The role of Th17 and Treg responses in the pathogenesis of RSV infection.

The respiratory syncytial virus (RSV) represents the leading cause of viral bronchiolitis and pneumonia in children worldwide and is associated with high morbidity, hospitalization rate, and significant mortality rates. The immune response elicited by RSV is one of the main factors contributing to the pathogenesis of the disease. Two subsets of the cellular immune response, the T helper 17 cell (Th17) and the regulatory T-cell (Treg), and more particularly the balance between these two subsets, might play a significant role in the pathogenesis of the RSV infection. The developmental pathways of Th17 and Treg cells are closely and reciprocally interconnected and plasticity has been demonstrated from Treg toward Th17. During an RSV infection, the functions of both subsets are opposed to one another regarding viral clearance and clinical severity. Th17 and Treg cells offer a promising new view on the pathogenesis of an RSV infection and deserve further exploration.

Risk Factors Associated with Severe RSV Infection in Infants: What Is the Role of Viral Co-Infections?

The respiratory syncytial virus (RSV) represents the leading cause of viral lower respiratory tract infections (LRTI) in children worldwide and is associated with significant morbidity and mortality rates. The clinical picture of an RSV infection differs substantially between patients, and the role of viral co-infections is poorly investigated. During two consecutive winter seasons from October 2018 until February 2020, we prospectively included children up to 2 years old presenting with an acute LRTI, both ambulatory and hospitalized. We collected clinical data and tested nasopharyngeal secretions for a panel of 16 different respiratory viruses with multiplex RT-qPCR. Disease severity was assessed with traditional clinical parameters and scoring systems. A total of 120 patients were included, of which 91.7% were RSV positive; 42.5% of RSV-positive patients had a co-infection with at least one other respiratory virus. We found that patients suffering from a single RSV infection had higher pediatric intensive care unit (PICU) admission rates (OR = 5.9, 95% CI = 1.53 to 22.74), longer duration of hospitalization (IRR = 1.25, 95% CI = 1.03 to 1.52), and a higher Bronchiolitis Risk of Admission Score (BRAS) (IRR = 1.31, 95% CI = 1.02 to 1.70) compared to patients with RSV co-infections. No significant difference was found in saturation on admission, O2 need, or ReSViNET-score. In our cohort, patients with a single RSV infection had increased disease severity compared to patients with RSV co-infections. This suggests that the presence of viral co-infections might influence the course of RSV bronchiolitis, but heterogeneity and small sample size in our study prevents us from drawing strong conclusions. IMPORTANCE RSV is worldwide the leading cause of serious airway infections. Up to 90% of children will be infected by the age of 2. RSV symptoms are mostly mild and typically mimic a common cold in older children and adolescents, but younger children can develop severe lower respiratory tract disease, and currently it is unclear why certain children develop severe disease while others do not. In this study, we found that children with a single RSV infection had a higher disease severity compared to patients with viral co-infections, suggesting that the presence of a viral co-infection could influence the course of an RSV bronchiolitis. As preventive and therapeutic options for RSV-associated disease are currently limited, this finding could potentially guide physicians to decide which patients might benefit from current or future treatment options early in the course of disease, and therefore, warrants further investigation.

Red cell distribution width (RDW) as a biomarker for respiratory failure in a pediatric ICU.

BACKGROUND: The red cell distribution width (RDW) is a widely available, inexpensive, and highly reproducible test that reflects the range of the red cell sizes. Any process that releases reticulocytes in the circulation will result in an increase in RDW. Elevated RDW values are linked to worsened pulmonary function in the adult population. We performed a retrospective cohort study to describe the association between RDW and respiratory failure in critically ill children in a in a pediatric intensive care unit (PICU) in a tertiary university hospital. SUBJECTS: All patients admitted between January 2009 and June 2015 were considered eligible for inclusion. METHODS: Retrospective cohort study. RESULTS: In total, 960 patients were included in the cohort analysis. Of those patients, 149 (15.5%) had elevated RDW values. RDW on admission was associated with lower 28 day ventilator-free days. The highest quintile of RDW was associated with the need for mechanical ventilation, even when correcting for anaemia, age and Pediatric Risk of Mortality (PRISM) scores. In the subgroup of ventilated patients, RDW was associated with nadir PaO2/FiO2(P/F) ratios. CONCLUSION: The RDW value on admission of our PICU patients is associated with a greater need for invasive mechanical ventilation, lower 28 day ventilator-free days and lower nadir P/F ratios in the patients with highest RDW values on admission. RDW may be a valuable, cheap and universally available, prognostic parameter for respiratory dysfunction in the PICU.

Increased levels of tumor necrosis factor-alpha and decreased levels of interleukin-12 p 70 in tracheal aspirates, within 2 hrs after birth, are associated with mortality among ventilated preterm infants.

OBJECTIVE: To determine the association of antibacterial interleukin (IL)-12 p 70 levels as well as the pathogen-induced proinflammatory cytokine response in tracheal aspirate (TA) to respiratory failure and mortality among ventilated preterm infants. DESIGN: A prospective observational clinical cohort study with measurements of cytokine levels and microbial cultures of TA from ventilated preterm neonates. Interleukin (IL)-1 beta, IL-8, IL-6, IL-10, IL-12 p 70, and tumor necrosis factor (TNF)-alpha were measured in TA within 2 hrs of birth, and comorbidity characteristics were recorded prospectively. The association between cytokine levels in TA and neonatal mortality was determined, with correction for comorbidity factors by means of multivariate stepwise logistic regression. SETTING: A single tertiary neonatal intensive care unit at the University Hospital of Antwerp, Belgium. PATIENTS: One hundred forty-one neonates born before a gestational age of 31 wks and who required ventilation were enrolled in the study; 31 (22%) died and 37 (26%) had airway colonization. MEASUREMENTS AND MAIN RESULTS: The airway colonization rate was significantly greater among deceased neonates (45% vs. 21%; chi-square, 7.4; p=.007). Neonates who died had a significantly lower IL-12 p 70 cytokine level (6 pg/mL vs. 11 pg/mL; p<.05) in their TA. Neonates with a low IL-12 p 70 cytokine level had more pronounced respiratory failure (significantly higher oxygenation index, higher degree of radiologic respiratory distress syndrome, higher critical index for babies score, and more surfactant use). Multivariate analysis revealed that, after correction for severity of disease by critical index for babies score, the degree of intraventricular hemorrhage (odds ratio, 5.0 [95% confidence interval, 2.6-9.7]), low IL-12 p 70 levels (odds ratio, 4.9 [95% confidence interval, 2.1-11.7]), and high TNF-alpha levels in TA (odds ratio, 3.5 [95% confidence interval, 1.6-7.5]) were significantly associated with neonatal mortality. CONCLUSIONS: Pathogen-induced excessive production of the proinflammatory cytokine TNF-alpha and lack of antibacterial IL-12 p 70 response in the TA are associated with increased neonatal mortality among ventilated preterm infants.

Decreasing incidence of neonatal nosocomial bloodstream infections in a neonatal intensive care unit: antenatal corticosteroid treatment an innocent bystander?

UNLABELLED: We studied the effect of the use of antenatal steroid treatment on the incidence of nosocomial bloodstream infections (NBSI). All episodes of culture proven NBSI occurring after 96 h of hospitalisation were identified retrospectively during a 10-year period (1991-2001). Throughout the study period, the use of antenatal steroids, demographic characteristics and morbidity of the patients were recorded prospectively. Since 1996 more efforts were made to use antenatal steroids to decrease neonatal morbidity and mortality. The incidence rates of NBSI were compared between period 1 (1991-1995) and period 2 (1996-2001). The overall incidence rate of NBSI dropped significantly from 7.4% (6.1%-8.9%) in period 1 to 5.0% (4.0%-6.2%) in period 2 and was most pronounced in the birth weight category 1000 g-1500 g (11.7%, 7.9%-15.0% to 6.9%, 4.3%-10.5%) and 1500 g-2500 g (3.6%, 2.2%-5.6% to 1.4%, 0.6%-2.8%). Antenatal use of steroids increased overall from 19% in 1991 to 51% in 2001 ( P<0.001). Since 1996 there was a decreasing number of ventilation days ( P=0.011) and decreasing incidence of patent ductus arteriosus ( P=0.001), while the incidence of neonatal surgery, chronic lung disease and duration of hospitalisation remained constant over time. CONCLUSION: increased use of antenatal steroids is associated with a decreasing incidence rate of nosocomial bloodstream infections in neonates with birth weights between 1000 g and 2500 g, probably by decreasing the incidence of patent ductus arteriosus and/or due to improved respiratory outcome. This finding needs to be confirmed by randomised control trials or by a large prospective cohort study in similar population groups.

Internal and external validation of the NOSEP prediction score for nosocomial sepsis in neonates.

OBJECTIVE: To evaluate the performance of a scoring system (NOSEP) to predict nosocomial sepsis in neonates at the hospital where the score was developed (internal validation) and in an independent data set from other centers (external validation). DESIGN: Multiple center prospective cohort study. SETTING: Six neonatal intensive care units from the Flanders in Belgium. PATIENTS: We analyzed two groups of patients: 62 episodes of presumed nosocomial sepsis in the internal validation cohort and 93 episodes of presumed nosocomial sepsis in a multiple center external validation cohort. INTERVENTIONS: Assessment of the predictive power of the NOSEP score 24 hrs preceding sepsis workup and the patients' basic demographic characteristics and co-morbidity was performed. Diagnosis of nosocomial sepsis and the microbiology results were registered. MAIN RESULTS: The NOSEP score's discriminative capability was very good in the internal validation (area under receiver operating characteristic curve = 0.73 +/- 0.08 [sem]). The NOSEP score performed satisfactory in the external validation (area under receiver operating characteristic curve = 0.66 +/- 0.06). The calibration capability in both validation sets as measured by goodness-of-fit tests (internal validation, p =.56; external validation, p =.48) was good. An improvement of the NOSEP score was obtained for the external centers by redefining the cut-off of the items of the NOSEP score (area under receiver operating characteristic curve for NOSEP-NEW-I = 0.71 +/- 0.05) or adding co-morbidity factors (area under receiver operating characteristic curve for NOSEP-NEW-II = 0.82 +/- 0.04), with good calibration performance (goodness-of-fit test, p >.50). Finally, the fit of the NOSEP score demonstrated no significant variation across subgroups of patients. CONCLUSIONS: The predictive power of the original NOSEP score is very good in neonates at the original neonatal intensive care unit. In other neonatal intensive care units, its discriminatory performance is satisfactory but could be improved after modification of the variables in the model or adding additional variables. To use such a NOSEP score in other neonatal intensive care units, its accuracy has to be validated and adjusted if necessary.