IL1RL1 Gene Variants and Nasopharyngeal IL1RL-a Levels Are Associated with Severe RSV Bronchiolitis: A Multicenter Cohort Study

Targets for intervention are required for respiratory syncytial virus (RSV) bronchiolitis, a common disease during infancy for which no effective treatment exists. Clinical and genetic studies indicate that IL1RL1 plays an important role in the development and exacerbations of asthma. Human IL1RL1 encodes three isoforms, including soluble IL1RL1-a, that can influence IL33 signalling by modifying inflammatory responses to epithelial damage. We hypothesized that IL1RL1 gene variants and soluble IL1RL1-a are associated with severe RSV bronchiolitis.We studied the association between RSV and 3 selected IL1RL1 single-nucleotide polymorphisms rs1921622, rs11685480 or rs1420101 in 81 ventilated and 384 non-ventilated children under 1 year of age hospitalized with primary RSV bronchiolitis in comparison to 930 healthy controls. Severe RSV infection was defined by need for mechanical ventilation. Furthermore, we examined soluble IL1RL1-a concentration in nasopharyngeal aspirates from children hospitalized with primary RSV bronchiolitis. An association between SNP rs1921622 and disease severity was found at the allele and genotype level (p = 0.011 and p = 0.040, respectively). In hospitalized non-ventilated patients, RSV bronchiolitis was not associated with IL1RL1 genotypes. Median concentrations of soluble IL1RL1-a in nasopharyngeal aspirates were >20-fold higher in ventilated infants when compared to non-ventilated infants with RSV (median [and quartiles] 9,357 [936-15,528] pg/ml vs. 405 [112-1,193] pg/ml respectively; p<0.001).We found a genetic link between rs1921622 IL1RL1 polymorphism and disease severity in RSV bronchiolitis. The potential biological role of IL1RL1 in the pathogenesis of severe RSV bronchiolitis was further supported by high local concentrations of IL1RL1 in children with most severe disease. We speculate that IL1RL1a modifies epithelial damage mediated inflammatory responses during RSV bronchiolitis and thus may serve as a novel target for intervention to control disease severity

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Aspecific complaints of a gastrostomy feeding tube caused by Group A Streptococcus.

A seven-year old girl with a gastrostomy feeding tube presented with aspecific symptoms such as discomfort and a foul smell. No cause could be found but a culture revealed Group A Streptococcus. These were eradicated by antibiotic treatment and the symptoms resolved immediately. In patients with a gastrostomy feeding tube presenting with aspecific complaints for which a cause can not be found, a culture for Group A Streptococcus should be obtained

Computerized Assessment of Wheezing in Children With Respiratory Syncytial Virus Bronchiolitis Before and After Hypertonic Saline Nebulization

BACKGROUND: Studies suggest an effect of nebulized hypertonic saline solution on air-flow limitation in subjects with respiratory syncytial virus (RSV) bronchiolitis, but results are based on subjective scores of clinical severity and are not clear. In this observational study, we used a noninvasive computerized tool to quantify wheezing before and after nebulization with hypertonic saline in children admitted for RSV infection. METHODS: Twenty-seven children (≤ 24 months old) admitted to the pediatric ward of the Medical Center Leeuwarden with polymerase chain reaction-confirmed RSV bronchiolitis were included. Subjects were simultaneously assessed both clinically and by computerized acoustic monitoring before and 15 min after treatment with nebulized hypertonic saline solution. RESULTS: Clinical assessment, defined by the Respiratory Distress Assessment Instrument score, did not change after nebulization (n = 27, 5.0 vs 4.7, P = .17). Computerized acoustic monitoring showed no improvement in wheezing (n = 27, 3.4% vs 2.0%, P = .05) or inspiration/expiration ratio (0.85 vs 0.85, P = .93) after nebulization. CONCLUSIONS: Hypertonic saline nebulization does not improve air flow, as assessed by both clinical and computerized acoustic scores, in children admitted for RSV

Dynamics of Nasopharyngeal Pneumococcal Carriage During the Course of Viral Bronchiolitis

The effect of viral infection on nasopharyngeal carriage of Streptococcus pneumoniae during childhood is not well known. We studied dynamics of pneumococcal colonization by quantitative PCR during the natural course of viral bronchiolitis. At time of admission, 47 (47%) of 100 patients with bronchiolitis carried pneumococci. In patients with viral bronchiolitis who did not receive antibiotics, pneumococcal load decreased from time of admission to discharge (n = 35, cycle threshold 23 vs. 25, P = 0.0017) and from discharge to follow-up (n = 22, cycle threshold 25 vs. 40, P = 0.003). We conclude that viral respiratory infection is negatively associated with pneumococcal colonization of the upper airways. Pediatr Pulmonol. 2016;51:863–867