Cytokine landscape in hospitalized children with multisystem inflammatory syndrome.

The etiology of multisystem inflammatory syndrome in children (MIS-C), frequently observed following COVID-19 infection, remains elusive. This study unveils insights derived from cytokine analysis in the sera of MIS-C patients, both before and after the administration of intravenous immunoglobulin (IVIG) and glucocorticosteroids (GCS). In this study, we employed a comprehensive 45-cytokine profile encompassing a spectrum of widely recognized proinflammatory and antiinflammatory cytokines, as well as growth factors, along with other soluble mediators. The analysis delineates three principal cytokine-concentration patterns evident in the patients' sera. Pattern no.1 predominantly features proinflammatory cytokines (IL-6, IL-15, IL-1ra, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor α (TNFα), C-X-C motif chemokine ligand 10 (CXCL10/ IP-10), and IL-10) exhibiting elevated concentrations upon admission, swiftly normalizing post-hospital treatment. Pattern no. 2 includes cytokines (IL-17 A, IL-33, IFNγ, vascular endothelial growth factor (VEGF), and programmed death ligand (PD-L1)) with moderately elevated levels at admission, persisting over 7-10 days of hospitalization despite the treatment. Pattern no. 3 comprises cytokines which concentrations escalated after 7-10 days of hospitalization and therapy, including IL-1α, IL-1ß, IL-2, IL-13, platelet-derived growth factor AA/BB (PDGF AA/BB). The observed in cytokine profile of MIS-C patients showed a transition from acute inflammation to sustaining inflammation which turned into induction of humoral memory mechanisms and various defense mechanisms, contributing to recovery.

A Comparison of Kawasaki Disease during the SARS-CoV-2 Pandemic with Multisystem Inflammatory Syndrome in Children.

OBJECTIVES: The purpose of this study was to compare and contrast Kawasaki disease (KD) with multisystem inflammatory syndrome in children (MIS-C) during the SARS-CoV-2 pandemic. METHODS: A retrospective analysis of the medical records of patients diagnosed with KD and MIS-C at a single institution from July 2020 to November 2021 was performed. RESULTS: The study included 39 MIS-C patients (84.6% male) with a median age of 138 months and 17 KD patients (58.8% male) with a median age of 36 months. The MIS-C patients were older (p < 0.001) and had prolonged hospitalizations (p = 0.023), elevated neutrophil counts (p < 0.001), C-reactive protein (p < 0.001), procalcitonin (p < 0.001), interleukin-6 (p < 0.014), ferritin (p < 0.001), fibrinogen (p < 0.001), troponin I (p = 0.001), NT-proBNP (p < 0.001), and D-dimer levels (p < 0.001). There were more cases of hypotension (p = 0.024), decreased left ventricular function (p = 0.023), and a greater need for corticosteroids (p < 0.001), enoxaparin (p = 0.045), and therapeutic plasma exchange (p < 0.001). Kawasaki disease patients had a greater incidence of rash (p < 0.001), changes in oral mucosa (p < 0.001), conjunctival injection (p < 0.001), extremity changes (p < 0.001), and cervical lymphadenopathy (p < 0.001). They had a longer duration of fever (p < 0.001), elevated white blood cell count (p < 0.001), platelet count (p < 0.001), and alanine aminotransferase level (p < 0.001). The two groups were similar regarding the hemoglobin levels, erythrocyte sedimentation rates, albumin levels, and the frequency of coronary aneurysm, myocarditis, pericarditis, invasive mechanical ventilatory support, and intravenous immunoglobulin treatment. CONCLUSIONS: Advanced patient age, a greater presence of gastrointestinal and cardiac findings associated with hypotension, increased NT-proBNP levels, decreased left ventricular function, the use of various treatment modalities, and longer hospital stays suggest MIS-C, whereas prolonged fever and classical clinical features of KD favor KD.

Short- and medium-term longitudinal outcomes of children diagnosed with multisystem inflammatory syndrome in children - report from a single centre in Pakistan.

OBJECTIVE: To determine the short- and medium-term cardiac outcomes in children admitted with multisystem inflammatory syndrome in children at a tertiary care centre in Pakistan. METHODS: Children fulfilling the criteria for multisystem inflammatory syndrome and admitted to the hospital between April 2020 and March 2022 were enrolled in this prospective longitudinal cohort study. From admission to discharge, laboratory and cardiac parameters were recorded for all patients, who were subsequently followed up in clinics at various intervals. Data analysis was conducted using STATA version 15.0. RESULTS: A total of 51 children were included, with viral myocarditis (41.2%) and toxic shock syndrome (33.3%) being the most common phenotypes. The cardiovascular system was most commonly affected in 27 children (53%) with laboratory evidence of inflammation and myocardial injury with median and interquartile levels of ferritin 1169 (534-1704), C-reactive protein 83 (24-175), lactate dehydrogenase 468 (365-1270), N-terminal pro-B-type natriuretic peptide 8,656 (2,538-31,166), and troponin 0.16 (0.02-2.0).On admission, decreased left ventricular ejection fraction was observed in 58.8% of patients and impaired global longitudinal strain in 33.3%. At discharge, left ventricular ejection fraction had normalised in 83% of patients. Pericardial effusion resolved in all patients, and valvulitis resolved in 86% by 12 months. Paediatric ICU admission was required in 42 (82%) of patients with an overall mortality of 12% (n = 6). CONCLUSION: Our study finds high hospital mortality for multisystem inflammatory syndrome in children compared to 1-2% from previous studies. Yet, in Pakistan, surviving children with multisystem inflammatory syndrome show favourable short- to medium-term cardiac outcomes.

Kawasaki Disease Diagnosis and Treatment in over 1000 Patients: A Continuum of Dysregulated Inflammatory Responses.

BACKGROUND: Kawasaki disease (KD) is a pediatric vasculitis, leading to coronary artery aneurysms (CAAs) in ~4-14%. Attention to the etiology and course of KD was generated by the close mimic of a SARS-CoV-2-induced phenotype, called multisystem inflammatory syndrome in children (MIS-C). METHODS: A total of 1179 cases were collected from 2012 with ~50% of cases retrospectively included. Clinical characteristics were described and risk factors for CAA (persistence) were investigated. Phenotypic patterns of the prospectively included KD patients were evaluated. These patterns were also compared to the seronegative KD and seropositive MIS-C cases identified during the SARS-CoV-2 pandemic. RESULTS: KD mostly affected boys and children < 5 years. IVIG resistance, CAAs, and giant CAAs occurred in 24.5%, 21.4%, and 6.6%, respectively. Giant CAAs were significantly more likely to normalize to a normal Z score in patients that were younger than 2.5 years old at the time of initial giant CAA (χ2 test p = 0.02). In our prospective (SARS-CoV-2-seronegative) KD series, there was a diminishing male predominance over time, whereas the proportions of incomplete presentations (p < 0.001) and patients with circulatory shock (p = 0.04) increased since the COVID-19 pandemic. Pre- and post-pandemic KD cases presented with different levels of C-reactive protein, thrombocyte counts, and hemoglobin levels over the years. Compared to pandemic KD, SARS-CoV-2-seropositive MIS-C patients were older (p < 0.001), and more often required intensive care admission (p < 0.001), with a gradual decrease over time between 2020 and 2022 (p = 0.04). KD carried a substantial risk of CAA development in contrast to MIS-C. CONCLUSION: the phenotypic changes seen over the last twelve years of our prospective follow-up study suggest a spectrum of hyperinflammatory states with potentially different triggering events within this clinical entity.

Multisystem inflammatory syndrome in children across 16 Latin American countries: A multicenter study from the REKAMLATINA Network.

Objectives: Our aim was to describe the epidemiology and outcomes of multisystem inflammatory syndrome in children (MIS-C) in Latin America. Methods: We conducted an observational, retrospective, and prospective multicenter study that gathered information from 84 participating centers across 16 Latin American countries between August 1, 2020 and June 30, 2022. Results: Of the 1239 reported children with MIS-C, 84.18% were previously healthy. The most frequent clinical manifestation in our studied population was abdominal pain (N = 804, 64.9%), followed by conjunctival injection (N = 784, 63.3%). The median duration of fever at the time of hospital admission was 5 days and a significant number of subjects required admission to an intensive care unit (N = 589, 47.5%). Most of the subjects (N = 1096, 88.7%) were treated with intravenous immunoglobulin, whereas 76.7% (N = 947) were treated with steroids, of whom 10.6% (N = 100) did not receive intravenous immunoglobulin. The death rate attributed to MIS-C was 4.88%, with a rate of 3.39% for those initially diagnosed with MIS-C and 8.85% for those whose admission diagnosis was not MIS-C (P <0.001, odds ratio 2.76, 95% confidence interval 1.6-4.6). Conclusions: One of the most significant findings from our study was the death rate, especially in those not initially diagnosed with MIS-C, in whom the rate was higher. This highlights the importance of increasing awareness and making an earlier diagnosis of MIS-C in Latin America.

Cardiac manifestations and outcomes of COVID-19 vaccine-associated myocarditis in the young in the USA: longitudinal results from the Myocarditis After COVID Vaccination (MACiV) multicenter study.

Background: We aimed to study the clinical characteristics, myocardial injury, and longitudinal outcomes of COVID-19 vaccine-associated myocarditis (C-VAM). Methods: In this longitudinal retrospective observational cohort multicenter study across 38 hospitals in the United States, 333 patients with C-VAM were compared with 100 patients with multisystem inflammatory syndrome in children (MIS-C). We included patients ≤30 years of age with a clinical diagnosis of acute myocarditis after COVID-19 vaccination based on clinical presentation, abnormal biomarkers and/or cardiovascular imaging findings. Demographics, past medical history, hospital course, biochemistry results, cardiovascular imaging, and follow-up information from April 2021 to November 2022 were collected. The primary outcome was presence of myocardial injury as evidenced by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. Findings: Patients with C-VAM were predominantly white (67%) adolescent males (91%, 15.7 ± 2.8 years). Their initial clinical course was more likely to be mild (80% vs. 23%, p < 0.001) and cardiac dysfunction was less common (17% vs. 68%, p < 0.0001), compared to MIS-C. In contrast, LGE on CMR was more prevalent in C-VAM (82% vs. 16%, p < 0.001). The probability of LGE was higher in males (OR 3.28 [95% CI: 0.99, 10.6, p = 0.052]), in older patients (>15 years, OR 2.74 [95% CI: 1.28, 5.83, p = 0.009]) and when C-VAM occurred after the first or second dose as compared to the third dose of mRNA vaccine. Mid-term clinical outcomes of C-VAM at a median follow-up of 178 days (IQR 114-285 days) were reassuring. No cardiac deaths or heart transplantations were reported until the time of submission of this report. LGE persisted in 60% of the patients at follow up. Interpretation: Myocardial injury at initial presentation and its persistence at follow up, despite a mild initial course and favorable mid-term clinical outcome, warrants continued clinical surveillance and long-term studies in affected patients with C-VAM. Funding: The U.S. Food and Drug Administration.

Cardiac effects of COVID-19 infection in children.

BACKGROUND: It is known established that the cardiac effects of COVID-19 infection are associated with poor prognosis and high mortality rates in infected patients. The aim of this study was to evaluate the cardiac effects of COVID-19 infection in paediatric patients and identify the correlations between clinical and laboratory data and the degree of cardiac involvement. MATERIALS AND METHODS: A retrospective data analysis was conducted on 64 paediatric patients at Gazi University Department of Pediatrics who were treated as inpatients with a diagnosis of COVID-19. Patients were classified as "COVID-19-related cardiac involvement cases" if their electrocardiogram and echocardiogram results indicated a pathology and/or if their laboratory data indicated increased cardiac enzymes. All patients were divided into subgroups based on whether they had cardiac involvement and whether they were diagnosed with multisystem inflammatory syndrome in children. RESULTS: In comparison to patients who did not have cardiac involvement, those with cardiac involvement had significantly higher levels of hs-Troponin T, Pro-BNP, and D-dimer. Patients with multisystem inflammatory syndrome in children had significantly longer PR intervals than those without multisystem inflammatory syndrome in children (p = 0.0001). Patients with multisystem inflammatory syndrome in children had a significantly higher rate of pathological valve insufficiencies (68.1%) than those without multisystem inflammatory syndrome in children (14.2%) (p = 0.001). CONCLUSION: In our study, the strongest predictive biomarker of cardiac involvement in paediatric patients with COVID-19 infection was determined to be hs-Troponin T. It was observed that pathologic electrocardiogram changes could reflect cardiac involvement in the absence of any other signs. Patients with multisystem inflammatory syndrome in children exhibited significantly greater rates of pathologic echocardiogram findings and myocardial dysfunction than those without multisystem inflammatory syndrome in children. In all patients, pathologic electrocardiogram and echocardiogram findings were found to be strongly associated with the severity of inflammation.

Long-term health outcome and quality of life in children with multisystem inflammatory syndrome: findings from multidisciplinary follow-up at an Italian tertiary-care paediatric hospital.

Multisystem inflammatory syndrome is a severe complication of SARS-CoV-2 infection in children (MIS-C). To date, data on long-term sequelae mainly concern cardiac outcomes. All ≤ 18 year olds consecutively admitted to the Buzzi Children's Hospital with a diagnosis of MIS-C between October 1, 2020, and May 31, 2022, were followed up for up to 12 months by a dedicated multidisciplinary team. They underwent laboratory tests, multi-organ clinical and instrumental assessments, and psychosocial evaluation. 56/62 patients, 40 M, mean age 8.7 years (95% CI 7.7, 9.7), completed the follow-up. Cardiological, gastroenterological, pneumological, and neurological evaluations, including IQ and EEG, were normal. Alterations of HOMA-IR index and/or TyG index, observed in almost all patients during hospitalisation, persisted in about a third of the population at 12 months. At 6 and 12 months respectively, impairment of adaptive functions was observed in 38/56 patients (67.9%) and 25/56 (44.6%), emotional and behavioural problems in 10/56 (17.9%) and 9/56 (16.1%), and decline in QoL in 14/56 (25.0%) and 9/56 (16.1%). Psychosocial well-being impairment was significantly more frequent in the subgroup with persistent glycometabolic dysfunction at 12 months (75% vs. 40.9% p < 0.001). CONLUSION: The mechanisms that might explain the long-term persistence of both metabolic alterations and neuro-behavioural outcomes and their possible relationship are far from being clarified. Our study points out to the potential long-term effects of pandemics and to the importance of a multidisciplinary follow-up to detect potential negative sequelae in different areas of health, both physical and psychosocial. WHAT IS KNOWN: • Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. • Few data exist on the medium- and long-term outcomes of MIS-C, mostly focused on cardiac involvement. Emerging evidence shows neurological and psychological sequelae at mid- and long-term follow-up. WHAT IS NEW: • This study reveals that MIS-C may lead to long-term glycometabolic dysfunctions joined to impairment in the realm of general well-being and decline in quality of life, in a subgroup of children. • This study highlights the importance of a long-term multidisciplinary follow-up of children hospitalised with MIS-C, in order to detect the potential long-term sequelae in different areas of health, both physical and psychosocial well-being.

Características del síndrome inflamatorio multisistémico asociado a COVID-19 en niños atendidos en un hospital peruano, 2020-2022 / Characteristics of COVID-19-associated multisystemic inflammatory syndrome in children treated in a Peruvian hospital, 2020-2022

RESUMEN El propósito del estudio fue describir las características del síndrome inflamatorio multisistémico asociado a COVID-19 (SIM-C) en los primeros tres años de pandemia en niños de un hospital pediátrico del Perú. Se realizó un estudio observacional, descriptivo con datos de 73 pacientes y se describieron las características clínicas, laboratoriales, tratamiento y complicaciones según la ola de la pandemia y si tuvieron shock. La mediana de edad fue 6 años, las manifestaciones gastrointestinales y mucocutáneas fueron frecuentes en las tres olas. El fenotipo similar a enfermedad de Kawasaki se presentó en 34 (46,6%) pacientes y 21 (28,8%) pacientes desarrollaron shock. El tratamiento más usado fue la inmunoglobulina (95,9%), ácido acetil salicílico (94,5%) y corticoide (86,3%). Cinco (7%) pacientes tuvieron aneurisma coronario y 17 (23,3%) ingresaron a la unidad de cuidados intensivos (UCI). Los pacientes con shock tuvieron mayor alteración laboratorial y necesidad de ventilación mecánica. En conclusión, el SIM-C ha disminuido en los primeros tres años de pandemia posiblemente por la vacunación de COVID-19 en niños.

ABSTRACT This study aimed to describe the characteristics of multisystemic inflammatory syndrome associated with COVID-19 (MIS-C) in the first three years of the pandemic in children in a pediatric hospital in Peru. We conducted an observational, descriptive study with data from 73 patients and described the clinical and laboratory characteristics, treatment and complications according to the wave of the pandemic and whether they had shock. The median age was 6 years, gastrointestinal and mucocutaneous manifestations were frequent in the three waves. Kawasaki disease-like phenotype was present in 34 (46.6%) patients and 21 (28.8%) patients developed shock. The most commonly used treatment was immunoglobulin (95.9%), followed by acetylsalicylic acid (94.5%) and corticosteroid (86.3%). Five (7%) patients had coronary aneurysm and 17 (23.3%) were admitted to the intensive care unit (ICU). Patients with shock had greater laboratorial alteration and need for mechanical ventilation. In conclusion, MIS-C has decreased in the first three years of the pandemic, possibly due to COVID-19 vaccination in children.

The changes of coagulation profiles in Kawasaki disease and its associations with clinical classification, intravenous immunoglobulin responsiveness and coronary artery involvement.

Coagulation disorders are common in Kawasaki disease (KD). The main objectives of the present study were to probe the associations of coagulation profiles with clinical classification, IVIG responsiveness, coronary artery abnormalities (CAAs) in the acute episode of KD. A total of 313 KD children were recruited and divided into six subgroups, including complete KD (n = 217), incomplete KD (n = 96), IVIG-responsive KD (n = 293), IVIG-nonresponsive KD (n = 20), coronary artery noninvolvement KD (n = 284) and coronary artery involvement KD (n = 29). Blood samples were collected within 24-h pre-IVIG therapy and 48-h post-IVIG therapy. Coagulation profiles, conventional inflammatory mediators and blood cell counts were detected. Echocardiography was performed during the period from 2- to 14-day post-IVIG infusion. In addition, 315 sex- and age-matched healthy children were enrolled as the controls. (1) Before IVIG therapy, coagulation disorders were more prone to appear in KD patients than in healthy controls, and could be overcome by IVIG therapy. FIB and DD significantly increased in the acute phase of KD, whereas reduced to normal levels after IVIG therapy. (2) PT and APTT were significantly longer in patients with complete KD when compared with their incomplete counterparts after IVIG therapy. (3) The larger δDD, δFDP and the smaller δPT, δINR predicted IVIG nonresponsiveness. (4) The higher δDD and δFDP correlated with a higher risk for CAAs (DD: r = -0.72, FDP: r = -0.54). Coagulation disorders are correlated with complete phenotype, IVIG nonresponsiveness and CAA occurrence in the acute episode of KD, and can be rectified by synergistic effects of IVIG and aspirin.

Criteria for Cytokine Storm Syndromes.

In the past two decades, there has been a great deal of work aimed to devise diagnostic guidelines, classification criteria, and diagnostic scores for cytokine storm syndromes (CSSs). The most notable effort has been the large-scale multinational study that led to the development of the 2016 classification criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). Future studies should scrutinize the validity of the proposed criteria, particularly in systemic JIA patients treated with biologics, in children with subtle or incomplete forms of MAS, and in patients with MAS complicating other rheumatologic disorders. More generic CSS criteria are also available but often lack sensitivity and specificity in a wide variety of patient populations and CSSs of different etiologies. The coronavirus disease 2019 (COVID-19)-related lung disease led to an evolution of the concept of a "cytokine storm." Emerging and unsolved challenges in the diagnosis of the different forms of CSSs highlight the need for diagnostic tools and well-established classification criteria to enable timely recognition and correct classification of patients.

Kawasaki Disease-Associated Cytokine Storm Syndrome.

Kawasaki disease (KD) is a hyperinflammatory syndrome manifesting as an acute systemic vasculitis characterized by fever, nonsuppurative conjunctival injection, rash, oral mucositis, extremity changes, and cervical lymphadenopathy. KD predominantly affects young children and shares clinical features and immunobiology with other hyperinflammation syndromes including systemic juvenile idiopathic arthritis (sJIA) and multisystem inflammatory syndrome in children (MIS-C). Cytokine storm syndrome (CSS) is an acute complication in ~2% of KD patients; however, the incidence is likely underestimated as many clinical and laboratory features of both diseases overlap. CSS should be entertained when a child with KD is unresponsive to IVIG therapy with recalcitrant fever. Early recognition and prompt institution of immunomodulatory treatment can substantially reduce the mortality and morbidity of CSS in KD. Given the known pathogenetic role of IL-1ß in both syndromes, the early use of IL-1 blockers in refractory KD with CSS deserves consideration.

COVID-19-Related Multi-systemic Inflammatory Syndrome in Children (MIS-C).

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections in children. This syndrome manifests about a month after the initial viral infection and is characterized by fever, multiorgan dysfunction, and systemic inflammation. This chapter will review the emergence, epidemiology, clinical characteristics, diagnosis, pathophysiology, immunomodulatory treatment, prognosis, outcomes, and prevention of MIS-C. While the pathophysiology of MIS-C remains to be defined, it is a post-infection, hyperinflammatory syndrome of childhood with elevated inflammatory cytokines.

SARS-CoV-2 parental vaccination and risk of multisystem inflammatory syndrome in children: a single-center retrospective study.

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) usually causes a mild disease in children and the most serious consequence is multisystem inflammatory syndrome in children (MIS-C). Currently, there are no data about the protective role of vaccination performed by parents on children regarding the development of MIS-C. The aim of our study is to establish whether parental vaccination is related to MIS-C and the protective value of SARS-CoV-2 vaccination performed by parents against the occurrence of MIS-C in their children. Materials and Methods: Our retrospective single center study included 124 patients aged 1 month to 18 years admitted to emergency department from April 2020 to March 2022 for coronavirus disease 2019 disease. Results: Parental vaccination was negatively correlated with the development of MIS-C: 4% of patients with both parents vaccinated developed MIS-C, while patients with no parent vaccinated to have developed MIS-C were 20%. Conclusion: Parental vaccination could be an important factor influencing the course of the disease and reduces the probability that a child would develop MIS-C by 83% if both parents vaccinated.

Hospitalized children with COVID-19 infection during large outbreak of SARS-CoV-2 Omicron strain: a retrospective study in Chaozhou, Guangdong, China.

OBJECTIVE: We aimed to investigate the clinical findings of hospitalized paediatric COVID-19 patients by the end of 2022. METHOD: All confirmed children with COVID-19 infection admitted into Chaozhou Central Hospital during the COVID-19 outbreak from 19 December 2022 to 1 February 2023 were included. Detailed clinical data of those children were evaluated retrospectively. RESULTS: A total of 286 children, ranging in age from 1 month to 13 years old, were diagnosed with SARS-CoV-2 infection. Among these cases, 138 (48.3%) were categorized as mild, 126 (44.0%) as moderate and 22 (7.7%) as severe/critical. Symptoms varied among the children and included fever, upper respiratory tract symptoms, convulsions, sore throat, poor appetite, dyspnoea and gastrointestinal symptoms. Notably, febrile convulsions were observed in 96 (33.6%) patients, while acute laryngitis was documented in 50 (17.5%) cases. Among the severe/critical patients, eight developed multisystem inflammatory syndrome in children (MIS-C), and tragically, one patient's condition worsened and resulted in death. Furthermore, MRI scans revealed abnormal brain signals in six severe/critical patients. The severe/critical group also exhibited more pronounced laboratory abnormalities, including decreased haemoglobin and elevated ALT, AST, LDH and CK levels. CONCLUSIONS: Febrile convulsions and acute laryngitis are frequently observed in children diagnosed with SARS-CoV-2 Omicron infection. Moreover, MIS-C and abnormal neuroimaging appear to be relatively common phenomena in severe/critical cases.

Effectiveness of early Anakinra on cardiac function in children with multisystem inflammatory syndrome of COVID-19: a systematic review.

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) associated with SARS-CoV-2 can lead to severe cardiovascular complications. Anakinra, an interleukin-1 receptor antagonist, is proposed to benefit the hyperinflammatory state of MIS-C, potentially improving cardiac function. This systematic review evaluated the effectiveness of early Anakinra administration on cardiac outcomes in children with MIS-C. METHODS: A comprehensive search across PubMed, Embase, and Web of Science until March 2024 identified studies using Anakinra to treat MIS-C with reported cardiac outcomes. Observational cohorts and clinical trials were included, with data extraction focusing on cardiac function metrics and inflammatory markers. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Six studies met the inclusion criteria, ranging from retrospective cohorts to prospective clinical studies, predominantly from the USA. Anakinra dosages ranged from 2.3 to 10 mg/kg based on disease severity. Several studies showed significant improvements in left ventricular ejection fraction and reductions in inflammatory markers like C-reactive protein, suggesting Anakinra's role in enhancing cardiac function and mitigating inflammation. However, findings on vasoactive support needs were mixed, and some studies did not report significant changes in acute cardiac support requirements. CONCLUSION: Early Anakinra administration shows potential for improving cardiac function and reducing inflammation in children with MIS-C, particularly those with severe manifestations. However, the existing evidence is limited by the observational nature of most studies and lacks randomized controlled trials (RCTs). Further high-quality RCTs are necessary to conclusively determine Anakinra's effectiveness and optimize its use in MIS-C management for better long-term cardiac outcomes and standardized treatment protocols.

An epidemiological study of multisystem inflammatory syndrome in children (MIS-C) and young adults among COVID-19-positive patients - data from National Inpatient Sample database.

During the pandemic of COVID-19, a novel atypical set of clinical findings was seen among several children with recent or current exposure to the virus. It was termed the "multisystem inflammatory syndrome in children" (MIS-C). Our study used the 2021 National Inpatient Sample to study the associations of sex, race, and age with the incidence of MIS-C among COVID-19-positive children. Out of 69,440 COVID-19-positive children, 2,790 (4.0%) reported MIS-C. The incidence of MIS-C was highest among those aged 8 years old (17,130 MIS-C cases per 100,000 COVID-19 patients), Asian or Pacific Islanders (API) (5,346 MIS-C per 100,000 COVID-19 cases), and males (4,734 cases per 100,000 COVID-19 cases). Furthermore, 7.9% of MIS-C cases met the classification of Kawasaki disease.

Multisystem inflammatory syndrome in children with COVID-19 in a multitransfused patient.

Multi-system inflammatory syndrome in children associated with COVID19 (MIS-C) is a unique clinical syndrome characterised by fever, gastrointestinal symptoms, skin and oral rash and or neurological symptoms in the presence of raised acute phase reactants and coagulopathy. Ferritin is an acute phase reactant which is used as a marker of inflammation. Diagnosis of MIS-C in the background of transfusion dependent thalassemia with iron overload needs a strong clinical suspicion. Early diagnosis and prompt treatment are necessary to ensure a rapid uneventful recovery. A three-year-old male child born to non-consanguineously related parents reported to pediatric emergency with difficulty breathing and pain abdomen for one day. The child was a diagnosed case of Beta thalassemia major since the age of one year and was on regular transfusions and was on iron chelation for past eleven months with deferrasirox. Initial clinical examination showed a sick and irritable child with tachypnea tachycardia and hypoxia. Initial investigations showed raised acute phase reactants along with severe anemia. The child was investigated for MIS-C because of unexpected rise of serum ferritin from 1980 ng/mL (October 2020) to 6686 ng/mL (in January 2021) despite being on regular chelation. Antibody titre for SARS COVID-19 was positive. The patient was treated with intravenous corticosteroids and improved with the same. The advent of COVID19 pandemic saw most children having a mild disease with no or minimal symptoms. Some kids however presented with more serious delayed symptoms of MIS-C. To diagnose same in multi transfused patients a strong clinical suspicion and just judgement based on the clinical and laboratory findings should be done. Unexplained rise in ferritin levels, typical symptoms and high probability of exposure to COVID19 helped in clinching diagnosis.

MIS-C Treatment: Is glucocorticoid monotherapy enough for mild cases?

BACKGROUND: The effectiveness of using only glucocorticoids (GCs) in mild multisystem inflammatory syndrome (MIS-C) cases was compared with combined treatment [GCs + Intravenous immune globulin (IVIG)]. METHODS: This retrospective cohort study was conducted between June 1, 2020, and June 1, 2022, in a tertiary care center in Istanbul, Turkey. Clinical and investigational data of the MIS-C patients were analyzed. The patients were divided into two groups: those who received only GCs and those who received the GCs + IVIG combination. The primary outcome focused on assessing the deterioration of the patient's clinical condition, the occurrence of shock, admission to the pediatric intensive care unit (PICU), and the need for additional immunosuppressive medication. Secondary outcomes included evaluating the course of cardiovascular and infection-related complications observed at the one-year follow-up. RESULTS: Ninety-seven MIS-C patients with a median age of 41 (3- 214) months were enrolled. Fifty-six (57.7%) patients were male. All the patients had fever at admission with a temperature of 39 °C (37.5 °C-40.1 °C). Thirty-two patients (33%) had cardiac findings on echocardiography [left ventricular dysfunction (n= 13, 13.5%), coronary artery involvement (n= 11, 11.3%), and dilation of cardiac cavities and/or increased cardiac muscle thickness (n= 8, 8.2%)]. Thirteen patients (13.5%) required intensive care. All patients received GCs [only GCs (group I; n= 65, 67%)], and 32 patients (33%) with severe manifestations and/or cardiac involvement received GCs + IVIG (group II). No mortality was observed. None of the patients had any complaints at the one-year follow-up, and all echocardiography findings were normal. CONCLUSION: This study provides preliminary evidence that GC monotherapy is a safe treatment alternative for mild MIS-C cases without cardiac involvement.

Human Genetic and Immunological Determinants of SARS-CoV-2 Infection and Multisystem Inflammatory Syndrome in Children.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces pneumonia and acute respiratory failure in Coronavirus Disease 2019 (COVID-19) patients with inborn errors of immunity to type I interferon (IFN-I). The impact of SARS-CoV-2 infection varies widely, ranging from mild respiratory symptoms to life-threatening illness and organ failure, with a higher incidence in men than in women. Approximately 3 to 5% of critical COVID-19 patients under 60 and a smaller percentage of elderly patients exhibit genetic defects in IFN-I production, including X-chromosome-linked TLR7 and autosomal TLR3 deficiencies. Around 15 to 20% of cases over 70 years old, and a smaller percentage of younger patients, present with preexisting autoantibodies neutralizing type I interferons. Additionally, innate errors affecting the control of the response to type I interferon have been associated with pediatric multisystem inflammatory syndrome (MIS-C). Several studies have described rare errors of immunity, such as XIAP deficiency, CYBB, SOCS1, OAS1/2, and RNASEL, as underlying factors in MIS-C susceptibility. However, further investigations in expanded patient cohorts are needed to validate these findings and pave the way for new genetic approaches to MIS-C. This review aims to present recent evidence from the scientific literature on genetic and immunological abnormalities predisposing individuals to critical SARS-CoV-2 infection through IFN-I. We will also discuss multisystem inflammatory syndrome in children (MIS-C). Understanding the immunological mechanisms and pathogenesis of severe COVID-19 may inform personalized patient care and population protection strategies against future serious viral infections.