Myeloid cells from Langerhans cell histiocytosis patients exhibit increased vesicle trafficking and an altered secretome capable of activating NK cells.

Langerhans cell histiocytosis (LCH) is a potentially life-threatening inflammatory myeloid neoplasia linked to pediatric neurodegeneration, whereby transformed LCH cells form agglomerated lesions in various organs. Although MAP-kinase pathway mutations have been identified in LCH cells, the functional consequences of these mutations and the mechanisms that cause the pathogenic behavior of LCH cells are not well understood. In our study, we used an in vitro differentiation system and RNA-sequencing to compare monocyte-derived dendritic cells from LCH patients to those derived from healthy controls or patients with Crohn's disease, a non-histiocytic inflammatory disease. We observed that interferon-γ treatment exacerbated intrinsic differences between LCH patient and control cells, including strikingly increased endo- and exocytosis gene activity in LCH patients. We validated these transcriptional patterns in lesions and functionally confirmed that LCH cells exhibited increased endo- and exocytosis. Furthermore, RNA-sequencing of extracellular vesicles revealed the enrichment of pathological transcripts involved in cell adhesion, MAP-kinase pathway, vesicle trafficking and T-cell activation in LCH patients. Thus, we tested the effect of the LCH secretome on lymphocyte activity and found significant activation of NK cells. These findings implicate extracellular vesicles in the pathology of LCH for the first time, in line with their established roles in the formation of various other tumor niches. Thus, we describe novel traits of LCH patient cells and suggest a pathogenic mechanism of potential therapeutic and diagnostic importance.

Short- and Long-Term Outcome in Critically Ill Children After Acute Interhospital Transport to a PICU in Sweden.

OBJECTIVES: Data on long-term survival in children after interhospital transport to a PICU are scarce. The main objective was to investigate short- and long-term outcome after acute interhospital transport to a PICU for different age and risk stratification groups. Secondary aims were to investigate whether neonatal patients would have higher mortality and be more resource demanding than older patients. DESIGN: Single-center, retrospective cohort study. SETTING: Specialist pediatric transport team and a tertiary PICU in Sweden. PATIENTS: Critically ill children 0-18 years old, acutely transported by a specialist pediatric transport team to a PICU in Sweden (January 1, 2008, to December 31, 2016). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 401 acute transport events were included. Overall mortality was 15.7% with a median follow-up time of 3.4 years (range, 0-10.2 yr). Median predicted death rate was 4.9%. There was no mortality during transport. Cumulative mortality almost doubled within the first 6 months after PICU discharge, from 6.5% to 12.0%. Of late deaths, 66.7% occurred in the risk stratification group predicted death rate 0-10%, and 95% suffered from severe comorbidity. There were no deaths after PICU discharge in the neonatal group. Cumulative mortality in multiple transported patients was 36.4%. CONCLUSIONS: This is the first report on long-term survival after acute pediatric interhospital transport. For the entire cohort, there was significant mortality after PICU discharge, especially in multiple transported patients. In contrast, survival in the subgroup of neonatal patients was high after PICU discharge.

Unnecessary harm is avoided by reliable paediatric index of mortality2 scores without arterial gas sampling.

AIM: To investigate whether unnecessary harm could be avoided in children admitted to paediatric intensive care (PICU), we analysed the impact of arterial blood gas on the paediatric index of mortality score2 (PIM2) and the derived predicted death rate (PDR). METHODS: From January 1, 2008 to December 31, 2010, 1793 consecutive admissions, newborn infants to 16 years of age (median 0.71 years) from a single, tertiary PICU in Gothenburg Sweden, were collected. Admission information on arterial oxygen tension (PaO2 ) and fraction of inspired oxygen (FiO2 ) was extracted from 990 admissions. RESULTS: There was close agreement between PIM2 score and PDR regardless of whether the PaO2 /FiO2 ratio was omitted or not. In the subgroup of admissions with a respiratory admission diagnosis, the inclusion of the PaO2 /FiO2 ratio increased the accuracy of the PIM2 score as well as the PDR. The standard mortality ratio was slightly but not significantly overestimated by excluding the PaO2 /FiO2 ratio. CONCLUSION: To avoid unnecessary harm to children admitted to PICU, an arterial blood gas analysis should only be performed if clinically indicated or if the child has a respiratory admission diagnosis. Estimation of the PIM2 score and PDR will not be less accurate by this approach.

Risks for death after admission to pediatric intensive care (PICU)-A comparison with the general population.

OBJECTIVE/AIM: The aim of the study was to quantify excess mortality in children after admission to a Pediatric Intensive Care Unit (PICU), compared to the age and sex matched general Swedish population. DESIGN: Single-center, retrospective cohort study. SETTING: Registry study of hospital registers, a national population register and Statistics Sweden. PATIENTS: Children admitted to a tertiary PICU in Sweden in 2008-2016. INTERVENTIONS: None. MAIN RESULTS: In total, 6,487 admissions (4,682 patients) were included in the study. During the study period 444 patients died. Median follow-up time for the entire PICU cohort was 7.2 years (IQR 5.0-9.9 years). Patients were divided into four different age groups (0-28 d, > 28 d -1 yr, > 1-4 yr, and > 4 yr) and four different risk stratification groups [Predicted Death Rate (PDR) intervals: 0-10%, > 10-25%, > 25-50%, and > 50%] at admission. Readmission was seen in 929 (19.8%) patients. The Standardized Mortality Ratios (SMRs) were calculated using the matched Swedish population as a reference group. The SMR for the entire study group was 49.8 (95% CI: 44.8-55.4). For patients with repeated PICU admissions SMR was 108.0 (95% CI: 91.9-126.9), and after four years 33.9 (95% CI: 23.9-48.0). Patients with a single admission had a SMR of 35.2 (95% CI: 30.5-40.6), and after four years 11.0 (95% CI: 7.0-17.6). The highest SMRs were seen in readmitted children with oncology/hematology (SMR = 358) and neurologic (SMR = 192) diagnosis. Children aged >1-4 years showed the highest SMR (325). In PDR group 0-10% children with repeated PICU admissions (n = 798), had a SMR of 100. CONCLUSION: Compared to the matched Swedish population, SMRs were greatly elevated up to four years after PICU admission, declining from over 100 to 33 for patients with repeated PICU admissions, and from 35 to 11 for patients with a single PICU admission.

Influence of altitude on cerebral and splanchnic oxygen saturation in critically ill children during air ambulance transport.

OBJECTIVE: The aim of the current study was to investigate how cerebral and splanchnic oxygen saturation (rSO2-C and rSO2-A) in critically ill children transported in air ambulance was affected by flight with cabin pressurization corresponding to ≥ 5000 feet. A second aim was to investigate any differences between cyanotic and non-cyanotic children in relation to cerebral and splanchnic oxygen saturation during flight ≥ 5000 feet. The variability of the cerebral and splanchnic Near Infrared Spectroscopy (NIRS) sensors was evaluated. DESIGN: NIRS was used to measure rSO2-C and rSO2-A during transport of critically ill children in air ambulance. rSO2 data was collected and stored by the NIRS monitor and extracted and analyzed off-line after the transport. Prior to evaluation of the NIRS signals all zero and floor-effect values were removed. SETTING: The Pediatric Intensive Care Unit (PICU) at Astrid Lindgren Children's Hospital, Karolinska University Hospital in Stockholm, Sweden. PATIENTS: In total, 44 critically ill children scheduled for inter-hospital transport by a specialized pediatric transport team were included in the study between January 2014 and January 2019 (convenience sampling). INTERVENTION: No interventions were conducted. MEASUREMENTS: All study patients were monitored with a cerebral NIRS-sensor placed over the forehead and an abdominal NIRS-sensor placed in the infra-umbilical area for cerebral and splanchnic regional oxygen saturation monitoring, rSO2-C and rSO2-A, respectively. MAIN RESULTS: Complete rSO2-C and rSO2-A data was obtained in 39 patients. Median age was 12 days. Cyanotic congenital heart malformations were present in 9 patients (23%). In 22 patients (56%) rSO2-C decreased at altitude ≥ 5000 feet and in 24 patients (61%) rSO2-A decreased at altitude ≥ 5000 feet compared to baseline (p<0.0001). In 25 patients (64%) the rSO2-C/rSO2-A ratio was greater at altitude ≥ 5000 feet than at baseline. A ratio ≥ 1 was seen in 77% of patients at altitude ≥ 5000 feet compared to in 67% of patients at baseline. CONCLUSION: Both cerebral and splanchnic oxygen saturation decreased at altitude ≥ 5000 feet compared to baseline. In most patients, both cyanotic and non-cyanotic, cerebral oxygen saturation was preserved more than splanchnic oxygen saturation.