Interleukin-7 Links T Lymphocyte and Intestinal Epithelial Cell Homeostasis

Interleukin-7 (IL-7) is a major survival factor for mature T cells. Therefore, the degree of IL-7 availability determines the size of the peripheral T cell pool and regulates T cell homeostasis. Here we provide evidence that IL-7 also regulates the homeostasis of intestinal epithelial cells (IEC), colon function and the composition of the commensal microflora. In the colon of T cell-deficient, lymphopenic mice, IL-7-producing IEC accumulate. IEC hyperplasia can be blocked by IL-7-consuming T cells or the inactivation of the IL-7/IL-7R signaling pathway. However, the blockade of the IL-7/IL-7R signaling pathway renders T cell-deficient mice more sensitive to chemically-induced IEC damage and subsequent colitis. In summary, our data demonstrate that IL-7 promotes IEC hyperplasia under lymphopenic conditions. Under non-lymphopenic conditions, however, T cells consume IL-7 thereby limiting IEC expansion and survival. Hence, the degree of IL-7 availability regulates both, T cell and IEC homeostasis

Effects of lumacaftor—ivacaftor therapy on cystic fibrosis transmembrane conductance regulator function in F508del homozygous patients with cystic fibrosis aged 2–11 years

Rationale: Lumacaftor/ivacaftor was approved for the treatment of patients with cystic fibrosis who are homozygous for F508del aged 2 years and older following positive results from phase three trials. However, the improvement in CFTR function associated with lumacaftor/ivacaftor has only been studied in patients over 12 years of age, while the rescue potential in younger children is unknown.Methods: In a prospective study, we aimed to evaluate the effect of lumacaftor/ivacaftor on the CFTR biomarkers sweat chloride concentration and intestinal current measurement as well as clinical outcome parameters in F508del homozygous CF patients 2–11 years before and 8–16 weeks after treatment initiation.Results: A total of 13 children with CF homozygous for F508del aged 2–11 years were enrolled and 12 patients were analyzed. Lumacaftor/ivacaftor treatment reduced sweat chloride concentration by 26.8 mmol/L (p = 0.0006) and showed a mean improvement in CFTR activity, as assessed by intestinal current measurement in the rectal epithelium, of 30.5% compared to normal (p = 0.0015), exceeding previous findings of 17.7% of normal in CF patients homozygous for F508del aged 12 years and older.Conclusion: Lumacaftor/ivacaftor partially restores F508del CFTR function in children with CF who are homozygous for F508del, aged 2–11 years, to a level of CFTR activity seen in patients with CFTR variants with residual function. These results are consistent with the partial short-term improvement in clinical parameters

Peanut‐induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry

Background Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%-1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents. Methods Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre. Results 3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004). Conclusions The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition

Multiple breath washout is feasible in the clinical setting and detects abnormal lung function in infants and young children with cystic fibrosis.

BACKGROUND Cystic fibrosis (CF) lung disease starts in the first months of life often before the onset of clinical symptoms. Multiple breath washout (MBW) detects abnormal lung function in infants and young children in the laboratory setting. OBJECTIVE The aim of this study was to determine the feasibility of MBW in 0- to 4-year-old children with CF and non-CF controls in the clinical setting. METHODS Fourteen children with CF (mean age 1.3 ± 1.0 years) and 26 age-matched non-CF controls were sedated with chloral hydrate and MBW was performed with sulfur hexafluoride. RESULTS MBW measurements were successful in 27 of 40 children (67.5%). The mean lung clearance index (LCI) was significantly higher in CF patients compared to non-CF controls (p = 0.006). Further, the frequency of elevated LCI (z-score >1.96) was significantly increased in CF patients compared to controls (p = 0.0003). CONCLUSIONS We conclude that MBW is feasible and sensitive to detect abnormal lung function in infants and young children with CF in the clinical setting

CFTR Modulator Therapy with Lumacaftor/Ivacaftor Alters Plasma Concentrations of Lipid-Soluble Vitamins A and E in Patients with Cystic Fibrosis

Rationale: Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leads to impaired pancreatic function and therefore reduced intestinal absorption of lipids and fat-soluble vitamins especially in patients with CF developing pancreatic insufficiency (PI). Previous studies showed that CFTR modulator therapy with lumacaftor-ivacaftor (LUM/IVA) in Phe508del-homozygous patients with CF results in improvement of pulmonary disease and thriving. However, the effects of LUM/IVA on plasma concentration of the lipid soluble vitamins A and E remain unknown. Objectives: To investigate the course of plasma vitamin A and E in patients with CF under LUM/IVA therapy. Methods: Data from annual follow-up examinations of patients with CF were obtained to assess clinical outcomes including pulmonary function status, body mass index (BMI), and clinical chemistry as well as fat-soluble vitamins in Phe508del-homozygous CF patients before initiation and during LUM/IVA therapy. Results: Patients with CF receiving LUM/IVA improved substantially, including improvement in pulmonary inflammation, associated with a decrease in blood immunoglobulin G (IgG) from 9.4 to 8.2 g/L after two years (p &lt; 0.001). During the same time, plasma vitamin A increased significantly from 1.2 to 1.6 µmol/L (p &lt; 0.05), however, levels above the upper limit of normal were not detected in any of the patients. In contrast, plasma vitamin E as vitamin E/cholesterol ratio decreased moderately over the same time from 6.2 to 5.5 µmol/L (p &lt; 0.01). Conclusions: CFTR modulator therapy with LUM/IVA alters concentrations of vitamins A and vitamin E in plasma. The increase of vitamin A must be monitored critically to avoid hypervitaminosis A in patients with CF

Acute exacerbations in children’s interstitial lung disease

Introduction: Acute exacerbations (AEs) increase morbidity and mortality of patients with chronic pulmonary diseases. Little is known about the characteristics and impact of AEs on children's interstitial lung disease (chILD). Methods: The Kids Lung Register collected data on AEs, the clinical course and quality of life (patient-reported outcomes - PRO) of rare paediatric lung diseases. Characteristics of AEs were obtained. Results: Data of 2822 AEs and 2887 register visits of 719 patients with chILD were recorded. AEs were characterised by increased levels of dyspnoea (74.1%), increased respiratory rate (58.6%) and increased oxygen demand (57.4%). Mostly, infections (94.4%) were suspected causing an AE. AEs between two register visits revealed a decline in predicted FEV1 (median −1.6%, IQR −8.0 to 3.9; p=0.001), predicted FVC (median −1.8%, IQR −7.5 to 3.9; p=0.004), chILD-specific questionnaire (median −1.3%, IQR −3.6 to 4.5; p=0.034) and the physical health summary score (median −3.1%, IQR −15.6 to 4.3; p=0.005) compared with no AEs in between visits. During the median observational period of 2.5 years (IQR 1.2–4.6), 81 patients died. For 49 of these patients (60.5%), mortality was associated with an AE. Conclusion: This is the first comprehensive study analysing the characteristics and impact on the clinical course of AEs in chILD. AEs have a significant and deleterious effect on the clinical course and health-related quality of life in chILD

The effect of nutritional parameters on the prognosis of childhood interstitial lung diseases

International audienceBackground-Aim: Data on malnutrition in childhood interstitial lung diseases (chILD) are scarce. We aimed to evaluate malnutrition in chILD and to investigate factors leading to poor nutritional status.Methods: Data source Kids Lung Register. From baseline and follow-up data we analyzed nutritional parameters, severity scores, treatment modalities, PFT data (ppFEV1 and ppFVC) and disease severity (using Fan severityscore).Results: Data of 3,334 register visits from 759 children were included. At baseline, 94/759 children (12%) had PEG/fundoplication. For children 2 years, at baseline, malnutrition was present in 157/427 (37%) children. The most common ILD categories in these children were DPLD: related to alveolar surfactant region (n=49, 31%), exposures (n=26, 17%), and systemic disease processes (n=26; 17%). At one year follow up,malnutrition decreased to 90/365 (25%) children. Lower ppFEV1 (p<0.001), ppFVC (p<0.001) and disaese severity (p=0.047) were correlated with malnutrition.Conclusion: Malnutrition is common in chILD. Further studies are needed to determine if early nutritional intervention improves the prognosis of patients with child (CRC chILD-EU)

IL-7R signaling protects Rag⁻ mice from DSS-induced colitis.

<p>(<b>A, B</b>) WT (n = 4), Rag⁻ (n = 8), Rag⁻IL-7R⁻ (n = 7) and Rag⁻OT-I⁺ mice (n = 6) received dextran sulfate sodium (DSS) via the drinking water. From day 5 on, DSS-free drinking water was provided. (<b>A</b>) Body weight was determined every day and calculated in relation to the initial body weight. Shown are the mean relative body weight ± SEM and the time after onset of DSS treatment. (<b>B, C</b>) Colon samples were taken at day 8 and analyzed histologically. Shown are histological scores for groups of untreated (open symbols; n = 4) and DSS-treated mice (closed symbols; n = 6–8). (<b>C</b>) Shown are representative colon sections from the indicated mice. (<b>A–C</b>) Data represent one experiment.</p

Elevated levels of IL-7 expression and IEC hyperplasia in the colon of Rag⁻ mice.

<p>(<b>A</b>) Representative bioluminescence (BL) images for Rag-competent (Rag⁺; n = 31) and Rag-deficient IL-7GCDL mice (Rag⁻; n = 21) are shown. BL was determined (<b>B</b>) in the intestine and (<b>C</b>) thymus, heart, lung, liver, skin and kidney of Rag⁺ (n = 12) and Rag⁻ IL-7GCDL mice (n = 12). (<b>A–C</b>) BL is shown in photons per s per cm² per steradian. (<b>D, E</b>) Colon sections from Rag⁺ (n = 5–8) and Rag⁻ IL-7GCDL mice (n = 6–8) were stained with (<b>D</b>) periodic acid-Schiff (PAS)/Alcian blue (AB) or (<b>E</b>) DAPI and antibodies for IL-7 and EpCam. (<b>D</b>) Differentiated goblet cells stain positive for PAS (red) and appear purple/magenta. Acidic mucopolysaccharides/glycosaminoglycans are visualized by AB. Arrows indicate the distance between the basis of the crypts and the colon lumen. (<b>D, E</b>) Data are representative for 3 independent experiments and 2–3 staining reactions per mouse.</p