Identification of natural killer markers associated with fatal outcome in COVID-19 patients

IntroductionIncreasing evidence has shown that coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunological response. Previous studies have demonstrated that natural killer (NK) cell dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of NK cell markers as a driver of death in the most critically ill patients.MethodsWe enrolled 50 non-vaccinated hospitalized patients infected with the initial virus or the alpha variant of SARS-CoV-2 with moderate or severe illness, to evaluate phenotypic and functional features of NK cells.ResultsHere, we show that, consistent with previous studies, evolution NK cells from COVID-19 patients are more activated, with the decreased activation of natural cytotoxicity receptors and impaired cytotoxicity and IFN-γ production, in association with disease regardless of the SARS-CoV-2 strain. Fatality was observed in 6 of 17 patients with severe disease; NK cells from all of these patients displayed a peculiar phenotype of an activated memory-like phenotype associated with massive TNF-α production.DiscussionThese data suggest that fatal COVID-19 infection is driven by an uncoordinated inflammatory response in part mediated by a specific subset of activated NK cells

Phenotypic and etiological characterization of sarcoidosis (Episarc study)

La sarcoïdose est une maladie multisystémique dont les manifestations, la gravité et l'évolution clinique sont extrêmement hétérogènes et varient selon les groupes ethniques et socio-démographiques. Pour mieux comprendre cette maladie et améliorer la prise en charge des patients, nous avons examiné l'état actuel des connaissances, les lacunes et les besoins en matière de recherche dans les domaines clinique, génétique, et environnemental. Nous avons ensuite proposé des pistes de recherche. Tout d’abord, une meilleure caractérisation de la maladie a été réalisée à partir des larges bases de données sanitaires qui offrent une opportunité unique dans l’étude des maladies rares. Ces études montrent que, même si la sarcoïdose est une maladie rare d’assez faible prévalence, elle a un impact socio et médico économique sur la vie personnelle, professionnelle et sur la perte de revenus des malades atteints. Elles rapportent aussi que la sarcoïdose est associée à de nombreuses comorbidités générales (comme l’obésité), néoplasique, hématologiques et auto immunes. Cependant, ces résultats sont à prendre avec les limites de bases de données dont la qualité des variables n’est pas contrôlable. Ensuite, au sein de la cohorte nationale EPISARC, la sarcoïdose a été caractérisée par l’identification que nous avons réalisée à l’aide d’une méthodologie avancée de 5 phénotypes distincts de la maladie. Ces phénotypes mettaient en évidence des atteintes d’organes différents. Ils étaient aussi en partie déterminés par des variables socio-démographiques (sexe, origines géographiques) ou environnementales (catégories socioprofessionnelles). Toujours dans la cohorte EpiSarc, nous avons déterminé les facteurs environnementaux professionnels associés à l’existence d’une sarcoïdose. Par rapport à la population générale, parmi les patients atteints de sarcoïdose, les ouvriers étaient les plus représentés. Cela suggère que l'exposition anormale aux particules environnementales peut être à l’origine de l’apparition des granulomes. Cette hypothèse environnementale étant un des axes principaux à développer dans la recherche étiologique au cours de la sarcoïdose et dans la mise en œuvre de mesures de prévention. La poursuite de l’étude de l’exposome en lien avec le génotype et les phénotypes permettrait d’améliorer la compréhension des mécanismes étiologiques au cours de la sarcoïdose et la prise en charge thérapeutique mais aussi préventive.Sarcoidosis is a multisystemic disease with extremely heterogeneous manifestations, severity and clinical course, varying between ethnic and socio-demographic groups. To better understand this disease and improve patient outcomes, we reviewed the current state of knowledge, research gaps and needs in the clinical, genetic and environmental domains. We then proposed some avenues of research. First, a better characterisation of the disease was achieved using large health databases that offer a unique opportunity in the study of rare diseases. These studies show that, although sarcoidosis is a rare disease of relatively low prevalence, it has a socio-economic impact on personal and professional life and on the loss of income of those affected. These studies also report that sarcoidosis is associated with numerous general (such as obesity), neoplastic, haematological and autoimmune co-morbidities. However, these results must be taken with the limits of databases whose variable quality is not controllable... Then, within the national EPISARC cohort, sarcoidosis was characterised by the identification of 5 distinct phenotypes of the disease based on the difference in the involved organs. These phenotypes were also partly determined by socio-demographic variables (sex, geographical origins) or environmental variables (socio-occupational categories). Also, in the EPISARC cohort, we determined the occupational environmental factors associated with the existence of sarcoidosis. Compared to the general population, sarcoidosis patients were more likely to be blue collar workers. This could be explained by the suggestion that abnormal exposure to environmental particles may be the cause of granuloma development. This environmental hypothesis is one of the main axes to be developed in the etiological research of sarcoidosis and in the actuation of preventive measures. Further study of the exposome - but also of the link with genotype - in relation to phenotypes using current genetic, epigenetic and immunological tools as well as study approaches that integrate environmental exposures and precise clinical phenotyping would improve the understanding of etiological mechanisms in sarcoidosis with a view to prevention

Giant-cell arteritis-related mortality in France: A multiple-cause-of-death analysis

International audienceOBJECTIVES: Giant-cell arteritis (GCA) is a large vessel vasculitis. Data regarding mortality are controversial. We describe the mortality data of the French death certificates for the period of 2005 to 2014.METHODS: Using multiple-cause-of-death (MCOD) analysis, we calculated age-adjusted mortality rates for GCA, examined differences in mortality rates according to age and gender and analyzed the underlying causes of death (UCD).RESULTS: We analyzed 4628 death certificates listing a diagnosis of GCA as UCD or non-underlying cause of death (NUCD). The mean age of death was 86 (±6.8) years. The overall age-standardized mortality rate among GCA patients was 7.2 per million population. Throughout the study period, the mean age of death was significantly increased (r = 0.17, p  1 in GCA-associated mortality compared with the general population mortality was observed for tuberculosis, pneumonia and cardiovascular diseases.CONCLUSION: In this analysis of French death certificates mentioning GCA, we observed a stable standardized mortality rate between 2005 and 2014. The most frequent associated diseases were cardiovascular diseases and infections

Clinical phenotypes of extrapulmonary sarcoidosis: an analysis of a French, multi-ethnic, multicentre cohort

International audienceSarcoidosis is a rare disease of unknown cause with wide heterogeneity in clinical features and outcomes. We aimed to explore sarcoidosis phenotypes and their clinical relevance with particular attention to extrapulmonary subgroups. The Epidemiology of Sarcoidosis (EpiSarc) study is a French retrospective multicentre study. Sarcoidosis patients were identified through national hospitalisation records using appropriate codes from 11 hospital centres between 2013 and 2016 according to a standardised protocol. Medical charts were reviewed. The phenotypes of sarcoidosis were defined using a hierarchical cluster analysis. A total of 1237 patients were included (562 men and 675 women). The mean age at sarcoidosis diagnosis was 43.5±13 years. Hierarchical cluster analysis identified five distinct phenotypes according to organ involvement and disease type and symptoms: 1) erythema nodosum, joint involvement and hilar lymph nodes (n=180); 2) eye, neurological, digestive and kidney involvement (n=137); 3) pulmonary involvement with fibrosis and heart involvement (n=630); 4) lupus pernio and a high percentage of severe involvement (n=41); and 5) hepatosplenic, peripheral lymph node and bone involvement (n=249). Phenotype 1 was associated with being European/Caucasian and female and with non-manual work, phenotype 2 with being European/Caucasian, and phenotypes 3 and 5 with being non-European/Caucasian. The labour worker proportion was significantly lower in phenotype 5 than in the other phenotypes. This multicentre study confirms the existence of distinct phenotypes of sarcoidosis, with a non-random distribution of organ involvement. These phenotypes differ according to sex, geographical origin and socioprofessional category

Workload, well-being and career satisfaction among French internal medicine physicians and residents in 2018

International audienceOBJECTIVES:This work aimed to study the prevalence and risk factors associated with well-being and career satisfaction among French internal medicine physicians and residents.METHODS:A total of 1689 French internal medicine physicians or trainees were surveyed to evaluate their workload, well-being and career satisfaction during February 2018.RESULTS:The response rate was 620/1689 (37%). The mean age of the participants was 37 years (±12); 49% of the participants were female, 27% worked in the Paris area, 74% worked in a university hospital and 49% were residents. Sixty-six per cent of the responders were satisfied with their work, and 66% would choose the internal medicine specialty again. However, 71% of the responders worked more than 50 hours a week, 21% worked more than 60 hours a week and 70% believed that they did not have enough time for personal/family activities. Twenty-five per cent of the responders had at least one sign of burnout (19% of the physicians in practice and 32% of the residents). Compared with the graduate physicians in practice, the residents worked more hours a week, had more activities at night, spent more time on administrative tasks, had a worse global appreciation of their work and felt that their work was less meaningful. In multivariate analysis, the factors associated with global satisfaction at work were autonomy and meaningful work.CONCLUSIONS:French internal medicine physicians have a high rate of career satisfaction. However, residents have a higher workload, less time for personal/family activities and feel that their work is less meaningful

Persistent risk of adult T-cell leukemia/lymphoma after neonatal HTLV-1 infection through exchange transfusion

International audienceA 36-year-old Caucasian male presented with adult T-cell leukemia/lymphoma (ATL). HTLV-1 contamination was attributed to a neonatal exchange transfusion. Remission was achieved but 11 years later he presented with symptoms suggesting ATL relapse. Molecular studies of T-cell clonality and virus integration sites revealed a clonal disease, distinct from the first tumor

Foetal exposure to heavy metals and risk of atopic diseases in early childhood

International audienceBackground: Accumulating evidence suggests that in utero exposures can influence the development of the immune system and thus contribute to disease development. Studies investigating the association between prenatal exposures to heavy metals and atopic diseases, however, are scarce.Methods: Children from the EDEN birth cohort were prospectively followed up using parental questionnaires with validated questions on asthma, allergic rhinitis, eczema, and food allergy symptoms. The questionnaires were administered every 4 months during the children's first year, and then every year until the age of 5, with a final survey at the age of 8. Serum concentrations of lead (Pb), cadmium (Cd), and manganese (Mn) were assessed in maternal blood samples collected during mid-pregnancy and in cord blood of 651 mother-children pairs. Hazard ratios (HR) for the incidence of each atopic disease in relation to the exposure to metals were calculated using Cox proportional hazard models.Results: Levels of Cd in cord blood were associated with greater risk of asthma (hazard ratio [95% confidence interval] for upper vs lower quartile: 1.81 [1.00-3.29]), eczema (1.60 [1.09-2.35]), and food allergy (3.17 [1.36-7.38]), while Mn levels in maternal serum were associated with eczema (1.55 [1.05-2.28]). These associations were similar in males and females and were confirmed using log concentrations of metals as exposures.Conclusions: Our results support the hypothesis that fetal exposure to heavy metals may affect the development of asthma, eczema, and food allergy in childhood and suggest that timing of exposure in utero may have a role in these associations

Efficacité rapide de l'anifrolumab dans le lupus érythémateux cutané réfractaire : une étude prospective de 11 patient atteints de lupus érythémateux systémiques

for the EMSED (Etude des maladies systémiques en dermatologie) study group.International audienceNo abstract availabl

Sentinel Lymph Node Biopsy in Cutaneous Squamous Cell Carcinoma Series of 37 Cases and Systematic Review of the Literature

Cutaneous squamous cell carcinoma (cSSC) is one of the most common skin cancers and can lead to patient death. Early detection of node metastasis is a major goal for dermatologists and oncologists. The procedure sentinel lymph node biopsy has been proposed to improve early detection of node metastasis. The aim of this study was to evaluate the efficacy and impact of this technique on the prognosis of cSSC. A total of 37 patients (Saint Louis Hospital, Paris, France) who had undergone sentinel lymph node biopsy and 290 cases from the literature were analysed. The mean rate of positive sentinel lymph node biopsy was 0.14 [95% CI 0.09–0.22]. However, relapse-free survival and overall survival were not affected by sentinel lymph node status (log-rank test; p = 0.08 and p = 0.31, respectively), suggesting that this procedure is not mandatory in the management of cSSC

BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in systemic lupus erythematosus

International audienceObjectives Our aim was to evaluate systemic lupus erythematosus (SLE) disease activity and SARS-CoV-2-specific immune responses after BNT162b2 vaccination.Methods In this prospective study, disease activity and clinical assessments were recorded from the first dose of vaccine until day 15 after the second dose in 126 patients with SLE. SARS-CoV-2 antibody responses were measured against wild-type spike antigen, while serum-neutralising activity was assessed against the SARS-CoV-2 historical strain and variants of concerns (VOCs). Vaccine-specific T cell responses were quantified by interferon-γ release assay after the second dose.Results BNT162b2 was well tolerated and no statistically significant variations of BILAG (British Isles Lupus Assessment Group) and SLEDAI (SLE Disease Activity Index) scores were observed throughout the study in patients with SLE with active and inactive disease at baseline. Mycophenolate mofetil (MMF) and methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody response (β=−78, p=0.007; β=−122, p<0.001, respectively). Anti-spike antibody response was positively associated with baseline total immunoglobulin G serum levels, naïve B cell frequencies (β=2, p=0.018; β=2.5, p=0.003) and SARS-CoV-2-specific T cell response (r=0.462, p=0.003). In responders, serum neutralisation activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients.Conclusion MMF, MTX and poor baseline humoral immune status, particularly low naïve B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating patients with SLE who might need adapted vaccine regimens and follow-up