Inherited deficiency of the OAS-RNase L pathway in children with MIS-C

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Consistent with the absence of pneumonia in these patients, epithelial cells and fibroblasts defective for this pathway restricted SARS-CoV-2 normally. This contrasted with IFNAR1-deficient cells from patients prone to hypoxemic pneumonia without MIS-C. Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNASEL deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV- 2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-but not RNase L- deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.Copyright © 2023 Elsevier Inc.

Enhanced TLR7 immunity drives innate protection against SARS-CoV-2 with chilblains as collateral damage

Outbreaks of chilblains, a hallmark sign of type I interferonopathies, have been reported during the COVID-19 pandemic. These cases occurred mostly in patients who were asymptomatic and showed negative results from PCR and serology tests for SARS-CoV-2. We hypothesized that chilblain patients are predisposed to mount a robust innate immunity against the virus, which clinically manifests as chilblains and promotes early viral clearance, thereby preventing pulmonary disease and precluding adaptive responses. By profiling skin lesions in the early stage following chilblain onset, we uncover a transient IRF7-dependent type I interferon (IFN) signature that is driven by the acral infiltration of systemically activated plasmacytoid dendritic cells (pDCs). Patients' peripheral blood mononuclear cells (PBMCs) demonstrate increased production of IFNalpha when exposed to SARS-CoV-2 and influenza A, but not herpes simplex virus 1 (HSV-1), indicating a heightened ability to detect RNA -but not DNA- viruses. Further investigations revealed enhanced responsiveness of pDCs in chilblain patients to the RNA sensor TLR7, but not the DNA sensor TLR9. Collectively, our study establishes a two-step model for the immunopathology of SARS-CoV-2-related chilblains: enhanced TLR7 immunity in pDCs, likely triggered by SARS-CoV-2 exposure at the mucosal site, leads to prompt viral clearance, which explains the lack of infection markers in most cases. Subsequently, systemic spread of activated pDCs and infiltration of the toes in response to mechanical stress or acral coldness, may result in IFN-mediated tissue damage with development of chilblains.Copyright © 2023

Inflammatory markers and auto-Abs to type I IFNs in COVID-19 Convalescent Plasma

Background: COVID-19 convalescent plasma (CCP) contains neutralizing anti-SARS- CoV- 2 antibodies that may be useful as COVID-19 passive immunotherapy in patients at risk of developing severe disease. Aim(s): Such plasma from convalescent patients may also have additional immune-modulatory properties when transfused to COVID-19 patients. Method(s): CCP (n = 766) were compared to control non-convalescent plasma (n = 166) for soluble inflammatory markers, ex-vivo inflammatory bioactivity on endothelial cells, neutralizing auto-Ab to type I IFNs, and reported adverse events in the recipients. Result(s): CCP exhibited significantly higher IL-6 and TNF-alpha (0.531+/-0.04 vs 0.271+/-0.04;p = 0.0061 and 0.900+/-0.07 vs 0.283+/-0.07 pg/ml;p < 0.0001), respectively) and lower IL-10 (0.731+/-0.07 vs 1.22+/-0.19 pg/ ml, p = 0.0034) levels than control plasma. Other inflammatory markers as well as ex-vivo bioactivity did not differ significantly between CCP and control plasma. Neutralizing auto-Abs against type I IFNs were detected in 14/766 (1.8 %) CCP. They were not associated with reported adverse events when transfused (n = 14). Inflammatory markers and bioactivity in CCP with or without auto-Ab, or in CCP associated or not with adverse events in transfused patients, did not differ significantly. Overall, CCP exhibited moderately increased inflammatory markers compared to control plasma with no discernable differences in ex-vivo bioactivity. Auto-Ab to type I IFNs, detected in a small fraction of CCP, were not associated with reported adverse events or differences in inflammatory markers. Conclusion(s): Further defining the clinical relevance of these findings will require further studies including careful clinical evaluation of patients treated with CCP.

Virological and clinical features of acute respiratory failure associated with COVID-19 in pregnancy: a case-control study

Objective: Pregnancy is a risk factor for acute respiratory failure (ARF) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We hypothesised that SARS-CoV-2 viral load in the respiratory tract might be higher in pregnant intensive care unit (ICU) patients with ARF than in non-pregnant ICU patients with ARF as a consequence of immunological adaptation during pregnancy. Design: Single-centre, retrospective observational case- control study. Setting: Adult level 3 ICU in a French university hospital. Participants: Eligible participants were adults with ARF associated with coronavirus disease 2019 (COVID-19) pneumonia. Main outcome measure: The primary endpoint of the study was viral load in pregnant and non-pregnant patients. Results: 251 patients were included in the study, including 17 pregnant patients. Median gestational age at ICU admission amounted to 28 + 3/7 weeks (interquartile range [IQR], 26 + 1/7 to 31 + 5/7 weeks). Twelve patients (71%) had an emergency caesarean delivery due to maternal respiratory failure. Pregnancy was independently associated with higher viral load (-4.6 +/- 1.9 cycle threshold;P < 0.05). No clustering or over-represented mutations were noted regarding SARS-CoV-2 sequences of pregnant women. Emergency caesarean delivery was independently associated with a modest but significant improvement in arterial oxygenation, amounting to 32 +/- 12 mmHg in patients needing invasive mechanical ventilation. ICU mortality was significantly lower in pregnant patients (0 v 35%;P < 0.05). Age, Simplified Acute Physiology Score (SAPS) II score, and acute respiratory distress syndrome were independent risk factors for ICU mortality, while pregnancy status and virological variables were not. Conclusions: Viral load was substantially higher in pregnant ICU patients with COVID-19 and ARF compared with non-pregnant ICU patients with COVID-19 and ARF. Pregnancy was not independently associated with ICU mortality after adjustment for age and disease severity.

Caractéristiques des patients présentant des infections sévères à SARS-CoV-2 avec des auto-anticorps neutralisant les Interférons de type I et étude de l'impact des anti-IL6

Les interférons (IFN) de type I jouent un rôle important dans l'immunité protectrice contre le SARS-CoV-2. La présence d'auto-anticorps (auto-Ac) neutralisant les IFN de type I est significativement associée à des atteintes de COVID-19 critiques ou sévères. Nous avons cherché à évaluer la prévalence et l'impact clinique des auto-Ac anti IFN de type I et du tocilizumab en Seine-Saint-Denis sur le pronostic des patients. Nous avons testé la présence d'auto-Ac neutralisants contre les IFN de type I chez des patients préalablement identifiés pour une pneumonie sévère au COVID-19 hospitalisés au printemps 2020 dans les services de médecine de l'hôpital Robert Ballanger d'Aulnay sous-bois. Il s'agissait d'une cohorte comprenant tous les patients hospitalisés entre début mars et fin avril 2020 ayant nécessité 6 litres ou plus d'oxygène pour une infection SARS CoV-2. Au sein de cette cohorte, les patients ayant encore des prélèvements sériques disponibles en sérothèque ont été testés pour rechercher les auto-Ac et nous avons étudié en parallèle leurs caractéristiques cliniques et pronostiques. Parmi les 246 patients, seuls 139 avaient encore un prélèvement sérique disponible en sérothèque lors de la réalisation de l'étude. Nous avons trouvé des auto-anticorps circulants présentant une activité neutralisante vis-à-vis des IFN de type I chez 7,9 % des patients (11 sur 139). La présence d'auto-Ac neutralisants était associée à un risque accru de mortalité et ces auto-Ac ont été détectés chez 21 % des patients décédés d'une pneumonie au COVID-19. La technique Gyros a trouvé que 107/139 (77 %) des patients présentaient des anticorps anti IFN. Cette méthode n'était donc pas performante pour identifier une activité neutralisante des anticorps. Un kit ELISA commercial a également été évalué pour la détection des auto-Ac anti-IFN-alpha et des titres élevés d'anticorps par cette technique étaient bien corrélés à l'activité neutralisante. De façon intéressante, le taux de mortalité parmi les patients présentant des auto-Ac est de 100 % (5/5) chez les patients n'ayant pas reçu de tocilizumab versus 17 % 1/6) chez les patients traités par tocilizumab (p < 0,001). Parmi les 128 patients n'ayant pas d'anticorps neutralisants, le taux de mortalité entre les patients traités par tocilizumab 16 % (12/74) versus ceux non traités 20 % (11/54) ne présentait pas de différence significative (p = 0,64). Ces résultats confirment l'importance de la voie IFN-I dans la défense contre l'infection par le SARS-CoV-2. La détection des auto-Ac neutralisants contre les IFN de type I est associée à une plus grande mortalité. Le tocilizumab pourrait avoir une efficacité chez ces patients. Ces résultats nécessitent néanmoins d'être confirmés sur des échantillons de patients plus importants. (French) [ FROM AUTHOR] Copyright of Revue de Médecine Interne is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Le déficit en interféron de type I n’altère pas la réponse lymphocytaire B mémoire contre le SARS-CoV-2 après vaccination par ARNm

Introduction Les vaccins à ARN messagers ont joué un rôle majeur dans la lutte contre la pandémie de SARS-CoV-2 grâce à une excellente efficacité et sécurité clinique. Ces vaccins ont été développés suite à des années de recherche fondamentale, dont l’une des étapes cruciales a été de remplacer l’uridine de l’ARNm par de la 1-méthyl-pseudo-uridine afin d’éviter la reconnaissance par les récepteurs de l’immunité innée, notamment le toll-like-receptor (TLR) 7. Une hypothèse, très fréquemment défendue mais jamais étayée expérimentalement, est que cet ARN modifié garde une activité immunostimulatrice à bas bruit permettant la production d’interféron de type I, agissant comme un adjuvant du vaccin. Les interférons de type I sont des cytokines antivirales essentielles et les patients ayant un déficit dans les voies de l’interféron de type I sont à haut risque de COVID-19 sévère. Dans ce travail, nous avons analysé la réponse lymphocytaire B au vaccin à ARNm de patients présentant l’absence de signalisation par les interférons de type I. Ceci nous a permis de savoir si les vaccins par ARNm permettaient d’établir une réponse lymphocytaire B robuste en l’absence d’interféron de type I. Patients et méthodes Nous avons constitué trois cohortes de patients (i) des patients avec des déficits génétiques sur les voies de l’interféron de type I : 2 patients avec une mutation homozygote d’IRF7 (facteur de transcription responsable de la production d’interférons de Type I, notamment en aval de TLR7) et un patient avec une déficit hémizygote de TLR7 (ii) des patients ayant des auto-anticorps neutralisant les interférons alpha et oméga, dans le cadre d’une polyendocrinopathie auto-immune de type I (APS-1, n = 14) (iii) des patients ayant des auto-anticorps neutralisant les interféron, associés à l’âge, une entité récemment décrite et particulièrement fréquente chez les sujets âgés (n = 8). Ces sujets ont été comparés à 29 contrôles sains. Tous étaient naïfs du COVID-19 et ont reçu 2 doses de vaccin à ARNm (BNT162n2 ou mRNA1273). Les patients ont été prélevés à différents point de temps, dans les 3 premiers mois et entre 3 et 7 mois après la seconde dose. La réponse sérologique a été évaluée par ELISA anti-IgG et IgA RBD (receptor binding domain de la Spike) et la neutralisation sérique a été testée in vitro contre le D614G-SARS-CoV-2. Les lymphocytes B (LB) mémoires CD19 + IgD-CD27± spécifiques du RBD ont été analysés en cytométrie en flux et triés en cellule unique pour séquençage des régions variables de la chaîne lourde de l’immunoglobuline. Résultats La réponse sérologique anti-RBD IgG et IgA était comparable aux temps précoces et tardifs de la réponse vaccinale, évoluant de façon similaire chez les patients déficients en interféron de type I et les sujets sains. La capacité de neutralisation des sérums contre le SARS-CoV-2 était également identique dans tous les groupes, et corrélait fortement avec le taux d’IgG anti-RBD, suggérant que le RBD était également la cible de la réponse neutralisante chez les patients déficients en interféron de type I. Des LB mémoires circulants spécifiques du RBD étaient retrouvés dans toutes les cohortes de patients déficients en interféron de type I au cours des 3 mois suivant la vaccination. Ceux-ci se maintenaient dans le temps et étaient encore présents entre 3 et 7 mois après la vaccination (0,18 % des LB IgD-CD27+ chez les sujets sains, 0,24 % chez les sujets avec déficit génétiques, 0,16 % chez les APS-1 et 0,26 % chez les AAB, pas de différence statistiquement significative). Le séquençage de la chaîne lourde des régions variables de l’immunoglobuline des LB mémoires spécifiques du RBD révélait l’accumulation progressive des mutations jusqu’à 7 mois chez les sujets sains, témoignant d’une réaction des centres germinatifs permettant la maturation d’affinité et la génération de lymphocytes B mémoires à longue durée de vie. Chez les patients IRF7 déficients, les LB mémoires spécifiques du RBD acquerraient progressivement des mutations de M1 à M6, et les LB mémoires spécifiques du RBD de patients TLR7 et APS-1 arboraient un nombre élevé de mutation dès M4, témoignant que même en l’absence de réponse à l’interféron de type I, le vaccin permettait la génération des LB mémoire issus des centres germinatifs, comme chez les sujets sains. Enfin, des clones partagés étaient retrouvés entre les sujets sains et les patients déficient en interféron de type I témoignant d’une réponse qualitativement normale. Conclusion Notre travail apporte des données rassurantes sur la vaccination de ces patients à haut risque de forme de grave de COVID-19 et suggère que l’ARNm contenu dans les vaccins n’a pas de rôle adjuvant intrinsèque.

Type i Interferon Autoantibodies Are Detected in Those with Critical COVID-19, Including a Young Female Patient

Background. Approximately 10-20% of patients with critical COVID-19 harbor neutralizing autoantibodies (auto-Abs) that target type I interferons (IFN), a family of cytokines that induce critical innate immune defense mechanisms upon viral infection. Studies to date indicate that these auto-Abs are mostly detected in men over age 65. Methods. We screened for type I IFN serum auto-Abs in sera collected < 21 days post-symptom onset in a subset of 103 COVID-19 inpatients and 24 outpatients drawn from a large prospective cohort study of SARS-CoV-2 infected patients enrolled across U.S. Military Treatment Facilities. The mean age of this n = 127 subset of study participants was 55.2 years (SD = 15.2 years, range 7.7 - 86.2 years), and 86/127 (67.7%) were male. Results. Among those hospitalized 49/103 (47.6%) had severe COVID-19 (required at least high flow oxygen), and nine subjects died. We detected neutralizing auto-Abs against IFN-α, IFN-ω, or both, in four inpatients (3.9%, 8.2% of severe cases), with no auto-Abs detected in outpatients. Three of these patients were white males over the age of 62, all with multiple comorbidities;two of whom died and the third requiring high flow oxygen therapy. The fourth patient was a 36-year-old Hispanic female with a history of obesity who required mechanical ventilation during her admission for COVID-19. Conclusion. These findings support the association between type I IFN auto-antibody production and life-threatening COVID-19. With further validation, reliable high-throughput screening for type I IFN auto-Abs may inform diagnosis, pathogenesis and treatment strategies for COVID-19, particularly in older males. Our finding of type I IFN auto-Ab production in a younger female prompts further study of this autoimmune phenotype in a broader population.

P.0034 Covid-19 strict home confinement decreased caregivers burden of people with cognitive impairment and mild dementia

Residente que presente;Amanda Vega Núñez;Jessica Marian Goodman Casanova;Elena Durá Pérez. Background: COVID-19 outbreak in Spain has deeply affected the care of elderly people with dementia. The Spanish government decided to declare a national state of alarm implementing restrictive measures like lockdown, home confinement, social distancing and isolation, from the 15th of March 2020 until the 21st of June 2020. These measures also led to a change in health care access (1). Since dementia is a pathology which requires continuous care, the restrictive measures and reduced support availability may have significantly increased caregiver burden. The aim of this study was to explore to what extend mandatory restrictive COVID-19 measures affected the burden in caregivers of people with mild cognitive impairment and mild dementia. Methods: This cohort study was conducted in the Spanish region of Andalucía (Málaga). In total 151 caregivers for people with mild cognitive impairment or mild dementia (PMCI/MD), from the SMART4MD (n=75) (2) and TV-AssistDem (n=76) (3) randomized clinical trials (RCTs), were interviewed by telephone between May 11 and June 26 2020. All participants had undergone between 1-3 assessments (in 6 month-intervals) on burden and quality of life prior to the COVID-19 breakout. The mean time between the last assessment of the RCTs (TO) and the interview during lockdown (T1) was 199.33 days (SD=52.43, Range=67-395). The mean time from the start of the lockdown and home-confinement measures to the interview was 70.36 days (SD=12.40, Range: 52-102). Demographic variables assessed were: patients´ age, sex, marital status, educational level, caregiver relationship with the patient and type of cohabitation. Caregiver burden was measured with the Zarit Caregiver Burden Interview (ZBI-12) (4). Patient´s quality of life was evaluated with Alzheimer Quality of Life-Alzheimer's Disease Scale (QoL-AD) (5). Wilcoxon Signed Rank Test was used to compare ZBI-12 and QoL-AD scores before and during confinement because scores did not have a normal distribution. A linear regression model was built to test variables associated with ZBI-12 scores during confinement. Results: 151 matched pairs were assessed for this study. Mean patient age was 59.24 (SD = 15.39). The majority of the patients were women (68,6%) and were married (64,6%). Educational level was primary or less in 61%. The majority of caregivers were spouses (42%) or children (38.7%). Wilcoxon signed-rank test showed that ZBI-12 scores decreased after COVID19 confinement (mean negative rank = 62.37, mean positive rank = 52.51, Z = -3.69, p < 0,001). Patients´ quality of life decreased with confinement (QoL-AD mean negative rank = 89.75, mean positive rank = 42.88, Z = -5.881, p < 0,001). In the regression model, only ZBI-12 before confinement showed significant association with ZBI-12 score after confinement (Squared R = 0,44), while other variables were not significant. Conclusion: Although quality of life of people with mild cognitive impairment is significantly decreased, Caregiver burden did not increase during COVID19 confinement. No conflict of interest

Autoantibodies Against Type I IFNs in Patients with Ph-Negative Myeloproliferative Neoplasms

Background. The classic Ph-negative myeloproliferative neoplasms (MPN) are a group of clonal haematopoietic disorders, including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), whose shared and diverse phenotypic signatures are caused by a dysregulated JAK/STAT signal transduction because of acquired somatic mutations. It has been demonstrated that autoimmune diseases and MPN can be associated (Kristinsson et al., Haematologica. 2010 Jul;95(7):1216-20.), suggesting a common background of immune dysregulation (Barosi, Curr Hematol Malig Rep. 2014 Dec;9(4):331-9). SARS-CoV-2 infection displays extreme inter-individual clinical variability, ranging from silent infection to lethal disease. It has been described that at least 10% of patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia have neutralizing autoantibodies (AAbs) against type I IFNs, that precede SARS-CoV-2 infection (Bastard et al., Science. 2020 Oct 23;370(6515):eabd4585). In this study we searched for AAbs against type I IFNs in a cohort of MPN patients to evaluate the prevalence of these AAbs in the MPN population and to check for clinical correlations, including severity of COVID-19. Methods. Plasma samples from consecutively referred MPN patients were prospectively collected between November 2020 and June 2021 and frozen at -30°C immediately after collection. Levels of AAbs against type I IFN subtypes including IFNs alpha, beta and omega were measured using the enzyme-linked immunosorbent assay (ELISA) and a neutralization assay, as previously reported (Bastard et al., Science. 2020 Oct 23;370(6515):eabd4585;Moreews et al., Sci Immunol. 2021 May 25;6(59):eabh1516). Results. We included a total of 219 MPN patients (101 ET, 76 PV, 36 MF and 6 MPN unclassificable). Neutralizing AAbs to type I IFNs were detected in 29 patients (13.2%, 95%CI: 9.1% - 18.5%). Comparing patients with and without AAbs we observed a significant difference in terms of distribution of MPN diagnosis (P = 0.029) and driver mutations (P = 0.019), while we did not observe a difference in terms of age, sex, and treatment (Table 1). Overall, 29 patients (13%) got SARS-CoV-2 infection and 8 of them (28%) required hospitalization due to severe COVID-19. AAbs against type I IFNs were detected in 4 of the 29 SARS-CoV-2 infected patients. A higher rate of hospitalization for severe COVID-19 was observed in patients with AAbs to type I IFNs (2 of 4 patients, 50%) compared to those without these AAbs (6 of 25 patients, 24%), although the difference did not reach a statistical significance (P = 0.300). Conclusions. In this study, we detected a prevalence of AAbs against type I IFNs which is much higher in our MPN cohort (13%) than in the general population (2-3%). We also found a correlation between the presence of AAbs to type I IFNs and both the hematological diagnosis and the driver mutation. Despite a comparable prevalence of SARS-CoV-2 infection between MPN patients with or without AAbs to type I IFNs, we observed a different rate of hospitalization due to severe COVID-19 which is almost twice in those with AAbs against type I IFNs compared to those without these AAbs. However, this difference did not reach a statistical significance, probably because of the low number of SARS-CoV-2 infection in the subgroup of patients with AAbs against type I IFNs. Thus, further studies to analyse the prevalence of AAbs against type I IFNs in patients with MPN, their association with other forms of auto-immunity and severe COVID-19 are warranted. [Formula presented] Disclosures: Arcaini: Gilead Sciences: Research Funding;Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy;Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses;Celgene: Speakers Bureau. Rumi: Novartis, Abbvie: Consultancy.

Polyclonal expansion of TCR VBETA 21.3+ CD4+ and CD8+ T CELLS is a hallmark of multisystem inflammatory syndrome in children

Introduction: At the end of April 2020, European clinicians warned the Public Health Agencies about an abnormal increase of Kawasakilike diseases and myocarditis requiring critical care support in the context of the ongoing COVID-19 epidemic in children. American clinicians also reported a large outbreak of severe inflammation in children following COVID-19 infection, a condition that is now named Pediatric Inflammatory Multisystemic Syndrome (PIMS) or Multisystem Inflammatory Syndrome in children (MIS-C). Objectives: As MIS-C combines clinical features of Kawasaki disease (KD) and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. Methods: We analysed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. Results: We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-a, IFNg, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19;this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV- 2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Conclusion: Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

Student satisfaction with online teaching in times of COVID-19

Higher education is one of the driving forces behind the social and economic development of countries, with the ultimate aim of providing quality academic training. At present, teaching-learning models in virtual environments face a number of important challenges, particularly in the current situation caused by COVID-19. Some of these challenges will be addressed in this study. We worked with 225 third-year undergraduate students in health science degrees over two academic years during the pandemic. The objectives were: (1) to ascertain whether there were significant differences in student satisfaction with the teaching process in the first year of the pandemic (e-learning teaching) vs. the second year (b-learning teaching);(2) to determine whether there were significant differences in academic performance between the two groups. Quantitative research (using a 2x2 factorial design, ANOVA and ANCOVA) and qualitative research (using a comparative design with categorisation analysis) were carried out. The results indicate differences in some aspects of satisfaction and learning outcomes in favour of teaching in the second of the two years. Students rated the use of active methodologies and technological resources positively, although they concluded that their use required more work time. Future studies will seek to compare student satisfaction in other areas of knowledge. © 2021. COMUNICAR. All Rights Reserved.

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-a subtypes and/or IFN-;one had anti-IFN-beta and another anti-IFN-T, but none had anti-IFN-. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

Measles Sclerosing Subacute PanEncephalitis (SSPE), an intriguing and ever-present disease: Data, assumptions and new perspectives.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a rare, non-treatable and fatal neurological complication of measles, still present due to the return of the epidemic linked to the loosening of vaccination policies. Its mechanism remains unexplained. OBJECTIVE: The main objective was to investigate explanatory variables relating to the risk of developing SSPE and its pathophysiology. METHODS: Literature analysis was focused on different varieties of SSPE: perinatal forms, short-incubation forms similar to acute measles inclusion body encephalitis (MIBE), rapidly evolving forms, forms occurring in the immunosuppressed, adult forms, and family forms. In addition, several studies on the parameters of innate immunity and interferon responses of patients were analyzed. RESULTS: Two main data were highlighted: a relationship between the so-called fulminant forms and the prescription of corticosteroids was established. In familial SSPE, two groups were individualized according to the duration of the latency period, prompting an analysis of patient exomes. CONCLUSION: Treatment with corticosteroids should be banned. Knowledge of the genes involved and epigenetics should be useful for understanding the pathophysiology of SSPE and other late-onset neurological infections with RNA viruses.

Early impact of COVID on the activity of a clinical research oncology pharmacy unit at a tertiary care hospital

Background and importance The COVID-19 pandemic has impacted notably on clinical care and led to numerous challenges in the conduct of clinical trials (CT). Hospital pharmacies have had to develop new procedures and strategies to ensure pharmaceutical care, availability of treatment and patient safety. Aim and objectives To analyse the activity in a clinical research oncology pharmacy unit during the COVID-19 period. Material and methods We retrospectively collected the number of site initiation visits (SIV) and pharmaceutical care visits (screening visits, cycle 1 day 1 (C1D1) visits, follow-up visits, medical queries or patient's queries) performed in our unit from January to September 2020. Three phases were differentiated: 'pre-state of emergency' from 1 January to 13 March;'state of emergency' from 14 March to 21 June;and 'post-state of emergency' from 22 June to 30 September. Results During the 'pre-state of emergency' phase, 31 SIV and 273 pharmaceutical care visits were performed. Of these 273, 75 were screenings, 67 C1D1 visits, 26 follow-up visits, 28 medical queries and 77 patient queries. In the 'state of emergency' phase, 47 SIV and 206 pharmaceutical care visits were performed. Of these 206, 69 were screenings, 55 C1D1 visits, 10 follow-up visits, 35 medical queries and 37 patient queries. During the first 90 days of this emergency state, citizens were confined, so remote pharmaceutical care and remote SIV were implemented. 34 screenings were performed and 33 queries about interactions or drug instructions for patients were resolved. Medication was delivered to 139 patients. Four chemotherapy regimens were modified, extending in time administrations of pembrolizumab and cetuximab in four patients. 28 SIV were performed remotely (10 phase I CT, 7 phase II CT and 11 phase III CT). During the last phase, 60 SIV and 365 pharmaceutical care visits were performed. Of these 365, 83 were screenings, 79 C1D1 visits, 42 follow-up visits, 95 medical queries and 66 patient queries. Conclusion and relevance The oncohaematological CT pharmacy unit managed to maintain pharmaceutical activity and care during the state of emergency period due to COVID-19, highlighting a considerable increase in activity in the months after the state of emergency.