Relapsing myocarditis following initial recovery of post COVID-19 vaccination in two adolescent males - Case reports.

Whilst there has been significant public health benefits associated with global use of COVID-19 spike protein vaccines, potential serious adverse events following immunization have been reported. Acute myocarditis is a rare complication of COVID19 vaccines and often it is self-limiting. We describe two cases experiencing recurrent myocarditis following mRNA COVID-19 vaccine despite a prior episode with full clinical recovery. Between September 2021-September 2022 we observed two male adolescents with recurrent myocarditis related to mRNA-based-COVID19 vaccine. During the first episode both patients presented with fever and chest pain few days after their second dose of BNT162b2 mRNA Covid-19 Vaccine (Comirnaty®). The blood exams showed increased cardiac enzymes. In addition, complete viral panel was run, showing HHV7 positivity in a single case. The left ventricular ejection fraction (LVEF) was normal at echocardiogram but cardiac magnetic resonance scanning (CMR) was consistent with myocarditis. They were treated with supportive treatment with full recovery. The 6 months follow-up demonstrated good clinical conditions with normal cardiological findings. The CMR showed persistent lesions in left ventricle 's wall with LGE. After some months the patients presented at emergency department with fever and chest pain and increased cardiac enzymes. No decreased LVEF was observed. The CMR showed new focal areas of edema in the first case report and stable lesions in the second one. They reached full recovery with normalization of cardiac enzymes after few days. These case reports outline the need of strict follow-up in patients with CMR consistent with myocarditis after mRNA-based-COVID19 vaccine. More efforts are necessary to depict the underlying mechanisms of myocarditis after SARS-CoV2 vaccination to understand the risk of relapsing and the long-term sequelae.

Cardiopulmonary Exercise Testing in Children and Young Adolescents after a Multisystem Inflammatory Syndrome: Physical Deconditioning or Residual Pathology?

Multisystem inflammatory syndrome in children (MIS-C) is a serious health condition that imposes a long-term follow-up. The purpose of our pilot study is to evaluate the usefulness of the cardiopulmonary stress test (CPET) in the follow-up after MIS-C. All patients admitted for MIS-C in our hospital in the 12 months preceding the date of observation were considered for inclusion in the study. Pre-existing cardio-respiratory diseases and/or the lack of collaboration were the exclusion criteria. At enrolment, each subject passed a cardiological examination, rest ECG, echocardiogram, 24 h Holter-ECG, blood tests, and a CPET complete of spirometry. A total of 20 patients met the inclusion criteria (11.76 ± 3.29 years, 13 male). In contrast to the normality of all second-level investigations, CPET showed lower-than-expected peakVO2 and peak-oxygen-pulse values (50% of cases) and higher-than-expected VE/VCO2-slope values (95% of cases). A statistically significant inverse correlation was observed between P-reactive-protein values at admission and peakVO2/kg values (p = 0.034), uric acid values at admission, and peakVO2 (p = 0.011) or peak-oxygen-pulse expressed as a percentage of predicted (p = 0.021), NT-proBNP values at admission and peakVO2 expressed as a percentage of predicted (p = 0.046). After MIS-C (4-12 months) relevant anomalies can be observed at CPET, which can be a valuable tool in the follow-up after this condition.

Understanding COVID-19 in children: immune determinants and post-infection conditions.

Coronavirus disease 2019 in children presents with milder clinical manifestations than in adults. On the other hand, the presence of a wide range of inflammatory manifestations, including multisystem inflammatory syndrome in children (MIS-C), in the period after infection suggests a particular susceptibility of some children toward severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Both protective factors that prevent evolution to severe forms and risk factors for post-infectious conditions are likely to be found in age-related differences in the immune system. The prompt innate response with type I IFN production and the generation of neutralizing antibodies play a crucial role in containing the infection. The greater number of naive and regulatory cells in children helps to avoid the cytokine storm while the causes of the intense inflammatory response in MIS-C need to be elucidated. This review aims to analyze the main results of the recent literature assessing immune response to SARS-CoV-2 over the pediatric age group. We summarized such observations by dividing them into innate and acquired immunity, then reporting how altered immune responses can determine post-infectious conditions. IMPACT: The main immune markers of acute SARS-CoV-2 infection in children are summarized in this review. This paper reports a broad overview of age-related differences in the immune response to SARS-CoV-2 and emerging post-infection conditions. A summary of currently available therapies for the pediatric age group is provided.

COVID-19 in children: From afterthought to unknown.

Children were initially considered unsusceptible to severe COVID-19. Our knowledge after two years has changed dramatically, but there are still many unknowns. Here, we report the current knowledge about why children generally experience a milder COVID-19 course and highlight research questions about pediatric infection that require answers.

Safety of SARS-CoV2 vaccination and COVID-19 short-term outcome in pediatric acquired demyelinating disorders of central nervous system: A single center experience.

Introduction: Concern of a correlation between disease relapse in patients with acquired demyelinating disorders of central nervous system (CNS) and SARS-CoV2 vaccines has been raised. In this single center study, we retrospectively evaluated safety of SARS-CoV2 vaccination and COVID-19 short-term outcome in pediatric acquired demyelinating disorders of CNS. Materials and methods: Patients with multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) with disease onset before 18 years of age were included. Demographic and clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected. Results: We included nine patients with MOGAD. Six patients received SARS-CoV2 vaccination and complained pain at injection site while only one had fever and fatigue. Median follow-up was 28 weeks (range 20-48). Seven patients had COVID-19 occurring with mild flu-like symptoms and median follow-up was 28 weeks (range 24-34). Nobody had disease relapse. Five patients with NMOSD were included. All patients received SARS-CoV2 vaccination (BNT162b2-Pfizer-BioNTech). The median follow-up was 20 weeks (range 14-24) and only two patients complained pain at injection site, fever and fatigue. Three patients had also COVID-19 with mild flu-like symptoms, despite two of them being under immunosuppressive treatment. Lastly, forty-three patients with MS were included. 35 out of 43 received SARS-CoV2 vaccination with a median follow-up of 24 weeks (range 8-36). Fourteen patients had no side effects, while 21 complained mild side effects (mainly pain at injection site) and one experienced a disease relapse with complete recovery after steroid therapy. At vaccination, all but one were under treatment. Sixteen patients had COVID-19 occurring with mild symptoms. Discussion: COVID-19 outcome was good although many patients were under immunosuppressive treatment. Vaccine-related side effects were frequent but were mild and self-limited. Only one MS patient had a post-vaccination relapse with complete recovery after steroid therapy. In conclusion, our data support the safety of SARS-CoV-2 vaccines in pediatric MS, MOGAD and NMOSD.

Safety of SARS-CoV2 vaccination and COVID-19 short-term outcome in pediatric acquired demyelinating disorders of central nervous system: A single center experience

Introduction Concern of a correlation between disease relapse in patients with acquired demyelinating disorders of central nervous system (CNS) and SARS-CoV2 vaccines has been raised. In this single center study, we retrospectively evaluated safety of SARS-CoV2 vaccination and COVID-19 short-term outcome in pediatric acquired demyelinating disorders of CNS. Materials and methods Patients with multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) with disease onset before 18 years of age were included. Demographic and clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected. Results We included nine patients with MOGAD. Six patients received SARS-CoV2 vaccination and complained pain at injection site while only one had fever and fatigue. Median follow-up was 28 weeks (range 20-48). Seven patients had COVID-19 occurring with mild flu-like symptoms and median follow-up was 28 weeks (range 24-34). Nobody had disease relapse. Five patients with NMOSD were included. All patients received SARS-CoV2 vaccination (BNT162b2-Pfizer-BioNTech). The median follow-up was 20 weeks (range 14-24) and only two patients complained pain at injection site, fever and fatigue. Three patients had also COVID-19 with mild flu-like symptoms, despite two of them being under immunosuppressive treatment. Lastly, forty-three patients with MS were included. 35 out of 43 received SARS-CoV2 vaccination with a median follow-up of 24 weeks (range 8-36). Fourteen patients had no side effects, while 21 complained mild side effects (mainly pain at injection site) and one experienced a disease relapse with complete recovery after steroid therapy. At vaccination, all but one were under treatment. Sixteen patients had COVID-19 occurring with mild symptoms. Discussion COVID-19 outcome was good although many patients were under immunosuppressive treatment. Vaccine-related side effects were frequent but were mild and self-limited. Only one MS patient had a post-vaccination relapse with complete recovery after steroid therapy. In conclusion, our data support the safety of SARS-CoV-2 vaccines in pediatric MS, MOGAD and NMOSD.

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.

Higher Troponin Levels on Admission are associated With Persistent Cardiac Magnetic Resonance Lesions in Children Developing Myocarditis After mRNA-Based COVID-19 Vaccination.

BACKGROUND: Acute pericarditis/myocarditis is a rare complication of the mRNA-based vaccines and although mostly self-limiting, long-term sequelae remain unclear. METHODS: We enrolled all patients admitted to the emergency department between September 2021 and February 2022 meeting the CDC work case definition, with symptoms onset after mRNA-based COVID-19 vaccine. Alternative virologic causes were excluded. Clinical data, laboratory values, cardiologic evaluation, electrocardiogram (ECG), and echocardiogram (ECHO) were collected on admission, at discharge, and during follow-up in all patients. Cardiac Magnetic Resonance (CMR) was performed only in those with signs consistent with myocarditis. RESULTS: We observed 13 patients (11M and 2F), median age 15 years, affected by acute pericarditis/myocarditis after COVID-19 mRNA vaccination (11 after Comirnaty® and 2 after Spikevax®). Symptoms'onset occurred at a median of 5 days (range, 1 to 41 days) after receiving mRNA vaccine (13 Prizer 2 Moderna): 4 patients (31%) after the 1st dose, 6 (46%) after the 2nd, and 3 (23%) after 3rd dose. Increased levels of high-sensitive troponin T (hsTnT) (median 519,5 ng/mL) and N-terminal-pro hormone BNP (NT-proBNP) (median 268 pg/mL) and pathognomonic ECG and ECHO abnormalities were detected. On admission, 7 of 13 (54%) presented with myopericarditis, 3 (23%) with myocarditis, and 3 (23%) with pericarditis; CMR was performed in 5 patients upon pediatric cardiologist prescription and findings were consistent with myocarditis. At 12 weeks of follow-up, all but one patient (92%), still presenting mild pericardial effusion at ECHO, were asymptomatic with normal hsTnT and NT-proBNP levels and ECG. On CMR 6 of 9 patients showed persistent, although decreased, myocardial injury. Higher hsTnT levels on admission significantly correlated with persistent CMR lesions. CONCLUSION: Evidence of persistent CMR lesions highlights the need for a close and standardized follow-up for those patients who present high hsTnT levels on admission.

The Relationship Between Pediatric Gut Microbiota and SARS-CoV-2 Infection.

This is the first study on gut microbiota (GM) in children affected by coronavirus disease 2019 (COVID-19). Stool samples from 88 patients with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 95 healthy subjects were collected (admission: 3-7 days, discharge) to study GM profile by 16S rRNA gene sequencing and relationship to disease severity. The study group was divided in COVID-19 (68), Non-COVID-19 (16), and MIS-C (multisystem inflammatory syndrome in children) (4). Correlations among GM ecology, predicted functions, multiple machine learning (ML) models, and inflammatory response were provided for COVID-19 and Non-COVID-19 cohorts. The GM of COVID-19 cohort resulted as dysbiotic, with the lowest α-diversity compared with Non-COVID-19 and CTRLs and by a specific ß-diversity. Its profile appeared enriched in Faecalibacterium, Fusobacterium, and Neisseria and reduced in Bifidobacterium, Blautia, Ruminococcus, Collinsella, Coprococcus, Eggerthella, and Akkermansia, compared with CTRLs (p < 0.05). All GM paired-comparisons disclosed comparable results through all time points. The comparison between COVID-19 and Non-COVID-19 cohorts highlighted a reduction of Abiotrophia in the COVID-19 cohort (p < 0.05). The GM of MIS-C cohort was characterized by an increase of Veillonella, Clostridium, Dialister, Ruminococcus, and Streptococcus and a decrease of Bifidobacterium, Blautia, Granulicatella, and Prevotella, compared with CTRLs. Stratifying for disease severity, the GM associated to "moderate" COVID-19 was characterized by lower α-diversity compared with "mild" and "asymptomatic" and by a GM profile deprived in Neisseria, Lachnospira, Streptococcus, and Prevotella and enriched in Dialister, Acidaminococcus, Oscillospora, Ruminococcus, Clostridium, Alistipes, and Bacteroides. The ML models identified Staphylococcus, Anaerostipes, Faecalibacterium, Dorea, Dialister, Streptococcus, Roseburia, Haemophilus, Granulicatella, Gemmiger, Lachnospira, Corynebacterium, Prevotella, Bilophila, Phascolarctobacterium, Oscillospira, and Veillonella as microbial markers of COVID-19. The KEGG ortholog (KO)-based prediction of GM functional profile highlighted 28 and 39 KO-associated pathways to COVID-19 and CTRLs, respectively. Finally, Bacteroides and Sutterella correlated with proinflammatory cytokines regardless disease severity. Unlike adult GM profiles, Faecalibacterium was a specific marker of pediatric COVID-19 GM. The durable modification of patients' GM profile suggested a prompt GM quenching response to SARS-CoV-2 infection since the first symptoms. Faecalibacterium and reduced fatty acid and amino acid degradation were proposed as specific COVID-19 disease traits, possibly associated to restrained severity of SARS-CoV-2-infected children. Altogether, this evidence provides a characterization of the pediatric COVID-19-related GM.

Case report: A pediatric case of Bickerstaff brainstem encephalitis after COVID-19 vaccination and Mycoplasma pneumoniae infection: Looking for the culprit.

Bickerstaff brainstem encephalitis (BBE) is a rare, immune-mediated disease characterized by the acute onset of external ophthalmoplegia, ataxia, and consciousness disturbance. It has a complex multifactorial etiology, and a preceding infectious illness is seen in the majority of cases. Immune-mediated neurological syndromes following COVID-19 vaccination have been increasingly described. Here we report the case of a child developing BBE 2 weeks after COVID-19 vaccination. Despite nerve conduction studies and CSF analysis showing normal results, BBE was diagnosed on clinical ground and immunotherapy was started early with a complete recovery. Later, diagnosis was confirmed by positive anti-GQ1b IgG in serum. Even if there was a close temporal relationship between disease onset and COVID-19 vaccination, our patient also had evidence of a recent Mycoplasma pneumoniae infection that is associated with BBE. Indeed, the similarity between bacterial glycolipids and human myelin glycolipids, including gangliosides, could lead to an aberrantly immune activation against self-antigens (i.e., molecular mimicry). We considered the recent Mycoplasma pneumoniae infection a more plausible explanation of the disease onset. Our case report suggests that suspect cases of side effects related to COVID-19 vaccines need a careful evaluation in order to rule out well-known associated factors before claiming for a causal relationship.

Perinatally Human Immunodeficiency Virus-Infected Adolescents and Young Adults Demonstrate Distinct BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccine Immunogenicity.

BACKGROUND: Immunization of vulnerable populations with distinct immunity often results in suboptimal immunogenicity, durability, and efficacy. METHODS: Safety and immunogenicity profiles of BNT162b2 messenger RNA coronavirus disease 2019 (COVID-19) vaccine, among people living with human immunodeficiency virus (HIV), were evaluated in 28 perinatally HIV-infected patients under antiretroviral therapy (ART) and 65 healthy controls (HCs) with no previous history of COVID-19. Thus, we measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific humoral and CD4+ T cell responses. Samples were collected before vaccination (baseline, day [D] 0), at the second dose (D21), and at 4 weeks (D28) and 6 months (D180) after D0. Proteomic profiles at D0 and D28 were assessed with a multiplexed proximity extension assay (Olink) on plasma samples. RESULTS: All HIV-infected patients mounted similar anti-SARS-CoV-2 humoral responses to those of HCs, albeit with lower titers of anti-trimeric S at D28 (P = .01). Only peripheral blood mononuclear cells of HIV-infected patients demonstrated at D28 an impaired ability to expand their specific (CD40L+) CD4+ T-cell populations. Similar humoral titers were maintained between the 2 groups at 6-months follow-up. We additionally correlated baseline protein levels to either humoral or cellular responses, identifying clusters of molecules involved in immune response regulation with inverse profiles between the 2 study groups. CONCLUSIONS: Responses of ART-treated HIV-infected patients, compared to those of HCs, were characterized by distinct features especially within the proteomic compartment, supporting their eligibility to an additional dose, similarly to the HC schedule.

The Relationship Between Pediatric Gut Microbiota and SARS-CoV-2 Infection

This is the first study on gut microbiota (GM) in children affected by coronavirus disease 2019 (COVID-19). Stool samples from 88 patients with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 95 healthy subjects were collected (admission: 3–7 days, discharge) to study GM profile by 16S rRNA gene sequencing and relationship to disease severity. The study group was divided in COVID-19 (68), Non–COVID-19 (16), and MIS-C (multisystem inflammatory syndrome in children) (4). Correlations among GM ecology, predicted functions, multiple machine learning (ML) models, and inflammatory response were provided for COVID-19 and Non–COVID-19 cohorts. The GM of COVID-19 cohort resulted as dysbiotic, with the lowest α-diversity compared with Non–COVID-19 and CTRLs and by a specific β-diversity. Its profile appeared enriched in Faecalibacterium, Fusobacterium, and Neisseria and reduced in Bifidobacterium, Blautia, Ruminococcus, Collinsella, Coprococcus, Eggerthella, and Akkermansia, compared with CTRLs (p < 0.05). All GM paired-comparisons disclosed comparable results through all time points. The comparison between COVID-19 and Non–COVID-19 cohorts highlighted a reduction of Abiotrophia in the COVID-19 cohort (p < 0.05). The GM of MIS-C cohort was characterized by an increase of Veillonella, Clostridium, Dialister, Ruminococcus, and Streptococcus and a decrease of Bifidobacterium, Blautia, Granulicatella, and Prevotella, compared with CTRLs. Stratifying for disease severity, the GM associated to “moderate” COVID-19 was characterized by lower α-diversity compared with “mild” and “asymptomatic” and by a GM profile deprived in Neisseria, Lachnospira, Streptococcus, and Prevotella and enriched in Dialister, Acidaminococcus, Oscillospora, Ruminococcus, Clostridium, Alistipes, and Bacteroides. The ML models identified Staphylococcus, Anaerostipes, Faecalibacterium, Dorea, Dialister, Streptococcus, Roseburia, Haemophilus, Granulicatella, Gemmiger, Lachnospira, Corynebacterium, Prevotella, Bilophila, Phascolarctobacterium, Oscillospira, and Veillonella as microbial markers of COVID-19. The KEGG ortholog (KO)–based prediction of GM functional profile highlighted 28 and 39 KO-associated pathways to COVID-19 and CTRLs, respectively. Finally, Bacteroides and Sutterella correlated with proinflammatory cytokines regardless disease severity. Unlike adult GM profiles, Faecalibacterium was a specific marker of pediatric COVID-19 GM. The durable modification of patients’ GM profile suggested a prompt GM quenching response to SARS-CoV-2 infection since the first symptoms. Faecalibacterium and reduced fatty acid and amino acid degradation were proposed as specific COVID-19 disease traits, possibly associated to restrained severity of SARS-CoV-2–infected children. Altogether, this evidence provides a characterization of the pediatric COVID-19–related GM.

Two Pediatric Cases of Multisystem Inflammatory Syndrome with Overlapping Neurological Involvement Following SARS-CoV-2 Vaccination and Unknown SARS-CoV2 Infection: The Importance of Pre-Vaccination History.

The SARS-CoV-2 vaccine roll-out has been successful around the world. However, there are increasing concerns about adverse events. We report two pediatric cases of Multisystem-Inflammatory-Syndrome (MIS-C) with neurological involvement that occurred after SARS-CoV-2 vaccination and unknown recent SARS-CoV-2 infection. Brain magnetic resonance revealed mild-encephalopathy with reversible-splenial-lesion in both cases and complete resolution within 4 weeks. In conclusion, this report aims to describe rare emerging clinical entities that can help pediatricians to make an early diagnosis and to provide appropriate treatment. Multisystem-Inflammatory-Syndromes following COVID-19 vaccination remain rare events. When a history of a recent contact with SARS-CoV-2 is present, a careful evaluation by the clinicians in charge of immunization activities is suggested prior to proceeding with the vaccination.

Long-term Immune Response to SARS-CoV-2 Infection Among Children and Adults After Mild Infection.

Importance: Understanding the long-term immune response against SARS-CoV-2 infection in children is crucial to optimize vaccination strategies. Although it is known that SARS-CoV-2 antibodies may persist in adults 12 months after infection, data are limited in the pediatric population. Objective: To examine long-term anti-SARS-CoV-2 spike receptor-binding domain (S-RBD) IgG kinetics in children after SARS-CoV-2 infection. Design, Setting, and Participants: In this single-center, prospective cohort study, patients were enrolled consecutively from April 1, 2020, to August 31, 2021, at the COVID-19 Family Cluster Follow-up Clinic, Department of Women's and Children's Health, University Hospital of Padua. A cohort of 252 COVID-19 family clusters underwent serologic follow-up at 1 to 4, 5 to 10, and more than 10 months after infection with quantification of anti-S-RBD IgG by chemiluminescent immunoassay. Exposures: SARS-CoV-2 infection. Results: Among 902 study participants, 697 had confirmed SARS-CoV-2 infection, including 351 children or older siblings (mean [SD] age, 8.6 [5.1] years) and 346 parents (mean [SD] age, 42.5 [7.1] years). Among 697 cases, 674 (96.7%) were asymptomatic or mild. Children had significantly higher S-RBD IgG titers than older patients across all follow-up time points, with an overall median S-RBD IgG titer in patients younger than 3 years 5-fold higher than adults (304.8 [IQR, 139.0-516.6] kBAU/L vs 55.6 [24.2-136.0] kBAU/L, P < .001). Longitudinal analysis of 56 study participants sampled at least twice during follow-up demonstrated the persistence of antibodies up to 10 months from infection in all age classes, despite a progressive decline over time. Conclusions and Relevance: In this cohort study of Italian children and adults following SARS-CoV-2 infection different kinetics of SARS-CoV-2 antibodies were found across several age classes of individuals with asymptomatic or mild COVID-19, which could help in optimizing COVID-19 vaccination strategies and prevention policies. This work provides further evidence of sustained immune response in children up to 1 year after primary SARS-CoV-2 infection.

Evaluation of Safety and Immunogenicity of BNT162B2 mRNA COVID-19 Vaccine in IBD Pediatric Population with Distinct Immune Suppressive Regimens.

Patients affected by Inflammatory Bowel Disease (IBD) present higher risk for infection and suboptimal response upon vaccination. The immunogenicity of SARS-CoV2 vaccination is still largely unknown in adolescents or young adults affected by IBD (pIBD). We investigated the safety and immunogenicity of the BNT162B2 mRNA COVID-19 vaccine in 27 pIBD, as compared to 30 healthy controls (HC). Immunogenicity was measured by anti-SARS-CoV2 IgG (anti-S and anti-trim Ab) before vaccination, after 21 days (T21) and 7 days after the second dose (T28). The safety profile was investigated by close monitoring and self-reported adverse events. Vaccination was well tolerated, and short-term adverse events reported were only mild to moderate. Three out of twenty-seven patients showed IBD flare after vaccination, but no causal relationship could be established. Overall, pIBD showed a good humoral response upon vaccination compared to HC; however, pIBD on anti-TNFα treatment showed lower anti-S Ab titers compared to patients receiving other immune-suppressive regimens (p = 0.0413 at first dose and p = 0.0301 at second dose). These data show that pIBD present a good safety and immunogenicity profile following SARS-CoV-2 mRNA vaccination. Additional studies on the impact of specific immune-suppressive regimens, such as anti TNFα, on immunogenicity should be further investigated on larger cohorts.

Hemoadsorption for severe MIS-C in critically ill children, should we consider it as a therapeutic opportunity?

Multisystem inflammatory syndrome (MIS-C) is a new severe clinical condition that has emerged during the COVID-19 pandemic. MIS-C affects children and the young usually after a mild or asymptomatic COVID-19 infection. MIS-C has a high tropism for the cardiovascular system with need for inotropes and vasopressor support in 62% of cases. As of today a mortality from 1.5% to 1.9% related to MIS-C is reported. Hemoadsorption via the inflammatory mediator adsorber CytoSorb (CytoSorbents Europe, Berlin Germany) has been used as adjunctive therapy with the aim to restore the host response in septic shock and other hyper-inflammatory syndromes. We present the clinical experience of an adolescent boy with a refractory shock secondary to left ventricular dysfunction (LVD) in the context of MIS-C, treated with hemoadsorption, and continuous kidney replacement therapy (CKRT) in combination with immunomodulatory therapies. The therapeutic strategy resulted in hemodynamic and clinical stabilization as well as control of the hyperinflammatory response. Treatment appeared to be safe and feasible. Our findings are in line with previously published clinical cases on Cytosorb use in MIS-C showing the beneficial role of the hemoperfusion with Cytosorb in severe MIS-C to manage the cytokine storm. We provide an analysis and comparison of recent evidence on the use of hemoadsorption as an adjuvant therapy in critically ill children with severe forms of MIS-C, suggesting this blood purification strategy could be a therapeutic opportunity in severe LVD due to MIS-C, sparing the need for extracorporeal membrane oxygentation (ECMO) and other mechanical cardiocirculatory supports.

Case Report: Successful Treatment With Monoclonal Antibodies in One APDS Patient With Prolonged SARS-CoV-2 Infection Not Responsive to Previous Lines of Treatment.

We described the case of a patient affected by activated PI3K-kinase delta syndrome (APDS) and a long-lasting and pauci-symptomatic SARS-CoV-2 infection, treated with multiple therapeutic agents including remdesivir and SARS-CoV-2-neutralizing monoclonal antibodies. We detected the clearance of the virus 105 days from the first positive swab and 7 days after monoclonal antibody administration. At genotyping, the SARS-CoV-2 virus resulted as wild type on all samples tested. This case shows the monoclonal antibodies' good tolerability and efficacy in reducing viral shedding in long-lasting infections refractory to other treatments.

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.

Safety of Monoclonal Antibodies in Children Affected by SARS-CoV-2 Infection.

Monoclonal antibody therapies for COVID-19 have been frequently used in adults, whereas there are little data regarding the safety or efficacy of monoclonal antibody treatments in pediatric patients affected by COVID-19. We report our experience in the administration of mAb as a treatment for SARS-CoV-2 infection in children aged from 24 days to 18 years old.