Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.

Background: Severe acute asthma (SAA) in children can be life-threatening. There has been a significant rise in paediatric intensive care unit (PICU) admissions due to SAA over the past two decades. While asthma is a heterogeneous disease, its underlying pathophysiological pathways remain underexplored. This study aimed to assess the value of non-invasive targeted exhaled breath metabolomics analysis to better characterise SAA. Methods: Breath samples from 17 children admitted to the PICU with SAA (cases) and 27 children with controlled severe asthma (controls) were analysed using thermal desorption gas chromatography–mass spectrometry (TD-GC-MS). Results: A targeted volatile organic compound (VOC) analysis identified 25 compounds, of which 16 were shared between groups. Four VOCs were significantly more often present in SAA, and nine VOCs exhibited higher concentrations in SAA. Longitudinal analysis of VOCs from follow-up samples of 10 cases showed no significant temporal differences, reinforcing the reproducibility of identified biomarkers. Conclusions: This study exemplifies the potential of exhaled breath analysis to provide insights into the molecular background of SAA. Breath metabolomics may enable early recognition of severe asthma attacks and preventive therapeutic interventions in children with severe asthma.

Severe febrile illnesses in children, such as multi-system inflammatory syndrome in children (MIS-C), severe bacterial infection (SBI), severe viral infection (SVI), and Kawasaki disease (KD), have shared clinical features. We used immunophenotyping with mass cytometry and cell stimulation experiments to illustrate shared and distinct mechanisms of immune dysfunction in 74 children with MIS-C, 30 with SBI, 16 with SVI, 8 with KD, and 42 controls. We then used targeted gene expression analysis to explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. Immunophenotyping and clustering analysis revealed neutrophil activation and apoptosis and T cell activation to be prominent in MIS-C and SBI. Cell stimulation experiments showed T cells from patients with acute MIS-C were exhausted. SVI was characterized by phosphorylated STAT signaling but lower gene expression for interferon receptors. Improved understanding of immune dysfunction may improve immunomodulator therapy in severe childhood febrile illnesses.

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.

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 _s =-0.04 for pollen and r _s =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.

Pediatric intensive care admissions for severe acute asthma during the COVID-19 pandemicSomayeh Bazdar1, 2, 3*, Sarah van den Berg4, 5*, Niels W. Rutjes4, Lizan D. Bloemsma1, 2, 3, George S. Downward6, 7, Letty A. De Weger8, Suzanne W.J. Terheggen-Lagro3, Yolanda de Wit-van Wijck1, 2, 3, Anke H. Maitland van der Zee1, 2, 3,4, Berber Kapitein5Department of Pulmonary Medicine, Amsterdam UMC, Amsterdam, The NetherlandsAmsterdam Institute for Infection and Immunity, Amsterdam, The NetherlandsAmsterdam Public Health, Amsterdam, The NetherlandsDepartment of Pediatric Pulmonology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The NetherlandsPediatric Intensive Care Unit, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The NetherlandsDepartment of Environmental Epidemiology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The NetherlandsJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The NetherlandsLeiden University Medical Center, Department of Pulmonology and Department of Public Health and Primary Care, Postbus 9600, 2300 RC Leiden, The Netherlands* Co-first author: Both Somayeh Bazdar and Sarah van den Berg are first authors and contributed equally.Running title : Severe acute asthma during COVID-19