms underlying the adverse outcomes. These are initiated as part of fetal adaptation to obesity during pregnancy which are compounded by rapid weight gain during infancy and early childhood, a known complication of obesity during pregnancy. This newer evidence points toward the role of specific nutrients and changes in biome that may potentially modify the adverse outcomes observed in the offsprings of women with obesity.
Cell subtype proportion variability between samples contributes significantly to the variation of functional genomic properties such as gene expression or DNA methylation. Although the impact of the ...variation of cell subtype composition on measured genomic quantities is recognized, and some innovative tools have been developed for the analysis of heterogeneous samples, most functional genomics studies using samples with mixed cell types still ignore the influence of cell subtype proportion variation, or just deal with it as a nuisance variable to be eliminated. Here we demonstrate how harvesting information about cell subtype proportions from functional genomics data can provide insights into cellular changes associated with phenotypes. We focused on two types of mixed cell populations, human blood and mouse kidney. Cell type prediction is well developed in the former, but not currently in the latter. Estimating the cellular repertoire is easier when a reference dataset from purified samples of all cell types in the tissue is available, as is the case for blood. However, reference datasets are not available for most other tissues, such as the kidney. In this study, we showed that the proportion of alterations attributable to changes in the cellular composition varies strikingly in the two disorders (asthma and systemic lupus erythematosus), suggesting that the contribution of cell subtype proportion changes to functional genomic properties can be disease-specific. We also showed that a reference dataset from a single-cell RNA-seq study successfully estimated the cell subtype proportions in mouse kidney and allowed us to distinguish altered cell subtype differences between two different knock-out mouse models, both of which had reported a reduced number of glomeruli compared to their wild-type counterparts. These findings demonstrate that testing for changes in cell subtype proportions between conditions can yield important insights in functional genomics studies.
The asthma-obesity syndrome represents a major public health concern that disproportionately contributes to asthma severity and induces insensitivity to therapy. To date, no study has shown an ...intrinsic difference between human airway smooth muscle (HASM) cells derived from nonobese subjects and those derived from obese subjects. The objective of this study was to address whether there is a greater response to agonist-induced calcium mobilization, phosphorylation of myosin light chain (MLC), and greater shortening in HASM cells derived from obese subjects. HASM cells derived from nonobese and obese subjects were age and sex matched. Phosphorylation of MLC was measured after having been stimulated by carbachol. Carbachol- or histamine-induced mobilization of calcium and cell shortening were assessed in HASM cells derived from nonobese and obese donors. Agonist-induced MLC phosphorylation, mobilization of calcium, and cell shortening were greater in obese compared with non-obese-derived HASM cells. The MLC response was comparable in HASM cells derived from obese nonasthma and nonobese fatal asthma subjects. HASM cells derived from obese female subjects were more responsive to carbachol than HASM cells derived from obese male subjects. Insulin pretreatment had little effect on these responses. Our results show an increase in agonist-induced calcium mobilization associated with an increase in MLC phosphorylation and an increase in ASM cell shortening in favor of agonist-induced hyperresponsiveness in HASM cells derived from obese subjects. Our studies suggest that obesity induces a retained phenotype of hyperresponsiveness in cultured human airway smooth muscle cells.
Asthma is a common disease in childhood and adolescence with lifelong consequences particularly among those at risk of severe disease, poor control and/or frequent exacerbations. Specialist care is ...recommended for at-risk children and adolescents, yet access to specialist management in free-to-access healthcare settings remains poorly understood.
A Danish nationwide cohort of children and adolescents aged 2-17 years with persistent asthma, defined as repeated redemption of inhaled corticosteroids (ICS) during 2015, were followed for two years, to identify at-risk children and adolescents comprising those with severe asthma (classified according to GINA 2020 guidelines), poor control (defined as use of 400/600 (ages 2-11/12 +) annual doses of short-acting bronchodilators), or frequent exacerbations (defined as use of oral steroids or hospitalization), and access to specialist care. The population is chosen due to detailed medical records in the setting of universal health care.
The cohort comprised of 29,851 children and adolescents (59% boys), with a median age of 9 years. While 17% of children were on high dose ICS, 22% were on daily ICS below GINA low dose cut-off. Prevalence of severe asthma (3.0-6.5%) was lower than poor asthma control (6.4-25%); both declined from childhood to adolescence. Exacerbations occurred in 7.1-9.0% of children, with median number of exacerbations being 1 (IQR 1-1). Despite being classified as having mild-to-moderate asthma, 15% had poor asthma control and 3.8% experienced exacerbation(s), respectively. While 61% of children with severe asthma and 58% with exacerbation-prone disease were in specialist care, only 24% with uncontrolled disease were receiving specialist care. Of children and adolescents using high-dose ICS, 71% were managed in primary care, while the use of additional controllers was more common in specialist care.
Throughout childhood and adolescence, there was a high prevalence of severe asthma and poor control, although their prevalence declined with age. We demonstrate a large unmet need for specialist care among children with at-risk asthma, particularly among those with poorly controlled asthma, even in a system with free-to-access, tax-funded healthcare.
Childhood obesity contributes to many diseases, including asthma. There is literature to suggest that asthma developing as a consequence of obesity has a nonallergic or non‐T2 phenotype. In this ...review, obesity‐related asthma is utilized as a prototype of non‐T2 asthma in children to discuss several nonallergic mechanisms that underlie childhood asthma. Obesity‐related asthma is associated with systemic T helper (Th)1 polarization occurring with monocyte activation. These immune responses are mediated by insulin resistance and dyslipidemia, metabolic abnormalities associated with obesity, that are themselves associated with pulmonary function deficits in obese asthmatics. As in other multifactorial diseases, there is both a genetic and an environmental contribution to pediatric obesity‐related asthma. In addition to genetic susceptibility, differential DNA methylation is associated with non‐T2 immune responses in pediatric obesity‐related asthma. Initial investigations into the biology of non‐T2 immune responses have identified the upregulation of genes in the CDC42 pathway. CDC42 is a RhoGTPase that plays a key role in Th cell physiology, including preferential naïve Th cell differentiation to Th1 cells, and cytokine production and exocytosis. Although these novel pathways are promising findings to direct targeted therapy development for obesity‐related asthma to address the disease burden, there is evidence to suggest that dietary interventions, including diet modification, rather than caloric restriction alone, decrease disease burden. Adoption of a diet rich in micronutrients, including carotenoids and 25‐OH cholecalciferol, a vitamin D metabolite, may be beneficial since these are positively correlated with pulmonary function indices, while being protective against metabolic abnormalities associated with the obese asthma phenotype.
Background Pediatric obesity-related asthma is more severe and less responsive to medications than asthma in normal-weight children. Obese asthmatic children have nonatopic TH 1-polarized systemic ...inflammation that correlates with pulmonary function deficits, but the pathways underlying TH 1-polarized inflammation are not well understood. Objective We compared the CD4+ T-cell transcriptome in obese children with asthma with that in normal-weight children with asthma to identify key differentially expressed genes associated with TH 1-polarized inflammation. Methods CD4+ T-cell transcriptome–wide differential gene expression was compared between 21 obese and 21 normal-weight children by using directional RNA sequencing. High-confidence differentially expressed genes were verified in the first cohort and validated in a second cohort of 20 children (10 obese and 10 normal-weight children) by using quantitative RT-PCR. Results Transcriptome-wide differential gene expression among obese asthmatic children was enriched for genes, including VAV2 , DOCK5 , PAK3 , PLD1 , CDC42EP4 , and CDC42PBB , which are associated with CDC42, a small guanosine triphosphate protein linked to T-cell activation. Upregulation of MLK3 and PLD1 , genes downstream of CDC42 in the mitogen-activated protein kinase and mammalian target of rapamycin pathways and the inverse correlation of CDC42EP4 and DOCK5 transcript counts with FEV1 /FVC ratio together support a role of CDC42 in the TH 1 polarization and pulmonary function deficits found in patients with obesity-related asthma. Conclusions Our study identifies the CDC42 pathway as a novel target that is upregulated in TH cells of obese asthmatic children, suggesting its role in nonatopic TH 1-polarized systemic inflammation and pulmonary function deficits found in patients with pediatric obesity-related asthma.
Background
There is increased use of early nasal continuous positive airway pressure (NCPAP) to manage respiratory distress in preterm infants but optimal methods and factors associated with ...successful wean are not well defined. A systematic review was performed to define the corrected gestational age (CGA), weight to wean NCPAP and the methods associated with successful weaning of the NCPAP among preterm infants, along with factors affecting it.
Methods
Searches were made of PubMed using the keywords-NCPAP, CPAP, weaning, withdrawal, preterm, and infants from its inception to January 1st, 2014, for studies in all languages but limited to humans. Previous reviews (including cross references) were also searched. We included all randomized and quasi-randomized controlled trials where preterm neonates were randomized to different NCPAP weaning strategies. Details of CGA, weight and methods used for weaning NCPAP were extracted along with factors which affect its withdrawal.
Results
Seven studies met the search criteria. The successful wean was at 32 to 33 weeks CGA and at 1600 g. Three different methods were used for weaning were sudden, gradual pressure wean and gradual graded time off wean. Criteria for readiness, success and failure to wean were defined. Factors affecting successful weaning were intubation, anemia, infection and gastro-esophageal reflux.
Conclusions
The successful wean was at 32 to 33 weeks CGA and 1600 g. Criteria for readiness, success and failure to wean are well defined. Sudden weaning may be associated with a shorter weaning time. Future trials are needed comparing weaning methods using defined criteria for readiness and success of NCPAP wean and stratify the results by gestational age and birth weight.
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