Polyclonal expansion of TCR Vbeta 21.3+ CD4+ and CD8+ T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vß21.3 T cell receptor ß chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vß21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vß21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

Acute cerebellar ataxia during acute COVID-19: A case series and review of the literature.

Acute coronavirus disease 2019 (COVID-19)-associated cerebellar ataxia without multisystem inflammatory syndrome in children (MIS-C) or encephalopathy in children has been rarely reported. We reviewed medical records of hospitalized children who had developed cerebellar ataxia during the acute phase of COVID-19 infection, without MIS-C or encephalopathy, in our center. We also conducted a literature review and summarized the clinical characteristics, treatment, and outcomes. We found three cases in our center and additional three cases in the literature. All patients were male and five were preschool children. The cerebellar symptoms started between day 2 and day 10 during the acute phase of the COVID-19 infection. Two cases were complicated by mutism. One patient received therapy for acute cerebellar ataxia with corticosteroids, and others did not receive any specific therapy for acute cerebellar ataxia. The symptoms improved completely in all patients, with the recovery interval ranging from one week to two months. Further studies are warranted to elucidate the pathogenesis of acute cerebellar ataxia during acute COVID-19 in children.

TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.

Multisystem Inflammatory Syndrome in a Pediatric Patient With Sickle Cell Disease and COVID-19: A Case Report.

To this day, there are limited data about the effects and management of coronavirus disease infection in pediatric patients with sickle cell disease. We present the management and successful clinical course of an 8-year-old female with homozygous sickle cell disease (SS) and severe acute chest syndrome secondary to coronavirus disease 2019 infection, complicated by cortical vein thrombosis.

Evidence of SARS-CoV-2-Specific T-Cell-Mediated Myocarditis in a MIS-A Case.

A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.

Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction.

Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. Here we perform a comprehensive analysis of the plasma proteome of more than 1400 proteins in children with SARS-CoV-2. We hypothesize that the proteome would reflect heterogeneity in hyperinflammation and vascular injury, and further identify pathogenic mediators of disease. We show that protein signatures demonstrate overlap between MIS-C, and the inflammatory syndromes macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). We demonstrate that PLA2G2A is an important marker of MIS-C that associates with TMA. We find that IFNγ responses are dysregulated in MIS-C patients, and that IFNγ levels delineate clinical heterogeneity.

COVID-19 and abdominal pain: a pediatric case report and a point of view in pediatric emergency medicine.

COVID-19 is to date a global pandemic that can affect all age groups; gastrointestinal symptoms are quite common in patients with COVID-19 and a new clinical entity defined as Multisystem Inflammatory Syndrome in Children (MIS-C) has been described in children and adolescents previously affected by COVID-19. Presenting symptoms of this new disease include high fever and severe abdominal pain that can mimic more common causes of abdominal pain; patients can rapidly deteriorate presenting severe cardiac dysfunction and multiorgan failure. Some fatalities due to this serious illness have been reported. We describe the case of a ten-year-old patient presenting with persistent high fever associated with continuous and worsening abdominal pain. Various hypotheses were performed during his diagnostic workup and an initial appendectomy was performed in the suspect of acute appendicitis. As his clinical picture deteriorated, the child was subsequently diagnosed and successfully treated as a case of MIS-C. The objective of this case report and brief review of abdominal pain in children throughout the age groups is to provide the emergency pediatrician with updated suggestions in diagnosing abdominal pain in children during the COVID-19 pandemic.

Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications.

The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders.

Systemic Inflammation Is Associated With Neurologic Involvement in Pediatric Inflammatory Multisystem Syndrome Associated With SARS-CoV-2.

OBJECTIVE: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a severe immune-mediated disorder. We aim to report the neurologic features of children with PIMS-TS. METHODS: We identified children presenting to a large children's hospital with PIMS-TS from March to June 2020 and performed a retrospective medical note review, identifying clinical and investigative features alongside short-term outcome of children presenting with neurologic symptoms. RESULTS: Seventy-five patients with PIMS-TS were identified, 9 (12%) had neurologic involvement: altered conciseness (3), behavioral changes (3), focal neurology deficits (2), persistent headaches (2), hallucinations (2), excessive sleepiness (1), and new-onset focal seizures (1). Four patients had cranial images abnormalities. At 3-month follow-up, 1 child had died, 1 had hemiparesis, 3 had behavioral changes, and 4 completely recovered. Systemic inflammatory and prothrombotic markers were higher in patients with neurologic involvement (mean highest CRP 267 vs 202 mg/L, p = 0.05; procalcitonin 30.65 vs 13.11 µg/L, p = 0.04; fibrinogen 7.04 vs 6.17 g/L, p = 0.07; d-dimers 19.68 vs 7.35 mg/L, p = 0.005). Among patients with neurologic involvement, these markers were higher in those without full recovery at 3 months (ferritin 2284 vs 283 µg/L, p = 0.05; d-dimers 30.34 vs 6.37 mg/L, p = 0.04). Patients with and without neurologic involvement shared similar risk factors for PIMS-TS (Black, Asian and Minority Ethnic ethnicity 78% vs 70%, obese/overweight 56% vs 42%). CONCLUSIONS: Broad neurologic features were found in 12% patients with PIMS-TS. By 3-month follow-up, half of these surviving children had recovered fully without neurologic impairment. Significantly higher systemic inflammatory markers were identified in children with neurologic involvement and in those who had not recovered fully.

Endothelial Dysfunction as a Component of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children With Shock.

TRIAL REGISTRATION: NCT04420468. OBJECTIVES: Severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children is frequently associated with shock; endothelial involvement may be one of the underlying mechanisms. We sought to describe endothelial dysfunction during multisystem inflammatory syndrome in children with shock and then assess the relationship between the degree of endothelial involvement and the severity of shock. DESIGN: Observational study. SETTING: A PICU in a tertiary hospital. PATIENTS: Patients aged under 18 (n = 28) with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children and shock, according to the Centers for Disease Control and Prevention criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Correlations between endothelial marker levels and shock severity were assessed using Spearman coefficient. The median (interquartile range) age was 9 years (7.5-11.2 yr). Sixteen children presented with cardiogenic and distributive shock, 10 presented with cardiogenic shock only, and two presented with distributive shock only. The median left ventricular ejection fraction, troponin level, and lactate level were, respectively, 40% (35-45%), 261 ng/mL (131-390 ng/mL), and 3.2 mmol/L (2-4.2 mmol/L). Twenty-five children received inotropes and/or vasopressors; the median Vasoactive and Inotropic Score was 8 (5-28). Plasma levels of angiopoietin-2 (6,426 pg/mL [2,814-11,836 pg/mL]), sE-selectin (130,405 pg/mL [92,987-192,499 pg/mL]), von Willebrand factor antigen (344% [288-378%]), and the angiopoietin-2/angiopoietin-1 ratio (1.111 [0.472-1.524]) were elevated and significantly correlated with the Vasoactive and Inotropic Score (r = 0.45, p = 0.016; r = 0.53, p = 0.04; r = 0.46, p = 0.013; and r = 0.46, p = 0.012, respectively). CONCLUSIONS: Endothelial dysfunction is associated with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children with shock and may constitute one of the underlying mechanisms.

Multisystem Inflammatory Syndrome Following SARS-CoV-2 Infection in Children: One Year after the Onset of the Pandemic in a High-Incidence Area.

SARS-CoV-2 infection in children can trigger cardiovascular manifestations potentially requiring an intensive treatment and defining a new entity named Multisystem Inflammatory Syndrome in Children (MIS-C), whose features partially overlap with Kawasaki Disease (KD). A cross-sectional study including all diagnoses of MIS-C and KD from April 2020 to May 2021 in our metropolitan area was conducted evaluating clinical, laboratory (including immunological response, cytokines, and markers of myocardial damage), and cardiac (coronary and non-coronary) features at onset of the diseases. Evolution of ventricular dysfunction, valve regurgitations, and coronary lesions was documented. The severity of the disease was also considered based on the need for inotropic support and ICU admission. Twenty-four MIS-C were diagnosed (14 boys, median age 82 months): 13/24 cases (54.17%) presented left ventricular dysfunction, 12/24 (50%) required inotropic support, and 10/24 (41.67%) developed coronary anomalies (CALs). All patients received steroids and IVIG at a median time of 5 days (IQR1:4, IQR3:6.5) from onset of fever and heart function normalized 6 days (IQR1: 5, IQR3: 7) after therapy, while CALs persisted in one. One patient (12.5%) required infliximab because of refractory disease and still presented CALs 18 days after therapy. During the same study period, 15 KD were diagnosed: none had ventricular dysfunction, while 7/15 (46.67%) developed CALs. Three out of 15 patients (20%) still presented CALs 46 days from onset. Compared to KD, MIS-C pts have significantly higher IL8 and similar lymphocytes subpopulations. Despite a more severe presentation and initial cardiac findings compared to KD, the myocardial injury in MIS-C has a rapid response to immunomodulatory treatment (median time 6 days), in terms of ventricular function, valve regurgitations, and troponin. Incidence of CALs is similar at onset, but it tends to regress in most of the cases of MIS-C differently than in KD where CALs persist in up to 40% in the subacute stage after treatment.

Osteopontin as a biomarker for COVID-19 severity and multisystem inflammatory syndrome in children: A pilot study.

This study sought to evaluate the candidacy of plasma osteopontin (OPN) as a biomarker of COVID-19 severity and multisystem inflammatory condition in children (MIS-C) in children. A retrospective analysis of 26 children (0-21 years of age) admitted to Children's Healthcare of Atlanta with a diagnosis of COVID-19 between March 17 and May 26, 2020 was undertaken. The patients were classified into three categories based on COVID-19 severity levels: asymptomatic or minimally symptomatic (control population, admitted for other non-COVID-19 conditions), mild/moderate, and severe COVID-19. A fourth category of children met the Centers for Disease Control and Prevention's case definition for MIS-C. Residual blood samples were analyzed for OPN, a marker of inflammation using commercial ELISA kits (R&D), and results were correlated with clinical data. This study demonstrates that OPN levels are significantly elevated in children hospitalized with moderate and severe COVID-19 and MIS-C compared to OPN levels in mild/asymptomatic children. Further, OPN differentiated among clinical levels of severity in COVID-19, while other inflammatory markers including maximum erythrocyte sedimentation rate, C-reactive protein and ferritin, minimum lymphocyte and platelet counts, soluble interleukin-2R, and interleukin-6 did not. We conclude OPN is a potential biomarker of COVID-19 severity and MIS-C in children that may have future clinical utility. The specificity and positive predictive value of this marker for COVID-19 and MIS-C are areas for future larger prospective research studies.

Host Genetics and Antiviral Immune Responses in Adult Patients With Multisystem Inflammatory Syndrome.

COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1ß, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.

Multisystem Inflammatory Syndrome in Children Presenting With Pseudotumor Cerebri and a Review of the Literature.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening inflammatory immune response associated with severe acute respiratory syndrome coronavirus 2 infection. The majority of patients have been presented with hypotension, shock, gastrointestinal, cardiovascular and mucocutaneous symptoms. The incidence of neurologic symptoms in MIS-C is of rising concern as they are not well described and reported in fewer patients. An 8-year-old boy was admitted to the hospital with headache, fever, conjunctivitis, and hyperinflammatory findings diagnosed as MIS-C. Fundus examination performed with complaints of headache, vomiting, and conjunctivitis showed bilateral papilledema. Pseudotumor cerebri is a rare manifestation of MIS-C that can lead to vision loss and may not only be resolved with the standard treatment for MIS-C. We report a case of MIS-C presented with neurologic symptoms due to pseudotumor cerebri and successfully treated with intravenous immunoglobulin and acetazolamide.

Urticarial vasculitis: A potential signpost for multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a rare and serious complication of Sars-Cov-2 infection. Dermatologic manifestations are present in the majority of patients. Skin lesions found in children with MIS-C are classified into four categories: morbilliform, reticulated, scarlatiniform, and urticarial lesions. Clinicopathologic characterization within these categories is limited. Thus, we present a clear example of an urticarial lesion in the context of MIS-C with well-documented clinicopathologic phenomena. A previously healthy 16-year-old female presented with 3 weeks of an itchy, burning rash initially presenting on her right forearm (and lasting greater than 24 hours without migration) before spreading diffusely. She also reported fever, cough, myalgias, nausea, and vomiting of 4 weeks' duration. Physical examination revealed an edematous, maculopapular, nonblanching, erythematous rash covering the patient's upper extremities, abdomen, back, anterior thighs, and face. The patient tested positive for COVID-19. A low-grade leukocytoclastic vasculitis was noted along with intraluminal fibrin and rare microthrombi in vessels of the mid to deep dermis. The patient was diagnosed with MIS-C and urticarial vasculitis. She was treated with steroids and naproxen for subsequent MIS-C flares. Dapsone treatment was started for the urticarial vasculitis.

Characterizing the differences between multisystem inflammatory syndrome in children and Kawasaki disease.

To characterize the new SARS-Co-V-2 related multisystem inflammatory syndrome in children (MIS-C) among Israeli children and to compare it with Kawasaki disease (KD). We compared, in two medical centers, the clinical and laboratory characteristics of MIS-C, KD and an intermediate group, which met the case definitions of both conditions. MIS-C patients were older, were more likely to be hypotensive, to have significant gastrointestinal symptoms, lymphopenia and thrombocytopenia and to have non-coronary abnormal findings in their echocardiogram. Lymphopenia was an independent predictor of MIS-C. Most of our MIS-C patients responded promptly to corticosteroid therapy. KD incidence in both centers was similar in 2019 and 2020. Although there is clinical overlap between KD and MIS-C, these are separate entities. Lymphopenia clearly differentiates between these entities. MIS-C patients may benefit from corticosteroids as first-line therapy.

Multisystem Inflammatory Syndrome in Children Associated With Severe Acute Respiratory Syndrome Coronavirus-2 in an 8-Week-Old Infant.

We describe an 8-week-old infant with severe gastrointestinal symptoms, significant hypoalbuminemia, and mild carditis following asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infant's symptoms, including their temporal appearance, were consistent with multisystem inflammatory syndrome in children (MIS-C). A unique finding on colonic histology which may shed light on the pathogenesis of MIS-C was identified. The patient improved significantly following several anti-inflammatory treatments. The lag between the presentation of MIS-C and initial SARS-CoV-2 exposure, which may often be asymptomatic, together with the young age of our patient, makes this a challenging diagnosis. Clinicians should be aware of this entity, even in the neonatal and infantile age groups, to facilitate timely identification and treatment.

Differentiating multisystem inflammatory syndrome in children: a single-centre retrospective cohort study.

OBJECTIVE: Features of multisystem inflammatory syndrome in children (MIS-C) overlap with other febrile illnesses, hindering prompt and accurate diagnosis. The objectives of this study were to identify clinical and laboratory findings that distinguished MIS-C from febrile illnesses in which MIS-C was considered but ultimately excluded, and to examine the diseases that most often mimicked MIS-C in a tertiary medical centre. STUDY DESIGN: We identified all children hospitalised with fever who were evaluated for MIS-C at our centre and compared clinical signs and symptoms, SARS-CoV-2 status and laboratory studies between those with and without MIS-C. Multivariable logistic LASSO (least absolute shrinkage and selection operator) regression was used to identify the most discriminative presenting features of MIS-C. RESULTS: We identified 50 confirmed MIS-C cases (MIS-C+) and 68 children evaluated for, but ultimately not diagnosed with, MIS-C (MIS-C-). In univariable analysis, conjunctivitis, abdominal pain, fatigue, hypoxaemia, tachypnoea and hypotension at presentation were significantly more common among MIS-C+ patients. MIS-C+ and MIS-C- patients had similar elevations in C-reactive protein (CRP), but were differentiated by thrombocytopenia, lymphopenia, and elevated ferritin, neutrophil/lymphocyte ratio, BNP and troponin. In multivariable analysis, predictors of MIS-C included age, neutrophil/lymphocyte ratio, platelets, conjunctivitis, oral mucosa changes, abdominal pain and hypotension. CONCLUSIONS: Among hospitalised children undergoing evaluation for MIS-C, children with MIS-C were older, more likely to present with conjunctivitis, oral mucosa changes, abdominal pain and hypotension, and had higher neutrophil/lymphocyte ratios and lower platelet counts. These data may be helpful for discrimination of MIS-C from other febrile illnesses, including bacterial lymphadenitis and acute viral infection, with overlapping features.