Mortality risk factors among critically ill children with MIS-C in PICUs: a multicenter study.

BACKGROUND: This study evaluated of clinical characteristics, outcomes, and mortality risk factors of a severe multisystem inflammatory syndrome in children admitted to a the pediatric intensive care unit. METHODS: A retrospective multicenter cohort study was conducted between March 2020 and April 2021 at 41 PICUs in Turkey. The study population comprised 322 children diagnosed with multisystem inflammatory syndrome. RESULTS: The organ systems most commonly involved were the cardiovascular and hematological systems. Intravenous immunoglobulin was used in 294 (91.3%) patients and corticosteroids in 266 (82.6%). Seventy-five (23.3%) children received therapeutic plasma exchange treatment. Patients with a longer duration of the PICU stay had more frequent respiratory, hematological, or renal involvement, and also had higher D-dimer, CK-MB, and procalcitonin levels. A total of 16 patients died, with mortality higher in patients with renal, respiratory, or neurological involvement, with severe cardiac impairment or shock. The non-surviving group also had higher leukocyte counts, lactate and ferritin levels, and a need for mechanical ventilation. CONCLUSIONS: In cases of MIS-C, high levels of D-dimer and CK-MB are associated with a longer duration of PICU stay. Non-survival correlates with elevated leukocyte counts and lactate and ferritin levels. We were unable to show any positive effect of therapeutic plasma exchange therapy on mortality. IMPACT: MIS-C is a life-threatening condition. Patients need to be followed up in the intensive care unit. Early detection of factors associated with mortality can improve outcomes. Determining the factors associated with mortality and length of stay will help clinicians in patient management. High D-dimer and CK-MB levels were associated with longer PICU stay, and higher leukocyte counts, ferritin and lactate levels, and mechanical ventilation were associated with mortality in MIS-C patients. We were unable to show any positive effect of therapeutic plasma exchange therapy on mortality.

The Notch1/CD22 signaling axis disrupts Treg cell function in SARS-CoV2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

Increased Severe Cases and New-Onset Type 1 Diabetes Among Children Presenting With Diabetic Ketoacidosis During First Year of COVID-19 Pandemic in Turkey

Introduction There have been some significant changes regarding healthcare utilization during the COVID-19 pandemic. Majority of the reports about the impact of the COVID-19 pandemic on diabetes care are from the first wave of the pandemic. We aim to evaluate the potential effects of the COVID-19 pandemic on the severity of diabetic ketoacidosis (DKA) and new onset Type 1 diabetes presenting with DKA, and also evaluate children with DKA and acute COVID-19 infection. Methods This is a retrospective multi-center study among 997 children and adolescents with type 1 diabetes who were admitted with DKA to 27 pediatric intensive care units in Turkey between the first year of pandemic and pre-pandemic year. Results The percentage of children with new-onset Type 1 diabetes presenting with DKA was higher during the COVID-19 pandemic (p < 0.0001). The incidence of severe DKA was also higher during the COVID-19 pandemic (p < 0.0001) and also higher among children with new onset Type 1 diabetes (p < 0.0001). HbA1c levels, duration of insulin infusion, and length of PICU stay were significantly higher/longer during the pandemic period. Eleven patients tested positive for SARS-CoV-2, eight were positive for new onset Type 1 diabetes, and nine tested positive for severe DKA at admission. Discussion The frequency of new onset of Type 1 diabetes and severe cases among children with DKA during the first year of the COVID-19 pandemic. Furthermore, the cause of the increased severe presentation might be related to restrictions related to the pandemic;however, need to evaluate the potential effects of SARS-CoV-2 on the increased percentage of new onset Type 1 diabetes.

Notch1-CD22-Dependent Immune Dysregulation in the SARS-CoV2-Associated Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators NUMB and NUMBL . Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

Diagnostic and Prognostic Biomarkers of Coronavirus Disease 2019 in Children.

Predictors of early diagnosis and severe infection in children with coronavirus disease 2019 (COVID-19), which has killed more than 4 million people worldwide, have not been identified. However, some biomarkers, including cytokines and chemokines, are associated with the diagnosis, pathogenesis and severity of COVID-19 in adults. We examined whether such biomarkers can be used to predict the diagnosis and prognosis of COVID-19 in pediatric patients. Eighty-nine children were included in the study, comprising three patient groups of 69 patients (6 severe, 36 moderate and 27 mild) diagnosed with COVID-19 by real-time polymerase chain reaction observed for 2-216 months and clinical findings and 20 healthy children in the same age group. Hemogram, coagulation, inflammatory parameters and serum levels of 16 cytokines and chemokines were measured in blood samples and were analyzed and compared with clinical data. Interleukin 1-beta (IL-1ß), interleukin-12 (IL-12) and interferon gamma-induced protein 10 (IP-10) levels were significantly higher in the COVID-19 patients (p = 0.035, p = 0.006 and p < 0.001). Additionally, D-dimer and IP-10 levels were higher in the severe group (p = 0.043 for D-dimer, area under the curve = 0.743, p = 0.027 for IP-10). Lymphocytes, C-reactive protein and procalcitonin levels were not diagnostic or prognostic factors in pediatric patients (p = 0.304, p = 0.144 and p = 0.67). Increased IL-1ß, IL-12 and IP-10 levels in children with COVID-19 are indicators for early diagnosis, and D-dimer and IP-10 levels are predictive of disease severity. In children with COVID-19, these biomarkers can provide information on prognosis and enable early treatment.

Clinical features and outcomes of 76 patients with COVID-19-related multi-system inflammatory syndrome in children.

OBJECTIVES: Multi-system inflammatory syndrome in children (MIS-C) is a less understood and a rare complication of coronavirus disease-2019 (COVID-19). Given the scarce data regarding this novel disease, we aimed to describe the clinical features and outcomes of our patients with MIS-C and to evaluate the associated factors for the pediatric intensive care unit (PICU) admission. METHODS: The MIS-C patients under 18 years old diagnosed and treated in three referral centers between July 2020 and March 2021 were included. Data of the patients were retrospectively obtained from their medical records. RESULTS: Overall, 76 subjects (24 females) with a mean age of 8.17 ± 4.42 years were enrolled. Twenty-seven (35.5%) patients were admitted to the PICUs. The two most common systemic involvement patterns were cardiac and gastrointestinal. There was only one lethal outcome in a patient with underlying acute lymphoblastic leukemia. Those with higher procalcitonin levels at admission were found to stay longer in the hospital (r = 0.254, p = 0.027). The risk of PICU admission increased with age (aOR: 1.277; 95% CI: 1.089-1.498; p = 0.003) and with decreased initial serum albumin levels (aOR: 0.105; 95% CI: 0.029-0.378; p = 0.001). CONCLUSION: Although there is a wide clinical variability among the patients with MIS-C, we suggest that those with older age and lower initial serum albumin levels merit close monitoring due to their higher risk for PICU admission. Key Points • Although there is a wide variability regarding the management process among clinicians, MIS-C is a rare, severe, less understood complication of COVID-19 that may cause rapid clinical deterioration in the patients. • Clinicians should be aware of this condition in children with persistent fever and a family history of COVID-19. • Older age and low serum albumin levels are the independent predictors for the pediatric intensive care unit admission among MIS-C patients.

Posterior Reversible Encephalopathy Syndrome in a Pediatric COVID-19 Patient.

Novel coronavirus disease 2019 is a viral infectious disease which commonly involve the lungs with primarily radiologic manifestations of atypical or organizing pneumonia. It can cause multisystemic involvement including central nervous system symptoms. One of these neurologic manifestations is posterior reversible encephalopathy syndrome (PRES). It is suggested that the increased levels of cytokines and inflammatory mediators in the course of the disease are responsible for cerebrovascular endothelial dysfunction and disruption of the blood-brain barrier. To the best of our knowledge, no pediatric PRES has been reported related to coronavirus disease 2019. Here, we present a pediatric PRES case associated with severe acute respiratory syndrome coronavirus 2 infection.

COVID-19 in Turkey: A tertiary center experience.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a serious epidemic in our country and all over the world since December 2019 and has become a global health problem. The disease caused by the SARS-CoV-2 virus has been named as coronavirus disease 19 (COVID-19). METHODS: We report on the epidemiological and clinical features of 37 children diagnosed with COVID-19. RESULTS: The median age was of the children was 10 years and 57.1% were male. In addition, 78.3% of the children had a history of contact with adult patients who had been diagnosed with COVID-19, and 27.0% had coexisting medical conditions. We found that 40.5% of our patients had mild infection, while 32.4% had moderate infection, and 27.1% had developed severe or critical illness. The most common abnormal laboratory findings in our patients were decreased lymphocytes (45.9%) and increased D-dimer values (43.2%), while abnormal radiological findings were detected in 56.7% of the children. In addition, 64.8% of the children had received azithromycin, 59.4% had received oseltamivir, and hydroxychloroquine was used in combination with azithromycin in 35.1% of the children. Non-invasive mechanical ventilation was required in 27.0% of the children. CONCLUSIONS: Although COVID-19 infection is usually mild in children, severe illness can be seen in children with comorbidities, or even in children who were previously healthy.