Prolonged Elevations of Factor VIII and von Willebrand Factor Antigen After Multisystem Inflammatory Syndrome in Children.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a late systemic inflammatory response to a recent mild or asymptomatic coronavirus disease of 2019 infection. The pathophysiology is incompletely understood but it often features significant coagulopathy along with cardiac and endothelial dysfunction. Endothelial inflammation has been primarily described in acute coronavirus disease of 2019 infection, with less characterization in MIS-C. Here we describe novel findings of nearly universal severe and prolonged factor VIII (FVIII) and von Willebrand factor antigen elevations in an institutional cohort of patients with MIS-C ages younger than or 21 years old (N=31). All patients had elevated acute phase reactants and D-dimer at presentation and met published criteria for MIS-C. FVIII was high at presentation in 97% of patients but continued to rise during the ensuing weeks of treatment to a mean 429%, peaking on median day 17 of illness as an outpatient. FVIII levels were >600% in multiple patients. von Willebrand factor antigen was measured less frequently but showed similar trends. These escalations occurred amidst resolving cardiac dysfunction and acute phase reactant normalization and despite patients receiving multimodal anti-inflammatory treatments and aspirin and enoxaparin thromboprophylaxis. No thrombotic events occurred. Endothelial dysfunction represented by very elevated FVIII levels may persist longer than other acute phase reactants may reflect.

Ten-month follow-up of patients with covid-19 temporally related multi-system inflammatory syndrome in children: the experience of the children hospital of Palermo.

BACKGROUND: In Sicily, the first wave of COVID-19 showed a low epidemic impact in paediatric population, while the second and the third waves had a higher impact on clinical presentation of COVID-19 in children and a significantly higher severe outcome in patients with multisystem inflammatory syndrome in children (MIS-C), with a frequent life-threatening progression. METHODS: We describe a cohort of 22 Sicilian children (11 M; 11 F; age: 1.4-14 years), presenting with clinical features compatible with MIS-C. Patients with negative swab had a history of recent personal or parental infection. RESULTS: The following diagnostic criteria were detected: fever (100%); cheilitis and/or pharyngeal hyperaemia (86%); latero-cervical lymphadenitis (82%); rash (73%); abdominal pain and/or vomiting and/or diarrhoea (64%); conjunctivitis (64%); hands and feet oedema (18%). 59% showed cardiac involvement (6 pericardial effusion; 8 mitral valve insufficiency; 4 insufficiency of two valves; 3 coronary artery lesions (CAL)). In all the patients, treatment was started within 72 h after the admission, with intravenous immunoglobulins (IVIG) (2 g/Kg/dose), methylprednisolone (2 mg/Kg/day in 73% of patients; 30 mg/Kg/day for 3 days, followed by 2 mg/Kg/day in 27% of patients). Two patients were treated with enoxaparin. Two patients with shock, were additionally treated with vasoactive drugs, albumin, diuretics. Cardiac involvement evolved into the complete resolution of lesions in most of the patients. All the patients were included in a follow-up, to investigate on clinical outcome and resolution of organ involvement. Cardiac valve insufficiency persisted only in 18% of children, CAL persisted only in 33% of children with coronary involvement, however without the evolution into aneurisms. CONCLUSIONS: The preferred treatment strategy was more aggressive at the diagnosis of MIS-C, to block the cytokine cascade. Most of our patients, in fact, received a first-line treatment with IVIG and steroids. This approach could explain the favourable prognosis, the rapid restoring of cardiac function also in patients with MAS or shock, and the good outcome during the 10 months follow-up in all the patients.

Multisystem Inflammatory Syndrome in an Adult Following COVID-19 mRNA Vaccination: Successful Treatment With Medium-Dose Steroids and Colchicine.

Multisystem inflammatory syndrome in children and adults (MIS-C/A) was rarely reported as a complication of coronavirus disease 2019 (COVID-19) and potential adverse events following COVID-19 vaccination. Recently, the case definition of MIS-C/A was developed by the Brighton Collaboration Network. However, only a limited number of adult patients with MIS-A following immunization have been reported, and there is still little evidence for adequate treatment. A 57-year-old man presented with fever, headache, vomiting, and hypotension 24 days after receiving the second COVID-19 vaccination with the Pfizer-BioNTech vaccine. According to the Brighton Collaboration Case Definition, the patient met a definitive case of MIS-A after vaccination (level 1 of diagnostic certainty). After administration of medium-dose prednisolone (20 mg/d) with colchicine (1.2 mg/d), all symptoms and signs improved rapidly. The dose of prednisolone was gradually tapered from the third week, and the patient confirmed a full recovery without medication after 8 weeks. This is the first report showing that low-dose steroids in combination with colchicine may be an effective treatment option for MIS-A after vaccination.

COVID-19 and multisystem inflammatory syndrome in children and adolescents.

As severe acute respiratory syndrome coronavirus 2 continues to spread worldwide, there have been increasing reports from Europe, North America, Asia, and Latin America describing children and adolescents with COVID-19-associated multisystem inflammatory conditions. However, the association between multisystem inflammatory syndrome in children and COVID-19 is still unknown. We review the epidemiology, causes, clinical features, and current treatment protocols for multisystem inflammatory syndrome in children and adolescents associated with COVID-19. We also discuss the possible underlying pathophysiological mechanisms for COVID-19-induced inflammatory processes, which can lead to organ damage in paediatric patients who are severely ill. These insights provide evidence for the need to develop a clear case definition and treatment protocol for this new condition and also shed light on future therapeutic interventions and the potential for vaccine development. TRANSLATIONS: For the French, Chinese, Arabic, Spanish and Russian translations of the abstract see Supplementary Materials section.

Aseptic meningitis in multisystem inflammatory syndrome in children associated with coronavirus disease 2019: a case report.

BACKGROUND: As the coronavirus disease 2019 infections are still ongoing, there is an increasing number of case reports and case series with various manifestations of life-threatening multisystem inflammatory syndrome in children . Our case aims to remind all providers to scrutinize for clinical manifestations, including neurological symptoms, which may mimic aseptic meningitis. CASE PRESENTATION: A 5-year-old Albanian male child with obesity was admitted to the pediatric intensive care unit due to persistent fever, headache, vomiting, abdominal pain, mucocutaneous manifestations, and fatigue. Initial laboratory results revealed high level of inflammatory markers, including C-reactive protein of 156.8 mg/l, erythrocyte sedimentation rate of 100 mm/hour, procalcitonin of 13.84, leukocytosis with neutrophilia, and lymphopenia. Liver and renal functions, and capillary blood electrolytes (Na, K, Ca), were also altered. Cerebrospinal fluid was slightly turbid, with a white blood cell count of 128/mm3 (80% mononuclear cells and 20% polymorphonuclear), consistent with aseptic meningitis. The clinical presentation with prolonged fever, multiorgan dysfunction, and elevated inflammatory markers, with no plausible alternative diagnosis, matches the case definition of multisystem inflammatory syndrome in children. Combining corticosteroid methylprednisolone with intravenous immunoglobulin was effective. CONCLUSIONS: Apart from the most common presentation of multisystem organ dysfunction, neurological manifestations of multisystem inflammatory syndrome in children such as aseptic meningitis, may be present as an immune response post-viral to coronavirus disease 2019. Given the rapid deterioration of children with multisystem inflammatory syndrome, early treatment with immunoglobulins and corticosteroids should be considered.

Clinical characteristics and outcomes of the multisystem inflammatory syndrome in children (MIS-C) following COVID-19 infection in Iran: A multicenter study.

OBJECTIVES: This study aimed to assess the clinical characteristics, treatment and outcomes of the multisystem inflammatory syndrome in children (MIS-C) following COVID-19 in five different geographical regions of Iran. METHODS: In this multicenter observational study, patients <21 years were included between March 2020 and October 2021. By Disease Control and Prevention (CDC) checklist, demographic characteristics, comorbidities, clinical signs and symptoms, laboratory and radiology findings, and treatment were collected. Statistical analysis was using Chi-square and t-test in STATA14. RESULTS: In total 225 patients with median age of 55 (26-96) months were included that 59.56% boys. 57.33% were admitted to the PICU with a median of 7 days (4-10). 95.56% of patients were discharged with recovery and the rest died. All of the patients in our study were included based on the MIS-C criteria. However, some patients had Kawasaki symptoms, so we compared the clinical and epidemiological characteristics of the two groups. Conjunctival injection, cervical lymphadenopathy>1.5 cm diameter, and strawberry tongue in Kawasaki-like MIS-C patients were higher than of MIS-C patients, and this difference was significant(p<0.001). The most common comorbidity was obesity (24.86%). Most patients tested for COVID-19 and about 60% of the patients had a positive test by serology or reverse transcription-polymerase chain reaction (RT-PCR). Gastrointestinal (88.89%) and hematologic signs (84.44%) were most common. Most drugs used in patients were IVIG and steroids. 88.07% and 61.29% of the patients had at least one problem in echocardiography and lung CT, respectively. CONCLUSIONS: The best outcome was seen in patients who were treated with both IVIG and steroids on the first days of admission. Myocarditis was common in two groups of patients. According to most patients had echocardiography abnormal, screening of heart function is recommended for patients.

Use of broad-spectrum antibiotics in children diagnosed with multisystem inflammatory syndrome temporarily associated with SARS-CoV-2 infection in Poland: the MOIS-CoR study.

OBJECTIVES: Multisystem inflammatory syndrome in children (MIS-C) is the result of an immune response triggered by a previous exposure to SARS-CoV-2. The clinical presentation of MIS-C overlaps with other life-threatening bacterial infections, in which antimicrobials are the mainstay therapy. The aim of study was to describe the use of antibiotics in children with MIS-C in Poland. METHODS: The analysis of 345 children reported from 42 Polish cities to the national MultiOrgan Inflammatory Syndromes COVID-19 Related Study (MOIS-CoR Study) from June 2020 to April 2021. RESULTS: At least one antibiotic was used in 310 (90%) children, mainly third-generation cephalosporin (251/310). Broad-spectrum antibiotics were used in 258 (75%) children and 224 (87%) received this treatment for more than 3 days. Concentrations of serum procalcitonin >2 µg/l and the presence of lower respiratory symptoms were associated with increased odds of receiving any antibiotic. CONCLUSION: Although bacterial infections in patients with MIS-C are uncommon, we show that MIS-C poses a challenge to clinicians who are faced with the decision to start, continue, or stop antimicrobial therapy. Antibiotic stewardship in patients with MIS-C should be improved to ensure that likely pathogens are treated and that antimicrobials are stopped when bacterial infections are excluded and the diagnosis of MIS-C is made.

Severe myopathy complicating multisystem inflammatory syndrome in adults (MIS-A) in a young man.

We report the case of a man in his early 30s who presented with high fever, cervical lymphadenopathy, maculopapular rash and considerably elevated inflammatory markers. Further evaluations revealed cardiomyopathy and renal failure. During hospitalisation he developed profound generalised muscle weakness caused by diffuse myopathy without elevated creatine kinase. He was eventually diagnosed with multisystem inflammatory syndrome in adults (MIS-A) after it was established that he had been suffering from COVID-19 5 weeks prior to presentation. He was started on intravenous immunoglobulins and high-dose corticosteroids, after which symptoms resolved rapidly. MIS-A is a rare but severe complication of COVID-19, whose pathogenesis is insufficiently understood. This case provides further insight into this new disease entity by describing a previously unreported disease progression with severe inflammatory myopathy without elevated creatine kinase.

NT-proBNP Levels Following IVIG Treatment of Multisystem Inflammatory Syndrome in Children.

BACKGROUND AND OBJECTIVES: N-terminal of probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels are often elevated in multisystem inflammatory syndrome in children (MIS-C) secondary to inflammation, myocardial dysfunction, or increased wall tension. Intravenous immunoglobulin (IVIG), accepted treatment of MIS-C, may transiently increase myocardial tension and contribute to an increase in NT-proBNP. We sought to study the association between pre- and post-IVIG levels of NT-proBNP and CRP and their clinical significance. METHODS: This single-center, retrospective, cohort study included consecutive children, aged ≤21 years, with diagnosis of MIS-C who received IVIG from April 2020 to October 2021. Data collection included clinical characteristics, laboratory tests, management, and outcomes. Study cohort consisted of patients who received IVIG and had NT-proBNP levels available pre- and post-IVIG. RESULTS: Among 35 patients with MIS-C, 30 met inclusion criteria. Twenty-four, 80%, showed elevation in NT-proBNP post-IVIG. The median NT-proBNP level pre-IVIG was 1921 pg/mL (interquartile range 548-3956), significantly lower than the post-IVIG median of 3756 pg/mL (interquartile range 1342-7634)) (P = .0010). The median pre-IVIG CRP level was significantly higher than the post-IVIG level (12 mg/dL vs 8 mg/dL, P = .0006). All but 1 recovered before discharge, and none had signs of worsening cardiac function post-IVIG. In those who recovered, NT-proBNP had normalized by discharge or 1-week follow-up. CONCLUSIONS: Our study shows that NT-proBNP levels often transiently increase immediately after IVIG therapy without signs of worsening myocardial function. These values should be interpreted in the context of CRP levels and clinical recovery.

Cyclosporine for the treatment of multisystem inflammatory syndrome in children with coronary artery aneurysms.

Multisystem inflammatory syndrome in children (MIS-C) is a newly described syndrome related to the COVID-19, resembling other known aetiologies, including Kawasaki disease. Cardiovascular involvement is common; left ventricle dysfunction and coronary artery aneurysm (CAA) are also observed. Many treatment guidelines recommend using intravenous immunoglobulin (IVIG) alone or with glucocorticoids as the first-line therapy. Biological agents, such as anakinra, are recommended for refractory cases, but the evidence is still accumulating. Moreover, the use of other treatment agents can be beneficial, especially when anakinra is unavailable. Here, we report the case of a 9-year-old girl who presented with MIS-C with CAAs. She received cyclosporine because two rounds of IVIG treatment were ineffective and the use of anakinra is not approved in Japan. Her cytokine profile showed that cyclosporine prevented exacerbation. The case highlights that cyclosporine therapy can be an option for the treatment of refractory MIS-C with CAA.

Multisystem inflammatory syndrome in an adult with severe hypoxaemia and thyroiditis responsive to corticosteroid and interleukin 6 inhibitor treatment.

Multisystem inflammatory syndrome in adults (MIS-A) has been reported as a rare but severe consequence of COVID-19 infection. Adult patients were more likely to present with hypotension and cardiac illness when compared with multisystem inflammatory syndrome in children. Although the exact prevalence of MIS-A is unknown, more cases have been observed in men and younger adults. The pathophysiology of MIS-A is also unclear, but is thought to be caused by a delayed, dysregulated immune response. Given no established guideline for treatment of MIS-A, treatment has been based on case reports. We present a case of MIS-A in a woman in her 60s who had severe hypotension, progressive dyspnoea, massive pleural effusion, hypoxaemia, thyroiditis and multiple organ failure, which dramatically improved after treatment with corticosteroid and interleukin 6 inhibitor.

Two Distinct Illnesses Consistent With MIS-C in a Pediatric Patient.

Multisystem inflammatory syndrome in children (MIS-C) is a severe inflammatory response described in children after infection with severe acute respiratory syndrome coronavirus 2. We present a case of a 9-year-old African American boy with 2 distinct illnesses that were both consistent with MIS-C. He first presented in the early stages of our understanding of MIS-C with predominantly neurologic and gastrointestinal symptoms and demonstrated elevated inflammatory markers consistent with MIS-C. He was treated with intravenous immunoglobulin with complete resolution of signs and symptoms. After 7 months of good health, he returned with a second, distinct illness characterized by fever, rash, gastrointestinal symptoms, and elevated inflammatory markers that met the criteria for MIS-C. In addition, we identified new dilatation of the left anterior descending coronary artery. He improved rapidly after treatment with intravenous immunoglobulin, aspirin, and steroids. Our report highlights the need to achieve a better understanding of this entity's pathogenesis and clinical course and to improve anticipatory guidance for children with MIS-C.

Trends in Treatments for Multisystem Inflammatory Syndrome in Children (MIS-C), United States, February 2020 - July 2021.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a novel severe postinfectious condition associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The purpose of this report is to describe nationwide trends in the evolving clinical management of MIS-C. METHODS: Patients with MIS-C were reported from state and local jurisdictions to the Centers for Disease Control and Prevention's (CDC's) MIS-C national surveillance system. Patients' case reports were reviewed to ensure that they met the CDC MIS-C case definition and had sufficient data for analysis. The prevalence of use of treatments for MIS-C, temporal trends in use of these treatments, and frequency of administration of different treatment combinations were analyzed. RESULTS: There were 4470 patients meeting the MIS-C case definition with onset dates from 19 February 2020 to 31 July 2021. The proportion of patients admitted to an intensive care unit (ICU) has declined over time, from 78.7% in April 2020 to 57.5% in June 2021 (P = .001). The most common treatments were intravenous immunoglobulin (IVIG), given to 85.6% of patients; steroids (77.7%), and antiplatelet medications (73.7%); use of each of these treatments has increased over time, particularly in patients not requiring admission to an ICU (all P < .001). Older patients and non-Hispanic Black patients were more likely to receive additional modes of therapy including vasoactive medication, noninvasive respiratory support, anticoagulation medication, and intubation/mechanical ventilation. CONCLUSIONS: IVIG, steroids, and antiplatelet medication have become increasingly utilized as standard treatment for MIS-C patients, while the use of other treatments may be contingent on the type and severity of clinical findings.

Infliximab treatment for refractory COVID-19-associated multisystem inflammatory syndrome in a Japanese child.

Patients with multisystem inflammatory syndrome in children (MIS-C) can develop clinical features resembling Kawasaki disease (KD). A full picture of MIS-C in East Asia which has higher incidence of KD than other regions remains unclear. We report on a 15-year-old Japanese boy with refractory MIS-C who was successfully treated with infliximab. A Japanese boy who was diagnosed with coronavirus disease 2019 (COVID-19) before a month developed MIS-C with fulfilling six principal symptoms of KD. Laboratory data showed extreme hyperferritinemia (11,404 ng/mL), besides lymphopenia and thrombocytopenia. The patient was refractory to initial therapy with intravenous immunoglobulin (IVIG; 2 g/kg), aspirin, and prednisolone. He was therefore administered a second IVIG (2 g/kg) and infliximab (5 mg/kg) on days 7 and 8 from the onset of fever, respectively, which resulted in an improvement of clinical symptoms. Only four Japanese cases with MIS-C were reported and all of them were responsive to IVIG. The hyperferritinemia in this case was distinctive from previously reported MIS-C cases in Japan and other cohorts and may be associated with refractoriness to IVIG therapy. Marked elevation of circulating ferritin levels is known to be induced by tumor necrosis factor-α, which plays a key role in the pathogenesis of both KD and MIS-C. Thus, for MIS-C patients with hyperferritinemia, early intervention with adjunctive infliximab may induce a more rapid resolution of inflammation and improve outcome. Because MIS-C may be heterogeneous with respect to immunopathology, genetic background, clinical phenotypes and response to therapies, optimized treatment strategies according to immunopathogenesis are required.

Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years - United States, July-December 2021.

Multisystem inflammatory syndrome in children (MIS-C) is a severe postinfectious hyperinflammatory condition, which generally occurs 2-6 weeks after a typically mild or asymptomatic infection with SARS-CoV-2, the virus that causes COVID-19 (1-3). In the United States, the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine is currently authorized for use in children and adolescents aged 5-15 years under an Emergency Use Authorization and is fully licensed by the Food and Drug Administration for persons aged ≥16 years (4). Prelicensure randomized trials in persons aged ≥5 years documented high vaccine efficacy and immunogenicity (5),§ and real-world studies in persons aged 12-18 years demonstrated high vaccine effectiveness (VE) against severe COVID-19 (6). Recent evidence suggests that COVID-19 vaccination is associated with lower MIS-C incidence among adolescents (7); however, VE of the 2-dose Pfizer-BioNTech regimen against MIS-C has not been evaluated. The effectiveness of 2 doses of Pfizer-BioNTech vaccine received ≥28 days before hospital admission in preventing MIS-C was assessed using a test-negative case-control design¶ among hospitalized patients aged 12-18 years at 24 pediatric hospitals in 20 states** during July 1-December 9, 2021, the period when most MIS-C patients could be temporally linked to SARS-CoV-2 B.1.617.2 (Delta) variant predominance. Patients with MIS-C (case-patients) and two groups of hospitalized controls matched to case-patients were evaluated: test-negative controls had at least one COVID-19-like symptom and negative SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) or antigen-based assay results, and syndrome-negative controls were hospitalized patients without COVID-19-like illness. Among 102 MIS-C case-patients and 181 hospitalized controls, estimated effectiveness of 2 doses of Pfizer-BioNTech vaccine against MIS-C was 91% (95% CI = 78%-97%). All 38 MIS-C patients requiring life support were unvaccinated. Receipt of 2 doses of the Pfizer-BioNTech vaccine is associated with a high level of protection against MIS-C in persons aged 12-18 years, highlighting the importance of vaccination among all eligible children.

Management skin manifestation of multisystem inflammatory syndrome associated with SARS-CoV-2.

BACKGROUND: Multisystem inflammatory syndrome (MIS), which develops after a past covid-19 infection. MIS can be described in different tissue inflammation, including the heart, lung, kidney, brain, skin, eye, and or gastrointestinal organs at the presence of COVID-19. Initially, MIS was described in Europe in children infected with SARS-CoV-2, then it was recently seen in the USA in 2020. MIS is a rare but serious disease condition associated with COVID-19 that can affect children (MIS-C) and adults (MIS-A). CASE PRESENTATION: A 44-year-old male who showed MIS-A in 59-day after his first covid-19 contact history. The patient presented to our emergency department with complaints of high fever, nausea, weakness, redness of the eyes, headache, and joint pain. On the second day of his hospitalization, a maculopapular skin lesion was seen in most of the skin. His fever could not be controlled even given paracetamol and broad effective antibiotics. His clinical, radiological, and laboratory findings showed that he had MIS-A. The patient was given intravenous pulse methylprednisolone and intravenous immunoglobulin (IVIG). These treatments, then, resulted in improvement of his clinical conditions, including fever and skin lesions, on the second day of the treatment. The patient was discharged in 14 days after the treatment. CONCLUSION: This report indicated that diagnosis and treatment of MIS-A could result in reducing patient morbidity and mortality.