Factors affecting disease severity of multisystem inflammatory syndrome in children

Purpose: Multisystem inflammatory syndrome that occurs after SARS-Cov-2 infection with fever, cardiogenic shock and hyperinflammation in children, can be life threatening. In this study, it was aimed to investigate the effects of the complaint and duration at diagnosis on the severity of multisystem inflammatory syndrome in children. Materials and methods: The medical records of 99 pediatric patients, who were diagnosed multisystem inflammatory syndrome between September 2020 and August 2021 according to Centers for Disease Control and Prevention, were evaluated retrospectively. Demographic features, initial findings, and admission time of patients were noted. Patients were categorized according to intensive care necessity. Results: The median age of the patients was 10 (2-18) and 62 (62.6%) of patients were male. The median duration before admission was 4 (1-10) days. All patients has fever, 81.8% had gastrointestinal and 75.8% had cardiovascular involvement at admission. The patients (56.6%) who were accepted as severe and moderate MIS-C required intensive care. Prolonged fever, delayed admission, cardiovascular involvement, high inflammatory markers, lymphopenia and thrombocytopenia were found to key parameters determining the need for intensive care. Conclusion: Multisystem inflammatory syndrome in children is a new disease characterized by fever, signs of inflammation and organ dysfunction associated with SARS-CoV-2 infection. Delayed admission, high cardiac and inflammatory markers at diagnosis increase the need for intensive care. © 2022, Pamukkale University. All rights reserved.

MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN ACROSS 16 LATIN AMERICAN COUNTRIES: A MULTICENTER STUDY FROM THE REKAMLATINA NETWORK

BackgroundMultisystem Inflammatory Syndrome in Children (MIS-C) is one of the most feared complications following SARS-CoV2 infection in children and adolescents. Few multinational multicenter studies from Latin America have been published.ObjectivesTo describe the clinical presentation, management, and outcomes of MIS-C in Latin America.MethodsObservational, prospective and retrospective, multicenter study to gather information from 84 participating centers across 16 Latin American countries, between August January 1, 2020 and June 30, 2022.ResultsOf the 1,239 reported cases of MIS-C, 84.2% 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 days of fever at the time of hospital admission was 5 and a significant number of subjects required admission to an intensive care unit (N=589, 47.8%). A total of 538 (47.2%) patients had an abnormal initial echocardiogram. Most of the subjects (N= 1,096, 88.7%) were treated with intravenous immunoglobulin (IVIG), while 76.7% (N= 947) were treated with steroids, of which 10.6% (N= 100) did not receive IVIG. 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= 0.00001).ConclusionOne of the most significant findings from our study was the death rate, especially in those not initially diagnosed with MIS-C, in whom it was higher. This highlights the importance of increasing awareness and making an earlier diagnosis of MIS-C in Latin America.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

SINGLE CELL MULTIOMIC PROFILING OF DISRUPTED REGULATORY NETWORKS IN COVID19 ASSOCIATED MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN

BackgroundChildren infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) usually present minimal symptoms or are asymptomatic. Nevertheless, a subset of children 2-6 weeks after the initial SARS-CoV-2 infection develops a postinfectious SARS-CoV-2-related multisystem inflammatory syndrome in (MIS-C). Recently, transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation, however, the underlying pathophysiology of MIS-C is not fully understood [1].ObjectivesThe purpose of our project is to characterize the complexity of cell populations and capture cellular heterogeneity to uncover the regulatory networks and interactions that are disrupted during MIS-C flare with simultaneous profiling of gene expression and open chromatin regions from the same nuclei.MethodsSamples of peripheral blood mononuclear cells from patients with MIS-C diagnosed at the University Children's Hospital, University Medical Center Ljubljana, were collected during the initial presentation before any treatment and at 6-12 months in remission. The primary aim is to identify which regulatory networks are driving inflammation in MIS-C flare, for which we are performing single cell Multiome ATAC + Gene Expression Sequencing. To enable simultaneous profiling of epigenomic landscape and gene expression from the same nuclei, we are using Chromium Next GEM Single Cell Multiome ATAC + Gene Expression kit from 10X Genomics.ResultsWe included 32 patients with MIS-C from whom we collected paired blood samples during the initial presentation before treatment and at 6-12 months in remission. In single cell multiomic experiment we included 10 patients with paired samples, with the most viable cell count prior cryopreservation. All samples that are included into multiomic single cell analysis have 75% - 99% viability prior cryopreservation. In the protocol the key is to remove remaining granulocytes causing high mitochondrial RNA burden and extensively optimize the dilution factor of lysis buffer and the length of cell lysis step in order to get intact nuclei with no significant blebbing. Afterward, the single cell ATAC libraries as well as single-cell gene expression libraries are constructed and sequenced. Data are undergoing pairwise analysis to compare the cell population heterogeneity, expression profile and open chromatin landscape in the time of the initial presentation of MIS-C and in the remission, with Cell ranger software as well as with R package scREG [2], and custom scripting. In the second step we will inspect if the resulting altered transcriptomic signature from single-cell experiment is present on larger cohort. In that regard, we will perform bulk transcriptomic profiling on all paired collected samples during the initial presentation of MIS-C before treatment and at 6-12 months in remission.ConclusionThe results of this project are expected to enlighten the underlying pathophysiology of MIS-C flare and thus support clinical decision on more targeted treatment. The identified disrupted networks during MIS-C flare could lead the way to establish an early diagnosis and improve long-term outcome, including prevention of myocardial and neuropsychological impairment. Moreover, a better understanding of the disrupted regulatory networks that are driving inflammation in MIS-C, could lead to new insights into diseases with similar clinical presentations as is Kawasaki Disease.References[1]Sacco, K., Castagnoli, R., Vakkilainen, S. et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat Med 28, 1050–1062 (2022).[2]Duren, Z., Chang, F., Naqing, F. et al. Regulatory analysis of single cell multiome gene expression and chromatin accessibility data with scREG. Genome Biol 23, 114 (2022).AcknowledgementsThis research was supported by Slovenian research agency grant J3-3061 and Interreg ITA-SLO project Cattedra.Disclosure of InterestsNone Declared.

Rashford, racism, and bankrupt excuses

Ian Sinha and colleagues include the rising tide of food insecurity in their list of ways in which children's health and wellbeing are being sidelined by covid-19.1 The long term harm of poor health in childhood is well established, and a policy focus is urgently needed, they say. Children don't choose the poverty they are born into and live with, or the parental circumstances that lead to them being unvaccinated, unfed, or brought up on junk food.23 The incidence of covid-19 is low in children, but evidence grows of a rare, multisystem inflammatory syndrome related to Kawasaki disease.4 The illness is severe and disproportionately affects black children, although outcomes are favourable with intensive hospital care. The ISARIC study of 20 000 hospital inpatients clarifies the comorbidities that lead to hospital admission.7 But our ability to understand the high impact of covid-19 on ethnic minority patients and staff continues to be hampered by absent, limited, and poor quality data.

Hermes

B Medium-term cardiac outcomes in young people with multi-system inflammatory syndrome: the era of COVID-19 b I Wong J, Theocharis P, Regan W et al i I Pediatr Cardiol (2022) 43:1728-1736 i Multisystem inflammatory syndrome in children (MIS-C) is a complication of coronavirus disease 2019 (COVID-19). B European Pediatric [sic] Surgeons' Association survey on the use of splenic embolization in blunt splenic trauma in children b I Dariel A i I , i I Soyer T i I , i I Dingemann J et al i I Eur J Pediatr Surg (2022) 32:497-503 i The management of severe splenic injury in children has evolved, and currently the preferred management of even severe injury is nonoperative, with close observation. One of the complications of this and other open-heart procedures requiring cardiopulmonary bypass is acute kidney injury (AKI). [Extracted from the article] Copyright of Pediatric Radiology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Will the COVID-19 cloud change pediatric medicine forever?

With the United States still in the throes of a pandemic, nearly 400 pediatric health care providers share their struggles in getting patients back to the office, advocating for a COVID-19 vaccine, and working their way toward optimism in the face of the biggest health care challenge of their lives. [...]although the reasons around the pessimism remained the same in both 2013 and 2019 (insufficient time with patients, inadequate reimbursement, and health care reform), this year-no surprise-the top reason was concerns about adequately treating patients with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). In 2019, when asked what the top 2 challenges to their practice were, 45% of health care providers said transitioning to electronic health records (EHRs) and dealing with insurance (42%) were the greatest obstacles.

Multi-System Inflammatory Syndrome Presenting as Non-Specific Colitis: A Medical Diagnosis with a Surgical Presentation.

A 20-year-old woman with previous COVID-19 diagnosis presented with abdominal pain and colitis on CT scan. She was admitted in septic shock, with etiology of colitis unclear. After resuscitation, antibiotics, and steroids, she clinically deteriorated. Worsening Clostridioides difficile infection was most likely and she was taken to the operating room. Intraoperatively, only a segment of transverse colon appeared abnormal on gross and endoscopic evaluation. Total colectomy was deferred in favor of segmental resection. Given her unusual disease pattern and recent COVID-19 infection, diagnosis of MIS-C was considered. Steroids were continued and treatment broadened to include heparin and IVIG. The patient returned to the operating room for planned reexploration, endoscopy, and end colostomy. On hospital day three, the patient had an acute mental status change. Computed tomography demonstrated acute cerebral edema with brainstem herniation. The family chose comfort-care measures. Final pathology from the transverse colon demonstrated COVID-19-associated vasculitis.

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), 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.

Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort.

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a new condition that first appeared in children and adolescents during the COVID-19 pandemic. We aimed to describe the diagnostic course, clinical and biological manifestations, and treatment of MIS-C during the first three COVID-19 waves. Methods: We extracted patient data from the Juvenile Inflammatory Rheumatism (JIR) cohort. We analyzed data for patients meeting the World Health Organization diagnostic criteria for MIS-C from the start of the COVID-19 pandemic from March 2020 to June 30, 2021. We then compared data for patients in wave one to those in waves two and three. Results: We identified 136 patients with MIS-C. The median age decreased but not significantly during the waves, from 9.9 years to 7.3 years (p = 0.105). Boys represented 52.2% (n = 71) of patients, and 46% (n = 41) of patients originated from sub-Saharan Africa (p < 0.001). Patients presented less diarrhea (p = 0.004), respiratory distress (p < 0.001), and myocarditis (p < 0.001) with progressive waves. Biological inflammation also decreased, namely, C-reactive protein level (p < 0.001), neutrophil count (p = 0.004), and albumin level (p < 0.001). Patients received more corticosteroids (p < 0.001) and required less ventilation support (p < 0.01) and less inotrope treatment (p < 0.001) in the later waves. The duration of hospitalization gradually decreased (p < 0.001), as did critical care unit admissions (p = 0.002). Conclusion: Over the three COVID-19 waves, with a change in the management of MIS-C, children in the JIR cohort in France showed a less severe disease course, in particular, a greater use of corticosteroids. This observation may reflect the impact of both improved management and different SARS-CoV-2 variant.

Kawasaki Disease in the Time of COVID-19 and MIS-C - The International Kawasaki Disease Registry.

BACKGROUND: Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) and Kawasaki disease (KD) have overlapping clinical features. We compared demographics/clinical presentation, management, and outcomes of patients by evidence of prior SARS-CoV-2 infection. METHODS: The International KD Registry (IKDR) enrolled KD and MIS-C patients from sites from North, Central and South America, Europe, Asia and Middle East. Evidence of prior infection was defined as: Positive (+ve household contact or positive PCR/serology), Possible (suggestive clinical features of MIS-C and/or KD with negative PCR or serology but not both), Negative (negative PCR and serology and no known exposure), and Unknown (incomplete testing and no known exposure). RESULTS: Of 2345 enrolled patients SARS-CoV-2 status was Positive for 1541 (66%) patients, Possible 89 (4%), Negative 404 (17%) and Unknown for 311 (13%) patients. Clinical outcomes varied significantly between the groups, with more patients in the Positive/Possible groups presenting with shock, having admission to Intensive Care, receiving inotropic support, and having longer hospital stays. Regarding cardiac abnormalities, patients in the Positive/Possible groups had a higher prevalence of left ventricular dysfunction, while patients in the Negative and Unknown groups had more severe coronary artery abnormalities. results CONCLUSION: : There appears to be a spectrum of clinical features from MIS-C to KD with a great deal of heterogeneity, and one primary differentiating factor is evidence for prior acute SARS CoV2 infection/exposure. SARS-CoV-2 Positive/Possible patients had more severe presentations and required more intensive management, with a greater likelihood of ventricular dysfunction but less severe coronary artery adverse outcomes, in keeping with MIS-C.

Dermatologic findings associated with COVID-19 in pediatric patients

[...]a combined study of prospective testing in Eastern Spain and retrospective literature review of acral cases in both adults and children found only 13 out of 88 (14.8%) tested cases were positive for COV-ID-19 .5 The PCR/serology testing of 38 children (median age 13.5 years) with new onset pseudo-chilblains at a tertiary care hospital in Italy found all patients negative for RT-PCR and IgM, IgG, IgA antibodies.7 A potential confounding variable is lifestyle changes from staying indoors during a lockdown state, implemented by many countries in response to the COVID-19 pandemic. An in-depth study by Neri and colleagues8 of 8 adolescents with chilblains-like lesions revealed that they had increased risk factors for primary chilblains: body mass index (BMI) <50th percentile, increased cold exposure with barefoot or thin socks contacting with cold floors, and prolonged postural habits impeding robust peripheral circulation. Initial viral testing is biased towards patients with URI symptoms, the timing of retrospective testing is variable, and much is still unknown about COVID-19 antibodies-including the percentage of who acquires these antibodies and the duration of positive serology.9,10 Reports of pseudo-chilblains associated with COVID-19 have presented consistent histological findings of superficial, deep, and perivascular lymphocytic infiltrate regardless of positive or negative COVID-19 testing in the patient,6'11'12 suggesting an inflammatory-based etiology that differs from the post-infectious perniosis histology commonly involving cold agglutinins and cryoglobulins.13 Interestingly, even in some pediatric cases with negative SARS-CoV-2 PCR, biopsies still demonstrated SARS-CoV-2 positive im-munohisto chemistry in endothelial cells.12,14 The positive immunohis-tochemistry was confirmed on electron microscopy with coronavirus particles present in endothelial cell cytoplasm,12 suggesting that the virus may still play a role in inducing lymphocytic vasculitis in pseudo-chilblains, despite negative PCR or serum serology. The Pediatric Dermatology Research Alliance COVID-19 Response Task Force (PDCRTF) has developed an open registry for cases to study and better understand this phenomenon.18 Other vascular related skin manifestations such as livedo-reticularis and purpuric or petechial eruptions have been reported in adults and were felt to be a thrombotic phenomenon related to viral infection, but a literature search has not revealed such cases among children up to date of this publication except for one case of petechiae presenting in relation to other morbilliform and annular lesions discussed later.19 Nonspecific viral exanthems A series of cases highlight a varicella-like exanthem associated with COVID-19 among adult patients, particularly in Italy, who developed a monomorphic papulovesicular rash of the trunk that progressed to crusting over a few days with histology consistent with viral infection.20 Among children, Genovese and colleagues21 detailed a similar varicella-like papulovesicular exanthem, distributed symmetrically along the bilateral trunk.

Clinical Approaches to the COVID-19 Pandemic

SARS-CoV-2 is a highly contagious virus that can affect almost any system in the body. New developments in understanding its transmissibility, management, and sequelae are unfolding almost daily. However, no medical publication in 2021 would be complete without a snapshot of the current status of this pandemic. The virus continues to mutate to more contagious, and therefore more dangerous, strains. The best path forward through this pandemic is vaccination against SARS-CoV-2 for all those who are eligible. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

A final review: How are our children doing right now?

In caring for our pediatric patients, we will continue to live with the fact that the disruptions have not been uniformly felt, with increased impact on Black and Brown children and those living in poverty;additionally, levels of access to routine pediatric health services have varied throughout the pandemic.1 For all children, though, we have to make up much lost time when it comes to physical, mental, and academic concerns, as well as socialization issues. Because schools provide another resource for identifying and addressing mental health concerns, the complete or partial shift to virtual learning likely compounded the mental health crisis. According to one study, "the prevalence of depression and anxiety symptoms during the COVID-19 pandemic has doubled, compared with prepan-demic estimates. Early childhood: A profound degree of development takes place from birth to 5 years of life. Because of the pandemic, children 5 years and younger have spent all or a significant portion of their lives in social isolation alongside parents or caregivers.

Croatian Society for Infectious Diseases recommendations for diagnosis and treatment of multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children is a novel entity first described in April 2020. It is a complication of COVID-19 that appears with a latency of 2-6 weeks and is characterized by fever, multiorgan involvement, and elevated inflammatory markers. Diagnosis is based on certain diagnostic criteria, and in these recommendations we chose the World Health Organization case definition. Patients should be treated with intravenous immuno-globulin and glucocorticoids together with other symptomatic and supportive measures. Follow-up should be at least a year-long, and even longer in case of cardiac complications. The aim of these recommendations is to help clinicians in diagnosing and treating this disease.Copyright © 2022, University Hospital of Infectious Diseases. All rights reserved.

Multisystemic Inflammatory Syndrome in Children and Kawasaki Disease: Parallels in Pathogenesis and Treatment.

PURPOSE OF REVIEW: Since it first appeared, multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been compared to Kawasaki disease (KD). Although there were early parallels between MIS-C and KD, key differences emerged over time. Here, we aim to compare the pathogenesis, clinical presentation, treatment, and outcomes of MIS-C and KD. RECENT FINDINGS: In this article, we review and compare MIS-C and KD, highlighting differentiating features. We discuss the epidemiological and immunological factors along with clinical and laboratory features which discern MIS-C from KD. We also compare treatment and our understanding of long-term outcomes. Though parallels exist between MIS-C and KD, distinguishing the two is important for clinical management of patients, counseling about natural history, and determining long-term monitoring. While both MIS-C and KD are characterized by profound inflammation and inflammatory vasculopathy, further study is needed to determine whether they are distinct immunopathogenic disorders.

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.