Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication of infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently, neutralising autoantibodies against inflammatory receptor antagonists progranulin and interleukin-1 receptor antagonist (IL-1Ra) were found in adult patients with critical COVID-19. The aim of this study was to investigate the role of such autoantibodies in MIS-C. Methods: In this multicentre, retrospective, cohort study, plasma and serum samples were collected from patients (0-18 years) with MIS-C (as per WHO criteria) treated at five clinical centres in Germany and Spain. As controls, we included plasma or serum samples from children with Kawasaki disease, children with inactive systemic juvenile idiopathic arthritis, and children with suspected growth retardation (non-inflammatory control) across four clinical centres in Germany and Spain (all aged ≤18 years). Serum samples from the CoKiBa trial were used as two further control groups, from healthy children (negative for SARS-CoV-2 antibodies) and children with previous mild or asymptomatic COVID-19 (aged ≤17 years). MIS-C and control samples were analysed for autoantibodies against IL-1Ra and progranulin, and for IL-1Ra concentrations, by ELISA. Biochemical analysis of plasma IL-1Ra was performed with native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signalling reporter assay. Findings: Serum and plasma samples were collected between March 6, 2011, and June 2, 2021. Autoantibodies against IL-1Ra could be detected in 13 (62%) of 21 patients with MIS-C (11 girls and ten boys), but not in children with Kawasaki disease (n=24; nine girls and 15 boys), asymptomatic or mild COVID-19 (n=146; 72 girls and 74 boys), inactive systemic juvenile idiopathic arthritis (n=10; five girls and five boys), suspected growth retardation (n=33; 13 girls and 20 boys), or in healthy controls (n=462; 230 girls and 232 boys). Anti-IL-1Ra antibodies in patients with MIS-C belonged exclusively to the IgG1 subclass, except in one patient who had additional IL-1Ra-specific IgM antibodies. Autoantibodies against progranulin were only detected in one (5%) patient with MIS-C. In patients with MIS-C who were positive for anti-IL-1Ra antibodies, free plasma IL-1Ra concentrations were reduced, and immune-complexes of IL-1Ra were detected. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1Ra was observed in all patients with MIS-C who were positive for anti-IL-1Ra antibodies. Anti-IL-1Ra antibodies impaired IL-1Ra function in reporter cell assays, resulting in amplified IL-1ß signalling. Interpretation: Anti-IL-1Ra autoantibodies were observed in a high proportion of patients with MIS-C and were specific to these patients. Generation of these autoantibodies might be triggered by an atypical, hyperphosphorylated isoform of IL-1Ra. These autoantibodies impair IL-1Ra bioactivity and might thus contribute to increased IL-1ß-signalling in MIS-C. Funding: NanoBioMed fund of the University of Saarland, José Carreras Center for Immuno and Gene Therapy, Dr Rolf M Schwiete Stiftung, Staatskanzlei Saarland, German Heart Foundation, Charity of the Blue Sisters, Bavarian Ministry of Health, the Center for Interdisciplinary Clinical Research at University Hospital Münster, EU Horizon 2020.

Different Effects of Two Protocols for Pre-Procedural Analgosedation on Vital Signs in Neonates during and after Endotracheal Intubation.

BACKGROUND: Analgosedation is often used for endotracheal intubation in neonates, but no consensus exists on the optimal pre-procedural medication. AIMS: To compare the time to intubation and vital signs during and after intubation in 2 NICUs using different premedication protocols. METHODS: Prospective observational study in 2 tertiary NICUs, comparing fentanyl and optional vecuronium for elective neonatal endotracheal intubation (NICU-1) with atropine, morphine, midazolam and optional pancuronium (NICU-2). Primary endpoints were: time to intubate and number of intubation attempts; secondary endpoints were: deviations of heart rate, oxygen saturation and blood pressure from baseline until 20 min post intubation. RESULTS: 45 and 30 intubations were analyzed in NICU-1 and NICU-2. Time to intubation was longer in NICU-1 (7 min) than in NICU-2 (4 min; p=0.029), but the mean number of intubation attempts did not differ significantly. Bradycardias (34 vs. 1, p<0.001) and hypoxemias (136 vs. 48, p<0.001) were more frequent in NICU-1, and tachycardias (59 vs. 72, p<0.001) more frequent in NICU-2. Mean arterial blood pressure (MAP) increased in NICU-1 (+6.18 mmHg) and decreased in NICU-2 (-5.83 mmHg), whereas mean heart rates (HR) decreased in NICU-1 (-19.29 bpm) and increased in NICU-2 (+15.93 bpm). MAP and HR returned to baseline 6-10 min after intubation in NICU-1 and after 11-15 min and 16-20 min in NICU-2, respectively. CONCLUSIONS: The two protocols yielded significant differences in the time to intubation and in the extent and duration of physiologic changes during and post-intubation. Short acting drugs should be preferred and vital signs should be closely monitored at least 20 min post intubation. More studies are required to identify analgosedation protocols that minimize potentially harmful events during endotracheal intubation.

Corrigendum: Assessment of Inadequate Use of Pediatric Emergency Medical Transport Services: The Pediatric Emergency and Ambulance Critical Evaluation (PEACE) Study.

[This corrects the article DOI: 10.3389/fped.2019.00442.].

Analgosedation for diagnostic and interventional procedures: a countrywide survey of pediatric centers in Germany.

BACKGROUND: As more and more diagnostic and interventional options are becoming available for use in pediatric patients, techniques of procedural sedation analgesia (PSA) are being administered in considerably growing numbers as well. AIMS: The objective of this research effort was to conduct the first countrywide survey on the status quo of sedation analgesia as delivered to children and adolescents in Germany. METHODS: We dispatched letters to all pediatric hospital settings in Germany (n = 305), including a questionnaire that had been developed with existing guidelines taken into account. Its items were designed to elucidate the current practice of PSA throughout these pediatric centers regarding (a) organizational structures and (b) standards of medication and staffing. RESULTS: A total of 138 centers returned the questionnaire, hence the response rate was 45.2%. Numerous centers had implemented adequate structures and staffing standards. Deficits were nevertheless identified, most notably in terms of on-location equipment and staff provided to deliver sedations. Essential items of equipment were not provided in up to 26.8% of centers. Adequate staffing was not provided in up to 44.2% of centers, depending on the diagnostic or interventional procedures for which the PSA was delivered. The most widely used sedative agents were midazolam, ketamine/esketamine, and propofol. CONCLUSIONS: Adequate care structures for the management of procedural sedation analgesia have been implemented by many pediatric centers in Germany. On the downside, these findings also reveal deficits that will take efforts to be eliminated.

Assessment of Inadequate Use of Pediatric Emergency Medical Transport Services: The Pediatric Emergency and Ambulance Critical Evaluation (PEACE) Study.

Aim: To provide data on the inadequate use of emergency medical transports services (EMTS) in children and underlying contributing factors. Methods: This was a prospective single-center cohort study (01/2017-12/2017) performed at the Saarland University Children's Hospital, Homburg, Germany. Patients ≤20 years of age transported by EMTS for suspected acute illness/trauma were included and proportion of inadequate/adequate EMTS use, underlying contributing factors, and additional costs were analyzed. Results: Three hundred seventy-nine patients (mean age: 9.0 ± 6.3 years; 55.7% male, 44.3% female) were included in this study. The three most common reasons for EMTS use were: central nervous system (30.6%), respiratory system affection (14.0%), and traumas (13.2%). ETMS use was categorized as inadequate depending on physician's experience: senior physician (58.8%), pediatrician (54.9%), resident (52.7%). All three physicians considered 127 (33.5%) cases to be medically indicated for transportation by EMTS, and 177 (46.7%) to be medically not indicated. The following parameters were significantly associated with inadequate EMTS use: non-acute onset of symptoms (OR 2.5), parental perception as non-life-threatening (OR 1.7), and subsequent out-patient treatment (OR 4.0). Conversely, transport by an emergency physician (OR 3.5) and first time parental EMTS call (OR 1.7) were associated with adequate use of EMTS. Moreover, a significant relation existed between maternal, respectively, paternal educational status and inadequate EMTS use (each p = 0.01). Using multiple logistic regression analysis, non-acute onset of symptoms (OR 2.2) was associated with inadequate use of EMTS while first time parental EMTS call (OR 1.8), transport by an emergency physician (OR 3.3), and need for in-patient treatment (OR 4.0) were associated with adequate use of EMTS. Conclusion: A substantial number of pediatric EMTS is medically not indicated. Possibly, specific measures including multifaceted educational efforts may be helpful in reducing unnecessary EMTS use.

Propofol Versus 4-hydroxybutyric Acid in Pediatric Cardiac Catheterizations.

INTRODUCTION: Pediatric patients require deep sedation at least for cardiac catheterizations (CCs). Usually, we perform these CCs applying propofol, but we have seen several side effects of this sedative. We have had good experience with 4-hydroxybutyric acid for other sedations. To optimize our standardized CC procedure, we initiated a prospective, randomized trial to compare the two substances. METHODS: We analyzed our sedation protocols of all CCs within a period of 12 months. In addition to the primary endpoints, the feasibility of the CCs and the occurrence of severe complications, several other parameters were included in the analysis (vital parameters, blood gas analysis, intervention measures). The protocols were blinded for the first part of the evaluation. RESULTS: During the 12-month-period, 36 patients were included in each group. The propofol group showed lower blood pressure values towards the end of the sedations, while the blood gas analyses revealed lower pH levels and higher pCO2 values. The complication rate was low in both groups. CONCLUSION: Both procedures are suited for the safe performance of deep sedations for CCs. The application of 4-hydroxybutyric acid seems to have a few advantages with regard to spontaneous breathing, gas exchange, stability of cardiocirculatory parameters and sedation quality.

Bone marrow aspirations in oncological patients: experience from an in-house standard in paediatrics.

BACKGROUND: Nearly all paediatric patients require deep sedation when undergoing bone marrow aspiration (BMA). We analyzed the data from our protocols documented in a standardised procedure for bone marrow puncture over a period of 2 years. METHODS: Our standard included the documentation of personal data as well as vital parameters. In addition, we documented all medications administered, potential complications and required intervention measures, as necessary. RESULTS: A total of 107 protocols were available for the evaluation. Our standard covered the usage of midazolam and S­ketamine and resulted in complications in just 9 patients, which could be remedied using simple measures. For both active substances, the dosage necessary to reach sufficient deep analgosedation was significantly higher for patients under 24 months of age. CONCLUSIONS: Our standard for BMA provides a practical and feasible procedure. In addition to good examination conditions, our standard also helps ensure the safety of our patients.

Nucleated red blood cells and serum lactate values on days 2 and 5 are associated with mortality and morbidity in VLBW infants.

AIM: To correlate nucleated red blood cell counts and serum lactate concentrations on day 2 and 5 of life with morbidity and mortality in very low birth weight infants and to determine corresponding cutoff values. METHODS: Retrospective analysis in a cohort of very low birth weight infants. RESULTS: 250 very low birth weight infants were included in this study. Gestational age ranged from 23 to 35 weeks (mean 29.04) and birth weight was 320-1500 g (mean 1047.9). 55 (22%) patients developed intraventricular hemorrhage, 55 (22%) bronchopulmonary dysplasia, 12 (4.8%) periventricular leukomalacia, 93 (37.2%) retinopathy of prematurity, and 1 (0.4%) necrotizing enterocolitis. Mortality rate was 25/250 (10%). Nucleated red blood cells and serum lactate on day 2 of life were associated with mortality (p < 0.001). Serum lactate on day 5 of life demonstrated an association with retinopathy of prematurity (p = 0.017), bronchopulmonary dysplasia (p = 0.044), and intraventricular hemorrhage (p < 0.001). Cutoff values predicting mortality were >89.5 nucleated red blood cells/100 leucocytes (sensitivity 68.2%, specificity 89.0%) and serum lactate concentrations >8.5 mmol/l (sensitivity 69.6%, specificity 93.5%) on day 2 of life. CONCLUSION: We conclude that both nucleated red blood cell count and serum lactate concentration are valuable biomarkers in predicting important outcome parameters in very low birth weight infants.

[25 Years of ESPED as a Surveillance Tool for Rare Diseases in Children in Germany: A Critical Analysis]. / Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland (ESPED) ­ 25 Jahre pädiatrische Epidemiologie: Eine Bestandsaufnahme.

BACKGROUND: The German Paediatric Surveillance Unit (ESPED) was founded in 1992 to generate incidence data and detailed clinical descriptions of rare, childhood-onset diseases. METHODS: Retrospective analysis of the ESPED epidemiological data collection from 1992-2017, and analysis of all published national and international publications originating from ESPED surveys. Center of Disease Control and Prevention (CDC) criteria for evaluating surveillance systems (simplicity, flexibility, timeliness, usefulness, data quality, representativeness, stability and acceptability) were adopted and applied to available ESPED data. RESULTS: Between 1992 and 2017 ESPED completed 96 prospective studies on rare diseases in children. The 3 most frequent clinical entities were: Infectious/communicable disease (n=30), neurological diseases (n = 14) and hematologic diseases (n=10). Studies resulted in 337 publications in national and international journals. The median impact factor of the 192 journal publications with (impact factor) was 2,587 (range 0,032-28,409). The highest impact factors were seen in the fields of endocrinology/metabolism (n=130; median IF=3,534), infectious diseases (n=83; median IF=3,131) and hematology (n=37; median IF=2,497). Our analysis indicates that ESPED surveys meet CDC quality standards. CONCLUSION: ESPED surveys are an important contributor in the field of clinical epidemiology in children with rare diseases. The high quality of ESPED surveys is reflected by high-impact publications in both national and international journals.

Sedation and analgosedation performed by pediatricians--experience made with the implementation of an in-house sedation standard: Sedation and analgosedation-implemantation of an in-house standard.

BACKGROUND: (Analgo-) sedations for diagnostic and/or therapeutic procedures form part of the daily clinical routine for pediatric patients. National and international medical specialist associations have published guidelines indicating the general conditions of these procedures, yet the recommendations are not always consistent. Since anesthesiological activities are increasingly performed by nonanesthesiologists at our hospital, the Pediatric Clinic of the University Hospital of Saarland considered it necessary to develop an in-house standard. MATERIAL AND METHODS: On the basis of a standard dating back to 2005, which was developed and clinically applied by two of the authors of this article, we created our "Homburg standard", taking into account the guidelines of the specialist associations and the international literature. This standard covers patient information, the consumption of food and drink, monitoring before, during and after the sedation as well as documentation. We will present the process of how our standard was established by analyzing protocols of the "old" standard-applied for a period of 18 months-and the application of our standard to two new studies performed at our hospital. RESULTS: In total, 159 sedations of the 18-month reference period could be evaluated; the two studies accounted for 72 sedations for diagnostic and/or interventional cardiac catheter examinations and 40 sedations for outpatient TEE examinations. None of the procedures was associated with complications endangering the safety of a patient. Whereas the documentation of the two studies was nearly complete, it varied considerably in the case of the 159 sedations, depending on how much time had passed since the most recent training. CONCLUSION: Our standard is a practicable and safe method of performing sedations and analgosedations in pediatric patients. In addition, this standard allows clinical studies to be carried out and evaluated, taking into account certain organizational measures. The development of a specific guideline by the DGKJ and/or the GNPI is considered desirable.

Cellular and humoral coagulation profiles and occurrence of IVH in VLBW and ELWB infants.

BACKGROUND AND STUDY PURPOSE: Intraventricular hemorrhage (IVH) is a major complication in preterm neonates with significant long-term morbidity and an increased mortality rate. The role of the immature coagulation system in the pathogenesis of IVH in these infants is still under debate. The aim of this study was to provide reference values for coagulation studies within the first 24h of life, and to relate these findings to the incidence of IVH. PATIENTS AND METHODS: In this retrospective study, a total of 250 (male: 123/female: 127; VLBW: 150 and ELBW: 100) infants were included over a 4-year-period. Coagulation studies were performed within the first 24h of life in all infants. Multiple regression analysis was employed to demonstrate a potential association between IVH and a number of known risk and protective factors for IVH (antenatal steroids, birth weight, gender, IUGR, APGAR score at 10minutes, platelet count, INR, PTT, fibrinogen). RESULTS: Mean birth weight was 1047.9±305.6 (range: 320-1490g). Both cellular (platelets, nucleated red blood cells) and plasmatic coagulation parameters (INR, fibrinogen and antithrombin III) were dependent on birth weight. Moreover, INR levels (p<0.05) were significantly increased in neonates with IVH of any grade. Also, INR was positively correlated with the severity of IVH (Spearman's correlation coefficient: 0.193; p=0.003). While overall fibrinogen levels were not associated with IVH, a fibrinogen level<100mg/dL significantly increased the risk for IVH (p<0.01). CONCLUSIONS: Our data provide a robust set of reference values for both cellular and humoral coagulation studies in VLBW and ELBW infants for the first 24h of life. The results of our study indicate that abnormal INR levels and fibrinogen levels<100mg/dL are significantly associated with the occurrence of IVH in this susceptible cohort.

Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child.

BACKGROUND: The use of complementary and alternative medicine (CAM) is widespread in children with cancer and is poorly regulated. PATIENTS AND METHODS: Case report. RESULTS: We describe a case of severe cyanide poisoning arising from CAM use. A severely agitated, encephalopathic, unresponsive 4-year-old boy (initial Glasgow Coma Scale of 3) with a history of metastatic ependymoma was brought to our emergency department by ambulance services. Initial blood gas analysis demonstrated severe metabolic/lactic acidosis. On detailed questioning of the parents, the use of CAM including intravenous and oral "vitamin B 17" (amygdalin) and oral apricot kernel was reported. After administering sodium thiosulfate, rapid improvement in his medical condition with complete recovery without need for further intensive care treatment was seen. Serum cyanide level was markedly elevated. CONCLUSIONS: Cyanide poisoning can be the cause of severe encephalopathy in children receiving CAM treatment with substances containing cyanogenic glycosides.

Clinical recommendations of Cochrane reviews in pediatric gastroenterology: systematic analysis.

BACKGROUND: Systematic and up-to-date Cochrane reviews in pediatrics in general and in pediatric gastroenterology in particular are important tools in disseminating the best available evidence to the medical community, thus providing the physician at the bedside with invaluable information and recommendations with regard to specific clinical questions. METHODS: A systematic literature review was conducted, including all Cochrane reviews published by the Cochrane Review Group in the field of pediatric gastroenterology between 1993 and 2012, with regard to the percentage of reviews that concluded that a certain intervention provided a benefit, percentage of reviews that concluded that a certain intervention should not be performed, and percentage of studies that concluded that the current level of evidence was inconclusive. RESULTS: In total, 86 reviews in the field of pediatric gastroenterology were included. The majority of reviews assessed pharmacological interventions (46/86); other important fields included prevention (15/86) and nutrition (9/86). A total of 33/86 reviews issued definite recommendations (positive, 19/86; negative, 14/86). The remaining 53/86 reviews were either inconclusive (24/86) or only of limited conclusiveness (29/86). The percentage of inconclusive reviews increased from 9% (1998-2002) to 19% (2003-2007; P < 0.05) to finally 24% (2008-2012) (P < 0.05). The three most common reasons for the need for further research were heterogeneity of studies (26/86), small number of patients (18/86), and insufficient data (16/86). CONCLUSIONS: Further high-quality research is necessary to increase the proportion of reviews with clear recommendations. Funding and research agencies are key to selecting the most appropriate research programs.

Leukapheresis in children weighing less than 20 kg.

Augmentation of standard chemotherapy with peripheral blood stem cells (PBSC) rescue is a standard treatment strategy. However, in pediatric patients weighing less than 20 kg, the collection of PBSC presents a challenge. We report our experience with nine pediatric patients weighing between 4.33 and 19.9 kg and a total of 23 PBSC collection aphereses. None of our patients experienced any major complications. We conclude that PBSC apheresis in children is a safe method. It should be based on a standardized procedure that includes the determination of clinical and laboratory parameters and appropriate monitoring.

Successful treatment of Bacillus cereus meningitis following allogenic stem cell transplantation.

We report the case of a 19-yr-old boy, who received an allogeneic stem cell transplantation for the second relapse of Hodgkin's disease. The patient developed seizures and flaccid hemiparesis on day +10. Meningoencephalitis induced by Bacillus cereus was diagnosed. The treatment consisted of appropriate antibiotics, G-CSF and removal of the central venous line. Infection control and nearly full neurological recovery was achieved. Immunocompromised patients susceptible to B. cereus infection, indicated by the isolation of B. cereus in prior cultures, should receive antibiotic treatment covering B. cereus.