Multisystem inflammatory syndrome in children: A dysregulated autoimmune disorder following COVID-19.

Multisystem inflammatory syndrome in children (MIS-C) is a dysregulated autoimmune-mediated illness in genetically susceptible patients following COVID-19 with an interval of 2-6 weeks. The median age of patients with MIS-C is 6-11 years. Most common manifestations are involvement of gastrointestinal tract, cardiovascular system, hematological system, and mucocutaneous system. Respiratory tract, neurological system, musculoskeletal system, and kidney are less frequently affected. Mucocutaneous manifestations and coronary artery abnormalities characteristic for Kawasaki disease (KD) may be observed in a significant proportion of MIS-C patients that may make the differential diagnosis be difficult for some patients, especially in the post-pandemic era. The mortality rate is 1-3%. Management and prognosis of MIS-C are similar to that of KD. MIS-C and KD may share a common pathogenic process. Based on the observation of MIS-C-like illness in uninfected neonates, i.e. multisystem inflammatory syndrome in neonates, both MIS-C and KD may be a consequence of dysregulated, over-exaggerated humoral immune responses triggered by a specific infectious agent.

Prolonged Fever: Kawasaki Disease in a Pediatric Patient With COVID-19.

Kawasaki disease (KD) is the leading cause of acquired heart disease. The cardiac clinical features seen with KD require diagnosis and treatment within 10 days of symptoms to decrease the risk of complications. This case report examines the complexity of prolonged fever in a pediatric patient with a positive test for severe acute respiratory coronavirus 2 and meets the KD criteria.

Comparison of Characteristics and Outcomes of Multisystem Inflammatory Syndrome, Kawasaki Disease and Toxic Shock Syndrome in Children.

Background and Objectives: Since the first cases of multisystem inflammatory syndrome in children (MIS-C) in April 2020, the diagnostic challenge has been to recognize this syndrome and to differentiate it from other clinically similar pathologies such as Kawasaki disease (KD) and toxic shock syndrome (TSS). Our objective is to compare clinical signs, laboratory data and instrumental investigations between patients with MIS-C, KD and TSS. Materials and Methods: This retrospective observational study was conducted at the Children's Clinical University Hospital, Latvia (CCUH). We collected data from all pediatric patients <18 years of age, who met the Centers for Disease Control and Prevention case definition for MIS-C, and who presented to CCUH between December 2020 and December 2021. We also retrospectively reviewed data from inpatient medical records of patients <18 years of age diagnosed as having KD and TSS at CCUH between December 2015 and December 2021. Results: In total, 81 patients were included in this study: 39 (48.1%) with KD, 29 (35.8%) with MIS-C and 13 (16.1%) with TSS. In comparison with TSS and KD, patients with MIS-C more often presented with gastrointestinal symptoms (abdominal pain (p < 0.001), diarrhea (p = 0.003)), shortness of breath (p < 0.02) and headache (p < 0.003). All MIS-C patients had cardiovascular involvement and 93.1% of MIS-C patients fulfilled KD criteria, showing higher prevalence than in other research. Patients with KD had higher prevalence of cervical lymphadenopathy (p < 0.006) and arthralgias (p < 0.001). In comparison with KD and TSS, MIS-C patients had higher levels of ferritin (p < 0.001), fibrinogen (p = 0.04) and cardiac biomarkers, but lower levels of platelets and lymphocytes (p < 0.001). KD patients tended to have lower peak C-reactive protein (CRP) (p < 0.001), but higher levels of platelets. Acute kidney injury was more often observed in TSS patients (p = 0.01). Pathological changes in electrocardiography (ECG) and echocardiography were significantly more often observed in MIS-C patients (p < 0.001). Conclusions: This research shows that MIS-C, KD and TSS have several clinical similarities and additional investigations are required for reaching final diagnosis. All the patients with suspected MIS-C diagnosis should be examined for possible cardiovascular involvement including cardiac biomarkers, ECG and echocardiography.

A CASE OF KAWASAKI DISEASE IN AN EIGHT-YEAR-OLD BOY.

Kawasaki disease is an acute systemic disease characterized by the predominant lesions of middle and small arteries, alongside destructive and proliferative vasculitis development. The aetiology is currently being discussed. Infectious factors are mostly preferred, in addition, autoimmune mechanisms and genetic heredity are considered. The diagnosis of Kawasaki disease is established by clinical signs; laboratory changes are usually taken into account as are ancillary criteria. The article discusses the clinical case of Kawasaki disease in an 8-year-old boy. Given the variety and inconsistency of the clinical symptoms (the child had four of the five mandatory criteria together with prolonged fever), there was a late diagnosis, namely on day 10 of the disease. Due to the high risk of cardiovascular complications in the differential diagnosis of children with fever lasting more than 3 days should be considered Kawasaki disease, followed by mandatory heart echocardiography during the first 10 days of the disease, especially if the fever is accompanied by the increase of acute phase reactants. When treating children with chronic fever without a specific source, the doctor should be wary of Kawasaki disease, as it can clinically simulate acute respiratory viral disease, the onset of diffuse connective tissue disease, and infectious endocarditis, and can have common features and require differential diagnostics with coronavirus associated multisystem inflammatory syndrome.

Giant coronary aneurysms in an infant: Dilemma of MIS-C.

COVID-19 related multisystem inflammatory syndrome in children (MIS-C) can present with cardiovascular complications like shock, arrhythmias, pericardial effusion, and coronary artery dilatation. The majority of MIS-C associated coronary artery abnormalities are dilation or small aneurysms which are transient and resolve in a few weeks. We present here a case of a 3-month-old child who was noted to have giant aneurysms of her coronary arteries (LAD and RCA) 26 days after testing positive for COVID-19. She was treated with IVIG, infliximab, and glucocorticoids along with aspirin, clopidogrel, and enoxaparin. She did not show any signs of coronary ischemia or cardiac dysfunction but continued to have persistent giant coronary artery aneurysms involving the LAD (z-score ∼35) and RCA (z-score ∼30). This study emphasizes the importance of early detection and aggressive management of MIS-C to prevent potentially life-threatening consequences.

A comparison of pediatric inflammatory multisystem syndrome temporarily-associated with SARS-CoV-2 and Kawasaki disease.

The connection between Pediatric Inflammatory Multisystem Syndrome (PIMS) and Kawasaki Disease (KD) is not yet fully understood. Using the same national registry, clinical features and outcome of children hospitalized in Germany, and Innsbruck (Austria) were compared. Reported to the registry were 395 PIMS and 69 KD hospitalized patients. Patient age in PIMS cases was higher than in KD cases (median 7 [IQR 4-11] vs. 3 [IQR 1-4] years). A majority of both PIMS and KD patients were male and without comorbidities. PIMS patients more frequently presented with organ dysfunction, with the gastrointestinal (80%), cardiovascular (74%), and respiratory (52%) systems being most commonly affected. By contrast, KD patients more often displayed dermatological (99% vs. 68%) and mucosal changes (94% vs. 64%), plus cervical lymph node swelling (51% vs. 34%). Intensive care admission (48% vs. 19%), pulmonary support (32% vs. 10%), and use of inotropes/vasodilators (28% vs. 3%) were higher among PIMS cases. No patients died. Upon patient discharge, potentially irreversible sequelae-mainly cardiovascular-were reported (7% PIMS vs. 12% KD). Despite differences in age distribution and disease severity, PIMS and KD cases shared many common clinical and prognostic characteristics. This supports the hypothesis that the two entities represent a syndrome continuum.

Multisystem inflammatory syndrome in adults: Comparison with other inflammatory conditions during the Covid-19 pandemic.

BACKGROUND: Multisystem inflammatory syndrome in adults (MIS-A) is an increasingly recognized complication of Covid-19. We assessed risk factors, clinical characteristics, and outcomes of patients with MIS-A compared with other inflammatory conditions. METHODS: We analyzed a cohort of patients ≥21 years hospitalized with MIS-A in Quebec, Canada between February 2020 and March 2021. We included comparison groups that share symptomatology or pathophysiology with MIS-A, including Kawasaki disease, toxic shock syndrome, and other Covid-19 complications. We examined characteristics of men and women at admission, and identified preexisting factors associated with MIS-A through odds ratios (OR) and 95% confidence intervals (CI) from adjusted logistic regression models. RESULTS: Among 22,251 patients in this study, 52 had MIS-A, 90 Kawasaki disease, 500 toxic shock syndrome, and 21,609 other Covid-19 complications. MIS-A was associated with an elevated risk of respiratory failure compared with Kawasaki disease (OR 7.22, 95% CI 1.26-41.24), toxic shock syndrome (OR 4.41, 95% CI 1.73-11.23), and other Covid-19 complications (OR 3.03, 95% CI 1.67-5.50). Patients with MIS-A had a greater risk of cardiac involvement, renal failure, and mortality. The data pointed towards sex-specific differences in presentation, with more respiratory involvement in women and cardiac involvement in men compared with patients that had other Covid-19 complications. Except for allergic disorders and cancer, prior medical risk factors were not associated with a greater likelihood of MIS-A. CONCLUSIONS: Patients with MIS-A have an elevated risk of mortality compared with other inflammatory conditions, with women having a predominance of respiratory complications and men cardiovascular complications.

Immune and non-immune mechanisms that determine vasculitis and coronary artery aneurysm topography in Kawasaki disease and MIS-C.

The overlap between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) including coronary artery aneurysms (CAA) and broadly shared gastrointestinal and mucocutaneous disease is poorly defined. In this perspective, we highlight common age-related extravascular epicardial microanatomical and immunological factors that might culminate in CAA expression in both MIS-C and KD. Specifically, the coronary vasa vasorum originates outside the major coronary arteries. Widespread inflammation in the epicardial interstitial compartment in shared between KD and MIS-C. Age-related changes in the neonatal and immature coronary vasculature including the impact of coronary artery biomechanical factors including coronary vessel calibre, age-related vessel distensibility, flow, and vessel neurovascular innervation may explain the decreasing CAA frequency from neonates to older children and the virtual absence of CAA in young adults with the MIS-C phenotype. Other KD and MIS-C features including mucocutaneous disease with keratinocyte-related immunopathology corroborate that disease phenotypes are centrally influenced by inflammation originating outside vessel walls but a potential role for primary coronary artery vascular wall inflammation cannot be excluded. Hence, common extravascular originating tissue-specific responses to aetiologically diverse triggers including superantigens may lead to widespread interstitial tissue inflammation characteristically manifesting as CAA development, especially in younger subjects. Given that CAA is virtually absent in adults, further studies are needed to ascertain whether epicardial interstitial inflammation may impact on both coronary artery physiology and cardiac conduction tissue and contribute to cardiovascular disease- a hitherto unappreciated consideration.

Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines.

Coronavirus disease 2019-related Kawasaki syndrome: a case report.

BACKGROUND: Coronavirus disease 2019 has changed the pattern of some diseases in the world, especially in pediatrics. Despite data suggesting that the pediatric population is less affected by coronavirus disease-19 infection, new concerns have been raised owing to reported cases with hyperinflammatory conditions such as Kawasaki disease. CASE PRESENTATION: We report herein the case of a pediatric patient diagnosed and treated for classic Kawasaki disease in the setting of confirmed coronavirus disease 2019 infection. She was an 8-year-old, previously healthy, and fully immunized Iranian girl who initially presented to the pediatric emergency department with 5 days of intermittent fever, followed by abdominal pain, nausea, and vomiting. She was admitted for fever and abdominal pain to the surgery service of Akbar Hospital with suspected appendicitis. CONCLUSIONS: This case report may serve as a useful reference to other clinicians caring for pediatric patients affected by coronavirus disease 2019 infection. Standard therapeutic interventions for Kawasaki disease must be performed to prevent critical coronary aneurysm-related complications in the coronavirus disease 2019 era.

Refractory Cardiogenic Shock Secondary to Acute Myocarditis in a Child with Multisystem Inflammatory Syndrome Associated with COVID-19: A Case Report.

Children with Coronavirus disease 2019 infection usually have mild symptoms but rarely may present with a life-threatening condition called a multisystem inflammatory syndrome. We report a case of COVID-19-related multisystem inflammatory syndrome in an 8-year-old boy who presented with cardiogenic shock due to acute myocarditis with no features of Kawasaki disease. Cardiogenic shock was refractory to fluids and inotropes. Later, this case was successfully managed with hydrocortisone and intravenous immunoglobulin. Therefore, this case report highlights keeping a lookout for such atypical presentations and early referral to a higher center for timely intervention and aggressive therapy specifically directed against the underlying inflammatory process to ameliorate the outcomes. Keywords: cardiogenic shock; COVID-19; kawasaki disease; myocarditis; Nepal.

Incidence of Kawasaki Disease Before and After the COVID-19 Pandemic in Japan: Results of the 26th Nationwide Survey, 2019 to 2020.

Importance: Global studies have reported that the incidence of Kawasaki disease (KD) declined during the COVID-19 pandemic. These studies suggest that the global pandemic and its accompanying mitigation measures may provide an important opportunity to explore the hypothesis of a KD pathogenesis. Objective: To compare changes in KD incidence in Japan before and after the start of the COVID-19 pandemic. Design, Setting, and Participants: This cohort study was conducted using the data set from Japan's 26th nationwide KD survey that obtained information on patients who were diagnosed with KD in Japan from January 1, 2019, through December 31, 2020. Main Outcomes and Measures: Kawasaki disease incidence rates were calculated by referring to the national population data in the vital statistics data for Japan. Results: A total of 28 520 patients were identified (16 236 male individuals [56.9%]; median [IQR] age, 26 [14-44] months). A total of 17 347 patients were diagnosed with KD in 2019 and 11 173 were diagnosed in 2020, representing a 35.6% reduction in the number of patients diagnosed in 2020 compared with the previous year. Patient distributions for days of illness at the first hospital visit were almost identical in 2019 and 2020, suggesting that the decrease in KD incidence likely was not associated with pandemic-related delays in seeking treatment. The proportion of patients diagnosed with KD who were younger than 12 months was significantly larger in 2020 than in 2019 (21.6% vs 19.4%; P < .001). Compared with KD incidence among younger patients, the incidence among those 24 months and older declined rapidly after initiation of COVID-19 special mitigation measures, with a greater percentage reduction (58.3% reduction in July), but rebounded faster after the end of the special mitigation period. By contrast, the incidence among patients younger than 12 months declined moderately after the initiation of the special mitigation period, with a lower percentage reduction (40.3% reduction in October), and rebounded at a later phase. Conclusions and Relevance: In this cohort study, the number of patients diagnosed with KD decreased by approximately one-third across Japan in 2020, with no indication that parents avoided a hospital visit. Differences in KD incidence reduction patterns before and after the initiation of COVID-19 pandemic mitigation measures were found in patients with KD aged younger than 12 months compared with those 24 months or older, suggesting a potential KD pathogenesis involving transmission among children.

Circulating Endothelial Cells: A New Possible Marker of Endothelial Damage in Kawasaki Disease, Multisystem Inflammatory Syndrome in Children and Acute SARS-CoV-2 Infection.

BACKGROUND: Kawasaki Disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) are pediatric diseases characterized by systemic inflammation and vascular injury, potentially leading to coronary artery lesions (CALs). Data on vascular injury occurring during acute COVID-19 (AC19) in children are still lacking. The aim of our study was to investigate endothelial injury in KD-, MIS-C- and AC19-dosing circulating endothelial cells (CECs). METHODS: We conducted a multicenter prospective study. CECs were enumerated by CellSearch technology through the immunomagnetic capture of CD146-positive cells from whole blood. RESULTS: We enrolled 9 KD, 20 MIS-C and 10 AC19. During the acute stage, the AC19 and KD patients had higher CECs levels than the MIS-C patients. From the acute to subacute phase, a significant CEC increase was observed in the KD patients, while a mild decrease was detected in the MIS-C patients. Cellular clusters/syncytia were more common in the KD patients. No correlation between CECs and CALs were found in the MIS-C patients. The incidence of CALs in the KD group was too low to investigate this correlation. CONCLUSIONS: Our study suggests a possible role of CECs as biomarkers of systemic inflammation and endothelial dysfunction in KD and MIS-C and different mechanisms of vascular injury in these diseases. Further larger studies are needed.

Kawasaki Disease Associated with Covid-19 in a Pediatric Patient.

Kawasaki disease (KD) is a multisystemic vasculitis of small and medium-size vessels that mainly affects children under five years of age. The etiology of KD is still uncertain; however, evidence suggests that infectious agents and genetic susceptibility act as a trigger for its development, which could explain the increase in cases of children with COVID-19 who developed a classic or incomplete form of KD. The aim of this report is to discuss a case of a five-year-old boy diagnosed with incomplete KD associated with COVID-19.

Biologic disease-modifying antirheumatic drugs to treat multisystem inflammatory syndrome in children.

PURPOSE OF REVIEW: Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily affecting children. MIS-C shares features with Kawasaki disease (KD) and cytokine storm syndrome (CSS) frequently requiring intensive care support. Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs). Understanding the clinical features, inflammatory cytokines, and genetic associations provides rationale for bDMARD in treating severe MIS-C. RECENT FINDINGS: Children with MIS-C have clinical KD features and often present in hypovolemic and cardiogenic shock requiring volume repletion (gastrointestinaI losses) and cardiac pressor support (epinephrine). Investigation of MIS-C serum reveals elevated pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18, interferon gamma (IFNγ), tumor necrosis factor (TNF)], but to a lesser extent than other established CSS. Gene sequencing of MIS-C children identifies heterozygous mutations in CSS associated genes. Treatment of refractory (IVIg and GC) MIS-C with bDMARDs to IL-1, IL-6, and TNF is efficacious for survival as well as resolving cardiac and coronary artery inflammation. SUMMARY: MIS-C is a postinfectious complication of SARS-CoV-2 resembling KD and CSS, both genetically and by pro-inflammatory cytokines. MIS-C that is refractory to IVIg and GC is routinely responsive to bDMARDs targeting IL-1, IL-6, and TNF.

Novel coronavirus infection and Kawasaki disease.

There is a global problem of increment of the number of children with clinical features that mimic Kawasaki Disease (KD) during the ongoing Coronavirus Disease 2019 (COVID-19) pandemic. The disease was first reported by Tomisaku Kawasaki, a Japanese pediatrician, in a four-year-old child with a rash and fever at the Red Cross Hospital in Tokyo in January 1961. Now Kawasaki disease is recognized worldwide. The complexity of symptoms was defined as an «acute febrile mucocutaneous lymphnode syndrome". At the moment, it is still unclear whether the coronavirus itself can lead to development of mucocutaneous lymph node syndrome. However, it is believed that COVID-19 virus infection worsens the course of Kawasaki disease, and in some cases, children affected by SARS-V-2 may develop a disease that has a clinical picture similar to Kawasaki disease.

Explainable deep learning algorithm for distinguishing incomplete Kawasaki disease by coronary artery lesions on echocardiographic imaging.

BACKGROUND AND OBJECTIVE: Incomplete Kawasaki disease (KD) has often been misdiagnosed due to a lack of the clinical manifestations of classic KD. However, it is associated with a markedly higher prevalence of coronary artery lesions. Identifying coronary artery lesions by echocardiography is important for the timely diagnosis of and favorable outcomes in KD. Moreover, similar to KD, coronavirus disease 2019, currently causing a worldwide pandemic, also manifests with fever; therefore, it is crucial at this moment that KD should be distinguished clearly among the febrile diseases in children. In this study, we aimed to validate a deep learning algorithm for classification of KD and other acute febrile diseases. METHODS: We obtained coronary artery images by echocardiography of children (n = 138 for KD; n = 65 for pneumonia). We trained six deep learning networks (VGG19, Xception, ResNet50, ResNext50, SE-ResNet50, and SE-ResNext50) using the collected data. RESULTS: SE-ResNext50 showed the best performance in terms of accuracy, specificity, and precision in the classification. SE-ResNext50 offered a precision of 81.12%, a sensitivity of 84.06%, and a specificity of 58.46%. CONCLUSIONS: The results of our study suggested that deep learning algorithms have similar performance to an experienced cardiologist in detecting coronary artery lesions to facilitate the diagnosis of KD.

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.