Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations.

Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10-16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10-11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.

Reconstructive Surgery of the Laryngotracheal Junction. / Rekonstruktive Chirurgie des laryngo-trachealen Übergangs.

The laryngotracheal junction is an anatomical region with special pathophysiological features. This review presents clinical pictures and malformations that manifest pre-dilectively at this localisation in children and adolescents as well as in adults. The diagnostic procedure is discussed. The possibilities of surgical reconstruction are presented depending on the pathology and age of the patient.

First detected geographical cluster of BoDV-1 encephalitis from same small village in two children: therapeutic considerations and epidemiological implications.

BACKGROUND: The Borna disease virus (BoDV-1) is an emerging zoonotic virus causing severe and mostly fatal encephalitis in humans. METHODS AND RESULTS: A local cluster of fatal BoDV-1 encephalitis cases was detected in the same village three years apart affecting two children. While the first case was diagnosed late in the course of disease, a very early diagnosis and treatment attempt facilitated by heightened awareness was achieved in the second case. Therapy started as early as day 12 of disease. Antiviral therapy encompassed favipiravir and ribavirin, and, after bioinformatic modelling, also remdesivir. As the disease is immunopathogenetically mediated, an intensified anti-inflammatory therapy was administered. Following initial impressive clinical improvement, the course was also fatal, although clearly prolonged. Viral RNA was detected by qPCR in tear fluid and saliva, constituting a possible transmission risk for health care professionals. Highest viral loads were found post mortem in the olfactory nerve and the limbic system, possibly reflecting the portal of entry for BoDV-1. Whole exome sequencing in both patients yielded no hint for underlying immunodeficiency. Full virus genomes belonging to the same cluster were obtained in both cases by next-generation sequencing. Sequences were not identical, indicating viral diversity in natural reservoirs. Specific transmission events or a common source of infection were not found by structured interviews. Patients lived 750m apart from each other and on the fringe of the settlement, a recently shown relevant risk factor. CONCLUSION: Our report highlights the urgent necessity of effective treatment strategies, heightened awareness and early diagnosis. Gaps of knowledge regarding risk factors, transmission events, and tailored prevention methods become apparent. Whether this case cluster reflects endemicity or a geographical hot spot needs further investigation.

Interventional Bronchus Occlusion Using Amplatzer Devices - A Promising Treatment Option for Children with Persistent Air Leak.

BACKGROUND: Persistent air leak (PAL) is a severe complication of secondary spontaneous pneumothorax (SSP). Surgical interventions are usually successful when medical treatment fails, but can be associated with significant complications and loss of potentially recoverable lung parenchyma. METHODS: Retrospective analysis of efficacy and safety of interventional bronchus occlusions (IBO) using Amplatzer devices (ADs) in children with PAL secondary to SSP. RESULTS: Six patients (four males, 4-15 years of age) underwent IBO using ADs as treatment for PAL. Necrotizing pneumonia (NP) was the most common cause (n=4) of PAL. Three patients were previously healthy and three suffered from chronic lung disease. All patients required at least two chest tubes prior to the intervention for a duration of 15-43 days and all required oxygen or higher level of ventilatory support. In three cases, previous surgical interventions had been performed without success. All children improved after endobronchial intervention and we observed no associated complications. All chest tubes were removed within 5-25 days post IBO. In patients with PAL related to NP (n=4), occluders were removed bronchoscopically without re-occurrence of pneumothorax after a mean of 70 days (IQR: 46.5-94). CONCLUSION: IBO using ADs is a safe and valuable treatment option in children with PAL independent of disease severity and underlying cause. A major advantage of this procedure is its less invasiveness compared to surgery and the parenchyma- preserving approach.

Neutrophil gelatinase-associated lipocalin reflects inflammation and is not a reliable renal biomarker in neonates and infants after cardiopulmonary bypass: a prospective case-control study.

Introduction Acute kidney injury is a frequent complication after cardiac surgery with cardiopulmonary bypass in infants. Neutrophil gelatinase-associated lipocalin has been suggested to be a promising early biomarker of impending acute kidney injury. On the other hand, neutrophil gelatinase-associated lipocalin has been shown to be elevated in systemic inflammatory diseases without renal impairment. In this secondary analysis of data from our previous study on acute kidney injury after infant cardiac surgery, our hypothesis was that neutrophil gelatinase-associated lipocalin may be associated with surgery-related inflammation. METHODS: We prospectively enrolled 59 neonates and infants undergoing cardiopulmonary bypass surgery for CHD and measured neutrophil gelatinase-associated lipocalin in plasma and urine and interleukin-6 in the plasma. Values were correlated with postoperative acute kidney injury according to the paediatric Renal-Injury-Failure-Loss-Endstage classification. RESULTS: Overall, 48% (28/59) of patients developed acute kidney injury. Of these, 50% (14/28) were classified as injury and 11% (3/28) received renal replacement therapy. Both plasma and urinary neutrophil gelatinase-associated lipocalin values were not correlated with acute kidney injury occurrence. Plasma neutrophil gelatinase-associated lipocalin showed a strong correlation with interleukin-6. Urinary neutrophil gelatinase-associated lipocalin values correlated with cardiopulmonary bypass time. CONCLUSION: Our results suggest that plasma and urinary neutrophil gelatinase-associated lipocalin values are not reliable indicators of impending acute kidney injury in neonates and infants after cardiac surgery with cardiopulmonary bypass. Inflammation may have a major impact on plasma neutrophil gelatinase-associated lipocalin values in infant cardiac surgery. Urinary neutrophil gelatinase-associated lipocalin may add little prognostic value over cardiopulmonary bypass time.

Comparison of the AVPU Scale and the Pediatric GCS in Prehospital Setting.

OBJECTIVE: The pediatric Glasgow coma scale (pGCS) is a consciousness score that, although widely applied, requires skill to apply. The AVPU scale uses four simple categories (Alert; Verbal response; response to Pain; Unresponsive), but has not been studied in a large pediatric population. We compared the performance of the AVPU and pGCS scales in a large pediatric cohort in an acute, prehospital setting. METHODS: In a six-month-long prospective cohort study, AVPU and pGCS scores were determined by emergency physicians in children less than 10 years of age at their first prehospital encounter. RESULTS: We included 302 children (median age 2.3 years) with a broad spectrum of diagnoses. Data were complete for 287 children. AVPU and pGCS scores showed good a correlation in the extreme categories A and U (positive predictive values of 98% and 100%, respectively). Corresponding pGCS scores for each AVPU category were as follows: 11-15 for A; 5-15 for V; 4-12 for P; and 3-5 for U. The positive predictive value to detect patients with pGCS ≥ 8 for AVPU category V was 100%. CONCLUSIONS: We demonstrated good correlation of simple and fast consciousness AVPU scoring to the standard pGCS in a large cohort of pediatric patients in a prehospital setting. The AVPU category "V" identifies patients with a pGCS of or exceeding 8 and, therefore, identifies children at low risk requiring more invasive procedures or intensive care treatment. KEY WORDS: Glasgow coma scale (GCS); Alert-verbal-pain-unresponsive-score; AVPU-score; consciousness assessment; children, pediatric emergency.

Intraoperative renal near-infrared spectroscopy indicates developing acute kidney injury in infants undergoing cardiac surgery with cardiopulmonary bypass: a case-control study.

INTRODUCTION: Acute kidney injury (AKI) is a frequent complication after cardiac surgery with cardiopulmonary bypass in infants. Renal near-infrared spectroscopy (NIRS) is used to evaluate regional oximetry in a non-invasive continuous real-time fashion, and reflects tissue perfusion. The aim of this study was to evaluate the relationship between renal oximetry and development of AKI in the operative and post-operative setting in infants undergoing cardiopulmonary bypass surgery. METHODS: In this prospective study, we enrolled 59 infants undergoing cardiopulmonary bypass surgery for congenital heart disease for univentricular (n = 26) or biventricular (n = 33) repair. Renal NIRS was continuously measured intraoperatively and for at least 24 hours postoperatively and analysed for the intraoperative and first 12 hours, first 24 hours and first 48 hours postoperatively. The renal oximetry values were correlated with the paediatric risk, injury, failure, loss, end (pRIFLE) classification for AKI, renal biomarkers and the postoperative course. RESULTS: Twenty-eight (48%) infants developed AKI based on pRIFLE classification. Already during intraoperative renal oximetry and further in the first 12 hours, 24 hours and 48 hours postoperatively, significantly lower renal oximetry values in AKI patients compared with patients with normal renal function were recorded (P < 0.05). Of the 28 patients who developed AKI, 3 (11%) needed renal replacement therapy and 2 (7%) died. In the non-AKI group, no deaths occurred. Infants with decreased renal oximetry values developed significantly higher lactate levels 24 hours after surgery. Cystatin C was a late parameter of AKI, and neutrophil gelatinase-associated lipocalin values were not correlated with AKI occurrence. CONCLUSION: Our results suggest that prolonged low renal oximetry values during cardiac surgery correlate with the development of AKI and may be superior to conventional biochemical markers. Renal NIRS might be a promising non-invasive tool of multimodal monitoring of kidney function and developing AKI in infants undergoing cardiac surgery with cardiopulmonary bypass.

Monitoring of the microcirculation in children undergoing major abdominal and thoracic surgery: A pilot study.

BACKGROUND: Monitoring of the macrocirculation during surgery provides limited information on the quality of organ perfusion. OBJECTIVE: We investigated the feasibility of perioperative microcirculatory measurements in children. METHODS: Sublingual microvessels were visualized by handheld videomicroscopy in 11 children (19 mo - 10 yrs) undergoing surgery > 120 min at four time points: T0) after induction of anesthesia; T1) before end of anesthesia, T2) 6 h post surgery and T3) 24 h post surgery. RESULTS: Measurements were feasible in all children at T0 and T1. At T2 and T3, imaging was restricted to 6 and 4 infants, respectively, due to respiratory compromise and missing cooperation. The capillary density was reduced at T1 compared to T0 (8.1 mm/mm2 [4.0-17.0] vs. 10.6 mm/mm2 [5.1-19.3]; p = 0.01), and inversely related to norepinephrine dose (Pearson r = -0.65; p = 0.04). Microvascular flow and serum glycocalyx makers Syndecan-1 and Hyaluronan increased significantly from T0 to T1. CONCLUSION: Perioperative microcirculatory monitoring in children requires a high amount of personal and logistic resources still limiting its routine use. Major surgery is associated with microvascular alterations and glycocalyx perturbation. The possible consequences on patient outcome need further evaluation. Efforts should concentrate on the development of next generation devices designed to facilitate microcirculatory monitoring in children.

Self-reported muscle pain in adolescents with migraine and tension-type headache.

AIM: To identify possible associations between muscular pain and headache in adolescents in a large population-based sample. METHODS: Grammar school students were invited to fill in a questionnaire on headache and associated lifestyle factors. Headache was classified according to the German version of the International Classification of Headache Disorders (2nd edition). Muscular pain was assessed via denoting affected areas in schematic drawings of a body and via provoked muscular pain on controlled movements of head, neck and shoulder regions. RESULTS: Prevalence of any headache within the previous 6 months exceeded 80%. In all subjects muscular pain or pain on movement was most prominent in the neck and shoulder region, ranging from 9% to 27% in the non-headache population to up to 63% for individuals with migraine or mixed migraine and tension-type headache (TTH). Frequency of muscular pain increased significantly with growing chronicity of TTH. INTERPRETATION: A strong association between muscle pain in the neck/shoulder region and headache was observed, pointing to the importance of muscular pain for headache in adolescents. Also, in this age group muscular pain appears to be of particular importance in chronic TTH and - unexpectedly - in migraine, which is the most important new finding in our study.

Effects of a reduction of the number of electrodes in the EEG montage on the number of identified seizure patterns.

Continuous EEG monitoring (cEEG) is frequently used in neurocritical care. The detection of seizures is one of the main objectives. The placement of the EEG electrodes is time consuming, therefore a reduced montage might lead to an increased availability in the ICU setting. It is unknown whether such a reduction of electrodes reduces the number of seizure patterns that are detected. A total of 95 seizure and 95 control EEG sequences from a pediatric epilepsy monitoring unit (EMU) were anonymized and reduced to an eight-lead montage. Two experts evaluated the recordings and the seizure detection rates using the reduced and the full montage were compared. Sensitivity and specificity for the seizure detection were calculated using the original EMU findings as gold standard. The sensitivity to detect seizures was 0.65 for the reduced montage compared to 0.76 for the full montage (p = 0.031). The specificities (0.97 and 0.96) were comparable (p = 1). A total of 4/9 (44%) of the generalized, 12/44 (27%) of the frontal, 6/14 (43%) of the central, 0/1 (0%) of the occipital, 6/20 (30%) of the temporal, and 5/7 (71%) of the parietal seizure patterns were not detected using the reduced montage. The median time difference between the onset of the seizure pattern in the full and reduced montage was 0.026s (IQR 5.651s). In this study the reduction of the EEG montage from 21 to eight electrodes reduced the sensitivity to detect seizure patterns from 0.76 to 0.65. The specificity remained virtually unchanged.

Pulmonary alveolar proteinosis due to heterozygous mutation in OAS1: Whole lung lavages for long-term bridging to hematopoietic stem cell transplantation.

INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is defined by increased accumulation of surfactant in the alveolar space. PAP has been reported to be associated with a large number of clinical conditions and diseases. Whole lung lavages (WLLs) can be helpful to stabilize the clinical course of PAP until the underlying condition is identified, which may enable more specific treatment. Recently, heterozygous OAS1 gain-of-function variants were described as cause in patients with infantile-onset PAP combined with hypogammaglobulinemia. CASE PRESENTATION: At age 4 months, a female infant born to term was diagnosed with hypogammaglobulinemia and treated with monthly immunoglobulin injections. At age 15 months, the girl needed supplemental oxygen at night, and at age 18 months, also during the day. At age 2 years, PAP of unknown etiology was diagnosed by computed tomography scan and open lung biopsy. Subsequently, monthly WLLs were started, which stabilized the clinical course for over 2 years until a disease-causing OAS1 variant was diagnosed and the patient was successfully treated by hematopoietic stem cell transplantation (HSCT). CONCLUSION: Here, we describe the successful management of a female patient with severe PAP caused by a heterozygous OAS1 gain-of-function variant until a definitive diagnosis was made and cured by HSCT.

Autoimmune pulmonary alveolar proteinosis in children.

In childhood, a multitude of causes lead to pulmonary alveolar proteinosis (PAP), an excessive surfactant accumulation in the alveolar space, limiting gas exchange. Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) causing autoimmune PAP, the principal aetiology in adults, are rare. In this first case series on autoimmune PAP, we detail the presentation and management issues of four children. Whereas three children presented insidiously with progressive dyspnoea, one was acutely sick with suspected pneumonia. During management, one patient was hospitalised with coronavirus disease 2019, noninvasively ventilated, and recovered. All treatment modalities known from adults including whole-lung lavage, augmentation of GM-CSF by inhaled GM-CSF, removal of neutralising antibody by plasmapheresis and interruption of antibody production using rituximab were considered; however, not all options were available at all sites. Inhaled GM-CSF appeared to be a noninvasive and comfortable therapeutic approach. The management with best benefit-to-harm ratio in autoimmune PAP is unknown and specialised physicians must select the least invasive and most effective treatment. To collect this cohort in a rare condition became feasible as patients were submitted to an appropriate registry. To accelerate the authorisation of novel treatments for autoimmune PAP, competent authorities should grant an inclusion of adolescents into trials in adults.

Osteoarticular Infections in Pediatric Hospitals in Europe: A Prospective Cohort Study From the EUCLIDS Consortium.

Background: Pediatric osteoarticular infections (POAIs) are serious diseases requiring early diagnosis and treatment. Methods: In this prospective multicenter cohort study, children with POAIs were selected from the European Union Childhood Life-threatening Infectious Diseases Study (EUCLIDS) database to analyze their demographic, clinical, and microbiological data. Results: A cohort of 380 patients with POAIs, 203 with osteomyelitis (OM), 158 with septic arthritis (SA), and 19 with both OM and SA, was analyzed. Thirty-five patients were admitted to the Pediatric Intensive Care Unit; out of these, six suffered from shock, one needed an amputation of the right foot and of four left toes, and two had skin transplantation. According to the Pediatric Overall Performance Score, 36 (10.5%) showed a mild overall disability, 3 (0.8%) a moderate, and 1 (0.2%) a severe overall disability at discharge. A causative organism was detected in 65% (247/380) of patients. Staphylococcus aureus (S. aureus) was identified in 57.1% (141/247) of microbiological confirmed cases, including 1 (0.7%) methicillin-resistant S. aureus (MRSA) and 6 (4.2%) Panton-Valentine leukocidin (PVL)-producing S. aureus, followed by Group A Streptococcus (18.2%) and Kingella kingae (8.9%). K. kingae and PVL production in S. aureus were less frequently reported than expected from the literature. Conclusion: POAIs are associated with a substantial morbidity in European children, with S. aureus being the major detected pathogen. In one-third of patients, no causative organism is identified. Our observations show an urgent need for the development of a vaccine against S. aureus and for the development of new microbiologic diagnostic guidelines for POAIs in European pediatric hospitals.

Long-term follow-up and treatment of congenital alveolar proteinosis.

BACKGROUND: Clinical presentation, diagnosis, management and outcome of molecularly defined congenital pulmonary alveolar proteinosis (PAP) due to mutations in the GM-CSF receptor are not well known. CASE PRESENTATION: A 2 1/2 years old girl was diagnosed as having alveolar proteinosis. Whole lung lavages were performed with a new catheter balloon technique, feasible in small sized airways. Because of some interstitial inflammation in the lung biopsy and to further improve the condition, empirical therapy with systemic steroids and azathioprin, and inhaled and subcutaneous GMCSF, were used. Based on clinical measures, total protein and lipid recovered by whole lung lavages, all these treatments were without benefit. Conversely, severe respiratory viral infections and an invasive aspergillosis with aspergilloma formation occurred. Recently the novel homozygous stop mutation p.Ser25X of the GMCSF receptor alpha chain was identified in the patient. This mutation leads to a lack of functional GMCSF receptor and a reduced response to GMCSF stimulation of CD11b expression of mononuclear cells of the patient. Subsequently a very intense treatment with monthly lavages was initiated, resulting for the first time in complete resolution of partial respiratory insufficiency and a significant improvement of the overall somato-psychosocial condition of the child. CONCLUSIONS: The long term management from early childhood into young adolescence of severe alveolar proteinosis due to GMCSF receptor deficiency requires a dedicated specialized team to perform technically demanding whole lung lavages and cope with complications.

The influence of information about the circumstances of EEG recordings on the ability to identify seizure patterns.

Purpose To quantify the influence of prior knowledge about the patient and the EEG circumstances on the EEG-based seizure detection rate. Methods A sample of 95 EEGs with epileptic seizure patterns matched with 95 seizure-free control sequences were extracted from EEG video monitoring data. They were stripped of all additional information. These plain EEG recordings were evaluated by two board certified EEG reviewers. The results were compared with the interpretations of the original video monitoring evaluations. Results Using the plain EEG sequences, epileptic seizure patterns were detected with a sensitivity and specificity of 0.758 and 0.958, respectively. The classification of the seizure pattern localization and lateralization differed in 56% and 50%, respectively, from the results of the video monitoring evaluations. Conclusion Additional information about the patient and the events during an EEG recording leads to a clinically and statistically significant increase in the seizure detection rates. These results imply that the human evaluation of a plain EEG without further information may not be seen as the gold standard in EEG evaluation. The performance estimation of automated EEG evaluation methods should take this into account.

Recanalization strategies in childhood stroke in Germany.

Childhood arterial ischemic stroke (CAIS) is a rare event. Diverse etiologies, risk factors, symptoms and stroke mimics hamper obtaining a fast diagnosis and implementing immediate recanalization strategies. Over a period of 3 years (2015-2017), the data of 164 pediatric patients (> 28 days of life-18 years) with a first episode of AIS were submitted to a hospital-based nationwide surveillance system for rare disorders (ESPED). We report a subgroup analysis of patients who have undergone recanalization therapy and compare these data with those of the whole group. Twenty-eight patients (17%) with a median age of 12.2 years (range 3.3-16.9) received recanalization therapy. Hemiparesis, facial weakness and speech disturbance were the main presenting symptoms. The time from onset of symptoms to confirmation of diagnosis was significantly shorter in the intervention group (4.1 h vs. 20.4 h, p ≤ 0.0001). Only in one patient occurred a minor bleed. Cardiac disease as predisposing risk factor was more common in the recanalization group. Recanalization therapies are feasible and increasingly applied in children with AIS. High awareness, timely diagnosis and a large amount of expertise may improve time to treatment and make hyperacute therapy an option for more patients.

Comorbidity and long-term clinical outcome of laryngotracheal clefts types III and IV: Systematic analysis of new cases.

BACKGROUND: Long segment laryngotracheoesophageal clefts (LTECs) are very rare large-airway malformations. Over the last 40 years mortality rates declined substantially due to improved intensive care and surgical procedures. Nevertheless, long-term morbidity, comorbidity, and clinical outcomes have rarely been assessed systematically. METHODS: In this retrospective case series, the clinical presentation, comorbidities, treatment, and clinical outcomes of all children with long-segment LTEC that were seen at our department in the last 15 years were collected and analyzed systematically. RESULTS: Nine children were diagnosed with long segment LTEC (four children with LTEC type III and five patients with LTEC type IV). All children had additional tracheobronchial, gastrointestinal, or cardiac malformations. Tracheostomy for long-time ventilation and jejunostomy for adequate nutrition was necessary in all cases. During follow-up one child died from multiorgan failure due to sepsis at the age of 43 days. The clinical course of the other eight children (median follow-up time 5.2 years) was stable. Relapses of the cleft, recurrent aspirations, and respiratory tract infections led to repeated hospital admissions. CONCLUSIONS: Long-segment LTECs are consistently associated with additional malformations, which substantially influence long-term morbidity. For optimal management, a multidisciplinary approach is essential.

S2k guideline diagnosis and treatment of carbon monoxide poisoning.

Carbon monoxide (CO) can occur in numerous situations and ambient conditions, such as fire smoke, indoor fireplaces, silos containing large quantities of wood pellets, engine exhaust fumes, and when using hookahs. Symptoms of CO poisoning are nonspecific and can range from dizziness, headache, and angina pectoris to unconsciousness and death. This guideline presents the current state of knowledge and national recommendations on the diagnosis and treatment of patients with CO poisoning. The diagnosis of CO poisoning is based on clinical symptoms and proven or probable exposure to CO. Negative carboxyhemoglobin (COHb) levels should not rule out CO poisoning if the history and symptoms are consistent with this phenomenon. Reduced oxygen-carrying capacity, impairment of the cellular respiratory chain, and immunomodulatory processes may result in myocardial and central nervous tissue damage even after a reduction in COHb. If CO poisoning is suspected, 100% oxygen breathing should be immediately initiated in the prehospital setting. Clinical symptoms do not correlate with COHb elimination from the blood; therefore, COHb monitoring alone is unsuitable for treatment management. Especially in the absence of improvement despite treatment, a reevaluation for other possible differential diagnoses ought to be performed. Evidence regarding the benefit of hyperbaric oxygen therapy (HBOT) is scant and the subject of controversy due to the heterogeneity of studies. If required, HBOT should be initiated within 6 h. All patients with CO poisoning should be informed about the risk of delayed neurological sequelae (DNS).