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Background – The incidence of pediatric asthma exacerbations during the COVID-19 pandemic has been evaluated; however, the incidence of severe acute asthma (SAA) requiring a Pediatric Intensive Care Unit (PICU) admission is unknown. Furthermore, we examined several factors which might influence this incidence, such as environmental triggers or changes in COVID-19 lockdown regulations. Methods – In this single-center, retrospective cohort study running from 2018 to 2021, all PICU admissions for SAA of children above two years of age at a tertiary hospital in the Netherlands were included. Information on potential asthma triggers during the pandemic, including viral infections, concentrations of ambient fine particulate matter (PM2.5) and pollen index were evaluated. Results – In total, 168 children were included in this study. While we observed a decrease in PICU admissions for SAA during lockdown periods, there was an increase in the admission rates in the periods without a lockdown, with the highest peak from August to November of 2021. This peak in the fall of 2021 did not align with pollen or ambient PM2.5 concentrations (r =-0.04 for pollen and r =0.23 for PM2.5). Discussion – COVID-19 lockdowns influenced the admission rates for SAA at the PICU both during and after the lockdowns in the Netherlands. We hypothesize that an increase in viral infections after lockdown periods was the reason for the altered incidence of SAA at the PICU in late 2021, rather than air pollution and pollen concentrations.

Context – The negative effects of socioeconomic, environmental and ethnic inequalities on childhood respiratory diseases are known in the development of persistent asthma and can result in adverse outcomes. However, little is known about the effects of these disparities on pediatric intensive care unit (PICU) outcomes in respiratory diseases. Objective – The purpose of this systematic review is to evaluate the literature on disparities in socioeconomic, environmental and ethnic determinants on PICU outcomes. We hypothesize that these disparities negatively influence the outcomes of children’s respiratory diseases at the PICU. Methods – A literature search (in PubMed, Embase.com and Web of Science Core Collection) was performed up to September 30, 2022. Two authors extracted the data and independently evaluated the risk of bias with appropriate assessment methods. Articles were included if the patients were below 18 years of age (excluding neonatal intensive care unit admissions), they concerned respiratory diseases and incorporated socioeconomic, ethnic or environmental disparities. Results – Of 8746 references reviewed, 15 articles were included; seven articles on the effect of socioeconomic status, five articles on ethnicity, one on the effect of sex and lastly two on environmental factors. All articles but one showed an unfavorable outcome at the PICU. Conclusion – Disparities in socioeconomic (such as a low-income household, public health insurance), ethnic and environmental factors (such as exposure to tobacco smoke and diet) have been assessed as risk factors for the severity of children’s respiratory diseases and can negatively influence the outcomes of these children at the PICU.

Introduction: The clinical phenotype of severe acute asthma at the pediatric intensive care unit (PICU) is highly heterogeneous. However, current treatment is still based on a ‘one-size-fits-all approach’. Areas covered: We aim to give a comprehensive description of the clinical characteristics of pediatric patients with severe acute asthma admitted to the PICU and available immunological biomarkers, providing the first steps toward precision medicine for this patient population. A literature search was performed using PubMed for relevant studies on severe acute (pediatric) asthma. Expert opinion: Omics technologies should be used to investigate the relationship between cellular molecules and pathways, and their clinical phenotypes. Inflammatory phenotypes might guide bedside decisions regarding the use of corticosteroids, neutrophil modifiers and/or type of beta-agonist. A next step toward precision medicine should be inclusion of these patients in clinical trials on biologics.

Background: Respiratory syncytial virus (RSV) bronchiolitis is one of the most common respiratory tract infections in children, resulting in substantial global morbidity and mortality. However, we have limited insight in the burden of severe RSV bronchiolitis for which paediatric intensive care unit (PICU) admission is indicated. Our aim was to determine the PICU burden of severe RSV bronchiolitis in the Netherlands. Second, we aimed to define the potential impact of a maternal vaccination strategy on severe RSV bronchiolitis. Methods: We had access to a unique nationwide PICU registry to study patient characteristics and dynamics in 2161 children ≤24 months with a confirmed RSV infection from 2003 to 2016. We manually subtracted additional clinical data, respiratory support modes and outcome. We defined children born term and ≤3 months of age on admission as children who possibly could have benefitted from a maternal vaccination strategy. Results: The number of PICU admissions increased significantly during the study period (β 4.05, p=0.01). The use of non-invasive respiratory support in these children, especially high flow nasal cannula, increased significantly (β 8.86, p Conclusion: The burden of severe RSV bronchiolitis for the PICU has increased in the Netherlands. Concomitantly, the use of non-invasive mechanical ventilation modalities has increased. A maternal vaccination strategy may have a high beneficial impact on the PICU burden of RSV bronchiolitis.

Background: In some infants with bronchiolitis High-Flow Nasal Cannula (HFNC) oxygen therapy fails and other respiratory support is needed. Aim: Systematically review evidence around prognostic factors associated with HFNC failure in bronchiolitis. Methods: We included observational studies of infants Results: We included 13 studies (6/13 multicentre, 7/13 observational [6/7 retrospective]), involving 3,114 infants (85% had bronchiolitis). Studies were of reasonable quality, but considerable heterogeneity and low generalisability rendered overall quality of evidence very low. Reporting of methods, analysis and results were often inadequate. No infant characteristics (age/weight/comorbidity; 10 studies), or clinical observations/severity scores (6 studies) consistently predicted HFNC failure. When reported, markers of respiratory acidosis at HFNC initiation more consistently demonstrated statistically significant association with treatment failure (pH in 4/5 studies; pCO2 in 3/5 studies). Conclusion: No factors consistently predict failure of HFNC in bronchiolitis, but the quality of the evidence is very low. Respiratory acidosis may predict treatment failure but should be tested in prospective multicentre studies before being used to select respiratory support modalities for individual infants with bronchiolitis.

Background: Benefits of oral corticosteroids (OCS) for acute preschool wheeze are unclear. Aim: Systematically review evidence for OCS in preschool children presenting to the emergency department (ED) or hospitalised with acute wheeze. Methods: We included randomised controlled trials of OCS vs placebo for children Results: Four studies were eligible. Risk of bias was generally low except for selective outcome reporting. OCS did not reduce risk of hospitalisation (Risk ratio 0.94,95%CI 0.80,1.12; Figure 1). Of 3 studies reporting LOS, 2 showed statistically but not clinically significant reduction (placebo 9 hours [IQR 2-16] vs OCS 6.2 [2–11.8] p0.04; and placebo 7.7 hours[5.0-22.9] versus OCS 6.8[4–14] p0.03). Atopic history, and interval symptoms were not consistently associated with better response to OCS. Severity and prior diagnosis of asthma were associated with response in one study. Conclusion: High quality evidence suggests OCS should not be used in the ED in acute preschool wheeze. Effects on those with known asthma or hospitalised with severe illness are uncertain.

BACKGROUND: Organ dysfunction scores, based on physiological parameters, have been created to describe organ failure. In a general pediatric intensive care unit (PICU) population, the PEdiatric Logistic Organ Dysfunction-2 score (PELOD-2) score had both a good discrimination and calibration, allowing to describe the clinical outcome of critically ill children throughout their stay. This score is increasingly used in clinical trials in specific subpopulation. Our objective was to assess the performance of the PELOD-2 score in a subpopulation of critically ill children requiring plasma transfusions.METHODS: This was an ancillary study of a prospective observational study on plasma transfusions over a 6-week period, in 101 PICUs in 21 countries. All critically ill children who received at least one plasma transfusion during the observation period were included. PELOD-2 scores were measured on days 1, 2, 5, 8, and 12 after plasma transfusion. Performance of the score was assessed by the determination of the discrimination (area under the ROC curve: AUC) and the calibration (Hosmer-Lemeshow test).RESULTS: Four hundred and forty-three patients were enrolled in the study (median age and weight: 1 year and 9.1 kg, respectively). Observed mortality rate was 26.9 % (119/443). For PELOD-2 on day 1, the AUC was 0.76 (95 % CI 0.71-0.81) and the Hosmer-Lemeshow test was p = 0.76. The serial evaluation of the changes in the daily PELOD-2 scores from day 1 demonstrated a significant association with death, adjusted for the PELOD-2 score on day 1.CONCLUSIONS: In a subpopulation of critically ill children requiring plasma transfusion, the PELOD-2 score has a lower but acceptable discrimination than in an entire population. This score should therefore be used cautiously in this specific subpopulation.

Objective: Excipients used in oral or intravenous preparations may cause serious adverse events. Case Summary: We present the case of a 15-year-old boy with hypertrophic cardiomyopathy. In the pediatric intensive care unit, he received high doses of continuous intravenous esmolol (range = 20-400 µg/kg/min) for cardiac rhythm control. After a few days he developed a delirium not responding to high doses of antipsychotics or discontinuation of benzodiazepines. We eventually realized that the IV esmolol formulation contained high doses of propylene glycol and ethanol, which may accumulate after prolonged infusion and cause intoxication. Intoxication with propylene glycolcan cause neuropsychiatric symptoms. The boy’s propylene glycol plasma concentration was approximately 4 g/L, whereas clinical symptoms arise at concentrations above 1 to 1.44 g/L. Application of the Naranjo adverse drug reaction probability scale suggested a probable relationship (score 6) between the propylene glycol infusion and the delirium. After discontinuation of esmolol, the delirium disappeared spontaneously. Discussion: This is the first case describing excipient toxicity of esmolol, with an objective causality assessment revealing a probable relationship for the adverse event—namely, delirium—and esmolol. Conclusion: Although excipient toxicity is a well-known adverse drug reaction, this case stresses the importance for easily available information for and education of physicians.

Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) by factors such as contact of the blood with the foreign surface of the extracorporeal circuit, hypothermia, reduction of pulmonary blood flow during CPB and endotoxemia. SIRS is maintained in the postoperative phase, co-occurring with a counter anti-inflammatory response syndrome. Research on the effects of drugs administered before the surgery, especially in the induction phase of anesthesia, as well as drugs used during extracorporeal circulation, has revealed that they greatly influence these postoperative inflammatory responses. A better understanding of these processes may not only improve postoperative recovery but also enable tailor-made pharmacotherapy, with both health and economic benefits. In this review, we describe the pathophysiology of SIRS and counter anti-inflammatory response syndrome in the light of CPB in children and the influence of drugs used on these syndromes.

Over the last years insight in the complex interactions between innate and adaptive immunity in the regulation of an inflammatory response has increased enormously. This has revived the interest in stress proteins; proteins that are expressed during cell stress. As these proteins can attract and trigger an immunological response they can act as important mediators in this interaction. In this respect, of special interest are proteins that may act as modulators of both innate and adaptive immunity. Heat shock proteins (HSPs) are stress proteins that have these, and more, characteristics. More than two decades of studies on HSPs has revealed that they are part of intrinsic, “natural” mechanisms that steer inflammation. This has provoked comprehensive explorations of the role of HSPs in various human inflammatory diseases. Most studies have focused on classical autoimmune diseases. This has led to the development of clinical studies with HSPs that have shown promise in Phase II/III clinical trials. Remarkably, only very little is yet known of the role of HSPs in atopic diseases. In allergic disease a number of studies have investigated the possibility that allergen-specific regulatory T cell (Treg) function is defective in individuals with allergic diseases. This raises the question whether methods can be identified to improve the Treg repertoire. Studies from other inflammatory diseases have suggested HSPs may have such a beneficial effect on the T cell repertoire. Based on the immune mechanisms of atopic diseases, in this review we will argue that, as in other human inflammatory conditions, understanding immunity to HSPs is likely also relevant for atopic diseases. Specifically, we will discuss why certain HSPs such as HSP60 connect the immune response to environmental antigens with regulation of the inflammatory response. Thus they provide a molecular link that may eventually even help to better understand the immune pathological basis of the hygiene hypothesis.