The Notch1/CD22 signaling axis disrupts Treg cell function in SARS-CoV2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

Approaches to SARS-CoV-2 and other vaccinations in children with a history of multisystem inflammatory syndrome (MIS-C): An international survey.

Background: Following the Coronavirus Disease-19 (COVID-19) pandemic outbreaks, the hyperinflammatory condition termed Multisystem Inflammatory Syndrome in Children (MIS-C) became a healthcare issue worldwide. Since December 2020 the mRNA vaccine against SARS-CoV-2 has become available with a good safety profile. However, evidence regarding safety and vaccination strategies in children with previous MIS-C is still lacking. The aim of our study was to investigate the current approach of international centers to anti-SARS-CoV-2 and other vaccinations in children with a history of MIS-C. Methods: Physicians who care for patients with MIS-C were invited to anonymously complete a 15-question, web-based survey. The survey was open from October 6 to December 31, 2021. Results: A total of 290 replies from 236 centers in 61 countries were collected. Most respondents (86%) were pediatric rheumatologists. The anti-SARS-CoV-2 vaccine was available in 85% of the countries. Sixty-seven centers (28%) in 22 countries already vaccinated MIS-C patients without adverse reactions in most cases (89%). Six reported complications: 2 not specified, 3 mild symptoms and 1 reported a MIS-C-like reaction. Most centers (84%) favored vaccinating MIS-C patients against SARS-CoV-2, after 3-6 months (40%), 6-12 months (52%) or >12 months (8%). The survey revealed broad heterogeneity of responses among healthcare providers within the same country and within the same center. The variable with the greatest impact on the decision not to vaccinate MIS-C patients was the current lack of evidence (51%), followed by patient/parent objection (40%). The most relevant parameters in the vaccination strategy were time from MIS-C episode (78%), immunosuppressive treatment (35%), SARS-CoV-2 serologic status (32%), and MIS-C features (31%). Almost all centers favored continuing regular vaccination with non-live (99%) and live (93%) vaccines; however, with high variability in suggested timelines. Conclusion: To date, the experience of the international pediatric rheumatology community in vaccinating MIS-C patients against SARS-CoV-2 is overall reassuring. However, lack of evidence causes broad heterogeneity in vaccination strategy worldwide.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology Points to Consider for Diagnosis and Management of Autoinflammatory Type I Interferonopathies: CANDLE/PRAAS, SAVI, and AGS.

OBJECTIVE: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of "points to consider" to improve diagnosis, treatment, and long-term monitoring of patients with these rare diseases. METHODS: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, "points to consider" to guide patient management were developed. RESULTS: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS. CONCLUSION: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes.

Spontaneous NLRP3 inflammasome-driven IL-1-ß secretion is induced in severe COVID-19 patients and responds to anakinra treatment.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained. OBJECTIVES: To dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1ß, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes. METHODS: We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line. RESULTS: We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein-containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1ß in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation. CONCLUSIONS: These results provide further evidence that IL-1ß targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.

Protection against MIS-C outweighs the risk of myocarditis after Covid-19 vaccination in children.

From March 2020 to July 2022, in Liguria region (North-West Italy) incidence of MIS-C among pediatric patients infected by SARS-CoV-2 was 38.7/100.000, which is higher than that of myocarditis after COVID-19 vaccination. In our opinion severity of MIS-C-related cardiac disease outweigh the risk of myocarditis after COVID-19 vaccine.

Cardiovascular Manifestations in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19 According to Age.

Cardiac involvement in multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus-19 disease is often observed with a high risk of heart failure. The aim is to describe cardiovascular involvement, management and early outcome in MIS-C by comparing cardiovascular manifestations in children younger and older than 6 years old. This retrospective observational study included 25 children with MIS-C, admitted to a single pediatric center between March 2020 and September 2021. The median age was 5 years (13 patients under 6 years and 12 over 6 years); coronary artery abnormalities were observed in 77% of preschoolers, with small and medium aneurysms in half of the cases and two cases of mild ventricular dysfunction. School-age children presented myopericardial involvement with mild to moderate ventricular dysfunction in 67% of cases, and two cases of transient coronary dilatation. There was a significant NT-pro-BNP and inflammatory markers increase in 25 of the patients, and mild elevation of troponin I in 9. All patients were treated with intravenous immunoglobulin and corticosteroids, and 8 with anakinra. None of the patients needed inotropes or intensive care unit admission. Our study shows the frequent cardiovascular involvement in MIS-C with a peculiar distribution, according to different age group: coronary artery anomalies were more frequent in the younger group, and myopericardial disease in the older one. A prompt multitarget, anti-inflammatory therapy could probably contribute to a favorable outcome.

Notch1-CD22-Dependent Immune Dysregulation in the SARS-CoV2-Associated Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators NUMB and NUMBL . Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS.

OBJECTIVE: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of 'points to consider' to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases. METHODS: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, 'points to consider' to guide patient management were developed. RESULTS: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS. CONCLUSION: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.

COVID-19 Pneumomediastinum: Possible Role of Transesophageal Echo in Bedside Percutaneous Bicaval Double-Lumen ECMO Cannulation in Children. A Case Report.

COVID-19 is generally uneventful in children. Only 8% of severe acute respiratory distress syndrome corona virus 2 pediatric patients require intensive care; of these, 1% may need extracorporeal membrane oxygenation. Preexisting medical conditions are an independent risk factor for pediatric intensive care unit admission. We describe the case of an 11-year-old girl with adenosine deaminase 2 deficiency who presented severe COVID-19 acute respiratory distress syndrome, complicated by a massive air leak syndrome. The respiratory failure, refractory to conventional support, required veno-venous extracorporeal membrane oxygenation. To prevent viral diffusion, bicaval double-lumen cannulation was performed percutaneously at the bedside under exclusive echo guidance. Because of pneumomediastinum, pneumothorax, and subcutaneous emphysema, ultrasound visualization of the heart was possible only with transesophageal echo. To our knowledge, this is the first description of a transesophageal echo guided bedside percutaneous bicaval double-lumen extracorporeal membrane oxygenation cannulation in a pediatric patient. Pitfalls of the technique are highlighted.

Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.

BACKGROUND: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. METHODS: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). FINDINGS: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO2/FiO2), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO2/FiO2. In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10]). INTERPRETATION: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. FUNDING: Sobi.

Efficacy of early anti-inflammatory treatment with high doses of intravenous anakinra with or without glucocorticoids in patients with severe COVID-19 pneumonia.

BACKGROUND: IL-1 plays a pivotal role in the inflammatory response during cytokine storm syndromes. OBJECTIVE: Our aim was to analyze the efficacy and safety of early anti-inflammatory treatment (AIT) with intravenous anakinra with or without glucocorticoids in coronavirus disease 2019 (COVID-19) pneumonia. METHODS: We performed a retrospective single-center cohort study of patients admitted for COVID-19 pneumonia from February 26 to April 29, 2020, to assess the efficacy of early AIT with intravenous anakinra (100 mg every 8 hours for 3 days, with tapering) alone or in combination with a glucocorticoid (intravenous methylprednisolone, 1-2 mg/kg daily, with tapering). The standard of care (SOC) treatment was hydroxychloroquine and/or azithromycin with or without antivirals and anticoagulants. Late rescue AIT with anakinra or tocilizumab was also evaluated. Treatment effect on overall survival was assessed by a propensity score-adjusted Cox model. RESULTS: A total of 128 patients were analyzed; 63 patients received early AIT (30 received anakinra alone and 33 received anakinra plus a glucocorticoid) at admission, and 65 patients did not receive early AIT and were used as controls; of the latter 65 patients, 44 received the SOC treatment alone and 21 received the SOC treatment plus late rescue AIT. After adjustment for all the unbalanced baseline covariates, early AIT reduced the hazard of mortality by 74% (adjusted hazard ratio [HR] = 0.26; P < .001). The effect was similar in patients receiving anakinra alone (adjusted HR = 0.28; P = .04) and anakinra plus a glucocorticoid (adjusted HR = 0.33; P = .07). Late rescue treatment did not show a significant advantage over SOC treatment alone (adjusted HR = 0.82; P = .70). CONCLUSIONS: This study suggests, on a larger series of patients with COVID-19 pneumonia, the potential efficacy and safety of the early use of high doses of intravenous anakinra with or without glucocorticoids.

On the Alert for Cytokine Storm: Immunopathology in COVID-19.

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.