Elevated risk for psychiatric outcomes in pediatric patients with Multisystem Inflammatory Syndrome (MIS-C): A review of neuroinflammatory and psychosocial stressors.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a secondary immune manifestation of COVID-19 involving multiple organ systems in the body, resulting in fever, skin rash, abdominal pain, nausea, shock, and cardiac dysfunction that often lead to hospitalization. Although many of these symptoms resolve following anti-inflammatory treatment, the long-term neurological and psychiatric sequelae of MIS-C are unknown. In this review, we will summarize two domains of the MIS-C disease course, 1) Neuroinflammation in the MIS-C brain and 2) Psychosocial disruptions resulting from stress and hospitalization. In both domains, we present existing clinical findings and hypothesize potential connections to psychiatric outcomes. This is the first review to conceptualize a holistic framework of psychiatric risk in MIS-C patients that includes neuroinflammatory and psychosocial risk factors. As cases of severe COVID-19 and MIS-C subside, it is important for clinicians to monitor outcomes in this vulnerable patient population.

Concomitant Cytomegalovirus Viraemia in Multisystem Inflammatory Syndrome in Adults (MIS-A) following COVID-19.

Multisystem inflammatory syndrome in adults (MIS-A) is recognised as an infrequent complication of coronavirus disease 2019 (COVID-19). This syndrome occurs following COVID-19 infection in some individuals and is characterised by inflammation of multiple organ systems, such as the heart, liver, bowel, and lymph nodes. Cytomegalovirus (CMV) viraemia is associated primarily with immunosuppression. In COVID-19 patients, it has been reported in severe and critical cases. We present a case of an adult patient diagnosed with MIS-A and concomitant CMV viraemia.

A case report on multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 infection.

Key Clinical Message: Early recognition and treatment of Multisystem Inflammatory Syndrome in Children (MIS-C) within the context of COVID-19 infection is crucial for improved outcomes. Prompt intervention with IVIG and steroids leads to significant improvement in a severe case of MIS-C. Clinicians should be vigilant for MIS-C symptoms and initiate timely management. Abstract: We report a case involving a fourteen-year-old male with COVID-19 infection who developed multisystem inflammatory disease. A previously healthy child presented with a history of 10 days of fever and cough, along with diarrhea, and vomiting for 3 days. His COVID-19 infection was confirmed through Polymerase Chain Reaction (PCR), and the laboratory values were remarkable for high levels of C-reactive protein, D-dimers, B-type natriuretic peptide (BNP), and troponin I. He developed circulatory shock on the second day of the presentation and needed inotropic support. Steroids and intravenous immunoglobulin (IVIG) were started in light of Multisystem Inflammatory Syndrome in Children (MIS-C), which improved his condition. Thus, during the management of COVID-19 infection, early detection and a careful clinical characterization for MIS-C are essential.

Longitudinal Echocardiographic Follow-Up of a Pediatric Multisystem Inflammatory Syndrome Cohort.

OBJECTIVE: Significant involvement of the cardiovascular system is known in multisystem inflammatory syndrome in children (MIS-C). This study aimed to examine the recovery of affected cardiovascular parameters over a medium-term follow-up. METHODS: A cohort of 69 children was studied prospectively. Assessments of left ventricular (LV) function and coronary artery abnormalities (CAA) were conducted at admission, 1.5 months, and 3 months. Coronavirus Disease 2019 (COVID-19) antibody titers were assessed at these three time points. Echocardiographic and antibody parameters (rising/decreasing) were analyzed for correlation. Outcomes were assessed using logistic regression. RESULTS: At admission, among the 78.2% of patients who were tested, 88.9% tested positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A quarter of the patients had pericardial effusion, and half had valvulitis. Decreased ejection fraction, global circumferential strain (GCS), and global longitudinal strain (GLS) were seen in 54.4%, 68.6%, and 35.8% of patients, respectively. CAAs were observed in 27.78% of patients. Systolic dysfunction was significantly associated with older age. During follow-up, severe LV dysfunction normalized within 6-7 weeks, while mild to moderate dysfunction reached normalcy by two weeks. Both GCS and GLS reached normalcy within a median of two weeks. Diastolic parameters recovered by six weeks. Most small and moderate coronary aneurysms resolved, but a giant aneurysm in an infant remained large even after 15 months. Trends in antibodies and ejection fraction (EF) at three months were significantly correlated. Admission EF, GLS (at 6 weeks) and deceleration time (at 3 months) were significantly associated with intensive care unit (ICU) admission. The median segmental strain of the cohort remained low in certain segments at three months. CONCLUSION: Smaller CAAs resolve, whereas giant CAAs persist. EF and GLS are important predictors of Pediatric Intensive Care Unit (PICU) stay. The residual impairment of median segmental strain and persistent diastolic dysfunction at three months indicate the need for long-term follow-up.

Long-term global longitudinal strain abnormalities in paediatric patients after multisystem inflammatory syndrome in children correlate with cardiac troponin T: a single-centre cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children is an inflammatory syndrome related to severe acute respiratory syndrome coronavirus 2 with a high risk of cardiovascular complications (vasoplegia, cardiac shock). We investigated the cardiac outcomes in multisystem inflammatory syndrome in children, focusing on the identification of predictors for late cardiac function impairment. METHODS: Clinical characteristics, conventional echocardiography (left ventricle ejection fraction, fractional shortening), 4-chamber left ventricular global longitudinal strain, and cardiac MRI of multisystem inflammatory syndrome in children patients (n = 48) were collected during admission, 6 weeks, 6 months, >12-≤18 months, and >18-≤24 months post-onset. Paired over-time patterns were assessed and multivariable regression analyses were performed to identify predictors for late global longitudinal strain impairment. RESULTS: In total, 81.3% of patients had acute cardiac dysfunction (left ventricle ejection fraction <50% and/or fractional shortening <28%). The left ventricle ejection fraction and fractional shortening reached a plateau level ≤6 weeks, while the global longitudinal strain continued to decrease in the first 6 months post-onset (median -17.3%, P < 0.001 [versus acute]). At 6 months, 35.7% of the patients still had an abnormal global longitudinal strain, which persisted in 5/9 patients that underwent echocardiography >12-≤18 months post-onset and in 3/3 patients >18-≤24 months post-onset. In a multivariable analysis, soluble troponin T (>62.0 ng/L [median]) was associated with reduced global longitudinal strain at 6 months. Our cardiac MRI findings indicated acute myocardial involvement (increased T1/T2 value) in 77.8% (7/9), which recovered quickly without signs of fibrosis on convalescent cardiac MRIs. CONCLUSIONS: Late global longitudinal strain impairment is seen in some multisystem inflammatory syndrome in children patients up to one-year post-onset. Careful cardiac follow-up in patients with elevated troponin in the acute phase and patients with persistent abnormal global longitudinal strain is warranted until resolution of the global longitudinal strain since the long-term implications of such abnormalities are still unclear.

SARS-CoV-2 infects cells lining the blood-retinal barrier and induces a hyperinflammatory immune response in the retina via systemic exposure.

SARS-CoV-2 has been shown to cause wide-ranging ocular abnormalities and vision impairment in COVID-19 patients. However, there is limited understanding of SARS-CoV-2 in ocular transmission, tropism, and associated pathologies. The presence of viral RNA in corneal/conjunctival tissue and tears, along with the evidence of viral entry receptors on the ocular surface, has led to speculation that the eye may serve as a potential route of SARS-CoV-2 transmission. Here, we investigated the interaction of SARS-CoV-2 with cells lining the blood-retinal barrier (BRB) and the role of the eye in its transmission and tropism. The results from our study suggest that SARS-CoV-2 ocular exposure does not cause lung infection and moribund illness in K18-hACE2 mice despite the extended presence of viral remnants in various ocular tissues. In contrast, intranasal exposure not only resulted in SARS-CoV-2 spike (S) protein in different ocular tissues but also induces a hyperinflammatory immune response in the retina. Additionally, the long-term exposure to viral S-protein caused microaneurysm, retinal pigmented epithelium (RPE) mottling, retinal atrophy, and vein occlusion in mouse eyes. Notably, cells lining the BRB, the outer barrier, RPE, and the inner barrier, retinal vascular endothelium, were highly permissive to SARS-CoV-2 replication. Unexpectedly, primary human corneal epithelial cells were comparatively resistant to SARS-CoV-2 infection. The cells lining the BRB showed induced expression of viral entry receptors and increased susceptibility towards SARS-CoV-2-induced cell death. Furthermore, hyperglycemic conditions enhanced the viral entry receptor expression, infectivity, and susceptibility of SARS-CoV-2-induced cell death in the BRB cells, confirming the reported heightened pathological manifestations in comorbid populations. Collectively, our study provides the first evidence of SARS-CoV-2 ocular tropism via cells lining the BRB and that the virus can infect the retina via systemic permeation and induce retinal inflammation.

Corrigendum: Case report: Multisystem inflammatory syndrome in children with associated proximal tubular injury.

[This corrects the article DOI: 10.3389/fneph.2023.1194989.].

Factors associated to mortality in children with critical COVID-19 and multisystem inflammatory syndrome in a resource-poor setting.

SARS-CoV-2 infection in children is usually asymptomatic/mild. However, some patients may develop critical forms. We aimed to describe characteristics and evaluate the factors associated to in-hospital mortality of patients with critical COVID-19/MIS-C in the Amazonian region. This multicenter prospective cohort included critically ill children (1 mo-18 years old), with confirmed COVID-19/MIS-C admitted to 3 tertiary Pediatric Intensive Care Units (PICU) in the Brazilian Amazon, between April/2020 and May/2023. The main outcome was in-hospital mortality and were evaluated using a multivariable Cox proportional regression. We adjusted the model for pediatric risk of mortality score version IV (PRISMIV) score and age/comorbidity. 266 patients were assessed with 187 in the severe COVID-19 group, 79 included in the MIS-C group. In the severe COVID-19 group 108 (57.8%) were male, median age was 23 months, 95 (50.8%) were up to 2 years of age. Forty-two (22.5%) patients in this group died during follow-up in a median time of 11 days (IQR, 2-28). In the MIS-C group, 56 (70.9%) were male, median age was 23 months and median follow-up was 162 days (range, 3-202). Death occurred in 17 (21.5%) patients with a median death time of 7 (IQR, 4-13) days. The mortality was associated with higher levels of Vasoactive Inotropic-Score (VIS), presence of acute respiratory distress syndrome (ARDS), higher levels of Erythrocyte Sedimentation Rate, (ESR) and thrombocytopenia. Critically ill patients with severe COVID-19 and MIS-C from the Brazilian Amazon showed a high mortality rate, within 12 days of hospitalization.

Multisystem inflammatory syndrome in children (MIS-C) post-COVID-19 in Iran: clinical profile, cardiac features, and outcomes.

BACKGROUND: In April 2020, an association between multisystem inflammatory syndromes (MIS-C) was observed in children with severe acute respiratory syndrome coronavirus infection (SARS-CoV-2). Most patients had heart involvement alone, and most patients had pericardial effusion. This study aimed to express and emphasize cardiac involvement in pediatric patients with respiratory symptoms who were diagnosed with COVID-19. METHODS: This study was conducted in July 2021 in Kerman province, Southeastern Iran, during a notable surge in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The study included 904 pediatric patients diagnosed with COVID-19. Data collection involved a comprehensive assessment of clinical symptoms and manifestations. Patients with fever lasting more than five days were admitted to the hospital. Echocardiography was utilized for cardiac involvement diagnosis, with 47 patients undergoing this diagnostic procedure. RESULTS: Of the 904 patients, most of them had high fevers (74%). Fifty-five patients had a fever for more than five days and were hospitalized. Of the 47 patients who underwent echocardiography, 45 (81%) had heart involvement. In 75% of patients, pericardial effusion was the only cardiac involvement. Patients with pericardial effusion were treated with dexamethasone up to 3 mg every 8 h for 72 h. CONCLUSIONS: MIS-C has a wide range of clinical symptoms. In cases where the fever is prolonged and there are gastrointestinal symptoms, physicians have clinical suspicion to diagnose this syndrome. Most cases of pericardial effusion are alone and improve with treatment with glucocorticosteroids.

Clinical presentation and management of multisystem inflammatory syndrome in children associated with covid-19: a retrospective observational descriptive study in a pediatric hospital in Syria.

OBJECTIVE: Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a rare and serious medical condition. This study aims to review the clinical presentation, laboratory parameters, outcomes, and management of MIS-C cases in a pediatric hospital in Syria. METHODS: This retrospective observational study aimed to investigate MIS-C between May 2020 and October 2021. Data collection involved extracting information from medical records, and patients were identified based on the case definition established by the World Health Organization (WHO). Various laboratory investigations, diagnostic evaluations, clinical presentations, and treatments were performed to assess patients. Descriptive statistical analysis was conducted using Microsoft Excel. RESULTS: A total of 232 COVID-19 cases were reported with COVID-19 Infection. Among these cases, 25 (10.77%) were identified as MIS-C. The median age of the patients was 5.5 years, with the majority being male patients (72%). Patients experienced fever (100%), bilateral conjunctivitis (88%), rash (84%), gastrointestinal symptoms (76%), and cardiac dysfunction (72%). Other notable findings included oral cavity changes (64%), edema (36%), cervical lymphadenopathy (36%), and neurological manifestations (28%). Respiratory symptoms were uncommon (16%). All patients recovered, with no recorded deaths. CONCLUSION: The predominant presence of positive SARS-CoV-2 IgG in the majority of patients in this study supports the post-infectious nature of MIS-C. Respiratory symptoms were less prevalent in both pediatric COVID-19 and MIS-C patients. Early supportive care is crucial in management, although additional research is needed to establish definitive guidelines. Larger studies are necessary to overcome the limitations of this study and to enhance our understanding of MIS-C in pediatric COVID-19 patients.

Multisystem inflammatory syndrome in children with Kawasaki disease-like manifestations in MMA.

Not required for Clinical Vignette.

Cardiac injury progression in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection: a review.

The symptoms and signs of infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are milder in children than in adults. However, in April 2020, British pediatricians first reported that coronavirus disease 2019 (COVID-19) may present as multisystem inflammatory syndrome in children and adolescents (MIS-C), similar to that observed in Kawasaki disease. MIS-C can be associated with multiple systemic injuries and even death in children. In addition to digestive system involvement, cardiac injury is prominent. This article reviews the pathogenesis, clinical manifestations, and treatment of cardiac injury caused by MIS-C, which may help clinicians in early diagnosis and timely commencement of treatment.

Electrocardiography in Children Hospitalized for COVID-19 and Not Suffering from Multisystem Inflammatory Syndrome in Children (MIS-C): An Observational Study.

The risk of cardiac involvement with electrophysiological abnormalities during COVID-19 infection has been reported in adults but remains poorly studied in children. Our aim was to determine the frequency of cardiac involvement and the necessity of routine cardiac evaluation in children hospitalized for COVID-19. This observational study included 127 children, with a median (IQR) age of 2 (0.83-6.0) years, who were hospitalized for COVID-19 between 1 January 2021 and 31 August 2022, 62 (48.8%) of whom were males. Each patient underwent an ECG on admission and discharge as well as a laboratory assessment. A comparison between patients with COVID-19 and healthy controls showed significantly higher HR (p < 0.0001) and lower PR values (p = 0.02) in the first group. No arrhythmias or other electrocardiographic abnormalities were detected during hospitalization. The median levels of troponin, NT-proBNP, ferritin, and D-dimer were significantly higher in children aged <2 years, but they fell within the normal range for their age. Our results indicate that a detectable cardiac involvement is very rare in children hospitalized for COVID-19 and not suffering from Multisystem Inflammatory Syndrome in Children (MIS-C) and suggest that routine electrocardiographic assessment is not mandatory in these patients in the absence of cardiac symptoms/signs.

Case Report: Heart aneurysm of unknown origin in a two-year-old child diagnosed in the course of Multisystem Inflammatory Syndrome in Children.

We present a case of a 22-month-old boy with a hypokinetic and thin-walled aneurysm of the left ventricle apex. The lesion was diagnosed during routine echocardiography examination in the course of MIS-C, and its occurrence due to MIS-C is plausible. Cardiac magnetic resonance imaging revealed an akinetic aneurysm of the LV apex with a full-wall ischemic scar. Aortography confirmed a normal course of coronary arteries, with adequate perfusion of essential branches and no evidence of stenosis or aneurysms. The boy underwent consultation with the heart team and was deemed eligible for surgery. The aneurysm was excised up to the margin of healthy tissues, and both the surgery and the periprocedural period were uneventful. Determining the origin of the aneurysm is challenging. The most probable etiology appears to be a congenital lesion. Another consideration is an ischemic lesion that may have resulted from impaired coronary circulation during the complicated course of MIS-C. It is possible that this disturbance resolved spontaneously before aortography was performed. Additionally, a complication of pericarditis cannot be entirely ruled out.

Can Duvelisib and Eganelisib work for both cancer and COVID-19? Molecular-level insights from MD simulations and enhanced samplings.

SARS-CoV-2 has caused severe illness and anxiety worldwide, evolving into more dreadful variants capable of evading the host's immunity. Cytokine storms, led by PI3Kγ, are common in cancer and SARS-CoV-2. Naturally, there is a yearning to see whether any drugs could alleviate cytokine storms for both. Upon investigation, we identified two anticancer drugs, Duvelisib and Eganelisib, that could also work against SARS-CoV-2. This report is the first to decipher their synergic therapeutic effectiveness against COVID-19 and cancer with molecular insights from atomistic simulations. In addition to PI3Kγ, these drugs exhibit specificity for the main protease among all SARS-CoV-2 targets, with significant negative binding free energies and small time-dependent conformational changes of the complexes. Complexation makes active sites and secondary structures highly mechanically stiff, with barely any deformation. Replica simulations estimated large pulling forces in enhanced sampling to dissociate the drugs from Mpro's active site. Furthermore, the radial distribution function (RDF) demonstrated that the therapeutic molecules were closest to the His41 and Cys145 catalytic dyad residues. Finally, analyses implied Duvelisib and Eganelisib as promising dual-purposed anti-COVID and anticancer drugs, potentially targeting Mpro and PI3Kγ to stop virus replication and cytokine storms concomitantly. We also distinguished hotspot residues imparting significant interactions.

Treatment of multisystem inflammatory syndrome in children.

BACKGROUND: 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. DATA SOURCES: 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". RESULTS: 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. CONCLUSIONS: 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).

Should we be afraid of long-term cardiac consequences in children with multisystem inflammatory syndrome? Experience from subsequent waves of COVID-19.

The purpose of the study was to assess and compare short- and long-term cardiac complications of the multisystem inflammatory syndrome in children (MIS-C) by predominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants throughout the pandemic. The analysis of prospectively collected data comparing cardiac complications of MIS-C during and after hospitalization across the original/alpha, delta, and omicron waves. Cardiac complications were defined as cardiac failure with systolic function impairment or hypotension or abnormalities in echocardiographic findings (decrease in LVEF, FS, valvular insufficiency, pericardial effusion, or coronary artery abnormalities). A total of 120 patients with MIS-C admitted to the Children's Hospital of Krakow between November 1, 2020, and May 5, 2023, were included in the study (74 during original/alpha dominance, 31 delta, and 15 omicron). Patients in the omicron group were found to be younger than those in the alpha and delta groups (37 vs. 75 vs. 80 months, p = 0.03). The frequency of cardiac failure with systolic function impairment or hypotension was diagnosed more frequently in the original/alpha and delta groups than in the omicron group (44.59% vs. 41.94% vs. 13.33%, p = 0.08) also echocardiographic abnormalities changed, with rates of 60.8%, 35.5%, and 13.3% (p < 0.001) accordingly. The multivariable regression revealed an older age (OR = 1.19, 95% CI = 1.07-1.33, p = 0.002) as the only independent factors of cardiac failure with systolic function impairment or hypotension. In all patients, signs of cardiac failure resolved during the hospitalization. Moreover, in 98.3% of patients, all echocardiagraphic abnormalities resolved completely during the observation period.    Conclusion: The cardiac complications of MIS-C appeared to advance less severely in younger children during the Omicron outbreak. In long-term observation, symptoms of cardiac failure resolve completely. Similarly, also echocardiographic abnormalities normalize in the vast majority of patients. What is Known: • Knowledge about the long-term cardiac complications of MIS-C is still evolving and uncertain. • The greatest concern of MIS-C is cardiac complications, including cardiac failure and coronary artery dilatation. What is New: • Long-term observations revealed complete resolution of cardiac complications in the vast majority of patients with MIS-C, irrespective of the dominant variant. • Cardiac complications of MIS-C were less common in younger children during subsequent pandemic waves in our patient population.

IRF1 Mediates Growth Arrest and the Induction of a Secretory Phenotype in Alveolar Epithelial Cells in Response to Inflammatory Cytokines IFNγ/TNFα.

In COVID-19, cytokine release syndrome can cause severe lung tissue damage leading to acute respiratory distress syndrome (ARDS). Here, we address the effects of IFNγ, TNFα, IL-1ß and IL-6 on the growth arrest of alveolar A549 cells, focusing on the role of the IFN regulatory factor 1 (IRF1) transcription factor. The efficacy of JAK1/2 inhibitor baricitinib has also been tested. A549 WT and IRF1 KO cells were exposed to cytokines for up to 72 h. Cell proliferation and death were evaluated with the resazurin assay, analysis of cell cycle and cycle-regulator proteins, LDH release and Annexin-V positivity; the induction of senescence and senescence-associated secretory phenotype (SASP) was evaluated through ß-galactosidase staining and the quantitation of secreted inflammatory mediators. While IL-1 and IL-6 proved ineffective, IFNγ plus TNFα caused a proliferative arrest in A549 WT cells with alterations in cell morphology, along with the acquisition of a secretory phenotype. These effects were STAT and IRF1-dependent since they were prevented by baricitinib and much less evident in IRF1 KO than in WT cells. In alveolar cells, STATs/IRF1 axis is required for cytokine-induced proliferative arrest and the induction of a secretory phenotype. Hence, baricitininb is a promising therapeutic strategy for the attenuation of senescence-associated inflammation.