The Contribution of Neutrophils to the Pathogenesis of RSV Bronchiolitis.
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ABSTRACT:
SUBMITTER: Sebina I
PROVIDER: S-EPMC7472258 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
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The Contribution of Neutrophils to the Pathogenesis of RSV Bronchiolitis.
Sebina Ismail I Phipps Simon S
Viruses 20200727 8
Acute viral bronchiolitis causes significant mortality in the developing world, is the number one cause of infant hospitalisation in the developed world, and is associated with the later development of chronic lung diseases such as asthma. A vaccine against respiratory syncytial virus (RSV), the leading cause of viral bronchiolitis in infancy, remains elusive, and hence new therapeutic modalities are needed to limit disease severity. However, much remains unknown about the underlying pathogenic ...[more]
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Project description:The trends in hospitalization rates and risk factors for severe bronchiolitis have not been recently described, especially after the routine implementation of prophylaxis for respiratory syncytial virus (RSV) infections.To define the burden of hospitalizations related to RSV and non-RSV bronchiolitis in a tertiary-care children's hospital from 2002 to 2007 and to identify the risk factors associated with severe disease.Medical records of patients hospitalized for bronchiolitis were reviewed for demographic, clinical, microbiologic, and radiologic characteristics as well as the presence of underlying medical conditions. Differences were evaluated between children with RSV and non-RSV bronchiolitis, and multivariable logistic regression analyses were performed to identify independent risk factors for severe disease.Bronchiolitis hospitalizations in children younger than 2 years old (n = 4800) significantly increased from 536 (3.3%) in 2002 to 1241 (5.5%) in 2007, mainly because of RSV infections. Patients with RSV bronchiolitis (n = 2840 [66%]) were younger at hospitalization and had a lower percentage of underlying medical conditions than children hospitalized with non-RSV bronchiolitis (27 vs 37.5%; P < .001). However, disease severity defined by length of hospitalization and requirement of supplemental oxygen, intensive care, and mechanical ventilation was significantly worse in children with RSV bronchiolitis. RSV infection and prematurity, regardless of the etiology, were identified as independent risk factors for severe bronchiolitis.There was a significant increase in hospitalizations for RSV bronchiolitis from 2002 to 2007. A majority of the children with RSV bronchiolitis were previously healthy, but their disease severity was worse compared with those hospitalized with non-RSV bronchiolitis.
| S-EPMC3761792 | biostudies-literature
Project description:AimWe sought to determine the proportion of bronchiolitis episodes attributable to respiratory syncytial virus (RSV) among ICD-9 coded infant bronchiolitis episodes which were tested for RSV.MethodsBronchiolitis healthcare encounters were extracted from Kaiser Permanente Northern California databases for years 2006 to 2009. We used ICD-9 codes for bronchiolitis to capture bronchiolitis-related healthcare encounters including hospital admissions (Hospitalization), emergency department visits (EDV), and outpatient visits (OPV). We reported the monthly proportion of RSV-positive bronchiolitis episodes among tested bronchiolitis episodes. We used logistic regression to assess association between bronchiolitis episodes and patient demographic and health care characteristics. We also used logistic regression to assess association between decision to test and patient demographics and health care characteristics.ResultsAmong 10,411 ICD-9 coded infant bronchiolitis episodes, 29% were RSV tested. Fifty one percent of those tested were RSV positive. Between December and February, and in infants ?6 months, the proportion of bronchiolitis episodes that were attributable to RSV was 77.2% among hospitalized episodes, 78.3% among EDV episodes, and 60.9% among OPV episodes, respectively. The proportion of RSV-positive bronchiolitis episodes varied based upon infant age at diagnosis, level of health care service used, and time of the year of the episode.ConclusionEstimation of the proportion of ICD-9 coded bronchiolitis episodes attributable to RSV is more specific when restricting to bronchiolitis episodes during peak months, younger infant age, and those requiring higher level of healthcare.
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Project description:While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-? ratio in respiratory secretions. The IL-4/IFN-? ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-? ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.
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Project description:Between 75 000 and 125 000 U.S. infants are hospitalized for respiratory syncytial virus (RSV) bronchiolitis every year. Up to half will be diagnosed with asthma in later childhood. Vitamin D deficiency has been associated with susceptibility to asthma and respiratory infections. Measured vitamin D is largely bound to vitamin D-binding protein (VDBP); VDBP levels are influenced by its gene (GC) haplotype.We assessed the relationship between polymorphisms rs7041 and rs4588, which define haplotypes GC1s, GC1f, and GC2, and RSV bronchiolitis susceptibility and subsequent asthma.We retrospectively recruited 198 otherwise healthy children (93% White) hospitalized for severe RSV bronchiolitis in Boston and 333 parents into a follow-up study to assess asthma diagnosis. Data were analysed using family-based genetic association tests. We independently validated our results in 465 White children hospitalized with RSV bronchiolitis and 930 White population controls from the Netherlands.The rs7041_C allele (denoting haplotype GC1s) was overtransmitted (P = 0.02, additive model) in the entire Boston cohort, in Whites (P = 0.03), and especially in children subsequently diagnosed with asthma (P = 0.006). The GC1f haplotype was undertransmitted in the asthma subgroups (all races and White, both P < 0.05). The rs7041_C allele was also more frequent in the RSV bronchiolitis group compared with controls (OR 1.12, 95% CI 1.02, 1.4, P = 0.03) in the Netherlands, especially in mechanically ventilated patients (P = 0.009).GC1s haplotype carriage may increase the risk of RSV bronchiolitis in infancy and subsequent asthma development. The GC1s haplotype is associated with higher VDBP levels, resulting in less freely available vitamin D.Vitamin D-binding protein (VDBP) haplotypes influence free vitamin D levels. We report an association between a VDBP haplotype and hospitalization for RSV bronchiolitis in infancy in two independent cohorts.
| S-EPMC5062603 | biostudies-literature
Project description:BACKGROUND:The pathophysiological basis of severe respiratory syncytial virus (RSV) bronchiolitis in infancy is poorly understood and has hindered vaccine development. Studies implicate the cell-mediated immune response in the pathogenesis of the disease. A recent twin study estimated a heritable contribution of 22% to RSV bronchiolitis. Genetic epidemiology provides a new approach to identifying important immune determinants of disease severity. METHODS:A comprehensive high-density gene-region association study for severe RSV bronchiolitis in infancy at 5q31 across 11 genes including the Th2-cytokine cluster was performed. A haplotype tagging approach was used to analyse genetic variation at 113 single nucleotide polymorphisms (SNPs) in 780 independent cases and 1045 controls. The study had sufficient power to detect small effects, perform extensive haplotype analysis and analyse both a principal phenotype and a refined age-limited phenotype enriched for first-exposure RSV infection. RESULTS:SNP associations were found at IL4 and a highly significant risk haplotype was identified across IL13 CNS-1 and IL4 (odds ratio 1.69, p<0.0001), present in both case-control and family-based analyses. All associations were strongest for a phenotype limited to <6 months of age, implicating this locus in primary RSV disease. The same risk haplotype has previously been shown to be associated with increased IL13 expression. CONCLUSIONS:A haplotype at IL13-1L4, which is associated with increased IL13 production, confers an increased risk of severe primary RSV bronchiolitis in early infancy. This study, together with previous studies implicating the same locus in atopic sensitisation, suggests that primary RSV bronchiolitis and atopy share a genetic contribution at the IL13-IL4 locus.
| S-EPMC3015100 | biostudies-literature
Project description:BackgroundWe sought to identify predictors of asthma development following severe early childhood RSV bronchiolitis. Different definitions of asthma were also compared.MethodsThis longitudinal, observational study (N = 343) followed patients (<2 years old) from a placebo-controlled trial (N = 979) of montelukast after RSV bronchiolitis to identify clinical, demographic, or biochemical predictors of asthma, atopic disorders, and chronic asthma therapy use at 6 years of age (Clinical Trials Registry Number: NCT01140048). Asthma (primary definition) was based on parental identification of wheeze at 6 AND 12 months before 6 years of age; definitions based on physician diagnosis as well as parental identification of wheeze at 6 OR 12 months (to consider seasonal effect) were also assessed. Post-hoc analyses evaluated agreement among asthma diagnosis criteria.ResultsPrevalence of asthma (primary definition by parental identification), asthma (physician diagnosis), atopic disorders, and chronic asthma therapy use (parental identification) was 6.1%, 22.4%, 36.2%, and 14.5%, respectively. Predictors for asthma (primary definition) included male gender, a relative with asthma, and RAST positive for dog dander; for physician diagnosis of asthma, high severity score for RSV bronchiolitis, high respiratory rate, and asthma diagnosis before enrollment. Predictors of atopic disorders included allergic rhinitis before enrollment, a relative with asthma, and the plasma biomarkers IL-5, IL-16, and IL-18. Predictors of chronic asthma therapy use included asthma diagnosis before enrollment and geographic region (Europe and Africa). Only 42% of patients with asthma (primary definition) also met the asthma definition by physician diagnosis and chronic asthma therapy use.ConclusionAmong children with early RSV bronchiolitis, hereditary factors (i.e., having a relative with asthma) and RSV bronchiolitis severity were predictors of asthma and atopic disorders at 6 years of age. Of interest, there was poor agreement among the asthma definitions evaluated. Pediatr Pulmonol. 2016;51:1382-1392. © 2016 Wiley Periodicals, Inc.
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Project description:Bronchiolitis associated with the respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants aged < 1 year. The main objective of this work was to assess the nasal and fecal microbiota and immune profiles in infants with RSV bronchiolitis, and to compare them with those of healthy infants. For this purpose, a total of 58 infants with RSV-positive bronchiolitis and 17 healthy infants (aged < 18 months) were recruited in this case-control study, which was approved by the Ethics Committee of the Hospital Gregorio Marañón. Nasal and fecal samples were obtained and submitted to bacterial microbiota analysis by 16S rDNA sequencing and to analysis of several immune factors related to inflammatory processes. Nasal samples in which Haemophilus and/or Moraxella accounted for > 20% of the total sequences were exclusively detected among infants of the bronchiolitis group. In this group, the relative abundances of Staphylococcus and Corynebacterium were significantly lower than in nasal samples from the control group while the opposite was observed for those of Haemophilus and Mannheimia. Fecal bacterial microbiota of infants with bronchiolitis was similar to that of healthy infants. Significant differences were obtained between bronchiolitis and control groups for both the frequency of detection and concentration of BAFF/TNFSF13B and sTNF.R1 in nasal samples. The concentration of BAFF/TNFSF13B was also significantly higher in fecal samples from the bronchiolitis group. In conclusion, signatures of RSV-associated bronchiolitis have been found in this study, including dominance of Haemophilus and a high concentration of BAFF/TNFSF13B, IL-8 and sTNF.R1 in nasal samples, and a high fecal concentration of BAFF/TNFSF13B.
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Project description:Respiratory syncytial virus (RSV) infection is associated with oxidative lung injury, decreased levels of antioxidant enzymes (AOEs), and the degradation of the transcription factor NF-E2-related factor 2 (NRF2), a master regulator of AOE expression. Single nucleotide polymorphisms (SNPs) in AOE and NRF2 genes have been associated with various lung disorders. To test whether specific NRF2 and/or AOE gene SNPs in children with RSV lower respiratory tract infection were associated with disease severity, one hundred and forty one children <24 month of age with bronchiolitis were assessed for seven AOE and two NRF2 SNPs, and data were correlated with disease severity, which was determined by need of oxygen supplementation and intensive care support. One SNP in the promoter region of the catalase gene, rs1001179, which is associated with higher enzyme expression, was significantly underrepresented (p = 0.01, OR 0.38) among patients with moderate to severe RSV bronchiolitis, suggesting a protective effect against disease severity. Our results suggest that increasing catalase expression/activity could exert a protective role in the context of RSV infection and represent a potential novel therapeutic target to ameliorate viral-induced lung disease.
| S-EPMC7019864 | biostudies-literature
Project description:BackgroundAlthough rhinovirus infection is associated with increased risks of acute and chronic respiratory outcomes during childhood compared with respiratory syncytial virus (RSV), the underlying mechanisms remain unclear. We aimed to determine the differences in nasal airway microRNA profiles and their downstream effects between infants with rhinovirus and RSV bronchiolitis.MethodsAs part of a multicenter cohort study of infants hospitalized for bronchiolitis, we examined nasal samples obtained from 16 infants with rhinovirus and 16 infants with RSV. We tested nasal airway samples using microarrays to profile global microRNA expression and determine the predicted regulation of targeted transcripts. We also measured gene expression and cytokines for NF?B pathway components.ResultsBetween the virus groups, 386 microRNAs were differentially expressed (false discovery rate (FDR)<0.05). In infants with rhinovirus, the NF?B pathway was highly ranked as a predicted target for these differentially expressed microRNAs compared with RSV. Pathway analysis using measured mRNA expression data validated that rhinovirus infection had upregulation of NF?B family (RelA and NF?B2) and downregulation of inhibitor ?B family. Infants with rhinovirus had higher levels of NF?B-induced type-2 cytokines (IL-10 and IL-13; FDR<0.01).ConclusionIn infants with bronchiolitis, rhinovirus and RSV infections had different nasal airway microRNA profiles associated with NF?B signaling.
| S-EPMC6174252 | biostudies-literature
Project description:AimWe evaluated the use of computerized quantification of wheezing and crackles compared to a clinical score in assessing the effect of inhaled albuterol or inhaled epinephrine in infants with RSV bronchiolitis.MethodsComputerized lung sounds analysis with quantification of wheezing and crackles and a clinical score were used during a double blind, randomized, controlled nebulized treatment pilot study. Infants were randomized to receive a single dose of 1 mgr nebulized l-epinephrine or 2.5 mgr nebulized albuterol. Computerized quantification of wheezing and crackles (PulmoTrack) and a clinical score were performed prior to, 10 minutes post and 30 minutes post treatment. Results were analyzed with Student's t-test for independent samples, Mann-Whitney U test and Wilcoxon test.Results15 children received albuterol, 12 received epinephrine. The groups were identical at baseline. Satisfactory lung sounds recording and analysis was achieved in all subjects. There was no significant change in objective quantification of wheezes and crackles or in the total clinical scores either within the groups or between the groups. There was also no difference in oxygen saturation and respiratory distress.ConclusionComputerized lung sound analysis is feasible in young infants with RSV bronchiolitis and provides a non-invasive, quantitative measure of wheezing and crackles in these infants.
| S-EPMC1896161 | biostudies-literature