Bronchiolitis therapies and misadventures.

Viral bronchiolitis, which is most commonly caused by an infection with the respiratory syncytial virus (RSV), can lead to respiratory difficulties in young children which may require hospitalization. Despite years of research and medical trials, the mainstay of bronchiolitis treatment remains supportive only. This review provides an overview of the history of different treatments for bronchiolitis, including those that failed, as well as new therapies that are under study. Future studies for the treatment of bronchiolitis should consider different age-groups, important subgroups (i.e., those with a prior history of wheezing, those with a family history of asthma and those with non-RSV viral etiologies) whose response to treatment may differ from that of the composite group.

Neutrophil Extracellular Traps Do Not Induce Injury and Inflammation in Well-Differentiated RSV-Infected Airway Epithelium.

Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) causes a major burden of disease. The host response in RSV-LRTI is characterized by airway epithelial injury, inflammation and neutrophil influx, with the formation of neutrophil extracellular traps (NETs). However, the precise role of NETs in the pathophysiology of RSV-LRTI remains to be elucidated. Here, we used well-differentiated human airway epithelial cultures (HAE) of a pediatric and adult donor to study whether NETs cause airway epithelial injury and inflammation in the setting of RSV infection. The exposure of uninfected and RSV-infected HAE cultures to NETs, as produced by stimulation of neutrophils by a low dose of phorbol 12-myristate 13-acetate (PMA), did not induce or aggravate cell injury or inflammation. RSV infection of HAE cultures caused release of pro-inflammatory cytokines such as IL-6 and RANTES in both adult and pediatric cultures, but the differential gene expression for regulated cell death differed between culture donors. In this in vitro airway epithelial model, NETs in the setting of RSV infection did not cause or aggravate epithelial injury or inflammation.

Use of dornase alfa in the paediatric intensive care unit: current literature and a national cross-sectional survey.

OBJECTIVES: Airway mucus obstruction is a major challenge in children admitted to the paediatric intensive care unit (PICU). We aimed to evaluate the evidence and contemporary use of the mucolytic medication dornase alfa for non-cystic fibrosis conditions in the PICU. METHODS: (1) We performed a systematic review with searches in PubMed, EMBASE, and the Cochrane Library. Study selection: for quality assessment and data synthesis, we included only randomised controlled trials (RCTs) that compared dornase alfa to standard care or placebo in critically-ill paediatric patients (<18 years of age) in the PICU. However, non-randomised controlled studies and case series are also discussed. Data extraction: data were extracted independently by multiple reviewers using data extraction forms. The primary outcome was duration of mechanical ventilation. Data synthesis: The GRADE approach was used for quality assessment. No meta-analysis could be performed. (2) A national cross-sectional survey among all seven PICUs in the Netherlands was also performed. RESULTS: The systematic review yielded only one RCT, comparing dornase alfa with normal saline in children after cardiac surgery. In this study, dornase alfa led to a reduction in duration of mechanical ventilation by approximately 1 day (36% reduction). In addition, we found nine retrospective observational and case studies. The survey revealed high current use of dornase alfa in Dutch PICUs: 42% of the respondents reported prescribing dornase alfa at least once every week. Only 4% of the respondents reported having access to a local PICU dornase alfa protocol. CONCLUSIONS: The off-label use of dornase alfa in the PICU is frequent without strong evidence or local protocols, highlighting the need for further research on the effectiveness of this mucolytic agent.

Increasing burden of viral bronchiolitis in the pediatric intensive care unit; an observational study.

PURPOSE: Viral bronchiolitis is a major cause of pediatric intensive care unit (PICU) admission. Insight in the trends of bronchiolitis-associated PICU admissions is limited, but imperative for future PICU resource and capacity planning. MATERIALS AND METHODS: We retrospectively studied trends in PICU admissions for bronchiolitis in six European sites, including three full national registries, between 2000 and 2019 and calculated population-based estimates per 100,000 children where appropriate. Information concerning risk factors for severe disease and use of invasive mechanical ventilation was also collected when available. RESULTS: In total, there were 15,606 PICU admissions for bronchiolitis. We observed an increase in the annual number, rate and estimates per 100,000 children of PICU admissions for bronchiolitis at all sites over the last two decades, while the proportion of patients at high risk for severe disease remained relatively stable. CONCLUSIONS: The international increased burden of bronchiolitis for the PICU is concerning, and warrants further international attention and investigation.

The Association between Weather Conditions and Admissions to the Paediatric Intensive Care Unit for Respiratory Syncytial Virus Bronchiolitis.

Respiratory syncytial virus (RSV) bronchiolitis is a leading cause of global child morbidity and mortality. Every year, seasonal RSV outbreaks put high pressure on paediatric intensive care units (PICUs) worldwide, including in the Netherlands, and this burden appears to be increasing. Weather conditions have a strong influence on RSV activity, and climate change has been proposed as a potential important determinant of future RSV-related health care utilisation. In this national study spanning a total of 13 years with 2161 PICU admissions for RSV bronchiolitis, we aimed (1) to identify meteorological variables that were associated with the number of PICU admissions for RSV bronchiolitis in the Netherlands and (2) to determine if longitudinal changes in these variables occurred over time as a possible explanation for the observed increase in PICU burden. Poisson regression modelling was used to identify weather variables (aggregated in months and weeks) that predicted PICU admissions, and linear regression analysis was used to assess changes in the weather over time. Maximum temperature and global radiation best predicted PICU admissions, with global radiation showing the most stable strength of effect in both month and week data. However, we did not observe a significant change in these weather variables over the 13-year time period. Based on our study, we could not identify changing weather conditions as a potential contributing factor to the increased RSV-related PICU burden in the Netherlands.

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 (ß 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 (ß 7.71, SE 0.92, p < 0.01), in particular the use of high flow nasal cannula (HFNC) (ß 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.

Neutrophil Extracellular Traps Increase Airway Mucus Viscoelasticity and Slow Mucus Particle Transit.

Mucus obstruction is a key feature of many inflammatory airway diseases. Neutrophil extracellular traps (NETs) are released upon neutrophil stimulation and consist of extracellular chromatin networks studded with cytotoxic proteins. When released in the airways, these NETs can become part of the airway mucus. We hypothesized that the extracellular DNA and/or oxidative stress (e.g., by the release of reactive oxygen species and myeloperoxidase during NETs formation in the airways) would increase mucus viscoelasticity. We collected human airway mucus from endotracheal tubes of healthy patients admitted for elective surgery and coincubated these samples with NETs from phorbol 12-myristate 13-acetate-stimulated neutrophils. Unstimulated neutrophils served as controls, and blocking experiments were performed with dornase alfa for extracellular DNA and the free radical scavenger dimethylthiourea for oxidation. Compared with controls, the coincubation of mucus with NETs resulted in 1) significantly increased mucus viscoelasticity (macrorheology) and 2) significantly decreased mesh pore size of the mucus and decreased movement of muco-inert nanoparticles through the mucus (microrheology), but 3) NETs did not cause visible changes in the microstructure of the mucus by scanning EM. Incubation with either dornase alfa or dimethylthiourea attenuated the observed changes in macrorheology and microrheology. This suggests that the release of NETs may contribute to airway mucus obstruction by increasing mucus viscoelasticity and that this effect is not solely due to the release of DNA but may in part be due to oxidative stress.

Body Weight Changes after Deep Brain Stimulation for Obsessive-Compulsive Disorder or Depression.

BACKGROUND: In 2010, we published an often-cited case report describing smoking cessation and substantial weight loss after deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) in an obese patient. To test whether this single observation was also observed in the treated population at large, the weight changes of a larger cohort of patients who underwent DBS for OCD or major depressive disorder (MDD) were studied. RESULTS: Data were available for 46 patients (30 OCD and 16 MDD patients; mean age 46.2 years, SD 10.9) with an average baseline body mass index (BMI) of 28.0 (SD 7.3), 26 of whom (57%) were overweight (n = 11), obese (n = 12), or morbidly obese (n = 3). Mean follow-up was 3.8 years (range 10 months to 8.7 years, SD 2.3), after which the average BMI was 28.1 (SD 7.0), not significantly different from baseline. The average BMI of the 15 patients with (morbid) obesity at baseline decreased from 36.8 to 34.6 (ns), while the average BMI of the 31 normal or "only" overweight patients at baseline increased from 23.8 to 25.0 (ns). CONCLUSION: There was no significant change in body weight on group level after DBS for either OCD or MDD.

Incidence of polyneuropathy in Utrecht, the Netherlands.

OBJECTIVE: Ascertain the incidence of cryptogenic axonal polyneuropathy (CAP) and how this relates to the overall incidence of polyneuropathy. METHODS: Electronic diagnostic registries of all hospital-based neurologic practices in the province of Utrecht (population 1,224,852 = 7.4% of the Dutch population) were consulted in 2010 to identify incident cases with polyneuropathy. Medical files were reviewed to specify the final diagnosis. Age-adjusted incidence rates for the Netherlands were calculated using national age-specific population figures. RESULTS: The overall incidence of polyneuropathy was 77.0/100,000 person-years (95% confidence interval 71.1-82.8) in persons aged 18 years and older. Diabetic polyneuropathy (32%), CAP (26%), toxic polyneuropathy (14%), and immune-mediated polyneuropathy (9%) were the most frequent diagnoses. The incidence of CAP was 31.6/100,000 person-years (95% confidence interval 27.0-36.3) in persons aged 40 years and older. The incidence of polyneuropathy increased with age, as well as the proportion of patients diagnosed with CAP: 12% (40-49 years), 20% (50-59 years), 28% (60-69 years), 32% (70-79 years), and 35% (≥80 years) (χ(2) test, p = 0.005). CONCLUSIONS: The chance of establishing an etiologic diagnosis in patients presenting with a polyneuropathy decreases with age. Given the aging population, polyneuropathy in general and CAP in particular will pose a growing health care problem.