Environmental exposures and inflammation in young children with cystic fibrosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Blood
DISEASE(S): Cystic Fibrosis
PROVIDER: ST001079 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:BackgroundMechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously showed that young CF children with secondhand smoke exposure (SHSe) have increased susceptibility to respiratory infections. We aimed to define the impact of SHSe and other external factors upon the fecal bacteriome in early CF.MethodsTwenty CF infants and children were enrolled, clinical data recorded, and hair nicotine measured as an objective surrogate of SHSe. Fecal samples were collected at clinic visits and bacteriome 16S rRNA gene sequencing performed.ResultsSHSe was associated with increased alpha diversity and increased relative abundance of Acinetobacter and Akkermansia, along with decreased Bifidobacterium and Lactobacillus. Recent antibiotic exposure predicted bacterial population structure in children less than 2 years of age and was associated with decreased Bacteroides relative abundance. Age was the strongest predictor of overall fecal bacterial composition and positively associated with Blautia and Parabacteroides. Weight for length was negatively associated with Staphylococcus relative abundance.ConclusionsSHSe and other external factors such as antibiotics appear to alter fecal bacterial composition in young CF children, but the strongest predictor of overall composition was age. These findings have implications for understanding the intestinal microbiome in young CF children.
| S-EPMC7593804 | biostudies-literature
Project description:Cystic fibrosis (CF)-related diabetes (CFRD) is thought to result from beta-cell injury due in part to pancreas exocrine damage and lipofibrosis. CFRD pancreata exhibit reduced islet density and altered cellular composition. To investigate a possible etiology, we tested the hypothesis that such changes are present in CF pancreata before the development of lipofibrosis. We evaluated pancreas and islet morphology in tissues from very young CF children (<4 years of age), and adult patients with CF and CFRD. The relative number of beta-cells in young CF tissues was reduced by 50% or more when compared to age-matched controls. Furthermore, young CF tissues displayed significantly smaller insulin-positive areas, lower proportion of beta-cells positive for the proliferation marker Ki67 or the ductal marker CK19 vs. control subjects, and islet inflammatory cell infiltrates, independently of the severity of the exocrine lesion and in the absence of amyloid deposits. CFRD pancreata exhibited greater islet injury with further reduction in islet density, decreased relative beta-cell number, and presence of amyloid deposits. Together, these results strongly suggest that an early deficiency in beta-cell number in infants with CF may contribute to the development of glucose intolerance in the CF pediatric population, and to CFRD, later in life.
| S-EPMC5722914 | biostudies-literature
Project description:RationaleIn cystic fibrosis, abnormal glucose tolerance is associated with decreased lung function and worsened outcomes. Translational evidence indicates that abnormal glucose tolerance may begin in early life.ObjectivesTo determine whether very young children with cystic fibrosis have increased abnormal glucose tolerance prevalence compared with control subjects. The secondary objective was to compare area under the curve for glucose and insulin in children with cystic fibrosis with control subjects.MethodsThis is a prospective multicenter study in children ages 3 months to 5 years with and without cystic fibrosis.Measurements and main resultsOral glucose tolerance testing with glucose, insulin, and C-peptide was sampled at 0, 10, 30, 60, 90, and 120 minutes. Twenty-three children with cystic fibrosis and nine control subjects had complete data. All control subjects had normal glucose tolerance. Nine of 23 subjects with cystic fibrosis had abnormal glucose tolerance (39%; P = 0.03). Of those, two met criteria for cystic fibrosis-related diabetes, two indeterminate glycemia, and six impaired glucose tolerance. Children with cystic fibrosis failed to exhibit the normal increase in area under the curve insulin with age observed in control subjects (P < 0.01), despite increased area under the curve glucose (P = 0.02).ConclusionsAbnormal glucose tolerance is notably prevalent among young children with cystic fibrosis. Children with cystic fibrosis lack the normal increase in insulin secretion that occurs in early childhood despite increased glucose. These findings demonstrate that glycemic abnormalities begin very early in cystic fibrosis, possibly because of insufficient insulin secretion.
| S-EPMC5067820 | biostudies-literature
Project description:BackgroundInfection with nontuberculous mycobacteria (NTM) is of growing clinical concern in people with cystic fibrosis (CF). The epidemiology of infection in children and young people remains poorly understood. Our goal was to investigate the epidemiology of NTM infection in the pediatric age group using data from the UK CF Registry.MethodsData from 2010-2015 for individuals aged <16 years (23200 observations from 5333 unique individuals) were obtained. Univariate analysis of unique individuals comparing all key clinical factors and health outcomes to NTM status was performed. The significant factors that were identified were used to generate a multivariate logistic regression model that, following step-wise removal, generated a final parsimonious model.ResultsThe prevalence of individuals with a NTM-positive respiratory culture increased every year from 2010 (45 [1.3%]) to 2015 (156 [3.8%]). Allergic bronchopulmonary aspergillosis (odds ratio [OR], 2.66; P = 5.0 × 10-8), age (OR, 1.08; P = 3.4 × 10-10), and intermittent Pseudomonas aeruginosa infection (OR, 1.51; P = .004) were significantly associated with NTM infection.ConclusionsNTM infection is of increasing prevalence in the UK pediatric CF population. This study highlights the urgent need for work to establish effective treatment and prevention strategies for NTM infection in young people with CF.
| S-EPMC6376093 | biostudies-literature
Project description:Introduction: The responses of cystic fibrosis (CF) airway epithelial cells (AEC) to rhinovirus (RV) infection are likely to contribute to early pathobiology of lung disease with increased neutrophilic inflammation and lower apoptosis reported. Necrosis of AEC resulting in airway inflammation driven by IL-1 signaling is a characteristic finding in CF detectable in airways of young children. Being the most common early-life infection, RV-induced epithelial necrosis may contribute to early neutrophilic inflammation in CF via IL-1 signaling. As little is known about IL-1 and biology of CF lung disease, this study assessed cellular and pro-inflammatory responses of CF and non-CF AEC following RV infection, with the hypothesis that RV infection drives epithelial necrosis and IL-1 driven inflammation. Methods:Primary AEC obtained from children with (n = 6) and without CF (n = 6) were infected with RV (MOI 3) for 24 h and viable, necrotic and apoptotic events quantified via flow cytometry using a seven-step gating strategy (% total events). IL-1?, IL-1?, IL-1Ra, IL-8, CXCL10, CCL5, IFN-?, IL-28A, IL-28B, and IL-29 were also measured in cell culture supernatants (pg/mL). Results:RV infection reduced viable events in non-CF AEC (p < 0.05), increased necrotic events in non-CF and CF AEC (p < 0.05) and increased apoptotic events in non-CF AEC (p < 0.05). Infection induced IL-1? and IL-1? production in both phenotypes (p < 0.05) but only correlated with necrosis (IL-1?: r = 0.80; IL-1?: r = 0.77; p < 0.0001) in CF AEC. RV infection also increased IL-1Ra in non-CF and CF AEC (p < 0.05), although significantly more in non-CF AEC (p < 0.05). Finally, infection stimulated IL-8 production in non-CF and CF AEC (p < 0.05) and correlated with IL-1? (r = 0.63 & r = 0.74 respectively; p < 0.0001). Conclusions:This study found RV infection drives necrotic cell death in CF AEC. Furthermore, RV induced IL-1 strongly correlated with necrotic cell death in these cells. As IL-1R signaling drives airway neutrophilia and mucin production, these observations suggest RV infection early in life may exacerbate inflammation and mucin accumulation driving early CF lung disease. Since IL-1R can be targeted therapeutically with IL-1Ra, these data suggest a new anti-inflammatory therapeutic approach targeting downstream effects of IL-1R signaling to mitigate viral-induced, muco-inflammatory triggers of early lung disease.
| S-EPMC7161373 | biostudies-literature
Project description:Cystic fibrosis (CF) lung disease commences early in the disease progression and is the most common cause of mortality. While new CF disease-modifying agents are currently undergoing clinical trial evaluation, the implementation of such trials in young children is limited by the lack of age-appropriate clinical trial end points. Advances in infant and preschool lung function testing, imaging of the chest and the development of biochemical biomarkers have led to increased possibility of quantifying mild lung disease in young children with CF and objectively monitoring disease progression over the course of an intervention. Despite this, further standardization and development of these techniques is required to provide robust objective measures for clinical trials in this age group.
| S-EPMC5033038 | biostudies-literature
Project description:BackgroundCystic fibrosis is an inherited condition causing disease most noticeably in the lungs, digestive tract and pancreas. People with cystic fibrosis often have malnutrition and growth delay. Adequate nutritional supplementation does not improve growth optimally and hence an anabolic agent, recombinant growth hormone, has been proposed as a potential intervention.ObjectivesTo evaluate the effectiveness and safety of recombinant human growth hormone therapy in improving lung function, quality of life and clinical status of children and young adults with cystic fibrosis.Search methodsWe searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 15 May 2013.We conducted a search of relevant endocrine journals and proceedings of the Endocrinology Society meetings using Scopus and Proceedings First. Date of latest search: 15 March 2012.Selection criteriaRandomised and quasi-randomised controlled trials of all preparations of recombinant growth hormone compared to either no treatment, or placebo, or each other at any dose (high-dose and low-dose) or route and for any duration, in children or young adults aged up to 25 years diagnosed with cystic fibrosis (by sweat test or genetic testing).Data collection and analysisTwo authors independently screened papers, extracted trial details and assessed their risk of bias.Main resultsFour controlled trials were included in this review (with 161 participants in total), each with an unclear risk of bias. Analysis of data obtained from these trials shows improvement in height for all comparisons, but improvements in weight and lean tissue mass were only reported in the comparison of standard dose recombinant growth hormone versus no treatment. There is moderate improvement in one parameter of pulmonary function tests, functional vital capacity (per cent predicted) when comparing standard dose recombinant growth hormone and no treatment. Little evidence was found for improvement in quality of life. An improvement in fasting blood glucose levels was reported when comparing rhGH to placebo only. Exercise capacity improved in participants receiving standard dose recombinant growth hormone versus no treatment, but not for any other comparison. There is insufficient evidence to conclude any changes in hospitalisations, antibiotic use or significant adverse effects.Authors' conclusionsRecombinant growth hormone therapy is effective in improving the intermediate outcomes in height, weight and lean tissue mass when compared with no treatment. One measure of pulmonary function test showed moderate improvement. No significant changes in quality of life, clinical status or side-effects were observed in this review. Long-term, well-designed randomised controlled trials of recombinant growth hormone therapy in patients with cystic fibrosis are required prior to evaluation of human growth hormone treatment for routine use in patients.
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Project description:The immune landscape of the paediatric respiratory system remains largely uncharacterised and as a result, the mechanisms of globally important childhood respiratory diseases remain poorly understood. In this work, we used high parameter flow cytometry and inflammatory cytokine profiling to map the local [bronchoalveolar lavage (BAL)] and systemic (whole blood) immune response in preschool aged children with cystic fibrosis (CF) and aged-matched healthy controls. We demonstrate that children with CF show pulmonary infiltration of CD66b+ granulocytes and increased levels of MIP-1α, MIG, MCP-1, IL-8, and IL-6 in BAL relative to healthy control children. Proportions of systemic neutrophils positively correlated with age in children with CF, whilst systemic CD4 T cells and B cells were inversely associated with age. Inflammatory cells in the BAL from both CF and healthy children expressed higher levels of activation and migration markers relative to their systemic counterparts. This work highlights the utility of multiplex immune profiling and advanced analytical pipelines to understand mechanisms of lung disease in childhood.
| S-EPMC8554310 | biostudies-literature