Proteomic mapping identifies serum marker signatures associated with MIS-C specific hyperinflammation and cardiovascular manifestation.

Multisystem inflammatory syndrome in children (MIS-C) shares several clinical and immunological features with Kawasaki Disease (KD) and pediatric hyperinflammation, but the immuno-phenotypic overlap among these clinical mimics is still incompletely understood. Here we analyzed serum samples from treatment-naïve patients with MIS-C (n = 31) and KD (n = 11), pediatric hyperinflammation (n = 13) and healthy controls (HC, n = 10) by proximity extension assay (PEA) to profile 184 blood biomarkers. Collectively, immunophenotypic overlap between MIS-C and hyperinflammation exceeds overlap with KD. Overexpression of IL-17A in MIS-C and KD could best separate these conditions from hyperinflammatory conditions, while those were hallmarked by overabundance of adenosin deaminase and IL-18. Depletion in serum TNF-related subfamily member 9 (TNFRSF9) and apoptosis inducing ligand (TRAIL) linked with cardiovascular manifestations and myocarditis in MIS-C. Altogether, our analysis highlights important differences in molecular marker signatures also across different MIS-C and KD cohorts and suggests several previously unidentified molecular associations in context of cardiovascular inflammation.

Cardiovascular involvement in children with COVID-19 temporally related multisystem inflammatory syndrome (MIS-C): can cardiac magnetic resonance arrive to the heart of the problem?

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) shows a significant overlap of symptoms with other hyper-inflammatory diseases such as Kawasaki disease (KD), but the real difference of the two conditions is still matter of debate. Coronary artery lesions (CAL) are the most relevant complication in KD. Nonetheless, CAL, myocarditis, pericarditis, arrhythmia are the main cardiovascular complications in MIS-C. A close clinical assessment is mandatory, both at the diagnosis and during the follow-up, by ECG and echocardiography. Cardiac magnetic resonance (MRI) adds important data to ultrasound findings. However, cardiac MRI studies in MIS-C are limited to a small number of cohorts. METHODS: We enrolled 20 children (age:1-16 years; 11 F; 9 M) with cardiac involvement secondary to MIS-C, all evaluated by cardiac MRI. RESULTS: 8 children showed pathological cardiac MRI: 2 showed pericardial effusion; 2 showed myocardial oedema; 1 showed aortic insufficiency; 3 showed delayed enhancement (one for acute myocarditis with oedema; 2 for myocardial fibrosis). Delayed enhancement was reduced significantly 5.6-9 months after the first MRI evaluation. 25% of patients with pathological MRI had CAL associated with valvular insufficiency of 2 valves. 17% of patients with normal MRI had CAL, associated with valvular insufficiency of 1 valve in 1 patient. The correlations between haematological, clinical, cardiologic parameters, treatment, did not reach the statistical significance. 4 patients were treated with anakinra. Among those, 2 patients showed a normal cardiac MRI. Cardiac lesions resolved in all the patients during the follow-up. Some patients with pathological cardiac MRI could not underwent a control with MRI, for the low compliance. However, echocardiography and ECG, documented the resolution of the pathological data in these cases. CONCLUSIONS: A higher risk of CAL was documented in patients with an association of other cardiac lesions. Cardiac MRI is difficult to perform routinely; however, it is useful for evaluating the acute myocardial damage and the outcome of patients with MIS-C.

A case report on multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 infection.

Key Clinical Message: Early recognition and treatment of Multisystem Inflammatory Syndrome in Children (MIS-C) within the context of COVID-19 infection is crucial for improved outcomes. Prompt intervention with IVIG and steroids leads to significant improvement in a severe case of MIS-C. Clinicians should be vigilant for MIS-C symptoms and initiate timely management. Abstract: We report a case involving a fourteen-year-old male with COVID-19 infection who developed multisystem inflammatory disease. A previously healthy child presented with a history of 10 days of fever and cough, along with diarrhea, and vomiting for 3 days. His COVID-19 infection was confirmed through Polymerase Chain Reaction (PCR), and the laboratory values were remarkable for high levels of C-reactive protein, D-dimers, B-type natriuretic peptide (BNP), and troponin I. He developed circulatory shock on the second day of the presentation and needed inotropic support. Steroids and intravenous immunoglobulin (IVIG) were started in light of Multisystem Inflammatory Syndrome in Children (MIS-C), which improved his condition. Thus, during the management of COVID-19 infection, early detection and a careful clinical characterization for MIS-C are essential.

Vitamin D Supplementation in Neonatal and Infant MIS-C Following COVID-19 Infection.

To date, the SARS-CoV-2 pandemic still represents a great clinical challenge worldwide, and effective anti-COVID-19 drugs are limited. For this reason, nutritional supplements have been investigated as adjuvant therapeutic approaches in disease management. Among such supplements, vitamin D has gained great interest, due to its immunomodulatory and anti-inflammatory actions both in adult and pediatric populations. Even if there is conflicting evidence about its prevention and/or mitigation effectiveness in SARS-CoV-2 infection, several studies demonstrated a strict correlation between hypovitaminosis D and disease severity in acute COVID-19 and MIS-C (multisystem inflammatory syndrome in children). This narrative review offers a resume of the state of the art about vitamin D's role in immunity and its clinical use in the context of the current pandemic, specially focusing on pediatric manifestations and MIS-C. It seems biologically reasonable that interventions aimed at normalizing circulating vitamin D levels could be beneficial. To help clinicians in establishing the correct prophylaxis and/or supportive therapy with vitamin D, well-designed and adequately statistically powered clinical trials involving both adult and pediatric populations are needed. Moreover, this review will also discuss the few other nutraceuticals evaluated in this context.

A Case With Typical Clinical Manifestations of Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Temporally Associated With SARS-CoV-2 Infection.

Whether Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) temporally associated with SARS-CoV-2 infection are two distinct syndromes or part of the same spectrum is not fully understood. In this report, we present the case of a five-year-old boy who fully satisfied the diagnostic criteria for both KD and MIS-C associated with SARS-CoV-2 infection. He tested positive for SARS-CoV-2 on an oropharyngeal swab antigen test approximately four weeks before the onset of symptoms. He had severe abdominal pain. Abdominal ultrasound showed ascites. He improved with initial (2 g/kg) and additional (1 g/kg) intravenous immunoglobulin (IVIG) therapy and intravenous methylprednisolone (initial dose, 2 mg/kg/day). Our case may lead to clarification of the pathogenesis of both diseases. Additionally, the recent history of SARS-CoV-2 infection for children with prolonged fever and no clear focus of infection should be checked, and, if present, clinicians should consider MIS-C temporally associated with SARS-CoV-2 infection. IVIG therapy is important for children with MIS-C who meet the diagnostic criteria for KD, even if diagnosed with MIS-C.

Characteristics and Outcomes of Children With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Admitted to a Quaternary Hospital: A Single-Center Experience.

Objectives In the setting of the recent global pandemic, children infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causing the coronavirus disease 2019 (COVID-19) presented to our hospital with a variety of symptoms ranging from mild to severe disease including multiorgan dysfunction. Our objective was to study the clinical profile, risk factors, complications, and outcomes in pediatric patients admitted to our center with SARS-CoV-2 infection. Methods This retrospective observational study was conducted at a large quaternary center in Riyadh between May 2020 and September 2021. The study population was comprised of children between 0 and ≤14 years with SARS-CoV-2 suspicion or positivity. Results One hundred and fifty-six children were included in the study, the majority of whom were 1-10 years old. One hundred and twenty of them (76.93%) were SARS-CoV-2 positive. Fifty-nine patients (37.18%) were labelled as multisystem inflammatory syndrome in children (MIS-C) based on clinical and lab criteria, of whom 35 (22.44%) tested SARS-CoV-2 positive. Hematological disease was found to be the most common comorbidity, followed by neurological and chronic lung diseases. The most common symptoms encountered were fever, cough, vomiting, fatigue, and diarrhea. Eighty patients (51%) required pediatric intensive care unit (PICU) admission (length of stay: 5-12 days), among whom 32 (40%) required ventilation, 26 (32.5%) needed hemodynamic support, and three patients (3.75%) underwent continuous renal replacement therapy (CRRT). The overall mortality rate was 4.5% (seven patients) among the studied population. The most frequent lab abnormalities were found to be elevated serum ferritin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels. Ninety-one percent received antibiotics, and prophylactic anticoagulant was used in 32%. In the MIS-C subset, 80.5% received steroids, 71.43% intravenous immunoglobulin (IVIG), and 5.17% (three patients) tocilizumab. Conclusion The SARS-CoV-2 infection presented with a range of severity among our cohort of children; however, most of the patients responded well to appropriate supportive treatment. A slight male preponderance was noted. The most common symptoms encountered were fever, cough, vomiting, fatigue, and diarrhea. Inflammatory markers such as ESR, CRP, serum ferritin, and LDH levels were found to be elevated in nearly all patients. Raised serum lactate and serum creatinine and lymphopenia were of significant note in patients with MIS-C. Higher mortality rates were observed in patients with MIS-C and those requiring respiratory support. In addition to these two factors, the presence of comorbidities and the need for CRRT were associated with prolonged PICU length of stay.

In-hospital care of children with COVID-19.

Children have been reported to be less affected and to have milder severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than adults during the coronavirus disease 2019 (COVID-19) pandemic. However, children, and particularly those with underlying disorders, are still likely to develop critical illnesses. In the case of SARS-CoV-2 infection, most previous studies have focused on adult patients. To aid in the knowledge of in-hospital care of children with COVID-19, this study presents an expert review of the literature, including the management of respiratory distress or failure, extracorporeal membrane oxygenation (ECMO), multisystem inflammatory syndrome in children (MIS-C), hemodynamic and other organ support, pharmaceutical therapies (anti-viral drugs, anti-inflammatory or antithrombotic therapies) and management of cardiopulmonary arrest.

Cardiac Biomarkers Aid in Differentiation of Kawasaki Disease from Multisystem Inflammatory Syndrome in Children Associated with COVID-19.

Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 show clinical overlap and both lack definitive diagnostic testing, making differentiation challenging. We sought to determine how cardiac biomarkers might differentiate KD from MIS-C. The International Kawasaki Disease Registry enrolled contemporaneous KD and MIS-C pediatric patients from 42 sites from January 2020 through June 2022. The study population included 118 KD patients who met American Heart Association KD criteria and compared them to 946 MIS-C patients who met 2020 Centers for Disease Control and Prevention case definition. All included patients had at least one measurement of amino-terminal prohormone brain natriuretic peptide (NTproBNP) or cardiac troponin I (TnI), and echocardiography. Regression analyses were used to determine associations between cardiac biomarker levels, diagnosis, and cardiac involvement. Higher NTproBNP (≥ 1500 ng/L) and TnI (≥ 20 ng/L) at presentation were associated with MIS-C versus KD with specificity of 77 and 89%, respectively. Higher biomarker levels were associated with shock and intensive care unit admission; higher NTproBNP was associated with longer hospital length of stay. Lower left ventricular ejection fraction, more pronounced for MIS-C, was also associated with higher biomarker levels. Coronary artery involvement was not associated with either biomarker. Higher NTproBNP and TnI levels are suggestive of MIS-C versus KD and may be clinically useful in their differentiation. Consideration might be given to their inclusion in the routine evaluation of both conditions.

Cardiac manifestations of MIS-C: cardiac magnetic resonance and speckle-tracking data.

Background: Cardiac involvement is central in MIS-C and represents the main cause of morbidity. In this study, we aimed to assess myocardial damage in patients with MIS-C using cardiac magnetic resonance (CMR) during the acute phase, as well as left ventricular and atrial longitudinal strain on admission, at discharge, and after 3 months. Methods: We performed a single-center prospective cohort study and case-control study. Between September 2020 and February 2022, we enrolled 39 patients hospitalized for MIS-C at our center. We performed left ventricular and atrial longitudinal 2D strain analysis on admission and during follow-up; echocardiographic data were compared to a matched control population. Patients above 4 years old with increased troponin underwent CMR. Results: Of 24 patients (mean age: 8.2 ± 4.9 years) who underwent CMR, 14 (58%) presented myocardial edema and 6 (25%) late gadolinium enhancement (LGE). LGE was associated with older age (p < 0.01), increased BMI (p = 0.03), increased ferritin levels (p < 0.001), lower left ventricular (LV) ejection fraction (p < 0.001), LV longitudinal strain (p = 0.004), left atrial (LA) strain (p = 0.05), and prolonged hospital stay (p = 0.02). On admission, LV ejection fraction, LV longitudinal strain, and LA strain were impaired, but each improved gradually over time; LVEF was the fastest to recover, while global LV longitudinal strain was still impaired as compared to controls after 3 months (p = 0.01). Conclusion: Our study demonstrates that myocardial injury is present in a quarter of MIS-C patients, and impaired LA and LV myocardial deformation persist for at least several weeks after the acute phase. CMR and LV/LA strain could help us to individualize follow-up of MIS-C patients.

Characteristics of pediatric COVID-19 infections and the impact of influenza and COVID-19 vaccinations during the first two years of the pandemic.

The data regarding the demographics of SARS-CoV-2 in the pediatric population has been published based on several single-center experiences or on metanalyses over short time frames. This article reports data on the demographics of pediatric patients with COVID-19 on a global scale using the TriNetX COVID-19 Research Network. In addition, we examined the risk of COVID-19 infection in relation to the body mass index (BMI) category and the protective value of influenza and COVID-19 immunization against COVID-19 infection. The incidence of COVID-19 infection was higher in the younger age group (≤6 years old), but no gender differences. The incidence of COVID-19 infection was higher among African Americans/Black race (28.57%) White race (27.10%), and obese patients; across all age groups, all genders, all races, and ethnicities (p < 0.0001). The incidence of MIS-C was also higher in patients with obesity (OR 1.71, CI 1.36-2.14). We found that the patients who were neither vaccinated for COVID-19 nor influenza within one year before their COVID-19 diagnoses compared to those who received influenza vaccine only, had significantly higher odds for hospitalization (OR 1.19, CI 1.18-1.21), development of MIS-C (OR 1.52, CI 1.32-1.74), and more importantly mortality (OR 1.47, CI 1.26-1.71). In addition, those patients who were neither vaccinated for COVID-19 nor influenza within one year before their COVID-19 diagnoses, compared to those who received at least one dose of COVID-19 vaccine, had significantly higher odds for hospitalization (OR 1.11, CI 1.04-1.19). However, those patients who did not receive the influenza vaccine within one year before their COVID-19 diagnoses nor received the COVID-19 vaccine had much higher odds for hospitalization (OR 1.46, CI 1.41-1.51), MIS-C (OR 3.72, CI 2.11-6.56), and mortality compared to those who received both vaccinations (OR 13.55, CI 1.91-9.62). Using the multiplicative interaction scale, we found a positive interaction between the COVID-19 vaccine and the influenza vaccine; they both combined have a larger effect than each separately. Our study is the largest of its kind (to date) examining the global demographic of the pandemic and the first of a kind to find a link between influenza vaccine and COVID-19-related hospitalization, MIS-C, and mortality in the pediatric population.

Safety and efficacy of pharmacological approaches available for multisystem inflammatory syndrome in children (MIS-C): a systematic review.

BACKGROUND: To describe the existing pharmacological managements for Multisystem Inflammatory Syndrome in Children (MIS-C) in a systematic way, to identify the available pharmacological managements in MIS-C, evaluate its safety and efficacy and identify the best treatment procedures for practice recommendation. METHODS: A systematic search using six databases was conducted on August 18, 2021, updated in January 26th 2023. Terminologies that were used in this search are children, MIS-C/PIMS and SARS-CoV-2. A PRISMA flow diagram was used to report the study selection process. Quality analysis was done based on NOS and GRADE tools. Data synthesis was conducted by extracting the information on drugs used, efficacy and side effects. RESULTS: From the 32 articles included, a total of 2331 children with MIS-C were studied. The main pharmacological approaches were immunomodulatory therapy, i.e., intravenous immunoglobulin (IVIG) (77.3%), steroids (60.5%), and a combination of IVIG and steroids (41.3%). IVIG and steroids were found to be potentially effective and safe treatments for MIS-C. Combination of IVIG and steroids was found favorable in severe cases with higher recovery rate. Refractory treatments include second dose of initial treatment and biological response modifier drugs like anakinra, tocilizumab, infliximab. A small number of studies investigating supportive treatment consisted of vasoactive, inotropic and anticoagulation. The mortality rate was 1.28% and only three studies reported side effects from the treatment. Evidence of outcome from GRADE were mostly at moderate, low and very low levels. CONCLUSIONS: This review provides preliminary evidence to support the current standard treatment practices in managing MIS-C pharmacologically. However, comprehensive investigation is required using clinical trials to provide stronger outcome evidence.

Cardiovascular Manifestations of Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With COVID-19.

Since 2019, the global pandemic caused by the SARS-CoV-2 virus, also known as COVID-19, has dramatically affected every aspect of health and society. With wide-ranging socio-economic ramifications and the morbidity/mortality associated with the disease, a lot of research has been done on this disease. With recent surges and new variants of the COVID-19 virus, we must have regularly updated information on this disease to effectively manage this disease and to maximize outcomes for patients. Worldwide data, so far, has suggested that children have milder or asymptomatic acute infectious phase, most often presenting with mild upper respiratory infection (URI) symptoms compared to the adult population. However, in the post-acute phase, it was observed that children presented with a syndrome that strongly resembled Kawasaki's disease (KD), and like in KD, they could potentially develop severe life-threatening complications. The significant difference between KD and this syndrome is the association with COVID-19 infection. This syndrome was observed to affect almost all organ systems including cardiovascular, gastrointestinal, and integumentary and was later named multisystem inflammatory syndrome in children (MIS-C) by the Pediatric Intensive Care Society in April 2020. The cardiovascular manifestations of this clinical entity have been associated with significant morbidity and mortality. This review is an attempt to give consolidated information from the studies done so far about the cardiac changes that occur from SARS-CoV-2 infection/MIS-C.

Hypertension after multisystem inflammatory syndrome in children (MIS-C).

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is associated with SARS-CoV-2. Long-term consequences of MIS-C remain unknown. The objective was to describe the prevalence and clinical predictors of hypertension (HTN) and elevated blood pressure (BP) following MIS-C. METHODS: A retrospective study of children ≤ 18 years admitted to a tertiary center with MIS-C was performed. HTN and elevated BP were classified as per the 2017 American Academy of Pediatrics Clinical Practice Guidelines and indexed to the 95th percentile. Data included demographics, inpatient clinical measures, and echocardiograms over 1-year follow-up. Data were analyzed using Kruskal-Wallis, chi-square, and logistic regression. RESULTS: Among 63 children hospitalized with MIS-C (mean age 9.7 ± 4.2 years, 58.7% male, body mass index (BMI) z-score 0.59 ± 1.9), 14% had HTN, and 4% had elevated BP > 30 days post-hospitalization. Multivariate linear regression analysis showed that BMI z-score was significantly associated with higher mean systolic (ß = 2.664, CI = 1.307-3.980, p < 0.001) and diastolic (ß = 2.547, CI = 0.605-4.489, p = 0.012) BP index > 30 days post-hospitalization. Acute kidney injury (AKI) (23.8%) (OR = 2.977, CI = 1.778-4.987, p < 0.001), peak inpatient serum creatinine (OR = 2.524, CI = 1.344-4.740, p = 0.004), and maximum CRP (OR = 1.009, CI = 1.002-1.016, p = 0.014) were all associated with increased odds of post-hospitalization HTN. Left ventricular hypertrophy was present in 46% while hospitalized, compared to 10% at last follow-up. All had return of normal systolic function. CONCLUSIONS: Post-hospitalization HTN and elevated BP may be associated with MIS-C. Children with greater BMI or AKI may be at greater risk for developing HTN after MIS-C. MIS-C follow-up requires careful BP monitoring and antihypertensive medication consideration. A higher resolution version of the Graphical abstract is available as Supplementary information.

The Effect of Biologics in the Treatment of Multisystem Inflammatory Syndrome in Children (Mis-C): A Single-Center Propensity-Score-Matched Study.

Multisystem inflammatory syndrome in children (MIS-C) is a serious condition characterized by excessive inflammation that can arise as a complication of SARS-CoV-2 infection in children. While our understanding of COVID-19 and MIS-C has been advancing, there is still uncertainty regarding the optimal treatment for MIS-C. In this study, we aimed to compare the clinical and laboratory outcomes of MIS-C patients treated with IVIG plus corticosteroids (CS) to those treated with IVIG plus CS and an additional biologic drug. We used the propensity score (PS)-matching method to assess the relationships between initial treatment and outcomes. The primary outcome was a left ventricular ejection fraction of less than 55% on day 2 or beyond and/or the requirement of inotrope support on day 2 or beyond. We included 79 MIS-C patients (median age 8.51 years, 33 boys) followed in our center. Among them, 50 children (25 in each group) were allocated to the PS-matched cohort sample. The primary outcome was observed in none of the patients in the IVIG and CS group, while it occurred in eight patients in the IVIG plus CS and biologic group (p = 0.04). MIS-C is a disorder that may progress rapidly and calls for extensive care. For definitive recommendations, further studies, including randomized control trials, are required.

Longitudinal Assessment of Left Ventricular Function in Patients with Myopericarditis After mRNA COVID-19 Vaccination.

BACKGROUND: Multiple reports have described myopericarditis following mRNA COVID-19 vaccination. However, data on the persistence of subclinical myocardial injury assessed by left ventricular (LV) longitudinal strain (LVLS) is limited. OBJECTIVES: Our aim was to assess LV function longitudinally in our cohort of COVID-19 vaccine-related myopericarditis using ejection fraction (EF), fractional shortening (FS), LVLS, and diastolic parameters. METHODS: Retrospective, single-center review of demographic, laboratory, and management data was performed on 20 patients meeting diagnostic criteria for myopericarditis after mRNA COVID-19 vaccination. Echocardiographic images were obtained on initial presentation (time 0), at a median of 12 days (7.5, 18.5; time 1), and at a median of 44 days (29.5, 83.5; time 2). FS was calculated by M-mode, EF by 5/6 area-length methods, LVLS by utilization of TOMTEC software, and diastolic function by tissue Doppler. All parameters were compared across pairs of these time points using Wilcoxon signed-rank test. RESULTS: Our cohort consisted predominantly of adolescent males (85%) with mild presentation of myopericarditis. The median EF was 61.6% (54.6, 68.0), 63.8% (60.7, 68.3), 61.4% (60.1, 64.6) at times 0, 1, and 2, respectively. Upon initial presentation, 47% of our cohort had LVLS < -18%. The median LVLS was -18.6% (-16.9, -21.0) at time 0, -21.2% at time 1 (-19.4, -23.5) (p = 0.004) and -20.8% (-18.7, -21.7) at time 2 (p = 0.004, as compared to time 0). CONCLUSIONS: Though many of our patients had abnormal strain during acute illness, LVLS improved longitudinally, indicating myocardial recovery. LVLS can be used as marker of subclinical myocardial injury and risk stratification in this population.

Multisystem Inflammatory Syndrome in Children (MIS-C): Reduced Exercise Duration and Capacity at Six Month Follow-Up.

Myocarditis is common in Multisystem Inflammatory Syndrome in Children (MIS-C), and the mechanism may differ from idiopathic/viral myocarditis as MIS-C involves a hyper-inflammatory state weeks after COVID-19. We sought to evaluate exercise stress testing (EST) in these patients as EST may help guide return-to-play recommendations. Retrospective cohort study evaluating ESTs (standard Bruce treadmill protocol) from MIS-C patients from 2020 to 2022, compared to myocarditis patients and age, sex, and weight matched controls from 2005 to 2019. ESTs included 22 MIS-C patients (mean age 11.9 years) with 14 cardiopulmonary and 8 cardiovascular tests, 33 myocarditis (15.5 years), and 44 controls (12.0 years). Percent-predicted peak VO2 was abnormal (< 80% predicted) in 11/14 (79%) MIS-C patients, 13/33 (39%) myocarditis, and 17/44 (39%) controls (p = 0.04). Exercise duration was shorter in MIS-C than myocarditis or control cohorts (p = 0.01). Isolated atrial or ventricular ectopy was seen in 8/22 (36%) MIS-C, 9/33 (27%) myocarditis, and 5/44 (11%) controls (p = 0.049). No arrhythmias/complex ectopy or evidence of ischemia were noted, though non-specific ST/T wave abnormalities occurred in 4/22 (18%) MIS-C, 5/33 (15%) myocarditis, and 3/44 (7%) controls. Exercise duration and percent-predicted peak VO2 were significantly reduced in MIS-C at mean 6-month follow-up compared to pre-COVID era idiopathic/viral myocarditis and control cohorts. This may be secondary to deconditioning during the pandemic and/or chronic cardiopulmonary or autonomic effects of COVID/MIS-C. Although there were no exercise-induced arrhythmias in our MIS-C patients, larger cohort studies are warranted. EST in MIS-C follow-up may help evaluate safety and timing of return to play and potentially mitigate further deconditioning.

Complete Remission in a Child With Multisystem Inflammatory Syndrome and Stevens-Johnson Syndrome Treated With Infliximab.

COVID-19, caused by SARS-CoV-2, can present with various dermatological manifestations, including (albeit rarely) severe mucocutaneous manifestations such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis. In contrast, multisystem inflammatory syndrome in children (MIS-C) commonly presents with mucocutaneous manifestations. The presentation of SJS in a child with MIS-C deserves increased attention from clinicians because of its potential fatality. Here we describe a 10-year-old boy with a history of exposure to confirmed COVID-19 who presented with fever, bilateral subconjunctival hemorrhage, cracked and red lips, oral ulcers, and generalized hemorrhagic skin lesions with targetoid lesions. Laboratory tests revealed leukocytosis, neutrophilia, lymphopenia, elevated C-reactive protein, sedimentation rate, ferritin, and B-type natriuretic peptide. A skin biopsy revealed patchy vacuolar interface dermatitis with subepidermal edema and superficial and deep perivascular predominantly histiocytic infiltrates with scattered eosinophils, lymphocytes, and neutrophils suggestive of SJS. In addition to supportive treatment, he was treated with IV methylprednisolone, immunoglobulins, and infliximab, after which his symptoms improved and gradually resolved.

Multisystem Inflammatory Syndrome in Children (MIS-C), Possibly Due to COVID-19 mRNA Vaccination.

Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening childhood disease caused by SARS-CoV-2 infection, manifested by the persistence of fever and multi-organ dysfunction, elevated inflammatory markers, and the lack of an alternative diagnosis. It is still unknown if vaccination can precipitate or abrogate MIS-C or if a natural infection preceding or occurring at the time of vaccination plays any role. We present one case of MIS-C in a 16-year-old girl who was fully immunized against COVID-19 (Pfizer), with the second dose received three weeks prior to onset of the disease. She had no history of COVID-19 disease or contact with COVID-19 patients. At admission, she was somnolent, pale, and dehydrated, with cyanotic lips and cold extremities; she was hypotensive with tachycardia and poorly palpable pulses. Initial laboratory results revealed elevated levels of inflammatory markers, and high level of SARS-CoV-2 IgG spike antibodies, while testing for SARS-CoV-2 acute infection and other inflammatory etiologies were negative. Vaccine-related MIS-C was suspected in our case due to the development of MIS-C three weeks following the second dose of the COVID-19 mRNA vaccine, the absence of previous infection or exposure to SARS-CoV-2, and a positive result for IgG anti-spike (S) antibodies.

Clinical Course Associated with Aseptic Meningitis Induced by Intravenous Immunoglobulin for the Treatment of Multisystem Inflammatory Syndrome in Children.

Aseptic meningitis is a rare but potentially serious complication of intravenous immunoglobulin treatment. In this case series, meningitic symptoms following intravenous immunoglobulin initiation in patients with multisystem inflammatory syndrome were rare (7/2,086 [0.3%]). However, they required the need for additional therapy and/or readmission.