Platelet role in the prediction of MIS-C severity

IntroductionMultisystem inflammatory syndrome in children (MIS-C) has been reported as one of the cytokine storm syndromes associated with COVID-19. Despite the several proposed diagnostic criteria, MIS-C remains a diagnostic and clinical challenge. Recent studies have demonstrated that platelets (PLTs) play a crucial role in COVID-19 infection and its prognosis. This study aimed to investigate the clinical importance of PLT count and PLT indices in predicting MIS-C severity in children.Patients and methodsWe conducted a retrospective single-center study at our university hospital. A total of 43 patients diagnosed with MIS-C during a 2-year period (from October 2020 to October 2022) were included in the study. MIS-C severity was evaluated according to the composite severity score.ResultsHalf of the patients were treated in the pediatric intensive care unit. No single clinical sign was associated with a severe condition, except for shock (p = 0.041). All the routine biomarkers, such as complete blood count (CBC) and C-reactive protein (CRP), used for MIS-C diagnosis were significant in predicting MIS-C severity. Single PLT parameters, such as mean PLT volume, plateletcrit, or PLT distribution width, did not differ between the severity groups. However, we found that a combination of PLT count and the previously mentioned PLT indices had the potential to predict MIS-C severity.ConclusionsOur study emphasizes the importance of PLT in MIS-C pathogenesis and severity. It revealed that together with routine biomarkers (e.g., CBC and CRP), it could highly improve the prediction of MIS-C severity

Overuse of medical care in paediatrics: A survey from five countries in the European Academy of Pediatrics.

Studies and initiatives such as the "Choosing wisely" (CW) campaign emphasise evidence-based investigations and treatment to avoid overdiagnosis and overtreatment. The perception of the extent of medical overactivity among professionals and drivers behind are not well studied in the paediatric field. Aim We aimed to investigate the physicians' opinion and clarify the main drivers regarding medical overactivity in member countries of the European Academy of Paediatrics (EAP). Methods In this study, paediatricians, paediatric residents, primary care paediatricians, and family doctors treating children were surveyed in Norway, Lithuania, Ukraine, Italy, and Switzerland. Over-investigation was defined as "diagnostic work-up or referral that is unlikely to provide information which is relevant for a patient" and overtreatment was defined as "treatment that does not benefit or can harm more than benefit the patient." The original questionnaire was developed in 2018 by a working group from the Norwegian Paediatric Association. Results Overall, 1,416 medical doctors participated in the survey, ranging from 144 in Lithuania to 337 in Switzerland. 83% stated that they experienced over-investigation/overtreatment, and 81% perceived this as a problem. The majority (83%) perceived expectations from family and patients as the most important driver for overtreatment in their country. Other drivers for overuse were use of national guidelines/recommendations, worry for reactions, and reduction of uncertainty. Conclusion This is the first study investigating knowledge and attitude toward medical overactivity in European countries. Despite different cultural and economic environments, the patterns and drivers of increased investigations and medicalisation are similar

Over-investigation and overtreatment in pediatrics: a survey from the European Academy of Paediatrics and Japan Pediatric Society

IntroductionAvoiding over-investigation and overtreatment in health care is a challenge for clinicians across the world, prompting the international Choosing Wisely campaign. Lists of recommendations regarding medical overactivity are helpful tools to guide clinicians and quality improvement initiatives. We aimed to identify the most frequent and important clinical challenges related to pediatric medical overactivity in Europe and Japan. Based on the results, we aim to establish a (European) list of Choosing Wisely recommendations.MethodsIn an online survey, clinicians responsible for child health care in Europe and Japan were invited to rate 18 predefined examples of medical overactivity. This list was compiled by a specific strategic advisory group belonging to the European Academy of Paediatrics (EAP). Participants were asked to rate on a Likert scale (5 as the most frequent/important) according to how frequent these examples were in their working environment, and how important they were considered for change in practice.ResultsOf 2,716 physicians who completed the survey, 93% (n = 2,524) came from 17 countries, Japan (n = 549) being the largest contributor. Pediatricians or pediatric residents comprised 89%, and 51% had 10–30 years of clinical experience. Cough and cold medicines, and inhaled drugs in bronchiolitis were ranked as the most frequent (3.18 and 3.07 on the Likert scale, respectively), followed by intravenous antibiotics for a predefined duration (3.01), antibiotics in uncomplicated acute otitis media (2.96) and in well-appearing newborns. Regarding importance, the above-mentioned five topics in addition to two other examples of antibiotic overtreatment were among the top 10. Also, IgE tests for food allergies without relevant medical history and acid blockers for infant GER were ranked high.ConclusionOvertreatment with antibiotics together with cough/cold medicines and inhaled drugs in bronchiolitis were rated as the most frequent and important examples of overtreatment across countries in Europe and Japan

International Care programs for Pediatric Post-COVID Condition (Long COVID) and the way forward

Background: Pediatric Post-COVID-Condition (PPCC) clinics treat children despite limited scientific substantiation. By exploring real-life management of children diagnosed with PPCC, the International Post-COVID-Condition in Children Collaboration (IP4C) aimed to provide guidance for future PPCC care. // Methods: We performed a cross-sectional international, multicenter study on used PPCC definitions; the organization of PPCC care programs and patients characteristics. We compared aggregated data from PPCC cohorts and identified priorities to improve PPCC care. // Results: Ten PPCC care programs and six COVID-19 follow-up research cohorts participated. Aggregated data from 584 PPCC patients was analyzed. The most common symptoms included fatigue (71%), headache (55%), concentration difficulties (53%), and brain fog (48%). Severe limitations in daily life were reported in 31% of patients. Most PPCC care programs organized in-person visits with multidisciplinary teams. Diagnostic testing for respiratory and cardiac morbidity was most frequently performed and seldom abnormal. Treatment was often limited to physical therapy and psychological support. // Conclusions: We found substantial heterogeneity in both the diagnostics and management of PPCC, possibly explained by scarce scientific evidence and lack of standardized care. We present a list of components which future guidelines should address, and outline priorities concerning PPCC care pathways, research and international collaboration

Presentations of children to emergency departments across Europe and the COVID-19 pandemic: A multinational observational study

During the initial phase of the Coronavirus Disease 2019 (COVID-19) pandemic, reduced numbers of acutely ill or injured children presented to emergency departments (EDs). Concerns were raised about the potential for delayed and more severe presentations and an increase in diagnoses such as diabetic ketoacidosis and mental health issues. This multinational observational study aimed to study the number of children presenting to EDs across Europe during the early COVID-19 pandemic and factors influencing this and to investigate changes in severity of illness and diagnoses. Routine health data were extracted retrospectively from electronic patient records of children aged 18 years and under, presenting to 38 EDs in 16 European countries for the period January 2018 to May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRRs), using predicted counts for each site as offset to adjust for case-mix differences, were used to compare age groups, diagnoses, and outcomes. Reductions in pediatric ED attendances, hospital admissions, and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (IRR 2·26, 95% CI 1·90 to 2·70, p < 0.001) and in children aged <12 months (12 to <24 months IRR 0·86, 95% CI 0·84 to 0·89; 2 to <5 years IRR 0·80, 95% CI 0·78 to 0·82; 5 to <12 years IRR 0·68, 95% CI 0·67 to 0·70; 12 to 18 years IRR 0·72, 95% CI 0·70 to 0·74; versus age <12 months as reference group, p < 0.001). The lowering of pediatric intensive care admissions was not as great as that of general admissions (IRR 1·30, 95% CI 1·16 to 1·45, p < 0.001). Lower triage urgencies were reduced more than higher triage urgencies (urgent triage IRR 1·10, 95% CI 1·08 to 1·12; emergent and very urgent triage IRR 1·53, 95% CI 1·49 to 1·57; versus nonurgent triage category, p < 0.001). Reductions were highest and sustained throughout the study period for children with communicable infectious diseases. The main limitation was the retrospective nature of the study, using routine clinical data from a wide range of European hospitals and health systems. Reductions in ED attendances were seen across Europe during the first COVID-19 lockdown period. More severely ill children continued to attend hospital more frequently compared to those with minor injuries and illnesses, although absolute numbers fell. ISRCTN91495258 https://www.isrctn.com/ISRCTN91495258

Mesenchymale Stammzellen aus dem Knochenmark als Therapeutikum für durch Influenza-Viren verursachte Pneumonie

Influenza virus (IV) infects the upper respiratory tract and occasionally spreads to the alveolar compartment causing primary IV pneumonia. This frequently progresses to acute respiratory distress syndrome (ARDS) with severe alveolar damage, lung edema and hypoxemia, requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO) procedures. Antiviral therapies are only effective in the very beginning of infection and specific treatment strategies for IV-induced ARDS are still lacking. Mesenchymal stem cells (MSC) are multi-potent stromal cells with anti-inflammatory and regenerative potential: recently they were attributed a beneficial role in acute and chronic lung injury. This study investigated MSC delivery into the lung as a promising treatment strategy in IV-induced ARDS.In this study MSC were isolated from bone marrow (mBM-MSC) of C57Bl6. These MSC had fibroblast-like shape and expressed stem cell-specific markers and demonstrated de-differentiation potential upon defined culture conditions. No phenotypic changes were observed until passage 18. Genome array analysis revealed a strong up-regulation of the genes involved in cell proliferation (cell division, cyclins), in interferon signaling (ISGs) and virus resistance (Mx2, Bst2/Tetherin) in infected alveolar epithelial cells (iAECs) co-cultured with BM-MSC compared to iAECs in monoculture. In ex vivo infection experiments, BM-MSC as well as their conditioned medium (CM) strongly diminished IV replication, increased AEC regeneration and consequently decreased IV-induced AEC apoptosis. In vivo, intra-tracheal instillation of BM-MSC into C57BL/6 mice after 3 days post IV challenge strongly increased IV clearance, decreased alveolar injury and was associated with better outcome. Of note, BM-MSCs also increased the regenerative response of the epithelial stem/progenitor cell pool of the distal lung in vivo. Interferon alpha and beta receptor knockout (ifnar-/-) mice after IV infection could not clear the virus even under BM-MSCs treatment, demonstrating that the type I IFN pathway is responsible for the BM-MSC anti-viral (and concomitantly, anti-apoptotic) potential in vivo. In conclusion, our ex vivo as well as in vivo experiments show a beneficial role of BM-MSCs in IV pneumonia and demonstrate the therapeutic potential of these cells in IV-induced lung injury. Furthermore, the upregulation of type I IFN signaling-related pathways suggests that these cells are activated in a pathogen-specific way in presence of virus, which enhances their beneficial properties.Influenza Virus (IV) infiziert die oberen Atemwege, kann sich aber auch bis in die Alveolen ausbreiten und eine primäre virale Pneumonie verursachen. In schweren Fällen kommt es zum akuten Lungenversagen (Acute Lung Injury(ALI)/ Acute Respiratory Distress Syndrome (ARDS)). ARDS ist gekennzeichnet durch eine schwere Schädigung des alveolären Epithels, die Ausbildung einer refraktären Hypoxämie und die Bildung von Lungenödemen. Eine antivirale Therapie ist nur in den ersten Stunden nach der Infektion wirksam, weitere Therapiemöglichkeiten für IV-induziertes ALI/ARDS sind noch nicht vorhanden. Mesenchymale Stammzellen (MSC) sind multipotente Zellen, denen seit kurzem eine positive Wirkung auf die Entzündungsauflösung und Regenerierung des Lungenepithels bei akuter oder chronischer Verletzung zugeschrieben wird. In der vorliegenden Arbeit wurde die intratracheale Applikation von MSC als vielversprechende Behandlungsmöglichkeit bei IV-induziertem ARDS untersucht. In Rahmen dieser Studie wurden MSC aus dem Knochenmark (murine bone marrow MSC (BM-MSC)) von C57BL/6 Mäusen gewonnen. BM-MSC haben eine fibroblastenartige Form, exprimieren stammzellspezifische Marker und besitzen das Potential unter bestimmten Kulturbedingungen in andere Zelltypen zu differenzieren. Bis Passage 18 konnten keine phänotypischen Veränderungen in isolierten BM-MSC beobachtet werden. Der Einfluss von BM-MSC auf IV-infizierte primäre alveoläre Epithelzellen (infected alveolar epithelial cells (iAEC)) wurde in einem in vitro Ko-Kulturmodell untersucht und mit iAEC in Monokultur verglichen. Die Expressionsanalyse von ko-kultivierten iAEC zeigte eine deutliche Hochregulation von Genen, beteiligt an Prozessen der Zellproliferation (Zellteilung, Cycline), Interferon-Signalwegen (ISGs), sowie von Virusresistenzgenen (Mx2, Bst2/Tetherin). Des Weiteren wiesen iAEC in Ko-Kultur oder durch Zugabe von MSC-konditioniertem Medium eine stark verminderte Apoptose- und IV Replikationsrate, sowie eine erhöhte Regenerationsfähigkeit auf. In in vivo Versuchen konnte durch die intratracheale Applikation von BM-MSC die Viruslast sowie die Schädigung des Alveolarepithels in IV-infizierten Mäusen deutlich verringert werden. Darüber hinaus konnte auch eine erhöhte Proliferationsrate der epithelialen Stamm/Progenitorzellen in der distalen Lunge detektiert werden. Insgesamt zeigt dies eine Verbesserung der Regenerationsfähigkeit des Lungenepithels durch die Gabe von BM-MSC. In weiteren in vivo Infektionsversuchen mit Interferon-/-Rezeptor-Knockout-Mäusen (ifnar-/-) konnte gezeigt werden, dass Typ I Interferon-induzierte Signalwege an den beobachteten antiviralen Effekten der BM-MSC-Gabe beteiligt sind. Infizierte ifnar-/- -Mäuse waren, auch nach BM-MSC-Applikation, nicht in der Lage die Viruslast in der Lunge zu verringern. Zusammenfassend ist zu sagen, dass die positive Rolle von BM-MSC in der IV-induzierten Pneumonie und dem damit verbunden therapeutischen Potential in in vitro und in vivo Versuchen klar dargelegt werden konnte. Des Weiteren lässt die Hochregulation der durch Typ I Interferon induzierten Signalwege vermuten, dass BM-MSC in der Gegenwart von IV spezifisch aktiviert werden, wodurch sich ihre vorteilhaften anti-viralen Eigenschaften noch erhöhen

Younger Children with Respiratory Tract Infections Are More Exposed to Off-Label Treatments: An Exploratory Retrospective Study in a Pediatric Emergency Setting

Off-label drug use is prevalent in the pediatric population and represents a patient safety concern. We aimed to identify factors for off-label drug use in our pediatric emergency department (PED). Methods. We performed a retrospective data analysis. All patients aged 0–18 referred to PED from 1 September to 1 October 2022, were included. Further analysis was performed when respiratory tract infections were diagnosed. Data collected: gender, age, triage group, chronic diseases, vital signs, and PED-prescribed treatment (medications, dosages, methods of administration). Statistical analysis used SPSS 28.0, with significance at p p n = 16, 100%) and inappropriate use of salbutamol inhalations by age (34.8%, n = 16). Some medications were given orally instead of injections (ondansetron n = 5, 62.5%; dexamethasone n = 82, 98.7%) or intranasally instead of intravenously (IV) (midazolam n = 7, 87.5%). IV adrenalin was prescribed for inhalations (n = 46). Younger children were more likely to receive off-label treatment (p < 0.001). Conclusion. Our study highlights the widespread issue of off-label and unlicensed drug prescribing in pediatric emergency care. Further research is necessary, because this reliance on off-label prescribing raises concerns about patient safety and compliance, especially given the limited clinical trials and therapeutic options available

Unusual case of chronic recurrent multifocal osteomyelitis

Abstract Background Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory bone disorder that primarily affects young girls, with a mean age of 10 years at onset. Generally, it is a self-limited disease. However, recent data indicate that more than 50% of patients have a chronic persistent disease and about 20% a recurring course of this condition. Also, there are more cases reported with associated auto-inflammatory and autoimmune diseases. In this case report, we present a rare case of sporadic CRMO in which the patient eventually developed C-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies)-associated renal vasculitis and hyperparathyroidism. Case presentation A 14 year old female patient was brought to the emergency department with a sudden onset of left leg pain and oedema. After physical evaluation and initial investigation, she was diagnosed with femoral and pelvic deep vein thrombosis. While searching for possible thrombosis causes, osteomyelitis of the left leg was identified. Additional CT and MRI scans hinted at the CRMO diagnosis. Due to the multifocal lesions of CRMO, endocrinological evaluation of calcium metabolism was done. The results showed signs of hyperparathyroidism with severe hypocalcaemia. Moreover, when kidney damage occurred and progressed, a kidney biopsy was performed, revealing a C-ANCA associated renal vasculitis. Treatment was started with cyclophosphamide and prednisolone according to the renal vasculitis management protocol. Severe metabolic disturbances and hyperparathyroidism were treated with alfacalcidol, calcium and magnesium supplements. Secondary glomerulonephritis (GN) associated hypertension was treated with ACE (angiotenzine converting enzyme) inhibitors. Anticoagulants were prescribed for deep vein thrombosis. After 1.5 years of treatment, the patient is free of complaints. All microelement and parathormone levels are within normal range. Kidney function is now normal. To date, there are no clinical or diagnostic signs of deep vein thrombosis. Conclusions This case report presents a complex immunodysregulatory disorder with both auto-inflammatory and autoimmune processes. We hypothesize that the long lasting active inflammation of CRMO may induce an autoimmune response and result in concomitant diseases like C-ANCA-associated vasculitis in our patient. Any potential specific pathogenic relationships between these two rare pathologies may need to be further studied. Furthermore, there is a lack of specific biomarkers for CRMO and more studies are necessary to identify CRMO’s characteristic patterns and how to best monitor disease progression

Platelet-Derived Biomarkers: Potential Role in Early Pediatric Serious Bacterial Infection and Sepsis Diagnostics

Fever is the most common complaint of children who are attending a pediatric emergency department (PED). Most of the fever cases are of viral origin; however, the most common markers, such as leucocyte, neutrophil count, or C-reactive protein, are not sensitive or specific enough to distinguish the etiology of fever, especially if children present at the early phase of infection. Currently, platelets have been attributed a role as important sentinels in viral and bacterial infection pathogenesis. Thus, our aim was to analyze different platelet indices, such as PNLR (platelet-to-neutrophil/lymphocyte ratio), PNR (platelet-to-neutrophil ratio) as well as specific secreted proteins, such as sP-selectin, CXCL4, CXCL7, and serotonin. We included 68 children who were referred to PED with the early onset of fever (&lt;12 h). All children with comorbidities, older than five years, and psychiatric diseases, who refused to participate were excluded. All the participants were divided into viral, bacterial, or serious bacterial infection (SBI) groups. All the children underwent blood sampling, and an additional sample was collected for protein analysis. Our analysis revealed statistically significant differences between leucocyte, neutrophil, and CRP levels between SBI and other groups. However, leucocyte and neutrophil counts were within the age norms. A higher PNLR value was observed in a bacterial group, PNR-in viral. As we tested CXCL7 and sP-selectin, alone and together those markers were statistically significant to discriminate SBI and sepsis from other causes of infection. Together with tachypnoe and SpO2 &lt; 94%, it improved the prediction value of sepsis as well as SBI. CXCL4 and serotonin did not differ between the groups. Concluding, CXCL7 and sP-selectin showed promising results in early SBI and sepsis diagnosis