11 research outputs found
Caractérisation des lymphocytes effecteurs CX3CR1+ et de leur recrutement intestinal au cours de l'infection VIH-1 sous traitement antirétroviral
No full textThe gut is a major site of viral reservoir persistence during HIV-1 infection, which stands as an obstacle toward the reach of HIV remission. This reservoir is associated with an incomplete restoration of T CD4+ lymphocytes locally, a gut-barrier dysfunction, and an increase of bacterial translocation and local inflammation, despite effective prolonged antiretroviral therapy.Effector cellular immune response is crucial for infection control. HIV-1 induces a loss of intestinal resident memory lymphocytes and an increase in blood cells with a gut-tropic recirculating profile. CX3CR1-CX3CL1 axis may be a key to the recruitment of tissular effector cells but seem to be impacted by the chronic HIV-1 infection, even under ART, with an increase of circulating CX3CR1+ cells and an increase in soluble CX3CL1 in the plasma. Here, we aimed to characterize the effector CX3CR1+ cells in both the blood and the gut, search for environmental factors that could modulate this chemotactic axis and assess the impact of this axis modulation in the gut viral reservoir in a cohort of people living with HIV (PLWH) under long term ART.In a first work on γδ Vδ1 T cells, which frequencies were increased in the blood of PLWH, we highlighted the clonal expansion of a highly cytotoxic effector population of Vδ1 expressing CX3CR1 with a recirculating cell-like phenotype. This population correlated with HIV-1 infection reduction in the associated blood or duodenal compartment. We showed that cytomegalovirus (CMV) residual replication during HIV-1 infection was a major trigger for CX3CR1+ CD8 and Vδ1 T cells expansion, but this effect was in an interplay of tissular microbiome changes that were also associated with CMV.In a second work, we showed that CX3CR1+ CD8 T cells were increased in frequency in both the blood and the gut. However, in the colon this increase was associated with a loss of resident memory CX3CR1+ CD8 T cells with higher effector functions. This population was associated with lower viral reservoir, especially for with the fraction expressing CD39. CD8+ CX3CR1+ TRM expressed less exhaustion markers than non-TRM. The increase of CX3CR1+ CD8 T cells in the blood was correlated with CMV IgG index. Ex vivo, HIV-1 and CMV could induce the expression of ADAM10 and ADAM17 metalloproteinases on intestinal epithelial cells. We hypothesize that those metalloproteinases could participate to epithelial cleavage of CX3CL1 and CX3CR1+ CD8 T cells recirculation.L'intestin est le siège d'un réservoir viral majeur au cours de l'infection par le VIH-1, qui constitue un obstacle à l'obtention d'une rémission de l'infection. Ce réservoir est associé à un défaut de restauration de lymphocytes T CD4+ intestinaux, à une dysfonction de la barrière immunitaire intestinale, avec une augmentation des translocations micobiennes et une inflammation locale et systémique persistante, malgré un traitement antirétroviral efficace suivi de façon prolongée.La réponse immunitaire cellulaire effectrice joue un rôle crucial dans le contrôle de l'infection. Il a notamment pu être observé une perte des lymphocytes résidents mémoires (TRM) intestinaux et une augmentation de cellules ayant des marqueurs de tropisme pour l'intestin dans la circulation. L'axe de chimiotactisme CX3CR1-CX3CL1 semble être une voie majeure dans le recrutement de cellules effectrices tissulaires mais semble impacté par l'infection chronique par le VIH-1 même sous traitement, avec une augmentation des cellules circulantes CX3CR1+ et une augmentation de la fraction soluble de CX3CL1 dans le plasma. Dans ce travail, nous avons cherché à caractériser les cellules effectrices exprimant CX3CR1 dans le compartiment sanguin et intestinal, à étudier les facteurs environnementaux pouvant moduler cet axe de chimiotactisme et à évaluer l'impact de la modulation de cet axe sur le réservoir intestinal dans une cohorte de personnes vivant avec le VIH-1 (PvVIH) sous traitement antirétroviral au long cours.Dans un premier travail portant sur les lymphocytes γδ Vδ1 dont la fréquence est augmentée dans le sang des PvVIH, nous avons pu mettre en évidence que cette expansion de lymphocytes Vδ1 se faisait de façon clonale parmi une population particulièrement cytotoxique et exprimant CX3CR1 avec notamment un profil de cellules recirculantes intestinales. Ces lymphocytes Vδ1 CX3CR1+ cytotoxiques étaient corrélés à une moindre fréquence de lymphocytes T CD4+ avec une transcription résiduelle d'ARN VIH-1 dans le compartiment sanguin ou intestinal. Nous avons également pu montrer que la réplication résiduelle du cytomégalovirus (CMV) au cours de l'infection par le VIH-1 participait de façon majeure à l'expansion des populations de lymphocytes T CD8 et Vδ1 exprimant CX3CR1, mais que cet effet était en inter-relation avec les altérations du microbiote intestinal et transloqué.Dans un second travail, nous avons montré que les LT CD8 CX3CR1+ étaient augmentés en fréquence à la fois dans le sang et dans l'intestin. Cependant, dans le colon cette augmentation concernait des LT CD8 CX3CR1+ non-résidents mémoires (TRM) au détriment d'une perte des TRM CD8 CX3CR1+. Les TRM CD8+ CX3CR1+ avaient un profil de cytotoxicité et de production de cytokines pro-inflammatoire élevé et présentaient moins d'expression de marqueurs d'épuisement lymphocytaire que les non-TRM. Les TRM CD8+ CX3CR1+, notamment la population CD39+, étaient associés à un réservoir ADN VIH plus faible dans le colon, La perte des TRM CD8+ CX3CR1+ au profit de non-TRM, moins fonctionnelles, pourrait donc contribuer à la persistance du VIH-1. L'augmentation des LT CD8 CX3CR1+ sanguins était corrélée à l'index sérologique IgG du CMV. Ex-vivo, le VIH-1 et le CMV pouvaient induire l'expression des métalloprotéases ADAM10 et ADAM17 sur les cellules épithéliales intestinales, dont nous faisons l'hypothèse qu'elles pourraient participer au clivage épithélial de CX3CL1 et à un défaut de recrutement des LT CD8 CX3CR1+
Critically ill SARS-CoV-2-infected patients are not stratified as sepsis by the qSOFA
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Bordetella hinzii : an Unusual Pathogen in Human Urinary Tract Infection
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When to investigate for secondary hyperhidrosis: data from a retrospective cohort of all causes of recurrent sweating
No full textBackground: Identification of underlying diseases is crucial for secondary hyperhidrosis management, but data are lacking to guide appropriate investigation. Objective: To describe aetiologies of recurrent sweating in a hospital setting and the diagnostic performance parameters of their respective clinical/biological features. Patients and Methods: We performed a monocentric evaluative study in a tertiary care centre. Patients with recurrent generalised sweating were selected via the Clinical Data Warehouse (CDW) by screening all electronic hospital documents from the year 2018 using a keyword-based algorithm. All in and out-patients aged ≥ 18 years having reported recurrent sweating for at least 2 weeks in 2018 were included, with a minimum one-year follow-up after symptoms’ onset. Results: A total of 420 patients were included. Over 130 different aetiologies were identified; 70 patients (16.7%) remained without diagnosis. Solid organ cancers (14.3% with 13 lung cancers), haematologic malignancies (14.0% with 35 non-Hodgkin’s lymphomas) and Infectious Diseases (10.5% including 13 tuberculosis) were the most frequent diagnoses. Other aetiologies were gathered into inflammatory (16.9%) and non-inflammatory (27.6%) conditions. To distinguish non-inflammatory and undiagnosed hyperhidrosis from other causes, fever had a specificity of 94%, impaired general condition a sensitivity of 78%, and C-reactive protein (CRP) > 5.6 mg/l a positive predictive value of 0.86. Symptoms’ duration over 1 year was in favour of non-infectious and non-malignant causes (94% specificity). Conclusions: KEY MESSAGES: In a hospital setting, malignancies and infections are the most frequently associated diseases, but 1/5 remain without diagnosis. Fever is a specific but not sensitive sign to distinguish inflammatory conditions. Over 1 year duration of symptoms significantly reduce the probability of malignancy or infection as the underlying diagnosis
Rotavirus meningitis in an adult with transient aphasia
No full textInternational audienceWe identified an additional case of documented Rotavirus meningitis in an adult with full medical history. A previously healthy 37-year-old patient presented herself for transient aphasia associated with fever and headaches at the end of a one-week history of gastroenteritis. Cerebrospinal fluid (CSF) analysis revealed lymphocytic meningitis, and treatment with aciclovir was initiated. Rotavirus A reverse transcription-polymerase chain reaction (RT-PCR) was positive in CSF and the patient's stools in favor of Rotavirus meningitis. Testing for other viruses was negative. Magnetic resonance imaging (MRI) showed no signs of encephalitis. Aphasia was resolutive in less than 12 hours, and no neurological symptoms relapsed. All symptoms evolved favorably despite aciclovir discontinuation.Viral sequencing methods have recently identified unexpected viruses as potential causative agents in meningitis, including Rotavirus. We confirm the detectability of Rotavirus in the analysis of CSF in the context of Rotavirus gastroenteritis in an adult. This case suggests postviral headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) syndrome may be linked to previously undetected direct viral infection of the central nervous system.Therefore, clinicians should consider Rotavirus meningitis in diagnosing meningitis associated with gastroenteritis in adults
Cytotoxic CX3CR1+ Vδ1 T cells clonally expand in an interplay of CMV, microbiota, and HIV-1 persistence in people on antiretroviral therapy
No full textInternational audienceVδ 1 γδ T cells are key players in innate and adaptive immunity, particularly at mucosal interfaces such as the gut. An increase in circulating Vδ 1 cells has long been observed in people with HIV-1, but remains poorly understood. We performed a comprehensive characterization of Vδ 1 T cells in blood and duodenal intra-epithelial lymphocytes, obtained from endoscopic mucosal biopsies of 15 people with HIV-1 on antiretroviral therapy and 15 HIV-seronegative controls, in a substudy of the ANRS EP61 GALT study (NCT02906137). We deciphered the phenotype, functional profile, single-cell transcriptome and repertoire of Vδ 1 cells and unraveled their relationships with the possible triggers involved, in particular CMV and microbiota. We also assessed whether Vδ 1 T cells may play a role in controlling the HIV-1 reservoir. Vδ 1 T cells were mainly terminally differentiated effectors that clonally expanded in the blood with some trafficking with the gut of people with HIV-1. Most expressed CX3CR1 and displayed a highly cytotoxic profile, but low cytokine production, supported by a transcriptomic shift towards enhanced effector lymphocytes. This expansion was associated with CMV status and markers of occult replication, but also with changes in the duodenal and blood-translocated microbiota. Cytotoxic, but not IFN-γ-producing, Vδ 1 T cells were negatively associated with cell-associated HIV-1 RNA in both the blood and duodenal compartments. The increase in Vδ1 T cells observed in people with HIV-1 has multiple triggers, particularly CMV and microbiota, and may in turn contribute to the control of the HIV-1 reservoir
Réforme du 3e cycle et DES de Maladies Infectieuses et Tropicales : quel bilan? Une enquête transversale nationale
No full textInternational audienceIntroductionSince 2017, Infectious and Tropical Diseases (ID), previously a subspeciality, has been established as a full medical specialty in France, placing its course at the same level as other medical specialties. The final year of training grants the new status of Junior Doctor (JD), with the first JDs beginning their training in 2021.MethodsTo evaluate the new ID program, we conducted a cross-sectional survey in 2024 among newly trained ID physicians who had reached at least the JD status.Results63 out of 101 newly trained ID physicians in France responded to our survey, representing nearly all universitary subdivisions. 63% found the JD year aligned with their expectations. 65% were able to spend a semester in a different subdivision or abroad. However, 71% reported having limited time off for personal study, and 29% noted infrequent evaluation during their rotations. Respondents worked an average of 60 hours per week during residency; 41% reported experiencing burnout symptoms at least once, and 40% expressed concerns about their professional future. Despite this, 82% felt adequately prepared for their post-fellowship work by the end of their JD year.ConclusionThe overall satisfaction with ID training was rated 7.3 out of 10. ID degree and JD year implementations were globally wee-received. However, disparities persist among students and across subdivisions. Key concerts were raised regarding the roles and responsabilites of JDs, the quality of teaching, professional support, and work-life balance.IntroductionLa réforme du 3e cycle des études médicales effective depuis 2017 a permis la création d’un nouveau diplôme d’études spécialisées (DES) en Maladies Infectieuses et Tropicales (MIT). Cette réforme s’accompagne notamment d’une dernière phase d’un an, dite de consolidation, introduisant le nouveau statut de Docteur Junior (DJ) qui a pu être expérimenté pour la 1ère fois en 2021.MéthodesAfin d’évaluer la mise en place de ce nouveau DES, nous avons conduit une enquête transversale en 2024 réalisée auprès des personnes ayant au moins atteint le statut de DJ.Résultats63 des 101 sujets concernés ont répondu à l’enquête sur la quasi-totalité des facultés. 63 % des répondants ont déclaré que l’année de DJ correspondait globalement à leurs attentes. 65 % ont pu réaliser une mobilité au cours de leur internat. Cependant, 71 % n’ont que rarement pu prendre des demi-journées de formation personnelle et 29 % n’ont eu que rarement des évaluations de stage. Les répondants déclaraient travailler 60 h hebdomadaires en moyenne ; 41 % ont présenté au moins une fois des signes de burn-out et 40 % ont rapporté des appréhensions vis-à-vis de leur avenir professionnel. Malgré cela, 82 % se sentent prêt pour le post-internat au terme de l’année de DJ et le niveau de satisfaction global a été évalué à 7,3/10.ConclusionLe déroulé du DES MIT et l'année de DJ semblent globalement satisfaisants. Néanmoins, de grandes disparités existent entre les subdivisions et les étudiants.Des points de vigilance sont soulignés, notamment concernant les rôles et activités des DJ, la qualité des enseignements, l'accompagnement professionnel et la qualité de vie
Intact proviruses are enriched in the colon and associated with PD-1+TIGIT− mucosal CD4+ T cells of people with HIV-1 on antiretroviral therapyResearch in context
No full textSummary: Background: The persistence of intact replication-competent HIV-1 proviruses is responsible for the virological rebound off treatment. The gut could be a major reservoir of HIV-1 due to the high number of infected target cells. Methods: We collected blood samples and intestinal biopsies (duodenum, ileum, colon) from 42 people with HIV-1 receiving effective antiretroviral therapy. We used the Intact Proviral DNA Assay to estimate the frequency of intact HIV-1 proviruses in the blood and in the intestinal mucosa of these individuals. We analyzed the genetic complexity of the HIV-1 reservoir by performing single-molecule next-generation sequencing of HIV-1 env DNA. The activation/exhaustion profile of mucosal T lymphocytes was assessed by flow cytometry. Findings: Intact proviruses are particularly enriched in the colon. Residual HIV-1 transcription in the gut is associated with persistent mucosal and systemic immune activation. The HIV-1 intestinal reservoir appears to be shaped by the proliferation of provirus-hosting cells. The genetic complexity of the viral reservoir in the colon is positively associated with TIGIT expression but negatively with PD-1, and inversely related to its intact content. The size of the intact reservoir in the colon is associated with PD-1+TIGIT− mucosal CD4+ T cells, particularly in CD27+ memory cells, whose proliferation and survival could contribute to the enrichment of the viral reservoir by intact proviruses. Interpretation: Enrichment in intact proviruses makes the gut a key compartment for HIV-1 persistence on antiretroviral therapy. Funding: This project was supported by grants from the ANRS-MIE (ANRS EP61 GALT), Sidaction, and the Institut Universitaire de France
Impact of High-Dose Prophylactic Anticoagulation in Critically Ill Patients With COVID-19 Pneumonia
No full textInternational audienceBACKGROUND: Because of the high risk of thrombotic complications (TCs) during SARS-CoV-2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent. RESEARCH QUESTION: What is the incidence of TC in critically ill patients with COVID-19 and what is the relationship between the dose of anticoagulant therapy and the incidence of TC? STUDY DESIGN AND METHODS: All consecutive patients referred to eight French ICUs for COVID-19 were included in this observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high-dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight. RESULTS: Of 538 patients included, 104 patients experienced a total of 122 TCs with an incidence of 22.7% (95% CI, 19.2%-26.3%). Pulmonary embolism accounted for 52% of the recorded TCs. High-dose prophylactic anticoagulation was associated with a significant reduced risk of TC (hazard ratio, 0.81; 95% CI, 0.66-0.99) without increasing the risk of bleeding (HR, 1.11; 95% CI, 0.70-1.75). INTERPRETATION: High-dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill patients with COVID-19 without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results
COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study
No full textInternational audienceBackground: Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.Methods: In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.Findings: Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66-6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46-0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55-3·19, p=0·53).Interpretation: Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases
