Polyclonal expansion of TCR Vbeta 21.3+ CD4+ and CD8+ T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed 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. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, 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 Vß21.3 T cell receptor ß 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. Vß21.3+ 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. Thus, our data suggested that MIS-C is characterized by a polyclonal Vß21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

The immediate impact of Covid-19 infection and the resulting lockdown on nursing home residents / Impact immédiat d'une infection liée à la Covid-19 et du confinement consécutif sur les résidents d'un Ehpad

Introduction: Following the Covid-19 epidemic affecting 76 of the 97 residents (78.3 %) in a French nursing home, we assessed the impact of this cluster period on the physical and psycho-cognitive health of the residents, expecting in particular to observe effects that were dependent on their state of cognitive-behavioural dependence. Methods: We retained twenty-two variables, 5 relating to demographic data, 6 to the specific care linked to Covid-19 infection, 6 to somatic pathologies and psycho-behavioural disturbances before the epidemic and 5 to the period following it. Results: Eleven residents among those diagnosed positive died. Nine were transferred to a Covid unit, and 35 were asymptomatic. The main consequences of the period of infections were in particular behavioural, nutritional, and motor. A history of disruptive behaviours before the appearance of the cluster increased the risk of an aggravation of these behaviours by four (RR = 3.9, IC95 % = 1.38­11.02, p = 0.0042). Twenty per cent of the residents presented under-nutrition at the end of lockdown, but no specific risk factors could be identified. However, states of under-nutrition for the whole of 2020 were significantly more frequent than in 2019, in particular severe cases (χ² = 5.43, p = 0.02). A history of under-nutrition in the previous year increased twofold the likelihood of under-nutrition in the following year (RR = 2.07, IC95 % = 1.14­3.74, p = 0.02). The Covid cluster period also had an effect on the functional autonomy of certain patients. Conclusion: Our main hypothesis relating to cognitive-behavioural dependence was not completely validated. The impact of the occurrence of the cluster remained moderate, in particular because of the care resources afforded by the nursing home. The advantages of a "medicalised" facility, and the problems associated with the restrictions of lockdown, are viewed in the light of ethical considerations.

Introduction: Suite à une épidémie de Covid-19 ayant affecté 76 des 97 résidents d'un Ehpad, nous avons évalué l'impact de cette période de cluster sur la santé physique et psycho-cognitive des résidents pronostiquant notamment une altération en fonction de leur dépendance cognitivo-comportementale. Méthodes: Nous avons retenus vingt-deux variables relatives : aux données démographiques (5) ; aux prises en charge spécifiques liées à l'infection (6) ; aux pathologies somatiques et troubles psycho-comportementaux avant l'épidémie (6) et après la période de cluster (5). Résultats: Onze résidents diagnostiqués positifs sont décédés. Neuf ont été transférés en unité Covid et 35 étaient asymptomatiques. Les troubles consécutifs à la période de cluster concernaient la majoration des comportements perturbateurs et la dénutrition lorsque des antécédents existaient déjà (respectivement : RR = 3,9, IC95 % = 1,38­11,02, p = 0,0042 ; RR = 2,07, IC95 % = 1,14­3,74, p = 0,02), ainsi que la réduction des capacités motrices. Nous n'avons pu objectiver d'autres facteurs explicatifs spécifiques à ces altérations. Conclusion: Notre hypothèse principale en lien avec la dépendance cognitivo-comportementale n'apparaît pas totalement validée. L'impact de la période de cluster est resté modéré notamment grâce aux moyens médico-soignants dont l'Ehpad disposait. L'avantage d'un dispositif médicalisé et l'inconvénient des restrictions liées au confinement est discuté au regard de questions éthiques.

Recombinant human interleukin-7 reverses T cell exhaustion ex vivo in critically ill COVID-19 patients

BackgroundLymphopenia is a hallmark of severe coronavirus disease 19 (COVID-19). Similar alterations have been described in bacterial sepsis and therapeutic strategies targeting T cell function such as recombinant human interleukin 7 (rhIL-7) have been proposed in this clinical context. As COVID-19 is a viral sepsis, the objectives of this study were to characterize T lymphocyte response over time in severe COVID-19 patients and to assess the effect of ex vivo administration of rhIL-7.ResultsPeripheral blood mononuclear cells from COVID-19 patients hospitalized in intensive care unit (ICU) were collected at admission and after 20 days. Transcriptomic profile was evaluated through NanoString technology. Inhibitory immune checkpoints expressions were determined by flow cytometry. T lymphocyte proliferation and IFN-γ production were evaluated after ex vivo stimulation in the presence or not of rhIL-7. COVID-19 ICU patients were markedly lymphopenic at admission. Mononuclear cells presented with inhibited transcriptomic profile prevalently with impaired T cell activation pathways. CD4 + and CD8 + T cells presented with over-expression of co-inhibitory molecules PD-1, PD-L1, CTLA-4 and TIM-3. CD4 + and CD8 + T cell proliferation and IFN-γ production were markedly altered in samples collected at ICU admission. These alterations, characteristic of a T cell exhaustion state, were more pronounced at ICU admission and alleviated over time. Treatment with rhIL-7 ex vivo significantly improved both T cell proliferation and IFN-γ production in cells from COVID-19 patients.ConclusionsSevere COVID-19 patients present with features of profound T cell exhaustion upon ICU admission which can be reversed ex vivo by rhIL-7. These results reinforce our understanding of severe COVID-19 pathophysiology and opens novel therapeutic avenues to treat such critically ill patients based of immunomodulation approaches. Defining the appropriate timing for initiating such immune-adjuvant therapy in clinical setting and the pertinent markers for a careful selection of patients are now warranted to confirm the ex vivo results described so far.Trial registration ClinicalTrials.gov identifier: NCT04392401 Registered 18 May 2020, http:// clinicaltrials.gov/ct2/show/NCT04392401.

Antibodies against type I interferon: detection and association with severe clinical outcome in COVID-19 patients.

OBJECTIVES: Impairment of type I interferon (IFN-I) immunity has been reported in critically ill COVID-19 patients. This defect can be explained in a subset of patients by the presence of circulating autoantibodies (auto-Abs) against IFN-I. We set out to improve the detection and the quantification of IFN-I auto-Abs in a cohort of critically ill COVID-19 patients, in order to better evaluate the prevalence of these Abs as the pandemic progresses, and how they correlate with the clinical course of the disease. METHODS: The concentration of anti-IFN-α2 Abs was determined in the serum of 84 critically ill COVID-19 patients who were admitted to ICU in Hospices Civils de Lyon, France, using a commercially available kit (Thermo Fisher, Catalog #BMS217). RESULTS: A total of 21 of 84 (25%) critically ill COVID-19 patients had circulating anti-IFN-α2 Abs above cut-off (> 34 ng mL-1). Among them, 15 of 21 had Abs with neutralising activity against IFN-α2, that is 15 of 84 (18%) critically ill patients. In addition, we noticed an impairment of the IFN-I response in the majority of patients with neutralising anti-IFN-α2 Abs. There was no significant difference in the clinical characteristics or outcome of with or without neutralising anti-IFN-α2 auto-Abs. We detected anti-IFN-α2 auto-Abs in COVID-19 patients' sera throughout their ICU stay. Finally, we also found auto-Abs against multiple subtypes of IFN-I including IFN-ω. CONCLUSIONS: We reported that 18% of critically ill COVID-19 patients were positive for IFN-I auto-Abs, whereas all mild COVID-19 patients were negative, confirming that the presence of these antibodies is associated with a higher risk of developing a critical COVID-19 form.