Tamara Dekker

Effect of dexamethasone on tracheal viral load and interleukin-8 tracheal concentration in children with respiratory syncytial virus infection

Background. Lower respiratory tract infection caused by respiratory syncytial virus (RSV) is in part an immune-mediated disease. For that reason corticosteroids might be effective, especially in patients with severe RSV lower respiratory tract infection. Our aim was to assess the effect of dexamethasone on tracheal viral load and airway inflammation in patients with RSV infection. Methods. Mechanically ventilated children with proven RSV infection were randomized to receive dexamethasone (0.6 mg/kg/day in four doses for 48 h) or placebo. Daily tracheal aspirates were analyzed for viral load (by quantitative polymerase chain reaction), interleukin (IL)-8 and white blood cell count. Results. The RSV RNA concentrations decreased in a similar manner from baseline in the dexamethasone (9 patients) and in the placebo group (13 patients). IL-8 decreased from baseline in the dexamethasone group but increased in the placebo group during the first 48 h [change from baseline at 24 h, –2.3 vs. 0.9 ln ng/ml (95% confidence interval for difference, −4.2 to 0.3, P = 0.02) and at 48 h, –4.2 vs. 0.4 ln mg/ml (95% confidence interval for difference, −5.3 to –0.3; P = 0.03), respectively], without effect on the tracheal white blood cell count. Conclusion. Dexamethasone does not cause an impaired decline of tracheal RSV but lowers IL-8 of children mechanically ventilated for RSV lower respiratory tract infection, potentially leading to less inflammation and reduced phagocyte activation.

Early increased levels of matrix metalloproteinase-9 in neonates recovering from respiratory distress syndrome.

Aim: Matrix metalloproteinases (MMPs) play an eminent role in airway injury and remodelling. We explored the hypothesis that pulmonary MMP levels would differ early after birth (2–4 days) between infants with resolving respiratory distress syndrome (RDS) and infants developing chronic lung disease of prematurity (CLD). Methods: Thirty-two prematurely born infants (gestational age ≤30 weeks) diagnosed with RDS were included. In 13 infants RDS resolved while 19 developed CLD. MMP-2 and MMP-9 in bronchoalveolar lavage (BAL) fluids collected on postnatal days 2, 4, 7 and 10 were analyzed by zymography and densitometry. Immunochemistry was performed on BAL cells and lung tissue to identify cellular sources of MMP-9 in RDS and CLD. Results: Median MMP-9 levels increased significantly on day 2 in BAL fluid from patients with resolving RDS (median values MMP-9 = 42.0 arbitrary units (AU)) compared to CLD patients (MMP-9 = 5.4 AU). MMP-9 and neutrophil lipocalin-associated MMP-9 (NGAL) were significantly higher on day 4 in BAL fluid from resolving RDS (MMP-9 = 65.8 AU; NGAL = 16.1 AU) compared to CLD (MMP-9 = 25.4 AU; NGAL = 2.0 AU), Levels of MMP-9 and NGAL increased subsequently on days 7 and 10 in CLD. No differences in MMP-2 levels were detected between RDS and CLD. Neutrophils, macrophages and alveolar type-II epithelial cells were identified as potential sources of MMP-9. Conclusion: Our findings indicate differences in early MMP-9 BAL fluid levels between resolving RDS and developing CLD, which may relate to the ability to raise an early and adequate response to the initial injury.

Exhaled breath profiles in the monitoring of loss of control and clinical recovery in asthma

Asthma is a chronic inflammatory airway disease, associated with episodes of exacerbations. Therapy with inhaled corticosteroids (ICS) targets airway inflammation, which aims to maintain and restore asthma control. Clinical features are only modestly associated with airways inflammation. Therefore, we hypothesized that exhaled volatile metabolites identify longitudinal changes between clinically stable episodes and loss of asthma control.

Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome

Objective: Angiotensin-converting enzyme and its effector peptide angiotensin II have been implicated in the pathogenesis of acute respiratory distress syndrome. Recently, angiotensin-converting enzyme 2 was identified as the counter-regulatory enzyme of angiotensin-converting enzyme that converts angiotensin II into angiotensin-(1-7). The aim of this study was to determine pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in patients with acute respiratory distress syndrome. Design: Prospective observational pilot study. Setting: A PICU of a university hospital. Patients: Fourteen patients admitted, requiring mechanical ventilation for respiratory syncytial virus lower respiratory tract infection. Interventions: None. Measurements and Main Results: Two groups of patients were distinguished at admission: a group fulfilling the criteria for acute respiratory distress syndrome and a non–acute respiratory distress syndrome group. Angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity were measured in bronchoalveolar lavage fluid. Patients with acute respiratory distress syndrome had increased angiotensin-converting enzyme activity and decreased angiotensin-converting enzyme 2 activity (p < 0.001) compared with the control group. Conclusion: It is shown for the first time that in acute respiratory distress syndrome, enhanced angiotensin-converting enzyme activity is paralleled by a reduced angiotensin-converting enzyme 2 activity, similar to that found in an experimental rat model of acute respiratory distress syndrome. The reduced angiotensin-converting enzyme 2 activity may be counteracted by restoring angiotensin-(1-7) level, thereby offering a novel treatment modality for this syndrome.

An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5-responsive mouse model

Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics.

IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive anti-viral immunity

Background Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL‐33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive. Objective We hypothesized that IL‐33 is necessary to drive asthma exacerbations. We intervened with the IL‐33 cascade and sought to dissect its role, also in synergy with thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral activity, and lung function. We aimed to unveil the major source of IL‐33 in the airways and IL‐33–dependent mechanisms that underlie severe asthma exacerbations. Methods Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL‐33 receptor ST2, anti–TSLP, or both. Results We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL‐33 during virus‐driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL‐33 and not TSLP was necessary to drive exacerbations. IL‐33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN‐&bgr; expression and prevent the TH1‐promoting dendritic cell phenotype. IL‐33 also boosted luminal NETosis and halted cytolytic antiviral activities but did not affect the TH2 response. Conclusion Interventions targeting the IL‐33/ST2 axis could prove an effective acute short‐term therapy for virus‐induced asthma exacerbations. Graphical abstract Figure. No Caption available.

Su1252 Gastric Juice Composition and Acid Suppression in Pediatric Gastroesophageal Reflux Disease

INTRODUCTION: Gastric acid suppression is justified to prevent severe gastro esophageal reflux (GER) disease related complications. However, it does not reduce the total amount and proximal extent of GER in the esophagus and non-acid components are able to induce (extra-esophageal) GER symptoms as well. No data on the composition of gastric juice (GJ) in children using gastric acid suppression exists. We therefore aimed to assess whether the composition of gastric juice in children using proton pump inhibitors (PPIs) differs, compared to that of their controls. METHODS: Infants and children (0-18 years) on proton pump inhibitors (PPIs) for at least six weeks and a control group not using anti reflux medication, were included. GJ was obtained through an existing nasogastric or a percutaneous endoscopic gastrostomy tube/ Mic-key gastrostomy. In the collected GJ (5 ml), pH, pepsin activity, bile salts and endotoxin (LPS) levels were determined. Pepsin was measured using a fluorometric assay using 4-Methyl-Coumaryl-7-Amide (MCA) substrate with/without pepstatin. Concentrations of deconjugated and taurine/glycine-conjugated bile salts were assessed by reversephase HPLC. Levels of LPS were determined using the spectrophotometric Limulus Amebocyte Lysate assay. RESULTS: GJ was analyzed from 16 children with (median: 3.8 yrs, range: 17.6 years) and 16 children (4.0 yrs, range: 16.0) without PPI therapy. Median duration of PPI treatment was 24 weeks (range: 514 weeks). Gastric pH was 5.0 (range: 5.0) and 1.0 (range: 4.5) in the PPI and control group respectively (p <0.001). Pepsin, unconjugated bile salts, and endotoxin were not significantly different in the two groups. Total taurine conjugated bile salts, and specifically taurocholate, was significantly higher in the PPI group (p=0.01 and p=0.005). pH and concentration of deconjugated bile and conjugated bile salts were significantly associated (p=0.006 and p=0.02). Endotoxin and bile salts were not significantly associated. CONCLUSION: Taurine conjugated bile acids are significantly higher in children chronically using PPIs compared to controls. Moreover acidity of gastric pH correlated negatively with deconjugated and conjugated bile salts. These findings imply that GJ under chronic proton pump inhibition contains nonacid components potentially harmful to esophageal mucosa and bronchial tissue.