Multisystem inflammatory syndrome in children related with 2019 Novel Coronavirus infection.

Multisystem inflammatory syndrome in children (MIS-C) reported in the United States and European countries is a disease with multi-organ involved symptoms related with 2019 Novel Coronavirus infection, which has never been reported in China. Although its symptoms are similar to Kawasaki disease, MIS-C has characteristics of higher frequency in older children and adolescents, gastrointestinal symptoms, haemodynamic instability, myocarditis and elevated inflammatory markers. Most of the children need intensive care. The pathogenesis and long-term prognosis of the disease need further study.Copyright © 2020 by the Chinese Medical Association.

A comparative study of cardiac involvement of kawasaki disease and multisystem inflammatory syndrome post COVID (MISC) in children

Background and Aim: Kawasaki Disease remains an enigma to the world to this day since first described by Dr. Tomisaku Kawasaki in 1967. In the last half a century there has been wide-spread global research elaborating the clinical aspects and patho-genesis of this disease entity. Multisystem Inflammatory Syndrome post Covid (MISC) is a relatively new disease which was described in literature in mid 2020. The striking resemblance as well as differences in spectrum of cardiac involvement of both the conditions has been elaborated in this study from a tertiary care centre in Eastern India. Method(s): The study was conducted over a period of 3 years from June 2018 to June 2021. Fiftyone patients with Kawasaki disease (including atypical and incomplete cases) and sixty children diag-nosed with MISC were included in the study. Echocardiography details were noted by a single observer. Data regarding the patient particulars, clinical aspects, lab parameters, imaging details and treatment particulars were collected and analysed. Patients were followed up for a minimum period of six months to one year. Result(s): In the Kawasaki group(51), infants(20) presented with multiple (and larger) aneurysms. Older children (gt;5 years) had more of single coronary involvement, (mostly LAD) and also had more atypical presentation(18) associated with infections like Dengue, Staphylococcal infection, Scrub Typhus. There were 4 cases of Kawasaki shock syndrome, all below 5 years. In the MISC group (60), there was also multiple coronary involvement in infants (11). But LV dysfunction was more common in older children and adolesecents (20), of whom 18 (90%) presented with severe dysfunction (LVEFlt;35%). Those with coronary involve-ment had normal function and those with dysfunction had no coronary involvement. Mild to moderate aneurysmal dilation of coronaries was found in children one to five years of age. No giant aneurysm was found in MISC. Overall, LMCA with LAD was the commonest pattern of involvement in both the conditions. Conclusion(s): KD and MISC had similar pattern of coronary involve-ment, but absence of giant aneurysm and significantly severe dys-function in older children in MISC indicates a likely different pathogenesis for myocardial involvement in MISC.

Unique Treatment Challenges with Multisystem Inflammatory Syndrome in Children (MIS-C) compared to Kawasaki Disease Shock Syndrome

Background. Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) associated with Coronavirus Disease 2019 present similarly with mucocutaneous symptoms and fever. Both syndromes can progress to shock. Successful treatments for MIS-C are largely based on proven KD management. As more patients with MIS-C are treated, protocols are adjusted. Infectious Diseases (ID) specialists are often early consultants in these cases. Understanding differences in how body systems are affected in MIS-C versus KD is essential for management. Methods. This is a single hospital comparison of 25 cases of MIS-C with mucocutaneous presentation and symptoms of shock and 25 consecutive cases of KD Shock Syndrome (KDSS). Cases were compared for demographics, symptoms, cardiac abnormalities, medical treatments, and cardiac recovery. Results. Patients with MIS-C develop symptoms of shock including sustained hypotension and tachycardia at 3 times the rate of patients with KD (45% vs 13%;p< 0.001). On echocardiogram, left ventricular myocardial dysfunction, assessed by ejection fraction, is more commonly noted in cases of MIS-C than KDSS (fig 1). About half of patients with MIS-C show left ventricular myocardial dysfunction initially with normalization by 6 months post-presentation in the majority (96%). Conclusion. Cardiac changes and shock events related to KD and MIS-C are thought to be caused by differing inflammatory mediators. By comparing these two syndromes, we can determine ways to manage each optimally. MIS-C often results in left ventricular myocardial dysfunction, which is rarer in KD cases. Fluid resuscitation with multiple fluid boluses followed by inotropes to treat hypotension in cases of in MIS-C puts increased strain on the already weakened myocardium. Early intravenous immunoglobulin (IVIG) administration, even in the presence of mild hypotension, can simultaneously provide the patient with additional fluid and decrease the underlying inflammatory process. This prompt treatment might reduce the need for pressor support while protecting the myocardium from further damage. As early consultants in MIS-C, ID providers should be educated regarding the unique cardiac challenges of MIS-C and avoid delay in IVIG treatment and cardiologist and intensivist consultation.

Kawasaki disease shock syndrome in the COVID-19 pandemic.

Multisystem inflammatory syndrome in children is a new entity in association with SARS-CoV2. Clinical features of Kawasaki disease were noted from the first reported cases of MIS-C. Before the COVID-19 pandemic, Kawasaki disease shock syndrome was considered to be a distinct and unique form of KD. We present a representative case that prove the current difficulty in clearly distinguishing MIS-C from pre-COVID-19-KDSS and emphasie the overlap of the diagnostic criteria.

Inflammasome activation in Kawasaki disease and multisystem inflammatory syndrome in children

Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C) is a newly identified syndrome elicited by infection of acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although MIS-C shares several clinical features with Kawasaki disease (KD), a greater magnitude of systemic inflammation is usually associated with MIS-C. Inflammasome activation induces the secretion of pro-inflammatory cytokines, IL-1β and IL-18 and the inflammatory form of cell death, pyroptosis. To provide mechanistic insights into MIS-C and KD, we compared the expression and activation of the inflammasome in blood samples from MIS-C and KD patients. Methods: Expression levels of canonical and non-canonical inflammasome components, including NLRP3, CASP1, CASP4, CASP5, IL1B, and the inflammatory mediator, TIFA in whole blood from KD and convalescent patients were analyzed from microarray datasets. The expression of these inflammasomerelated genes was further examined in whole blood samples from MIS-C, KD, KD shock syndrome (KDSS) and convalescent patients using RT-qPCR. Inflammasome activation and TIFA expression were validated in granulocytes of febrile control, KD and MIS-C patients by Western blotting. Results:TIFA, NLRP3, CASP1, CASP4, CASP5, IL1B were upregulated in whole blood from MIS-C, KD, and KDSS patients as compared to convalescent patients. However, the differences were not significant among diseases. Although gene expression profiles were similar in KD, KDSS and MIS-C whole blood RNA, the processing of canonical and non-canonical inflammasome caspases, caspase-1, and caspase-4 were only observed in granulocytes isolated from MIS-C patients, but not KD and febrile controls. Moreover, TIFA was upregulated along with the activation of the inflammasome in granulocytes of MIS-C patients. Conclusions: Our results suggest that activation of inflammasomes, especially non-canonical inflammasome induction in granulocytes, is a hallmark of MIS-C, and differentiates it from KD.

Clinical manifestations of multisystem inflammatory syndrome in children following covid-19: A narrative review

Coronavirus 2 acute and severe respiratory infection virus (SARS-CoV2) has been identified as a pathogen of COVID-19 disease. Initially it was thought that children were safe from the virus, but several reports showed Multisystem Inflammatory Syndrome in Children (MIS-C) as a dangerous complication of COVID-19. There are similarities and differences between MIS-C and Kawasaki disease, Kawasaki shock syndrome, and toxic shock. It is a multisystem disease that affects major systems, including cardiovascular, respiratory, blood and coagulation, kidney, and nervous systems. Diagnosis of MIS-C is based on evidence of recent SARS-CoV2 infection and multiple system involvement, and laboratory criteria for high inflammation in the absence of other causes. In many of these patients chest imaging may show no evidence of COVID-19 involvement, or abnormal findings such as pleural effusion, ground glass patchy opacities, or local density and atelectasis may be seen. Echocardiography shows involvement of pericardium, myocardium, endocardium, and coronary arteries, which may be accompanied by cardiac arrhythmias. On abdominal imaging, evidence of ascites may be reported in these patients. In whole blood tests, lymphopenia, anemia, and thrombocytopenia are common, and inflammatory markers are very high. In mild cases, patients can be closely monitored, but many of these children develop severe forms and require hospitalization or pediatric intensive care unit. This study narratively reviews the clinical manifestations of multisystemic inflammatory syndrome in children following COVID-19.

Clinical features and laboratory findings of multisystem inflammatory syndrome in children (MIS-C)

Introduction: Children mostly have mild or asymptomatic forms of SARS-CoV-2 infection, but during pandemic a higher incidence of Kawasaki disease, Kawasaki-like syndrome and the emergence of a new clinical entity, multisystem inflammatory post-covid syndrome (MIS-C) has also been observed. Objectives: The aim of this study is to determine clinical features and laboratory findings in patients with MIS-C. Methods: Retrospective analysis of clinical features and laboratory findings of MIS-C patients treated at our tertiary referal center (Clinic of Pediatric, University Clinical Centre Nis, Serbia). Results: From 18th of March 2020 till 30st of April 2021 there were 10 patients diagnosed as MIS-C according to CDC criteria. Eight patients were male and two were female. Patients age was 2 to 13 years (average 7.9 years, median 7 years). All patients had SARS -CoV-2 N-protein IgG antibodies but without history of disease symptoms and had positive contact four weeks prior to the onset of MIS-C symptoms. First symptom of MIS-C was fever (over 38C) which lasted in average for 4.4 days (3-7 days). Muco-cutaneous and gastrointestinal manifestations were most common. All patients had bulbar conjuctivitis, rash was present in 8 patients (80%), hand/foot oedema in 6 cases (60%), anterior cervical lymphadenopathy and cheliitis in 4 cases (40%) and periobital oedema in one case (details presented in Table 1. Clinical features of MIS-C patients). Nine patients (90%) presented with gastrointestinal symptoms while nervous system was affected in 5 patients. Three patients developed heart insuffitiency and one patient developed early signs of right coronary arthery aneurism. All patients had elevated inflammatory markers. Complete blood count showed elevated levels of white blood cells in 9 patients. Hypoalbuminemia and hypoproteinemia, low levels of serum potassium and sodium were present during ten days after the onset of symptoms. Troponines were elevated in 4 cases, proBNP in 5 cases. Abdominal ultrasound was performed and 6 patients presented with hepatoplenomegaly, 3 with enlarged spleen, one with enlagred liver and 4 had ascites. All patients were treated with combination of two antibiotics till cultures were proven negative, corticosteroid therapy and antiaggregation therapy. Three patients received a IVIG in a single dose (2gr/kg). All patients had good response to corticosteroid therapy (2mg/kg). Corticosteroid therapy was continued for four weeks (tapering). Conclusion: MIS-C can be a life-threatening condition in children. Early diagnosis and timely adequate treatment are of paramount importance. In children less than 5 years of age, the distinction between Kawasaki (Kawasaki shock) syndrome and MIS-C might be difficult, influencing the decision to use IVIG or steroids alone.

Case Report: Kawasaki Shock Syndrome With Polycyclic Eruption: A Peculiar Brain Imaging.

Kawasaki disease (KD) is a childhood vasculitis of unknown etiology. The present study describes a case of KD shock syndrome that occurred in an infant (age, 16 months) following 7 days of high fever and persistent rash characterized by target-like and purpuric skin lesions. The child developed neurological manifestations such as altered consciousness and irritability. Consequently, brain magnetic resonance imaging (MRI) was performed, revealing an inflammatory involvement of the anterior perforated substance and the hypothalamus. Cerebral involvement on brain MRI is rarely described in KD but when reported is characterized mostly by cerebral vasculitis. We illustrate for the first time in KD an inflammation in the brain not related to vasculitis, reporting peculiar neuroradiological findings. This last aspect has fascinated us in light of recent evidence about the immunological spectrum of Multisystem Inflammatory Syndrome in Children (MIS-C) and Kawasaki-like syndrome in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak.

Laboratory parameters between multisystem inflammatory syndrome in children and Kawasaki disease.

Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been described to partially overlap with Kawasaki disease (KD) with regard to clinical symptoms, but they are unlikely to share the same disease entity. We conducted a systematic review and meta-analysis to characterize the laboratory parameters of MIS-C compared with those of KD and Kawasaki disease shock syndrome (KDSS). Databases were searched for studies on laboratory parameters of MIS-C (hematology, inflammatory markers, cardiac markers, and biochemistry) through May 31, 2021. Twelve studies with 3073 participants yielded 969 MIS-C patients. In terms of hematology, MIS-C patients had lower levels of leukocytes, absolute lymphocyte count and platelet count (PLT) than KD patients and had similar absolute neutrophil count (ANC) and hemoglobin (Hb) levels. In terms of inflammatory markers, MIS-C patients had higher levels of C-reactive protein, D-dimer and ferritin than KD patients and had similar levels of procalcitonin and erythrocyte sedimentation rate (ESR). In terms of cardiac markers, MIS-C patients had higher CPK levels than KD patients. The levels of N-terminal pro-brain natriuretic peptide, troponin and aspartate aminotransferase were not significantly different between MIS-C and KD patients. In terms of biochemistry, MIS-C patients had lower levels of albumin, sodium and alanine aminotransferase and higher levels of creatinine than KD patients. In addition, MIS-C patients had lower levels of PLT, Hb and ESR and higher levels of ANC than KDSS patients. Measurement of laboratory parameters might assist clinicians with accurate evaluation of MIS-C and further mechanistic research.

Perspective of Immunopathogenesis and Immunotherapies for Kawasaki Disease.

Kawasaki Disease (KD) is an acute inflammatory illness that mostly occurs in children below 5 years of age, with intractable fever, mucocutaneous lesions, lymphadenopathy, and lesions of the coronary artery (CAL). KD is sharing clinical symptoms with systemic inflammatory syndrome in children (MIS-C) which is related to COVID-19. Certain genes are identified to be associated with KD, but the findings usually differ between countries and races. Human Leukocyte Antigen (HLA) allele types and toll-like receptor (TLR) expression are also correlated to KD. The acute hyperinflammation in KD is mediated by an imbalance between augmented T helper 17 (Th17)/Th1 responses with high levels of interleukin (IL)-6, IL-10, IL-17A, IFN-γ, and IP-10, in contrast to reduced Th2/Treg responses with lower IL-4, IL-5, FoxP3, and TGF-ß expression. KD has varying phenotypic variations regarding age, gender, intravenous immunoglobulin (IVIG) resistance, macrophage activation and shock syndrome. The signs of macrophage activation syndrome (MAS) can be interpreted as hyperferritinemia and thrombocytopenia contradictory to thrombocytosis in typical KD; the signs of KD with shock syndrome (KDSS) can be interpreted as overproduction of nitric oxide (NO) and coagulopathy. For over five decades, IVIG and aspirin are the standard treatment for KD. However, some KD patients are refractory to IVIG required additional medications against inflammation. Further studies are proposed to delineate the immunopathogenesis of IVIG-resistance and KDSS, to identify high risk patients with genetic susceptibility, and to develop an ideal treatment regimen, such as by providing idiotypic immunoglobulins to curb cytokine storms, NO overproduction, and the epigenetic induction of Treg function.

Multisystemic Inflammatory Syndrome in Children Associated With SARS-CoV-2 Infection: A Case Series Report in a Pediatric Center in Mexico.

We report four cases of patients with multisystem inflammatory syndrome in children (MIS-C) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, of which three patients presented characteristics of Kawasaki disease (KD). All presented fever of more than 3 days, and gastrointestinal involvement, significant increase in C-reactive protein (CRP), polymorphonuclear cells, procalcitonin, D-dimer, fibrinogen and troponin, lymphopenia and hypoalbuminemia. Myocardial involvement was observed in two patients. All were treated with fluids resuscitation and vasoactive therapy, 75% received intravenous immunoglobulin (IVIG) and systemic steroids. Two patients developed a transient acute kidney injury, one patient presented as acute appendicitis and developed a bilateral pleural effusion. One patient required a second dose of IVIG and boluses of methylprednisolone. None required mechanical ventilation and there were no deaths.

Clinical aspects for differential diagnosis of Kawasaki disease shock syndrome: a case control study.

BACKGROUND: Because of the absence of a specific diagnostic test and pathognomonic clinical features, physicians must rely on the presence of specific clinical criteria and laboratory data that support the diagnosis of KD. To help clinicians distinguish KD, KDSS, septic shock, and TSS earlier, we suggest differential diagnosis and treatment guideline. METHODS: Medical records of immunocompetent patients who were admitted to the pediatric department with a diagnosis of KDSS, septic shock or TSS (SS group) were retrospectively reviewed. In addition, KD patients were selected by seasonal matching to each case of KDSS patient by date of admission (± 2 weeks). RESULTS: There were 13 patients with KDSS, 35 patients with SS group, and 91 patients with KD. In comparison between KDSS and septic shock group, KDSS group had significantly higher rate of coronary aneurysm incidence, and higher left ventricle dysfunction rate. In comparison between KDSS and TSS, patients with KDSS had a significantly higher erythrocyte sedimentation rate (ESR) and significantly lower creatinine. Receiver operation characteristic curve revealed that the optimal ESR cut off value for determining the KDSS was 56.0 (sensitivity 75.0%, specificity of 100.0%) and the optimal creatinine cut off value for determining the TSS was 0.695 (sensitivity 76.9%, specificity 84.6%). CONCLUSIONS: Clinical symptoms, laboratory finding, echocardiography, and culture studies can be used to differentiate KD, KDSS, septic shock and TSS.

Cardiovascular Involvement in Kawasaki Disease Is Much More Than Mere Coronary Arteritis.

Kawasaki disease (KD) is now a common cause of acquired heart disease in children. Coronary artery involvement is the most serious complication in children with KD. Several non-coronary complications have now been identified in this condition but these are often overlooked. Myocarditis is an integral component of KD and may be more common than coronary artery abnormalities. Pericardial involvement and valvular abnormalities have also been observed in patients with KD. KD shock syndrome is now being increasingly recognized and may be difficult to differentiate clinically from toxic shock syndrome. Endothelial dysfunction has been reported both during acute stage and also on follow-up. This may be a potentially modifiable cardiovascular risk factor.

Multisystem Inflammatory Syndrome in Children Related to COVID-19: the First Case in Korea.

Since mid-April 2020, cases of multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 that mimics Kawasaki disease (KD) have been reported in Europe and North America. However, no cases have been reported in Korea. We describe an 11-year old boy with fever, abdominal pain, and diarrhea who developed hypotension requiring inotropes in intensive care unit. His blood test revealed elevated inflammatory markers, thrombocytopenia, hypoalbuminemia, and coagulopathy. Afterward, he developed signs of KD such as conjunctival injection, strawberry tongue, cracked lip, and coronary artery dilatation, and parenchymal consolidation without respiratory symptoms. Microbiological tests were all negative including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction. However, serum immunoglobulin G against SARS-CoV-2 was positive in repeated tests using enzyme-linked immunosorbent assay and fluorescent immunoassay. He was recovered well after intravenous immunoglobulin administration and discharged without complication on hospital day 13. We report the first Korean child who met all the criteria of MIS-C with features of incomplete KD or KD shock syndrome.

Multisystem Inflammatory Syndrome in Children Temporally Related to COVID-19: A Case Report From Saudi Arabia.

The World Health Organization is still revising the epidemiology of multi-system inflammatory syndrome in children (MIS-C) and the preliminary case definition, although there is a dearth of robust evidence regarding the clinical presentations, severity, and outcomes. Researchers, epidemiologists, and clinicians are struggling to characterize and describe the disease phenomenon while taking care of the diseased persons at the forefronts. This report tackles the first case of a 13-year-old Saudi female with the MIS-C mimicking Kawasaki disease. Her main manifestations were fever, gastrointestinal symptoms, evidence of organ failure with an increase in inflammatory markers, and a history of coronavirus disease (COVID-19) infection. She had glucose-6-phosphate dehydrogenase (G6PD) deficiency and no significant previous history of any disease. She presented with signs of acute illness: high-grade fever (39.6°C) for five days accompanied by sore throat, malaise, reduced oral intake, abdominal pain, diarrhea, skin rash, bilateral non-suppurative conjunctivitis, and erythematous, cracked lips. Eventually, she died despite aggressive management based on the Centers for Disease Control and Prevention and the Saudi Ministry of Health guidelines for COVID-19 management. Based on this case, we suggest that pediatricians need to be aware of such atypical presentations and early referral to tertiary care is imperative for further early diagnosis and management. MIS-C is a rare yet severe and highly critical complication of COVID-19 infection in pediatrics, leading to serious and life-threatening illnesses. Knowledge about the wide spectrum of presenting signs and symptoms and disease severity, including early detection and treatment, is pivotal to prevent a tragic outcome.

Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19.

In atherosclerosis patients, vascular endothelial dysfunction is commonly observed alongside damage of the vascular endothelial glycocalyx, an extracellular matrix bound to and encapsulating the endothelial cells lining the blood vessel wall. Although atherosclerotic risk factors have been reported in severe patients with coronavirus disease 2019 (COVID-19), the exact mechanisms are unclear. The mortality associated with the COVID-19 outbreak is increased by comorbidities, including hypertension, diabetes, obesity, chronic obstructive pulmonary disease (COPD), and cardiovascular disease. Besides, older individuals and smokers have significantly worse outcomes. Interestingly, these comorbidities and risk factors are consistent with the pathophysiology that causes vascular endothelial glycocalyx damage. Moreover, vascular glycocalyx dysfunction causes microvascular leakage, which results in interstitial pulmonary abnormal shadows (multiple patchy shadows with a ground glass inter-pneumonic appearance). This is frequently followed by severe acute respiratory distress syndrome (ARDS), closely related to coagulo-fibrinolytic changes contributing to disseminated intravascular coagulation (DIC) and Kawasaki disease shock syndrome, as well as inducing activation of the coagulation cascade, leading to thromboembolism and multiple organ failure. Notably, SARS-CoV-2, the causative virus of COVID-19, binds to ACE2, which is abundantly present not only in human epithelia of the lung and the small intestine, but also in vascular endothelial cells and arterial smooth muscle cells. Moreover, COVID-19 can induce severe septic shock, and sepsis can easily lead to systemic degradation of the vascular endothelial glycocalyx. In the current review, we propose new concepts and therapeutic goals for COVID-19-related vascular endothelial glycocalyx damage, based on previous vascular endothelial medicine research.

COVID-19 associated Kawasaki-like multisystem inflammatory disease in an adult.

Recent reports have described a secondary Multisystem Inflammatory Syndrome in Children (MIS-C) after a prior COVID-19 infection that often has features of Kawasaki disease (KD). Here, we report the case of a 36-year-old woman who presented to the emergency department hypotensive and tachycardic after 1 week of fevers, abdominal pain, vomiting and diarrhea, and was found to have the classic phenotype of complete Kawasaki's Disease including nonexudative conjunctivitis, cracked lips, edema of the hands and feet, palmar erythema, a diffuse maculopapular rash, and cervical lymphadenopathy. Initial laboratory studies were significant for hyponatremia, elevated liver function tests including direct hyperbilirubinemia, and leukocytosis with neutrophilia. Imaging revealed mild gallbladder wall edema, a small area of colitis, and small pleural effusion. She was treated for Kawasaki Disease Shock Syndrome (KDSS) with pulse dose solumedrol, IVIG, and aspirin with near resolution of symptoms and normalization of vital signs within 1 day and subsequent improvement in her laboratory abnormalities. She was later found to be COVID-19 IgG positive, suggesting past exposure. This case represents an early report of a KD-like illness in an adult with serologic evidence of a previous COVID-19 infection, similar to MIS-C. It suggests that the virulent strain of SARS-CoV-2 appears to cause a post-infectious inflammatory syndrome similar to KD in adults, as well as children. Our understanding of the myriad of COVID-19 symptoms and sequelae is rapidly evolving. We recommend physicians remain vigilant for inflammatory syndromes that mimic KD/KDSS which may warrant prompt treatment with IVIG and steroids.