Severe Respiratory Syncytial Virus Bronchiolitis Research Articles

Respiratory syncytial virus subtypes in children with bronchiolitis: does it correlate with clinical severity?

BackgroundIn this retrospective study, we aimed to evaluate the factors associated with the severity of respiratory syncytial virus (RSV) bronchiolitis in children aged under 2 years who were admitted to the Children’s Hospital of Hebei between June 2018 and January 2019.MethodsSputum samples positive for RSV via multiplex PCR were subtyped using real-time PCR. Data collected included risk factors for disease severity, demographics, microbiology, and outcomes.ResultsOf the 82 children with RSV bronchiolitis, 79 were treated and discharged with improvement, while 3 died. All three patients had underlying medical conditions, including complex congenital heart disease and severe combined immunodeficiency. Further, disease severity was associated with preexisting underlying disease, fever duration, and bacterial co-infection, but not with the RSV subtype.ConclusionsOur findings suggest that an appropriate therapeutic regimen should include the detection of bacterial co-infections and the identification of underlying diseases for the effective management of severe RSV bronchiolitis.

Necrotizing Enterocolitis Complicating Severe RSV Bronchiolitis in PICU Settings.

This retrospective study aims to analyze the baseline characteristics and factors associated with poor outcomes in patients with necrotizing enterocolitis (NEC) complicating respiratory syncytial virus (RSV) infection. Using the Virtual Pediatric Systems data registry, patients under 2 years admitted to the pediatric intensive care unit (PICU) were screened. Patients with documented RSV infection and NEC, intestinal perforation, noninfectious gastroenteritis/colitis, or pneumatosis intestinalis occurring around the timing of RSV bronchiolitis diagnosis were included. Out of the screened patients, 41 were analyzed. Most patients (93%) were aged 30 days to 2 years, one-third had baseline anatomical cardiac defects, and 20% history of prematurity. Median PICU length of stay was 11.7 days. Seven patients died before hospital discharge. While not statistically significant, nonsurvivors tended to exhibit higher PRISM-3 scores, more acidemia, and lower systolic blood pressure. These findings emphasize the need for cautious assessment of gastrointestinal symptoms in critically ill patients with RSV infection.

Azithromycin therapy in infants hospitalized for respiratory syncytial virus bronchiolitis: Airway matrix metalloproteinase-9 levels and subsequent recurrent wheeze

BackgroundEarly life respiratory syncytial virus (RSV) bronchiolitis is a significant risk factor for childhood asthma. In vitro and in vivo studies suggested that decreasing levels of airway matrix metalloproteinase (MMP)-9 during RSV bronchiolitis may be associated with clinical benefits. ObjectiveTo investigate whether azithromycin therapy during severe RSV bronchiolitis reduces upper airway MMP-9 levels, whether upper airway MMP-9 levels correlate with upper airway interleukin IL-8 levels, and whether MMP-9 level reduction is associated with reduced post-RSV recurrent wheeze (RW). MethodsA total of 200 otherwise healthy 1- to 18-month-old infants hospitalized with RSV bronchiolitis were randomized into a double-blind, placebo-controlled trial of oral azithromycin (10 mg/kg daily for 7 days followed by 5 mg/kg daily for 7 days) or placebo. Infants were followed for 2 to 4 years for the outcome of RW (3 or more wheezing episodes). Nasal lavage samples for MMP-9 levels were obtained at baseline, day 14 (end of the study treatment), and after 6 months. ResultsUpper airway MMP-9 levels were highly correlated with IL-8 levels at all 3 time points: randomization, day 14, and 6 months (r = 0.80; P < .0001 for all time points). MMP-9 levels were similar between treatment groups at randomization, were lower on day 14 among children treated with azithromycin (P = .0085), but no longer different after 6 months. MMP-9 levels at baseline and change from baseline to day 14 were not associated with the development of RW (P = .49, .39, respectively). ConclusionAzithromycin therapy in children hospitalized with RSV bronchiolitis had a short-term anti-inflammatory effect in reducing upper airway MMP-9 levels. However, the reduction in MMP-9 levels did not relate to subsequent RW post-RSV. Trial RegistrationThis study is a secondary analysis of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis-II clinical trial registered at Clinicaltrials.gov (NCT02911935).

Serum bilirubin is associated with a reduced risk of subsequent recurrent wheezing following acute respiratory syncytial virus bronchiolitis.

Bilirubin is a potent antioxidant and anti-inflammatory molecule that has been shown to ameliorate airway inflammation. We aimed to study whether serum bilirubin is protective and can predict the development of subsequent recurrent wheezing in infants with severe respiratory syncytial virus (RSV) bronchiolitis. The medical records of 188 infants who were hospitalized during an initial episode of severe RSV bronchiolitis at 6 months of age or less were retrospectively reviewed. Our main outcome of interest was the development of subsequent recurrent wheezing by the age of 3years. Each infant's serum bilirubin concentration was extracted from their blood biochemical results. Seventy-one (37.8%) infants developed recurrent wheezing by the age of 3 and 117 (62.2%) did not. The serum total bilirubin, unconjugated bilirubin, and conjugated bilirubin levels at hospital admission were lower in infants who developed recurrent wheezing as compared to those who did not (p ＜ 0.001). The area under the receiver-operating characteristic curve of serum total bilirubin, unconjugated bilirubin, and conjugated bilirubin for the prediction of subsequent recurrent wheezing were 0.71 (95% confidence interval [CI], 0.64-0.78), 0.70 (95% CI, 0.63-0.78), and 0.67 (95% CI, 0.59-0.75), respectively. Higher admission serum total bilirubin levels were independently associated with a lower risk of development of subsequent recurrent wheezing (adjusted OR 0.17, p ＜ 0.001). During the first episode of severe RSV bronchiolitis in infants <6 months of age, moderately higher levels of serum bilirubin are associated with a reduced risk of developing subsequent recurrent wheezing by 3 years of age.

Respiratory Syncytial Virus is the Most Common Causative Agent of Viral Bronchiolitis in Young Children: An Updated Review.

Viral bronchiolitis is a common condition and a leading cause of hospitalization in young children. This article provides readers with an update on the evaluation, diagnosis, and treatment of viral bronchiolitis, primarily due to RSV. A PubMed search was conducted in December 2021 in Clinical Queries using the key terms "acute bronchiolitis" OR "respiratory syncytial virus infection". The search included clinical trials, randomized controlled trials, case control studies, cohort studies, meta-analyses, observational studies, clinical guidelines, case reports, case series, and reviews. The search was restricted to children and English literature. The information retrieved from the above search was used in the compilation of this article. Respiratory syncytial virus (RSV) is the most common viral bronchiolitis in young children. Other viruses such as human rhinovirus and coronavirus could be etiological agents. Diagnosis is based on clinical manifestation. Viral testing is useful only for cohort and quarantine purposes. Cochrane evidence-based reviews have been performed on most treatment modalities for RSV and viral bronchiolitis. Treatment for viral bronchiolitis is mainly symptomatic support. Beta-agonists are frequently used despite the lack of evidence that they reduce hospital admissions or length of stay. Nebulized racemic epinephrine, hypertonic saline and corticosteroids are generally not effective. Passive immunoprophylaxis with a monoclonal antibody against RSV, when given intramuscularly and monthly during winter, is effective in preventing severe RSV bronchiolitis in high-risk children who are born prematurely and in children under 2 years with chronic lung disease or hemodynamically significant congenital heart disease. Vaccines for RSV bronchiolitis are being developed. Children with viral bronchiolitis in early life are at increased risk of developing asthma later in childhood. Viral bronchiolitis is common. No current pharmacologic treatment or novel therapy has been proven to improve outcomes compared to supportive treatment. Viral bronchiolitis in early life predisposes asthma development later in childhood.

Hyper‐IgE syndrome presenting with early life craniosynostosis in monozygotic twin sisters

<scp>Hyper‐IgE</scp> syndrome presenting with early life craniosynostosis in monozygotic twin sisters

Expressions of Type I and III Interferons, Endogenous Retroviruses, TRIM28, and SETDB1 in Children with Respiratory Syncytial Virus Bronchiolitis.

Interferons (IFNs) and IFN-stimulated genes (ISGs) play essential roles for the control of viral infections. Their expression in infants with respiratory syncytial virus (RSV) bronchiolitis is poorly defined. Human endogenous retroviruses (HERVs) represent 8% of our genome and modulate inflammatory and immune reactions. TRIM28 and SETDB1 participate in the epigenetic regulation of genes involved in the immune response, including IFNs and HERVs. No study has explored the expression of HERVs, TRIM28, and SETDB1 during RSV bronchiolitis. We assessed, through a PCR real-time Taqman amplification assay, the transcription levels of six IFN-I ISGs, four IFNλs, the pol genes of HERV-H, -K, and -W families, the env genes of Syncytin (SYN)1 and SYN2, and of TRIM28/SETDB1 in whole blood from 37 children hospitalized for severe RSV bronchiolitis and in healthy children (HC). The expression of most IFN-I ISGs was significantly higher in RSV+ patients than in age-matched HC, but it was inhibited by steroid therapy. The mRNA concentrations of IFN-λs were comparable between patients and age-matched HC. This lack of RSV-driven IFN-III activation may result in the defective protection of the airway mucosal surface leading to severe bronchiolitis. The expression of IFN-III showed a positive correlation with age in HC, that could account for the high susceptibility of young children to viral respiratory tract infections. The transcription levels of every HERV gene were significantly lower in RSV+ patients than in HC, while the expressions of TRIM28/SETDB1 were overlapping. Given the negative impact of HERVs and the positive effects of TRIM28/SETDB1 on innate and adaptive immune responses, the downregulation of the former and the normal expression of the latter may contribute to preserving immune functions against infection.

Soluble Signal Inhibitory Receptor on Leukocytes-1 Is Released from Activated Neutrophils by Proteinase 3 Cleavage.

Signal inhibitory receptor on leukocytes-1 (SIRL-1) is an immune inhibitory receptor expressed on human granulocytes and monocytes that dampens antimicrobial functions. We previously showed that sputum neutrophils from infants with severe respiratory syncytial virus (RSV) bronchiolitis have decreased SIRL-1 surface expression compared with blood neutrophils and that SIRL-1 surface expression is rapidly lost from in vitro activated neutrophils. This led us to hypothesize that activated neutrophils lose SIRL-1 by ectodomain shedding. Here, we developed an ELISA and measured the concentration of soluble SIRL-1 (sSIRL-1) in patients with RSV bronchiolitis and hospitalized patients with COVID-19, which are both characterized by neutrophilic inflammation. In line with our hypothesis, sSIRL-1 concentration was increased in sputum compared with plasma of patients with RSV bronchiolitis and in serum of hospitalized patients with COVID-19 compared with control serum. In addition, we show that in vitro activated neutrophils release sSIRL-1 by proteolytic cleavage and that this diminishes the ability to inhibit neutrophilic reactive oxygen species production via SIRL-1. Finally, we found that SIRL-1 shedding is prevented by proteinase 3 inhibition and by extracellular adherence protein from Staphylococcus aureus. Notably, we recently showed that SIRL-1 is activated by PSMα3 from S. aureus, suggesting that S. aureus may counteract SIRL-1 shedding to benefit from preserved inhibitory function of SIRL-1. In conclusion, we report that SIRL-1 is released from activated neutrophils by proteinase 3 cleavage and that endogenous sSIRL-1 protein is present in vivo.

MLKL Regulates Rapid Cell Death-independent HMGB1 Release in RSV Infected Airway Epithelial Cells.

Respiratory syncytial virus (RSV)-induced bronchiolitis is a significant contributor to infant morbidity and mortality. Previously, we identified that necroptosis, a pro-inflammatory form of cell death mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3, and mixed lineage kinase domain like protein (MLKL), occurs in RSV-infected human airway epithelial cells (hAECs), mediating the release of the alarmin high mobility group box 1 (HMGB1). Here, we show that RSV infection of hAECs induces the biphasic release of HMGB1 at 6 (“early”) and 24 (“late”) hours post infection (hpi). The early phase of HMGB1 release at 6 hpi is cell death-independent, however, this release is nonetheless attenuated by inhibition of MLKL (primarily associated with necroptosis). The early release of HMGB1 promotes the late phase of HMGB1 release via the activation of RAGE (receptor for advanced glycation endproducts) and occurs with cell death. Treatment of hAECS with exogenous HMGB1 combined with a pan-caspase inhibitor induces hAEC necroptosis, and is attenuated by the RAGE antagonist, FPS-ZM1. Together, these findings demonstrate that RSV infection of hAECs leads to the early release of HMGB1, followed by a paracrine feed-forward amplification loop that further increases HMGB1 levels and promotes cell death. As the inhibition of MLKL or targeting of HMGB1/RAGE pathway attenuates the release of pro-inflammatory HMGB1 and decreases viral load, this suggests that the pharmacological targeting of these pathways may be of benefit for the treatment of severe RSV bronchiolitis.

TLR4 Gene Polymorphisms Interaction With Ascaris Infection in Severe RSV Bronchiolitis.

IntroductionThe identification of gene-environment interactions allows the recognition of groups with higher risk of morbidity. This study evaluated the interaction between the presence of TLR4 gene polymorphisms and Ascaris infection with severe bronchiolitis in a tropical Colombian region.MethodsWe included all infants younger than 24 months hospitalized due to bronchiolitis in Hospital centers in the county of Rionegro, Colombia. To identify interaction between severe bronchiolitis and presence of TLR4 polymorphisms and Ascaris infection, we used log-binomial regression.ResultsFour hundred and seventeen infants were hospitalized due to bronchiolitis, of which 115 (27%) had severe bronchiolitis. In infants with respiratory syncytial virus (RSV) acute infection and positive anti-Ascaris IgE, TLR4 Asp299Gly was associated to low risk of severe bronchiolitis (OR 0.09, CI 95% 0.01–0.48). Conversely, in infants RSV negative with negative anti-Ascaris IgE, TLR4 Asp299Gly was associated with an increased risk of severe bronchiolitis (OR 14.5, CI 95% 2.2–96).ConclusionIn our population there is an interaction between the presence of severe bronchiolitis, TLR4 Asp299Gly and Ile399Thr polymorphisms, anti-Ascaris IgE levels and RSV. This association should be evaluated in other populations to elucidate its role in the pathogenesis of severe bronchiolitis.

Azithromycin to Prevent Recurrent Wheeze Following Severe Respiratory Syncytial Virus Bronchiolitis

BackgroundEarly-life severe respiratory syncytial virus (RSV) bronchiolitis is a risk factor for childhood asthma. Because azithromycin may attenuate airway inflammation during RSV bronchiolitis, we evaluated whether it would reduce the occurrence of post-RSV recurrent wheeze.MethodsWe prospectively enrolled 200 otherwise healthy 1- to 18-month-old children hospitalized with RSV bronchiolitis in this single-center, double-blind, placebo-controlled study and randomly assigned them to receive oral azithromycin (10 mg/kg daily for 7 days, followed by 5 mg/kg daily for 7 days) or placebo. Randomization was stratified by recent open-label antibiotic use. The primary outcome was the occurrence of recurrent wheeze, defined as a third episode of post-RSV wheeze over the following 2 to 4 years.ResultsAs an indication of the biologic activity of azithromycin, nasal wash interleukin-8 levels, at day 14 after randomization, were lower among azithromycin-treated participants (P<0.01). Despite evidence of biologic activity, azithromycin did not reduce the risk of post-RSV recurrent wheeze (47% in the azithromycin group vs. 36% in the placebo group; adjusted hazard ratio, 1.45; 95% confidence interval [CI], 0.92 to 2.29; P=0.11). Azithromycin also did not modify the risk of recurrent wheeze among participants already receiving other antibiotic treatment at the time of enrollment (hazard ratio, 0.94; 95% CI, 0.43 to 2.07). There was a potential signal among antibiotic-naïve participants who received azithromycin to have an increased risk of recurrent wheeze (hazard ratio, 1.79; 95% CI, 1.03 to 3.1).ConclusionsAzithromycin therapy for 14 days during acute severe RSV bronchiolitis did not reduce recurrent wheeze occurrence over the following 2 to 4 years. Our data suggest no benefit of azithromycin administration with the goal of preventing recurrent wheeze in later life. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02911935.)

Azithromycin to Prevent Recurrent Wheeze Following Severe RSV bronchiolitis: The APW-RSV II Clinical Trial

Early life severe Respiratory Syncytial Virus (RSV) bronchiolitis is a risk factor for childhood asthma. As azithromycin may attenuate airway inflammation during RSV bronchiolitis, we evaluated if it would reduce the occurrence of recurrent wheeze (RW).

Loss of Health Promoting Bacteria in the Gastrointestinal Microbiome of PICU Infants with Bronchiolitis: A Single-Center Feasibility Study.

The feasibility of gastrointestinal (GI) microbiome work in a pediatric intensive care unit (PICU) to determine the GI microbiota composition of infants as compared to control infants from the same hospital was investigated. In a single-site observational study at an urban quaternary care children’s hospital in Western Michigan, subjects less than 6 months of age, admitted to the PICU with severe respiratory syncytial virus (RSV) bronchiolitis, were compared to similarly aged control subjects undergoing procedural sedation in the outpatient department. GI microbiome samples were collected at admission (n = 20) and 72 h (n = 19) or at time of sedation (n = 10). GI bacteria were analyzed by sequencing the V4 region of the 16S rRNA gene. Alpha and beta diversity were calculated. Mechanical ventilation was required for the majority (n = 14) of study patients, and antibiotics were given at baseline (n = 8) and 72 h (n = 9). Control subjects’ bacterial communities contained more Porphyromonas, and Prevotella (p = 0.004) than those of PICU infants. The ratio of Prevotella to Bacteroides was greater in the control than the RSV infants (mean ± SD—1.27 ± 0.85 vs. 0.61 ± 0.75: p = 0.03). Bacterial communities of PICU infants were less diverse than those of controls with a loss of potentially protective populations.

Incidence and risk factors of hospitalisations for respiratory syncytial virus among children aged less than 2 years.

The study aim was to examine the incidence and risk factors of respiratory syncytial virus (RSV) bronchiolitis hospitalisations and disease severity among infants. We compared demographic and health characteristics of children aged 0-23 hospitalised for RSV bronchiolitis (cases, n = 1227) during 2008-2018 and control children (n = 554) of the same age admitted for non-respiratory disease. RSV antigen was detected in nasal swabs by immunochromatography. Multiple logistic regression models were applied. The average annual incidence of hospitalisation for RSV bronchiolitis was 12.6 per 1000 and 1.7 per 1000 (P < 0.001) among infants and toddlers, respectively, with winter seasonality (November-March). The risk of hospitalisation for RSV bronchiolitis increased among children aged 0-5 months (OR 7.66; 95% CI 5.61-10.45) and 6-11 months (OR 12.88, 95% CI 8.48-19.55), compared to those aged 12-23 months. Additional risk factors were living in low vs. higher socio-economic status towns (OR 1.49; 95% CI 1.14-1.95), having chronic medical conditions (OR 2.75; 95% CI 1.61-4.70), birth month (October-January vs. June-September) (OR 2.19; 95% CI 1.60-2.99) and history of stay in neonatal intensive care unit at birth (OR 2.37; 95% CI 1.27-4.41). Male children and those who had pneumonia were more likely to have severe RSV bronchiolitis. In conclusion, the burden of hospitalisations for RSV bronchiolitis is high, especially in young infants. Effective preventive measures such as RSV active vaccines can reduce the risk of hospitalisations for RSV bronchiolitis among these vulnerable groups.

Lower respiratory tract infections in early life are associated with obstructive sleep apnea diagnosis during childhood in a large birth cohort.

Several birth cohorts have defined the pivotal role of early lower respiratory tract infections (LRTI) in the inception of pediatric respiratory conditions. However, the association between early LRTI and the development of obstructive sleep apnea (OSA) in children has not been established. To investigate whether early LRTIs increase the risk of pediatric OSA, we analyzed clinical data in children followed during the first 5 years in the Boston Birth Cohort (n = 3114). Kaplan-Meier survival estimates and Cox proportional hazards models adjusted by pertinent covariates were used to evaluate the risk of OSA by the age of 5 years between children with LRTI during the first 2 years of life in comparison to those without LRTI during this period. Early life LRTI increased the risk of pediatric OSA independently of other pertinent covariates and risk factors (hazard ratio, 1.53; 95% CI, 1.15 to 2.05). Importantly, the association between LRTI and pediatric OSA was limited to LRTIs occurring during the first 2 years of life. Complementarily to this finding, we observed that children who had severe respiratory syncytial virus bronchiolitis during infancy had two times higher odds of OSA at 5 years in comparison with children without this exposure (odds ratio, 2.09; 95% CI, 1.12 to 3.88). Children with severe LRTIs in early life have significantly increased risk of developing OSA during the first 5 years of life. Our results offer a new paradigm for investigating novel mechanisms and interventions targeting the early pathogenesis of OSA in the pediatric population.

Respiratory Syncytial Virus (RSV)-Specific Antibodies in Pregnant Women and Subsequent Risk of RSV Hospitalization in Young Infants.

BackgroundThe fusion (F) glycoprotein of respiratory syncytial virus (RSV) represents the major neutralizing antigen, and antibodies against the pre-F conformation have the most potent neutralizing activity. This study aimed to assess the correlation between maternal antibody titers against the pre-F, post-F, and G glycoproteins and the child’s risk of developing severe RSV bronchiolitis early in infancy.MethodsWe identified previously healthy term infants <3 months of age hospitalized with RSV bronchiolitis from December 2015 to March 2016. We measured IgG antibody titers to pre-F, post-F, and G proteins in maternal sera obtained at 9–12 weeks of pregnancy of these hospitalized infants’ mothers (n = 94) and compared them with serum antibody titers of control pregnant mothers (n = 130) whose children were not hospitalized.ResultsAll maternal samples (n = 224) had detectable pre-F antibodies. Pre-F antibody titers were significantly lower in mothers whose infants were hospitalized with RSV bronchiolitis compared with those mothers whose infants were not hospitalized (23.9 [range (or antibody titer range), 1.4–273.7] µg/L vs 30.6 [XXX, 3.4–220.0] µg/L; P = .0026). There were no significant differences in maternal post-F and G antibody titers between hospitalized and nonhospitalized infants.ConclusionsOur findings indicate that maternal pre-F antibodies are fundamental for providing immune protection to the infant.

The azithromycin to prevent wheezing following severe RSV bronchiolitis-II clinical trial: Rationale, study design, methods, and characteristics of study population

Severe respiratory syncytial virus (RSV) bronchiolitis in early life is a significant risk factor for future recurrent wheeze (RW) and asthma. The goal of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis II (APW-RSV II) clinical trial is to evaluate if azithromycin treatment in infants hospitalized with RSV bronchiolitis reduces the occurrence of RW during the preschool years.The APW-RSV II clinical trial is a double-blind, placebo-controlled, parallel-group, randomized trial, including otherwise healthy participants, ages 30 days-18 months, who are hospitalized due to RSV bronchiolitis. The study includes an active randomized treatment phase with azithromycin or placebo for 2 weeks, and an observational phase of 18–48 months. Two hundred participants were enrolled during three consecutive RSV seasons beginning in the fall of 2016 and were randomized to receive oral azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for an additional 7 days, or matched placebo. The study hypothesis is that in infants hospitalized with RSV bronchiolitis, the addition of azithromycin therapy to routine bronchiolitis care would reduce the likelihood of developing post-RSV recurrent wheeze (≥3 episodes). The primary clinical outcome is the occurrence of a third episode of wheezing, which is evaluated every other month by phone questionnaires and during yearly in-person visits.A secondary objective of the APW-RSV II clinical trial is to examine how azithromycin therapy changes the upper airway microbiome composition, and to determine if these changes are related to the occurrence of post-RSV RW. Microbiome composition is characterized in nasal wash samples obtained before and after the study treatments.This clinical trial may identify the first effective intervention applied during severe RSV bronchiolitis to reduce the risk of post-RSV RW and ultimately asthma.

Burden of respiratory syncytial virus bronchiolitis on the Dutch pediatric intensive care units

Respiratory syncytial virus (RSV) bronchiolitis causes substantial morbidity and mortality in young children, but insight into the burden of RSV bronchiolitis on pediatric intensive care units (PICUs) is limited. We aimed to determine the burden of RSV bronchiolitis on the PICUs in the Netherlands. Therefore, we identified all children ≤ 24 months of age with RSV bronchiolitis between 2003 and 2016 from a nationwide PICU registry. Subsequently we manually checked their patient records for correct diagnosis and collected patient characteristics, additional clinical data, respiratory support modes, and outcome. In total, 2161 children were admitted to the PICU for RSV bronchiolitis. The annual number of admissions increased significantly during the study period (β 4.05, SE 1.27, p = 0.01), and this increase was mostly driven by increased admissions in children up to 3 months old. Concomitantly, non-invasive respiratory support significantly increased (β 7.71, SE 0.92, p < 0.01), in particular the use of high flow nasal cannula (HFNC) (β 6.69, SE 0.96, p < 0.01), whereas the use of invasive ventilation remained stable.Conclusion: The burden of severe RSV bronchiolitis on PICUs has increased in the Netherlands. Concomitantly, the use of non-invasive respiratory support, especially HFNC, has increased.What is Known:• RSV bronchiolitis is a major cause of childhood morbidity and mortality and may require pediatric intensive care unit admission.• The field of pediatric critical care for severe bronchiolitis has changed due to increased non-invasive respiratory support options.What is New:• The burden of RSV bronchiolitis for the Dutch PICUs has increased. These data inform future strategic PICU resource planning and implementation of RSV preventive strategies.• There was a significant increase in the use of high flow nasal cannula at the PICU, but the use of invasive mechanical ventilation did not decrease.

Rapid weight gain in early life is associated with severity of respiratory syncytial virus (RSV) bronchiolitis in children.

This study aimed to investigate whether rapid weight gain in early life was associated with the severity of respiratory syncytial virus (RSV) bronchiolitis in children. We retrospectively reviewed 190 patients (1-24 months) hospitalized for RSV bronchiolitis. Parameters of bronchiolitis severity were compared between rapid (change in weight z-score from birth >0.67, n = 65) and normal weight gain groups (n = 125). We assessed for correlations between bronchiolitis severity and weight gain. Linear regression was performed to predict for bronchiolitis severity based on weight gain, controlling for covariates. SPSS was used for statistical analyses. The rapid weight gain group had longer mean durations of tachypnea (2.3±2.0 vs. 1.7±1.8 days, P = 0.027), wheezing (3.2±2.5 vs. 1.6±1.8 days, P < 0.001), and chest retractions (1.5±2.2 vs. 0.6±1.3 days, P = 0.007). Correlations of weight gain with tachypnea (r = 0.146), wheezing (r = 0.279), and chest retractions (r = 0.179) were statistically significant. Weight gain predicted for tachypnea (B = 0.485, P = 0.013) and wheezing (B = 0.846, P = 0.001) durations after adjusting for covariates of severity (age, sex, current weight, RSV type, coinfection, recurrent bronchiolitis, hospital stay, fever, oxygen supplementation, maximal respiratory and heart rates, and laboratory indices). Our findings suggest an association between weight gain and severity of RSV bronchiolitis in young children. Weight gain was significantly associated with the durations of tachypnea and wheezing. The trajectory of weight gain in early life may play a significant role in the clinical course of RSV bronchiolitis.

Serum metabolomic profiling reveals important difference between infants with and without subsequent recurrent wheezing in later childhood after RSV bronchiolitis.

We aimed to use serum metabolomics to discriminate infants with severe respiratory syncytial virus (RSV) bronchiolitis who later developed subsequent recurrent wheezing from those who did not and to investigate the relationship between serum metabolome and host immune responses with regard to the subsequent development of recurrent wheezing. Fifty-one infants who were hospitalized during an initial episode of severe RSV bronchiolitis at 6months of age or less were included and followed for up to the age of 3years. Of them, 24 developed subsequent recurrent wheezing and 27 did not. Untargeted serum metabolomics was performed by ultraperformance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-MS/MS). Cytokines were measured by multiplex immunoassay. Difference in serum metabolomic profiles was observed between infants who developed recurrent wheezing and those who did not. L-lactic acid level was significantly higher in infants with recurrent wheezing than those without. Pyrimidine metabolism, glycerophospholipid metabolism, and arginine biosynthesis were identified as the most significant changed pathways between the two groups. Moreover, L-lactic acid level was positively associated with serum CXCL8 level. This exploratory study showed that differential serum metabolic signatures during severe RSV bronchiolitis in early infancy were associated with the development of subsequent recurrent wheezing in later childhood.