Cardiac involvement is a key prognostic factor in multisystem inflammatory syndrome in children (MIS-C), a rare but serious inflammatory condition that typically occurs 2-6 weeks after SARS-CoV-2 infection and is characterized by fever, systemic inflammation, and multiorgan involvement. Biomarkers may aid in early detection, severity assessment, and treatment stratification.

To evaluate the diagnostic utility of established and emerging serum biomarkers in MIS-C, with an emphasis on cardiac dysfunction and disease severity.

A systematic search was conducted in PubMed, Scopus, and Web of Science up to April 2025. Eligible studies included pediatric MIS-C cases with reported serum biomarkers. Meta-analyses were performed for NT-proBNP and troponin using random-effects models. Descriptive profiling was applied to emerging biomarkers. Subgroup comparisons were explored between severe and moderate MIS-C. Quality assessment followed the Newcastle-Ottawa Scale, and publication bias was assessed via funnel plots and Egger's test.

A total of 67 studies were included, comprising >4000 pediatric MIS-C cases. NT-proBNP and troponin were consistently elevated (pooled means: 9697 pg/mL and 0.384 ng/mL, respectively), with a low risk of publication bias. Emerging biomarkers such as CXCL9, angiopoietin-2, and vitamin D revealed high inter-study variability but potential prognostic value. Subgroup analyses for selected studies (n = 5) suggested higher biomarker levels in severe MIS-C.

NT-proBNP and troponin are robust indicators of cardiac injury in MIS-C. Emerging biomarkers show promise but require validation. Future studies should include copeptin and adopt standardized reporting to refine biomarker-guided management.

We demonstrate an approach that integrates biomarker analysis with machine learning to identify protein signatures, using the example of SARS-CoV-2-induced Multisystem Inflammatory Syndrome in Children (MIS-C).

We used plasma samples collected from subjects diagnosed with MIS-C and compared them first to controls with asymptomatic/mild SARS-CoV-2 infection and then to controls with pneumonia or Kawasaki disease. We used mass spectrometry to identify proteins. Support vector machine (SVM) algorithm-based classification schemes were used to analyze protein pathways. We assessed diagnostic accuracy using internal and external cross-validation.

Proteomic analysis of a training dataset containing MIS-C (N=17), and asymptomatic/mild SARS-CoV-2 infected control samples (N=20) identified 643 proteins, of which 101 were differentially expressed. Plasma proteins associated with inflammation and coagulation increased and those associated with lipid metabolism decreased in MIS-C relative to controls. The SVM machine learning algorithm identified a three-protein model (ORM1, AZGP1, SERPINA3) that achieved 90.0% specificity, 88.2% sensitivity, and 93.5% area under the curve (AUC) distinguishing MIS-C from controls in the training set. Performance was retained in the validation dataset utilizing MIS-C (N=17) and asymptomatic/mild SARS-CoV-2 infected control samples (N=10) (90.0% specificity, 84.2% sensitivity, 87.4% AUC). We next replicated our approach to compare MIS-C with similarly presenting syndromes, such as pneumonia (N=17) and Kawasaki Disease (N=13) and found a distinct three-protein signature (VWF, SERPINA3, and FCGBP) that accurately distinguished MIS-C from the other conditions (97.5% specificity, 89.5% sensitivity, 95.6% AUC). We also developed a software tool that may be used to evaluate other protein pathway signatures using our data.

We used MIS-C, a novel hyperinflammatory illness, to demonstrate that the use of mass spectrometry to identify candidate plasma proteins followed by machine learning, specifically SVM, is an efficient strategy for identifying and evaluating biomarker signatures for disease classification.

Multisystem Inflammatory Syndrome in Children: A Comprehensive Review over the Past Five Years This review explores many facets of Multisystem Inflammatory Syndrome in Children (MIS-C) over the previous 5 years. In the time since the COVID 19 pandemic gripped our medical systems, we can now explore the data that has been collected from the previous years. The literature has allowed us to better understand the impact of COVID 19 and the post illness occurrence of a severe systemic inflammatory disease on our youngest patient populations. This paper will outline the pathophysiology of MIS-C, the treatments utilized, short and long-term patient outcomes including epidemiological factors.

The complement membrane attack complex involves C5b-mediated assembly of C6-C9 polymers to form pores in cell membranes during complement activation. Inactive complexes can become soluble C5b-9 (sC5b-9) when they bind to Protein S. Elevated sC5b-9 levels are associated with increased risk of hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA), a serious condition which can be improved with eculizumab therapy. Early detection of TA-TMA is essential for improving patient outcomes and optimizing the use of this costly treatment. We assessed the Quidel Microvue sC5b-9 Plus Enzyme Immunoassay on the Dynex-DS2 platform to screen for patients at risk of TA-TMA.

EDTA plasma samples were collected from bone marrow transplant (BMT) patients and others not at risk for TA-TMA. Assay validation included correlation with another laboratory, precision, linearity, and hemolysis interference. Additionally, clinical accuracy was assessed through retrospective patient data analyses.

The assay showed acceptable intra- and interday precision, with less than 13 % variation. Linearity ranged from 80 to 1600 ng/mL, and there was no hemolysis interference up to 800 mg/dL. Clinical data revealed that monitoring sC5b-9 levels could detect significant increases indicative of TA-TMA, facilitating timely eculizumab intervention. Analytically, changes in sC5b-9 by 2- to 3-fold were significant for patient monitoring of TA-TMA. Lastly, a retrospective analysis on utility of the assay demonstrated effective utilization at our institution.

The Quidel Microvue sC5b-9 Plus Enzyme Immunoassay demonstrated good analytical and clinical performance in screening patients with increased risk of TA-TMA.

As no unified treatment protocol or evidence yet exists for plasmapheresis without plasma, this study explored the outcomes of using 4% human albumin (ALB) solution as a replacement solution in patients undergoing plasma exchange for multiple myeloma (MM) patients with acute kidney injury (AKI). This study was prospectively registered (ChiCTR2000030640 and NCT05251896). Bortezomib-based chemotherapy plus therapeutic plasmapheresis (TPP) with 4% human ALB solution was assessed for three years in patients with MM aged >18 years, with AKI according to the Kidney Disease Improving Global Outcomes criteria, and without previous renal impairment from other causes. The primary endpoints were changes in renal function over 18 weeks and survival outcomes at 36 months. The secondary endpoints were the incidence of adverse reactions and symptom improvement. Among the 119 patients included in the analysis, 108 experienced renal reactions. The M protein (absolute changes: median -12.12%, interquartile ranges (IQRs) -18.62 to -5.626) and creatine (median -46.91 μmol/L, IQR -64.70 to -29.12) levels decreased, whereas the estimated glomerular filtration rate (eGFR) increased (median 20.66 mL/(min·1.73 m2), IQR 16.03-25.29). Regarding patient survival, 68.1% and 35.3% of patients survived for >12 and >36 months, respectively. The three symptoms with the greatest relief were urine foam, poor appetite, and blurred vision. All 11 patients (7.6%) who experienced mild adverse reactions achieved remission. In conclusion, in MM patients with AKI, plasma-free plasmapheresis with 4% human ALB solution and bortezomib-based chemotherapy effectively alleviated light chain damage to kidney function while improving patient quality of life.

The immunological pathways that cause Multisystem Inflammatory Syndrome after SARS-CoV-2 infection in children (MIS-C) remain under investigation.

The aim of this study was to prospectively compare the T-cell cytokine expression profile in unvaccinated children with acute MIS-C (MISC_A) before immunosuppression, convalescent MIS-C (one month after syndrome onset, MISC_C), convalescent COVID-19 (one month after hospitalization), and in healthy, unvaccinated controls. The intracellular expression of IL-4, IL-2, IL-17, IFNγ, TNF-α and Granzyme B, and the post SARS-CoV-2-Spike antigenic mix stimulation of T-cell subsets was analyzed by 13-color flow cytometry.

Twenty children with a median age (IQR) of 11.5 (7.25-14) years were included in the study. From the comparison of the flow cytometry analysis of the 14 markers of MISC_A with the other three groups (MISC_C, post-COVID-19 and controls), significant differences were identified as follows: 1. CD4+IL-17+/million CD3+: 293.0(256.4-870.9) vs. 50.7(8.4-140.5); p-value: 0.03, vs. 96.7(89.2-135.4); p-value: 0.03 and vs. 8.7(0.0-82.4); p-value: 0.03, respectively; 2. CD8+IL-17+/million CD3+: 335.2(225.8-429.9) vs. 78.0(31.9-128.9) vs. 84.1(0.0-204.6) vs. 33.2(0.0-114.6); p-value: 0.05, respectively; 3. CD8+IFNγ+/million CD3+: 162.2(91.6-273.4) vs. 41.5(0.0-77.4); p-value: 0.03 vs. 30.3(0.0-92.8); p-value: 0.08, respectively.

In children presenting with MIS-C one month after COVID-19 infection, T cells were found to be polarized towards IL-17 and IFNγ production compared to those with uncomplicated convalescent COVID-19, a finding that could provide possible immunological biomarkers for MIS-C detection.

Besides genetic susceptibility, infections due to viruses, bacteria and protozoa have been implicated in the development of autoimmune diseases (AD). AD can be triggered in a genetically susceptible individual by infections that disrupt immunological tolerance towards self-antigens. Pathogens can initiate autoimmunity by way of molecular mimicry, bystander activation, epitope spreading or persistent infection with polyclonal activation. This review covers two main topics: (i) the mechanisms by which an infectious agent can trigger or worsen autoimmunity; and (ii) the correlation between specific infectious agents and AD in humans with special emphasis on multisystem inflammatory syndrome in children (MIS-C).

Background: Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 varies widely in its presentation and severity, with low mortality in high-income countries. In this study in 16 Latin American countries, we sought to characterize patients with MIS-C in the pediatric intensive care unit (PICU) compared with those hospitalized on the general wards and analyze the factors associated with severity, outcomes, and treatment received. Study Design: An observational ambispective cohort study was conducted including children 1 month to 18 years old in 84 hospitals from the REKAMLATINA network from January 2020 to June 2022. Results: A total of 1239 children with MIS-C were included. The median age was 6.5 years (IQR 2.5-10.1). Eighty-four percent (1043/1239) were previously healthy. Forty-eight percent (590/1239) were admitted to the PICU. These patients had more myocardial dysfunction (20% vs 4%; P < 0.01) with no difference in the frequency of coronary abnormalities (P = 0.77) when compared to general ward subjects. Of the children in the PICU, 83.4% (494/589) required vasoactive drugs, and 43.4% (256/589) invasive mechanical ventilation, due to respiratory failure and pneumonia (57% vs 32%; P = 0.01). On multivariate analysis, the factors associated with the need for PICU transfer were age over 6 years (aOR 1.76 95% CI 1.25-2.49), shock (aOR 7.06 95% CI 5.14-9.80), seizures (aOR 2.44 95% CI 1.14-5.36), thrombocytopenia (aOR 2.43 95% CI 1.77-3.34), elevated C-reactive protein (aOR 1.89 95% CI 1.29-2.79), and chest x-ray abnormalities (aOR 2.29 95% CI 1.67-3.13). The overall mortality was 4.8%. Conclusions: Children with MIS-C who have the highest risk of being admitted to a PICU in Latin American countries are those over age six, with shock, seizures, a more robust inflammatory response, and chest x-ray abnormalities. The mortality rate is five times greater when compared with high-income countries, despite a high proportion of patients receiving adequate treatment.

We evaluated the short- and long-term effects of multisystem inflammatory syndrome in children (MIS-C) on their cardiovascular system. The study population consisted of 38 MIS-C patients and 55 control patients. Standard echocardiographic measurements and aortic stiffness parameters were compared between the two groups at different time points. During the standard echocardiographic examination at the time of diagnosis, mitral valve insufficiency was detected in 42% of the cases, left ventricular systolic dysfunction in 36%, aortic valve insufficiency in 3%, tricuspid valve insufficiency in 13%, and coronary artery dilatation in 31%. The ejection fraction, pulse pressure of the experimental group were significantly lower than the control group (p < 0.01, p = 0.045, respectively). When aortic stiffness parameters were compared, it was seen that the parameters increased in the experimental group and the difference was significant for aortic distensibility. (p = 0.105, p = 0.029 respectively). When comparing the experimental group's results at diagnosis and at the sixth month, there was a decrease in aortic stiffness parameters at the sixth month compared to the time of diagnosis, but the difference wasn't significant (p = 0.514, p = 0.334). However, no statistically significant difference was detected when comparing the aortic distensibility results of the experimental group with the control group at the sixth month (p = 0.667). Our results showed that many pathological echocardiographic findings detected at diagnosis in MIS-C patients returned to normal within six months. Therefore, we believe that the cardiovascular follow-up period of MIS-C cases should be at least six months.

NT-proBNP is a peptide related to brain natriuretic peptide, a cardiac biomarker and a member of the natriuretic family of peptides. NT-proBNP has demonstrated its clinical utility in the assessment of a wide spectrum of cardiac manifestations. It is also considered a more precise diagnostic and prognostic cardiac biomarker than brain natriuretic peptide. With the appearance of the Severe Acute Respiratory Syndrome Coronavirus 2 virus and the subsequent COVID-19 pandemic, diagnosis of heart implications began to pose an increasing struggle for the physician. Echocardiography is considered a central means of evaluating cardiac disorders like heart failure, and it is considered a reliable method. However, other diagnostic methods are currently being explored, one of which involves the assessment of NT-proBNP levels. In the literature that involves the adult population, significant positive correlations were drawn between the levels of NT-proBNP and COVID-19 outcomes such as high severity and fatality. In the paediatric population, however, the literature is scarce, and most of the investigations assess NT-proBNP in the context of Multiple Inflammatory Syndrome in Children, where studies have shown that cohorts with this syndrome had elevated levels of NT-proBNP when compared to non-syndromic cohorts. Thus, more large-scale studies on existing COVID-19 data should be carried out in the paediatric population to further understand the prognostic and diagnostic roles of NT-proBNP.

Multisystem inflammatory syndrome in children (MIS-C), a relatively uncommon but severe pediatric complication, is associated with coronavirus disease 2019 (COVID-19). A variety of treatment approaches, including intravenous immunoglobulins (IVIGs), glucocorticoids (GCs) and biologic agents, such as anakinra and infliximab, have been described for the management of COVID-19-related MIS-C. Anticoagulant therapy is also important. However, a well-developed treatment system has not been established, and many issues remain controversial. Several recently published articles related to the treatment of MIS-C have been released. Hence, in this review, we identified relevant articles published recently and summarized the treatment of MIS-C more comprehensively and systematically.

We reviewed the literature on the treatment of MIS-C through 20 September 2023. The PubMed/Medline, Web of Science, EMBASE, and Cochrane Library databases were searched with the combination of the terms "multisystem inflammatory syndrome", "MIS-C", "PIMS-TS", "therapy", "treatment", "drug", "IVIG", "GCs", "intravenous immunoglobulin", "corticosteroids", "biological agent", and "aspirin".

The severity of MIS-C varies, and different treatment schemes should be used according to the specific condition. Ongoing research and data collection are vital to better understand the pathophysiology and optimal management of MIS-C.

MIS-C is a disease involving multiple systems and has great heterogeneity. With the accumulation of additional experience, we have garnered fresh insights into its treatment strategies. However, there remains a critical need for greater standardization in treatment protocols, alongside the pressing necessity for more robust and meticulously conducted studies to deepen our understanding of these protocols. Supplementary file1 (MP4 208044 kb).

Acute kidney injury (AKI) in patients with multisystem inflammatory syndrome (MIS), COVID-19 related infection has been increasingly recognized with a paucity of data on AKI incidence, related mortality, and the requirement of renal replacement therapy in children with MIS (MIS-C).

This is a retrospective study evaluating the prevalence, severity, management and outcomes of AKI in a cohort of Egyptian children with MIS-children (MIS-C) post-COVID infection. Patients were included if they met the criteria for MIS-C based on CDC guidelines. All patients were evaluated for AKI diagnosis and staging according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria.

Between March 2021 and June 2023, a total of 655 confirmed COVID-19 cases were admitted and then followed up in our hospital, of whom 138 (21%) were diagnosed with MIS-C. Fifty-one patients developed AKI associated with MIS-C post-COVID infection, 42 of whom were included in the analysis. Thirty-one patients had AKI in a formerly healthy kidney, of whom 51% (16 patients) were classified as KDIGO stage 3, 5 patients needed hemodialysis and 13 needed mechanical ventilation. Higher WBCs count, and serum ferritin on admission were associated with more severe AKI (KDIGO stage 3) (p = 0.04), while multivariate analysis showed high serum ferritin to be independent predictor of more severe AKI (p = 0.02). Two patients (2/31) died during hospital admission, while no residual renal impairment was reported at the time of discharge of patients with previously normal kidney functions.

More than one-third of patients with MIS-C develop AKI. Avoidance of nephrotoxic drugs, early recognition, and prompt management of AKI, including well-timed commencement of dialysis in MIS-C cases, is associated with favorable outcomes.

Neutrophil extracellular traps (NETs) play a key role in thrombus formation in patients with coronavirus disease 2019 (COVID-19). However, the existing detection and observation methods for NETs are limited in their ability to provide quantitative, convenient, and accurate descriptions of in situ NETs. Therefore, establishing a quantitative description of the relationship between NETs and thrombosis remains a challenge.

We employed morphological observations of blood cells and statistical analyses to investigate the correlation between the NETs/neutrophilic segmented granulocyte ratio and mortality risk in patients with COVID-19.

Peripheral blood samples were collected from 117 hospitalized patients with COVID-19 between November 2022 and February 2023, and various blood cell parameters were measured. Two types of smudge cells were observed in the blood and counted: lymphatic and neutral smudge cells. Statistical data analysis was used to establish COVID-19 mortality risk assessment indicators.

Morphological observations of neutrophilic smudge cells revealed swelling, eruption, and NETs formation in the neutrophil nuclei. Subsequently, the NETs/neutrophilic segmented granulocyte ratio (NNSR) was calculated. A high concentration of NETs poses a fatal risk for thrombus formation in patients. Statistical analysis indicated that a high NNSR was more suitable for evaluating the risk of death in patients with COVID-19 compared to elevated fibrinogen (FIB) and D-dimer (DD) levels.

Observing blood cell morphology is an effective method for the detection of NETs, NNSR are important markers for revealing the mortality risk of patients with COVID-19.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare manifestation of Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2) infection that can result in increased morbidity and mortality. Mounting evidence describes sex disparities in the clinical outcomes of coronavirus disease 2019 (COVID-19). However, there is a lack of information on sex-specific differences in immune responses in MIS-C. This study is an observational and cross-sectional study and we wanted to examine immune parameters such as cytokines, chemokines, acute phase proteins (APPs), growth factors, microbial translocation markers (MTMs), complement components and matrix metalloproteinases (MMPs) in MIS-C children, based on sex. Male children were associated with heightened levels of pro-inflammatory cytokines-IFNγ, IL-2, TNFα, IL-1α, IL-1β, IL-6, IL-12, G-CSF and GM-CSF, chemokines-CCL2, CCL11, CXCL1, CXCL8 and CXCL10, acute phase proteins-α-2M, CRP, growth factors VEGF and TGFα, microbial translocation markers- iFABP, LBP, EndoCAb, complement components-C1q, MBL and C3 and matrix metalloproteinases MMP-8 and MMP-9 compared to female children with MIS-C. These results indicate that the heightened immune response in males is a characteristic feature of MIS-C. These findings might explain the differential disease pathogenesis in males compared to females with MIS-C and facilitate a deeper understanding of this disease.

Background: COVID-19 usually complicates respiratory failure; microvascular, macrovascular, and renal complications are common. Both micro and macrovascular complications are associated with multi-organ dysfunction and in-hospital mortality. Thrombotic microangiopathy (TMA) causes microvascular thromboses associated with organ failure, including acute kidney injury (AKI). Materials and Methods: This Retrospective Cohort study included 100 COVID-19 patients with thrombocytopenia, followed up in a university hospital's intensive care unit (ICU). The primary endpoints were in-hospital mortality or discharge from the hospital and assessing the occurrence of TMA and AKI during the hospitalization. The effect of thrombotic microangiopathy and acute kidney injury on mortality was investigated using logistic regression models in Stata software version 12.1. Results: The TMA and AKI were associated with in-hospital mortality in COVID-19 patients presenting with thrombocytopenia in multivariate regression analysis, adjusted for other variables. The effect of AKI on mortality was obtained (adjusted OR 4.09, 95% CI: 1.33-12.53, p = 0.01). Moreover, the odds of mortality due to TMA were ten-fold higher in the patients who had TMA than those who did not (adjusted OR 10.26, 95% CI: 1.26-83.76, p = 0.03). Conclusion: We outlined TMA in COVID-19 patients, which could be responsible for kidney injury and mortality in critically COVID-19 patients.

This report provides insight into three distinct pediatric cases exhibiting a nexus between multisystem inflammatory syndrome in children (MIS-C) and thrombotic microangiopathy (TMA) triggered by COVID-19. The aim is to underscore the range of clinical presentations and the essentiality of early interventions.

This report presents three cases aged 10 months, 7 years, and 3 years with persistent fever, diarrhea, nausea, and vomiting. The first case, a 10-month-old girl, demonstrated acute kidney injury (AKI) and microangiopathic hemolytic anemia (MAHA) following a COVID-19 infection. Despite initial negative SARS-CoV-2 RT-PCR results, her condition escalated rapidly, presenting increased levels of LDH (peaking at 4,200 U/L) and requiring renal replacement therapy (RRT) to manage deteriorating renal function. Interventions with eculizumab and anakinra led to marked improvements, with a stable follow-up of 13 months post-hospitalization. The second case involved a 7-year-old girl who developed symptoms of MIS-C, hemolytic uremic syndrome (HUS), and posterior reversible encephalopathy syndrome (PRES) post-exposure to COVID-19, evidenced by heightened LDH levels (3,522 U/L at peak). After a precarious period of deteriorating kidney function and exacerbated hypertension, she responded positively to treatments, inclusive of IVIG, steroid therapies, and eculizumab, with a favorable 6-month follow-up showcasing stable laboratory results. The third case discusses a 3-year-old boy, without any medical history, manifesting HUS symptoms and COVID-19 infection. He exhibited increased LDH levels (peaking at 3,946 U/L) alongside elevated creatinine, marking renal impairment. He responded well to hemodialysis, IVIG, and steroid therapy, showcasing substantial recovery by the 19th day of hospitalization, which marked his discharge with a tapering steroid regimen.

This case series underscores that MIS-C-associated TMA is a significant complication in pediatric COVID-19. Our findings illuminate the potential for treatment success but simultaneously emphasize the need for a more comprehensive understanding of the underlying pathophysiology.

Kidney injury is common in patients with Coronavirus Disease-19 (COVID-19), which is related to poor prognosis. We aim to summarize the clinical features, athological types, and prognosis of COVID-19 associated kidney injury caused by the Omicron strain. In this study, 46 patients with Omicron-associated kidney injury were included, 38 of whom performed renal biopsy. Patients were divided into two groups: group A for patients with onset of kidney injury after SARS-CoV-2 infection; group B for patients with pre-existing kidney disease who experienced aggravation of renal insufficiency after SARS-CoV-2 infection. The clinical, pathological, and prognostic characteristics of the patients were observed. Acute kidney injury (AKI) (35%) was the most common clinical manifestation in group A. Patients in group B mainly presented with chronic kidney disease (CKD) (55%) and nephrotic syndrome (NS) (40%). The pathological type was mainly IgA nephropathy (IgAN) (39% in group A and 45% in group B). Among all of them, one case presenting with thrombotic microangiopathy had worse kidney function at biopsy time. Mean serum C3 levels were 1.2 ± 0.5 and 1.0 ± 0.2 g/L in group A and group B, respectively. In renal tissues, C3 deposits were observed in 71.1% of patients. 11.8% (n = 2) patients experienced deterioration of renal function after treatment, but no patients developed to end-stage renal disease. In our single-center study in China, the main clinical manifestations were AKI, CKD, and NS, while the main pathological type was IgAN. Compared with previous strains of SARS-CoV-2, patients with the Omicron infection had a favorable prognosis.

Coronavirus disease 2019 (COVID-19) associated coagulopathy is multifactorial and involves inflammation driven hypercoagulability, endothelial dysfunction, platelet activation, and impaired fibrinolysis. Hospitalized adults with COVID-19 are at an increased risk of both venous thromboembolism and ischemic stroke, resulting in adverse outcomes, including increased mortality. Although COVID-19 in children follows a less severe course, both arterial and venous thromboses have been reported in hospitalized children with COVID-19. Additionally, some children develop a postinfectious, hyperinflammatory illness termed multisystem inflammatory syndrome of childhood (MIS-C), which is also associated with hypercoagulability and thrombosis. Several randomized trials have evaluated the safety and efficacy of antithrombotic therapy in adults with COVID-19, although similar pediatric data are lacking. In this narrative review, we discuss the postulated pathophysiology of COVID-19 coagulopathy and summarize principal findings of the recently completed adult trials of antithrombotic therapy. We provide an up-to-date summary of pediatric studies investigating the rate of venous thromboembolism and ischemic stroke in COVID-19 and multisystem inflammatory syndrome of childhood in addition to reviewing the findings of the single, nonrandomized pediatric trial investigating the safety of prophylactic anticoagulation. Lastly, we outline adult and pediatric consensus guidelines on the use of antithrombotic therapy in this cohort. A detailed discussion of the practical implementation and current limitations of published data will hopefully address the knowledge deficits surrounding the use of antithrombotic therapy in children with COVID-19 and generate hypotheses for future research.

Background: The causative agent of the new coronavirus infection SARS-CoV-2 has unique properties causing hyperinflammatory syndrome and cytokine storm, as well as widespread endotheliitis and thrombotic microangiopathy, initially detected in the lungs of adult patients who died from a severe form of the disease. Venous and arterial thrombosis in adults were identified as common causes of severe complications and deaths in new coronavirus infections. There are very few reports of thrombotic events in children with COVID-19 in the literature. Methods: We conducted a retrospective analysis of the histories of 60 patients in the Irkutsk Regional Children's Clinical Hospital from November 2020 to November 2022 with a MIS-C diagnosis established according to WHO criteria, of which 8 (13.3%) were diagnosed with venous and/or arterial thrombosis, confirmed by laboratory and ultrasound and/or X-ray methods. Results: The average age of children with thrombosis (Me) was 7.5 years (min 4 months, max 17 years), with a M:F ratio of 3.0. Venous thrombosis was detected in six of the eight patients, including in the deep veins of the lower extremities in four. Pulmonary embolism occurred in two (one of them was fatal), and cerebral venous sinus thrombosis and thrombosis of the branches of the upper and lower vena cava were found in one patient. Extensive bilateral stroke due to thrombosis of the large cerebral arteries occurred in two patients, including one in combination with distal gangrene. Secondary thrombotic renal microangiopathy took place in three of the eight patients. Among these three, atypical HUS was diagnosed in one case. Multiple thrombosis involving the venous and arterial bed was detected in four of the eight patients. High levels of D-dimer, thrombocytopenia, increased NT-proBNP, cerebral coma, and aseptic meningitis were the events most often associated with thrombosis. All patients received immunomodulatory therapy (immunoglobulin, dexamethasone/methylprednisolone), pathogenetic therapy for multiorgan failure, anticoagulant therapy with heparin/LMWH, and acetylsalicylic acid. Biologics were used in two patients. Conclusions: The main predictors of thrombosis in children with MIS-C were increased D-dimer, thrombocytopenia, hospitalization in the ICU, and noncardiogenic pulmonary edema. Thrombosis of the deep veins of the lower extremities, large cerebral arteries, and secondary thrombotic microangiopathy was common. There was a single death (12.5% of the eight patients), associated with PE.

The Coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) have been variably associated with thromboembolic events (TEs) in children. The aim of our study was to assess the prevalence of TEs in children hospitalized during a five-year period in a tertiary pediatric hospital, particularly in patients with COVID-19 and MIS-C. Overall, 38 patients were discharged with the diagnosis of TE: 20 in the pre-pandemic and 18 in the pandemic period. The prevalence of TEs was the same (0.08%) in the pre-pandemic and pandemic periods. The occurrence of TEs was higher in patients with COVID-19 or MIS-C (6/517, 1.16%) when compared to children without these conditions in the pandemic and in the pre-pandemic periods. The prevalence of TEs in children with MIS-C was significantly higher than the prevalence in patients with COVID-19. Five out of six of the patients with COVID-19 or MIS-C developing a TE had at least one predisposing factor to thrombosis. In conclusion, our study shows an increased prevalence of TEs in children hospitalized with COVID-19 or MIS-C, if compared to children without COVID-19 or MIS-C in the pandemic period and in the pre-pandemic period. The prevalence of TEs was significantly higher in patients with MIS-C.

Cytokine storm syndromes (CSS) represent a diverse group of disorders characterized by severe overactivation of the immune system. In the majority of patients, CSS arise from a combination of host factors, including genetic risk and predisposing conditions, and acute triggers such as infections. CSS present differently in adults than in children, who are more likely to present with monogenic forms of these disorders. Individual CSS are rare, but in aggregate represent an important cause of severe illness in both children and adults. We present 3 rare, illustrative cases of CSS in pediatric patients that describe the spectrum of CSS.

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.

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.

Coronavirus disease 2019 (COVID-19) has spread, with thrombotic complications being increasingly frequently reported. Although thrombosis is frequently complicated in septic patients, there are some differences in the thrombosis noted with COVID-19 and that noted with bacterial infections. The incidence (6-26%) of thrombosis varied among reports in patients with COVID-19; the incidences of venous thromboembolism and acute arterial thrombosis were 4.8-21.0% and 0.7-3.7%, respectively. Although disseminated intravascular coagulation (DIC) is frequently associated with bacterial infections, a few cases of DIC have been reported in association with COVID-19. Fibrin-related markers, such as D-dimer levels, are extremely high in bacterial infections, whereas soluble C-type lectin-like receptor 2 (sCLEC-2) levels are high in COVID-19, suggesting that hypercoagulable and hyperfibrinolytic states are predominant in bacterial infections, whereas hypercoagulable and hypofibrinolytic states with platelet activation are predominant in COVID-19. Marked platelet activation, hypercoagulability and hypofibrinolytic states may cause thrombosis in patients with COVID-19.

Thrombotic microangiopathy can present itself in the form of several clinical entities, representing a real challenge for diagnosis and treatment in pediatric practice. Our article aims to explore the evolution of two rare cases of pediatric thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) with extremely similar clinical pictures, which, coincidentally, presented at approximately the same time in our hospital. These cases and our literature review demonstrate the multiple facets of thrombotic microangiopathy, which can produce various determinations and salient manifestations even among the pediatric population. TTP and aHUS may represent genuine diagnostic pitfalls through the overlap of their clinical and biological findings, although they develop through fundamentally different mechanisms that require different therapeutic approaches. As a novelty, we underline that COVID-19 infection cannot be excluded as potential trigger for TTP and aHUS in our patients and we predict that other reports of such an association will follow, raising a complex question of COVID-19's implication in the occurrence and evolution of thrombotic microangiopathies. On this matter, we conducted literature research that resulted in 15 cases of COVID-19 pediatric infections associated with either TTP or aHUS. Taking into consideration the morbidity associated with TTP and aHUS, an elaborate differential diagnosis and prompt intervention are of the essence.

Multisystem inflammatory syndrome (MIS-C) is a rare paediatric hyper-inflammatory disorder that occurs following SARS-CoV-2 infection. Acute kidney injury (AKI) occurs in approximately one-quarter to one-third of the patients with MIS-C and is associated with poor prognosis in critically ill children. This systematic review is aimed to evaluate the incidence of AKI, mortality, and the need for kidney replacement therapy (KRT) in patients with MIS-C.

We searched databases from Medline, EMBASE, Cochrane Register, and Google Scholar from December 2019 to December 2021 with our search strategy. Studies meeting the following criteria were included in this systematic review: (1) articles on AKI in MIS-C; (2) studies providing AKI in MIS-C and COVID-19 infection separately; (3) studies reporting outcomes such as mortality, KRT, serum creatinine; length of hospital/ICU stay.

The quality of the included studies was independently assessed by using the National Heart Lung and Blood Institute (NHLBI) quality assessment tool for cohort studies and case series.

Outcomes and their 95% confidence intervals (CI) were reported if a meta-analysis of these outcomes was conducted. Heterogeneity was reported using I2 statistics, and heterogeneity ≥ 50% was considered high. We used Baujat's plot for the contribution of each study toward overall heterogeneity. In sensitivity analysis, the summary estimates were assessed by repeating meta-analysis after omitting one study at a time. Forest plots were used for reporting outcomes in each study and with their 95% CI. All statistical tests were performed using R software version 4.0.3.

A total of 24 studies were included in this systematic review and of these, 11 were included in the meta-analysis. The pooled proportion of patients with MIS-C developing AKI was 20% (95% CI: 14-28%, I2 = 80%). Pooled proportion of death in children with MIS-C was 4% (95% CI: 1-14%; I2 = 93%). The odds of death in patients with AKI were 4.68 times higher than in patients without AKI (95% CI: 1.06-20.7%; I2 = 17%). The overall pooled proportion of MIS-C-induced AKI patients requiring KRT was 15% (95% CI: 4-42%; I2 = 91%).

Approximately one-fifth of children with MIS-C develop AKI which is associated with higher odds of death. PROSPERO registration: CRD42022306170 A higher resolution version of the Graphical abstract is available as Supplementary information.

People with sickle cell disease (SCD) are at greater risk of severe illness and death from respiratory infections, including COVID-19, than people without SCD (Centers for Disease Control and Prevention, USA). Vaso-occlusive crises (VOC) in SCD and severe SARS-CoV-2 infection are both characterized by thrombo-inflammation mediated by endothelial injury, complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion, and activation of the coagulation cascade. Notably, lipid mediators, including thromboxane A2, significantly increase in severe COVID-19 and SCD. In addition, the release of thromboxane A2 from endothelial cells and macrophages stimulates platelets to release microvesicles, which are harbingers of multicellular adhesion and thrombo-inflammation. Currently, there are limited therapeutic strategies targeting platelet-neutrophil activation and thrombo-inflammation in either SCD or COVID-19 during acute crisis. However, due to many similarities between the pathobiology of thrombo-inflammation in SCD and COVID-19, therapies targeting one disease may likely be effective in the other. Therefore, the preclinical and clinical research spurred by the COVID-19 pandemic, including clinical trials of anti-thrombotic agents, are potentially applicable to VOC. Here, we first outline the parallels between SCD and COVID-19; second, review the role of lipid mediators in the pathogenesis of these diseases; and lastly, examine the therapeutic targets and potential treatments for the two diseases.

COVID-19 in the pediatric population is mostly asymptomatic. However, 1 out of 5 children presents non-specific neurologic symptoms such as headache, weakness, or myalgia. Furthermore, rarer forms of neurological diseases are increasingly being described in association to a SARS-CoV-2 infection. Encephalitis, stroke, cranial nerves impairment, Guillain-Barré syndrome or acute transverse myelitis have been reported and account for around 1% of pediatric COVID-19 cases. Some of these pathologies may occur during or after the SARS-CoV-2 infection. The pathophysiological mechanisms range from direct invasion of the central nervous system (CNS) by SARS-CoV-2 itself to postinfectious immune-mediated CNS inflammation. In most cases, patients presenting neurological pathologies related to SARS-CoV-2 infection are at greater risk of life-threatening complications and should be closely monitored. Further studies are needed to acknowledge the potential long-term neurodevelopmental consequences of the infection.

As the global pandemic continues, new complications of COVID-19 in pediatric population have turned up, one of them being hemolytic uremic syndrome (HUS), a complement-mediated thrombotic microangiopathy (CM-TMA) characterized by triad of thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury (AKI). With both multisystem inflammatory syndrome in children (MIS-C) and HUS sharing complement dysregulation as one of the key factors, the aim of this case report is to highlight differences between these two conditions and also emphasize the importance of complement blockade as a treatment modality.

We describe a 21-month-old toddler who initially presented with fever and confirmed COVID-19. His condition quickly deteriorated and he developed oliguria, accompanied with diarrhea, vomiting and oral intake intolerance. HUS was suspected, supported with compelling laboratory findings, including decreased platelets count and C3 levels, elevated LDH, urea, serum creatinine and sC5b-9 and presence of schistocytes in peripheral blood, negative fecal Shiga toxin and normal ADAMTS13 metalloprotease activity. The patient was given C5 complement blocker Ravulizumab and started to display rapid improvement.

Although reports of HUS in the setting of COVID-19 continue to pour in, the questions of exact mechanism and similarities to MIS-C remain. Our case for the first time accentuates the use of complement blockade as a valuable treatment option in this scenario. We sincerely believe that reporting on HUS as a complication of COVID-19 in children will give rise to improved diagnosis and treatment, as well as better understanding of both of these intricating diseases.

Severe acute respiratory syndrome Coronavirus-2 invades the cells via ACE2 receptor and damages multiple organs of the human body. Understanding the pathological manifestation is mandatory to endure the rising post-infection sequel reported in patients with or without comorbidities.

Our descriptive review emphasises the direct, indirect and post-infection damages due to COVID-19. We have performed an electronic database search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with selective inclusion and exclusion criteria.

The included studies substantiated the extensive damages in the multiple organs due to direct and indirect consequences of COVID-19. After an apparent recovery, the prolonged presentation of the symptoms manifests as post-COVID that can be related with persisting viral antigens and dysregulated immune response.

A few of the symptoms of respiratory, cardiovascular, and neuropsychiatric systems that persist or reappear as post-COVID manifestations. Vaccination and preventive programs will effectively reduce the prevalence but, the post-COVID, a multisystem manifestation, will be a significant tribulation to the medical profession. However, the issue can be managed by implementing public health programs, rehabilitation services, and telemedicine virtual supports to raise awareness and reduce panic.

Multisystem inflammatory syndrome in children (MIS-C) is a rare, life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MIS-C develops with high fever, marked inflammation and shock-like picture several weeks after exposure to, or mild infection with SARS-CoV-2. Deep immune profiling identified activated macrophages, neutrophils, B-plasmablasts and CD8 + T cells as key determinants of pathogenesis together with multiple inflammatory markers. The disease rapidly responds to intravenous immunoglobulin (IVIG) treatment with clear changes of immune features. Here we present the results of a comprehensive analysis of the complement system in the context of MIS-C activity and describe characteristic changes during IVIG treatment. We show that activation markers of the classical, alternative and terminal pathways are highly elevated, that the activation is largely independent of anti-SARS-CoV-2 humoral immune response, but is strongly associated with markers of macrophage activation. Decrease of complement activation is closely associated with rapid improvement of MIS-C after IVIG treatment.

The pathogenesis of autoantibody generation in anti-factor H (FH) antibody associated atypical hemolytic uremic syndrome (aHUS) is unknown and is perhaps triggered by an infectious or environmental agent. We observed an unusual increase of patients with anti-FH antibody associated aHUS coinciding with the second pandemic wave in New Delhi and suspected that SARS-CoV-2 infection might be a potential trigger.

We screened for SARS-CoV-2 infection using reverse transcriptase polymerase chain reaction (RT-PCR) and serology in 13 consecutive patients with anti-FH antibody associated aHUS during the past year in New Delhi.

We report 5 patients, 4-13 years old, who presented with a febrile illness without respiratory symptoms during the second pandemic wave. Of these, 3 patients presented with a relapse 25-85 months following the initial episode of aHUS. SARS-CoV-2 was detected by RT-PCR in 1 patient and by serology in 4 patients (median titer 47.1 cut-off index). Patients had high titers of anti-FH antibodies (median 2,300 AU/ml). Genetic studies, done in 3 of the 5 patients, showed homozygous CFHR1 deletion without other significant genetic abnormalities. Specific management comprised plasma exchanges and oral prednisolone, combined with either cyclophosphamide or mycophenolate mofetil. At median follow-up of 3.3 months, the estimated glomerular filtration rate in 4 patients ranged from 62 to 110 ml/min/1.73 m2; one patient was dialysis-dependent.

Increased vigilance is required during the pandemic, especially in patients with anti-FH associated aHUS, who might relapse despite quiescent disease for a prolonged period. A higher resolution version of the Graphical abstract is available as Supplementary information.

Coagulopathy, cytokine release, platelet hyperactivity and endothelial activation are regarded as potential major contributors to COVID-19 morbidity. Complement activation might provide a bridge linking these factors in severe COVID-19 illness. In this study, we investigated the prognostic significance of selected complement factors in hospitalized patients with severe COVID-19 infection. The study included 300 hospitalized adults with severe COVID-19 infection. Complement factors (C3, C3a, C4, sC5b-9) were assessed by commercial ELISA kits. Outcome parameters included mortality, intensive care unit admission and duration of hospital stay. It was found that survivors had significantly higher serum C3 (median (IQR): 128.5 (116.3-141.0) mg/dL vs 98.0 (70.0-112.8) mg/dL, p<0.001) and C4 (median (IQR): 36.0 (30.0-42.0) mg/dL vs 31.0 (26.0-35.0) mg/dL, p<0.001) levels when compared with non-survivors. On the other hand, it was shown that survivors had significantly lower C3a (median (IQR): 203.0 (170.3-244.0) ng/mL vs 385.0 (293.0-424.8) ng/mL, p<0.001) and sC5b-9 (median (IQR): 294.0 (242.0-318.8) ng/mL vs 393.0 (342.0-436.5) ng/mL, p<0.001) levels when compared with non-survivors. Multivariate logistic regression analysis identified C3a (OR: 0.97 (95% CI 0.96 to 0.99), p<0.001) and C4 (OR: 0.92 (95% CI 0.86 to 0.98), p=0.011) levels as significant predictors of mortality. In conclusion, serum levels of complement factors are related to mortality in severely ill patients with COVID-19.

Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2.

We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients <18 years, numbers of incident AIS cases among children (29 days to <18 years), frequency of SARS-CoV-2 testing for children with AIS, and numbers of childhood AIS cases positive for SARS-CoV-2 June 1 to December 31, 2020. Two stroke neurologists with 1 neuroradiologist determined whether SARS-CoV-2 was the main stroke risk factor, contributory, or incidental.

Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P<0.0001. Twenty-three of 335 AIS cases tested (6.9%) were positive for SARS-CoV-2 compared with 6/99 tested (6.1%) in March to May 2020, P=0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P=0.14.

The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism.

Given the limited information on the coagulation abnormalities of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in pediatric patients, we designed a systematic review to evaluate this topic. A comprehensive literature search was conducted for "SARS-CoV-2," "coagulopathy," and "pediatrics." Two authors independently screened the articles that the search returned for bleeding, thrombosis, anticoagulant and/or antiplatelet usage, and abnormal laboratory markers in pediatric patients with SARS-CoV-2, and the authors then extracted the relevant data. One hundred twenty-six publications were included. Thirty-four (27%) studies reported thrombotic complications in 504 patients. Thirty-one (25%) studies reported bleeding complications in 410 patients. Ninety-eight (78%) studies reported abnormal laboratory values in 6580 patients. Finally, 56 (44%) studies reported anticoagulant and/or antiplatelet usage in 3124 patients. The variety of laboratory abnormalities and coagulation complications associated with SARS-CoV-2 presented in this review highlights the complexity and variability of the disease presentation in infants and children.