Skewed pretransplant lymphocytes subpopulations correlate with opportunistic infection onset within the first two years following kidney transplantation

IntroductionAfter kidney transplantation (KT), there is no reliable assessment of the immunosuppressive state. We analysed pre-KT T-, B- and NK-cell populations in relation to the occurrence of opportunistic infections (OI) or acute rejection (AR) after KT.MethodsWe included 422 adult KT recipients from 01/2016 to 09/2020. Immune cells were analysed using flow cytometry in 283 recipients before KT in three groups: AR, OI or no event within 24 months after KT.ResultsThere were 49 recipients in the OI group, 44 in the AR group and 190 in the control group. Before KT, higher absolute counts and percentages of NK cells (p=0.001 and p=0.007 respectively), elevated absolute counts of plasmablasts and CD21-CD38- B cells (age-associated B cells) (p=0.045 and p=0.028 respectively), and a lower proportion of CD3+ T cells (p=0.022) were independently associated with the occurrence of OI within two years following kidney transplantation (KT). In recipients with OI occurring before three months, only absolute count of NK cells before KT remained independently associated with the occurrence of OI (p=0.002). None of the studied immune cell population was associated with AR.ConclusionOur results suggest that higher levels of pretransplant NK cells and age-associated B cells are correlated with the occurrence of OI within two years after KT. This result may improve stratification of individualized infectious risk prior to KT

Caractéristiques et prévention des infections du sujet immunodéprimé : apport de la recherche clinique dans l’évolution des pratiques

By definition, the immunocompromised patient is characterized by one or more deficiencies in his/her immune system and is therefore more challenged by the infectious risk. Immunocompromised individuals are exposed both to community-acquired and nosocomial infections. Indeed, despite advances in the management of cancer, HIV infection and organ transplantation, infection remains one of the main causes of mortality in these immunocompromised populations. Controlling the risk of infection is a key element in the management of the immunocompromised patient, and many preventive strategies exist today, such as immunization against vaccine-preventable diseases and drug prophylaxis, as with cotrimoxazole and valganciclovir, respectively, for pneumocystis pneumonia and CMV infection.Optimizing practices and recommendations can only be achieved through rigorously conducted clinical research studies, from bedside to bench.The aim of this PhD thesis is to present the methodology and results of three clinical research projects designed to answer a pertinent clinical question and to improve the management of infectious risk in three different immunosuppressive settings: sickle cell disease, kidney transplantation and treatment with chimeric antigen receptor T cells (CAR-T) in B cell malignancies.In the first study, the immunogenicity of polysaccharide and conjugate pneumococcal vaccines was assessed in a randomized, phase II, open-label trial in adult sickle cell patients. The study showed that, as for other immunocompromised populations, the 13-valent conjugate vaccine offers better immunogenicity than the polysaccharide vaccine alone. Indeed, in current recommendations, the conjugate vaccine has replaced the polysaccharide vaccine in the immunization strategy for immunocompromised patients, including sickle-cell patients, in France and worldwide.In the second study, a cohort of kidney transplant patients was retrospectively evaluated over a 10-year period, with the aim of comparing the incidence, characteristics and impact on patient and graft survival of late-onset opportunistic infections (OIs), occurring after the first year of transplantation, compared with early OI, in the first year after transplantation. While preventive strategies for early OIs after renal transplantation are well standardized, there are no recommendations for the prevention of late OIs. We were able to demonstrate in this large cohort that late-onset OIs are predominantly composed of herpes zoster and pneumocystis jirovecii pneumonia and are associated with a younger age at transplantation than patients with early-onset OIs. Late infection was not a risk factor for patient mortality or graft loss, only advanced age was associated with poorer survival. This study therefore suggests that prophylactic strategies beyond the first year of transplantation should be considered and evaluated in prospective studies, such as lifelong cotrimoxazole, or systematic vaccination of transplant recipients with inactivated herpes zoster vaccine.The third study assessed the evolution over time of prophylactic regimens against invasive fungal infections (IFI) in patients treated with chimeric antigen receptor T lymphocytes (CAR-T cells) for B cell malignancies in a large retrospective cohort study. The clinical finding is that overall, the incidence of IFI in this population is low, hence the importance of targeted rather than large-scale prophylaxis, to avoid antifungal toxicities and to prevent the emergence of microbial resistance. We demonstrated that the switch from large-scale prophylaxis between 2016 and 2020 to an individualized strategy for IFI, targeting individual risk factors, between 2000 and 2023, was not associated with an increase in the number of IFI.Par définition, le sujet immunodéprimé est celui qui présente une ou plusieurs failles dans son système immunitaire, et par conséquence est plus exposé au risque infectieux. Le patient immunodéprimé est exposé à la fois à des infections communautaires et nosocomiales, comme les pneumopathies et les bactériémies, mais aussi à des infections opportunistes, favorisées par l’immunodépression acquise. En effet, malgré les progrès dans la prise en charge des pathologies à l’origine de l’immunodépression, l’infection reste une des causes principales de mortalité chez le patient immunodéprimé. La maitrise du risque infectieux est un élément clef dans la prise en charge du patient immunodéprimé. L'optimisation des pratiques ne peut se faire que à partir d’une recherche clinique conduite de façon rigoureuse et adaptés aux questions posées.L’objectif de cette thèse de science sur travaux est de présenter la méthodologie et les résultats de trois projets de recherche clinique, dont le but est de répondre à une question clinique et d’améliorer la prise en charge du risque infectieux dans trois domaines : la drépanocytose, la transplantation d’organe et le traitement par lymphocytes T à récepteur antigénique chimérique (CAR-T) dans les hémopathies B.Dans le première étude, l’immunogénicité vaccinale des vaccins polysaccharidique et conjugué contre le pneumocoque est évaluée dans une étude randomisée, de phase II, en ouvert, chez des patients drépanocytaires adultes. Il est démontré que, comme dans d’autres populations d’immunodéprimés, le vaccin conjugué 13-valent présente une meilleure immunogénicité comparée au vaccin polysaccharidique seul. En effet, dans les recommandations en vigueur actuellement, le vaccin conjugué a remplacé le vaccin polysaccharidique dans la stratégie d’immunisation du patient immunodéprimé, y compris le patient drépanocytaire, en France et dans le monde.Dans la deuxième étude, une cohorte de patients transplantés rénaux est évaluée rétrospectivement dans un intervalle de temps de 10 ans, pour comparer l’incidence, les caractéristiques et l’impact sur la survie du patient et du greffon des infections opportunistes (IO) tardives (survenues après la première année de greffe), en comparaison avec les mêmes infections survenues précocement, dans l’année après la greffe. Or que les stratégies de prévention de l’IO précoce après greffe rénale sont bien standardisées, il n’existe pas de recommandations pour la prévention des IO tardives. Nous avons pu démontrer que les IO tardives sont composées en majorité de zona et de pneumocystoses, et sont associée avec un âge plus jeune à la greffe que les patients présentant une IO précoce. L’infection tardive n’était pas un facteur de risque de mortalité du patient ni de perte du greffon, seulement l’âge avancée était associé à une moins bonne survie. Cette étude suggère que des stratégies prophylactiques s’étendant au-delà de la première année de greffe doivent être prises en compte et évaluée dans des études prospectives, comme la poursuite a vie ou la reprise du cotrimoxazole, ou encore la vaccination systématique des transplantés avec le vaccin inactivé contre le zona.La troisième étude a évalué l’évolution dans le temps de la prophylaxie des infections fongiques invasives chez les patients traités par lymphocytes T à récepteur antigénique chimérique (CAR-T cell) pour une hémopathie B dans une large étude rétrospective de cohorte. Le constat clinique est celui d’une faible incidence des infections fongiques invasives dans cette population, d’où l’intérêt d’une prophylaxie ciblée et non à large échelle, pour éviter les toxicités des antifongiques et prévenir l’émergence de résistance microbienne. Nous avons en effet démontré que le passage d’une prophylaxie à large échelle, entre 2016- 2020 à une stratégie individualisée, ciblant les facteurs de risque du patient entre 2000 et 2023, n’était pas associé à une augmentation du nombre d’infections fongiques invasives

Gram-positive bacterial resistance: future treatment options

Gram-positive infections are a major burden on patients and healthcare systems globally, and the need to treat these infections correctly in an empirical manner has become paramount. Further complicating this changing etiology is the emergence of resistant strains which are no longer predictably susceptible to standard first-line antimicrobials such as oxacillin or vancomycin. Thus, new agents such as linezolid have been developed to alleviate the 'guesswork' of initial empirical prescribing in infections where Gram-positive pathogens may be present. Future agents also being developed for multiresistant Gram-positive infections include evernimicin antibiotics, daptomycin, oritavancin, glycylcyclines and novel broad-spectrum cephalosporins; however, these are still in the development phase

Relevance of EORTC Criteria for the Diagnosis of Invasive Aspergillosis in HIV-Infected Patients, and Survival Trends Over a 20-Year Period in France

International audienceBACKGROUND: Before the advent of combination antiretroviral therapy (cART), roughly 50% of cases of invasive aspergillosis (IA) associated with human immunodeficiency virus (HIV) infection involved individuals without classical predisposing host factors, and the median survival time was \textless4 months after diagnosis. We examined if the situation evolved over time using the revised European Organisation for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC) definition and analyzed survival trends after diagnosis over 20 years. METHODS: A data review committee evaluated 342 medical records that mentioned IA in the French Hospital Database on HIV. Validated cases were classified as fulfilling the EORTC criteria or otherwise as "HIV-related IA." Three periods were analyzed: pre-cART (before 1996), cART era prevoriconazole (1996-2001), and 2002-2011. RESULTS: Among 242 validated cases of IA, 124 (51%) fulfilled the EORTC criteria (EORTC-IA) and 118 (49%) were classified as "HIV-related," with similarly low CD4 cell counts in both groups. The proportion of EORTC-IA cases remained stable across the 3 periods (50%, 48%, and 54%, respectively). The 3-month survival rate improved after the advent of cART (38% vs 69%), with no difference between EORTC-IA and HIV-related IA (hazard ratio [HR], 1.2 95% confidence interval [CI] \0.7-1.8\). Voriconazole exposure decreased mortality in 2002-2011 (HR, 0.1 95% CI [0.01-0.8]). CONCLUSIONS: In the cART era, EORTC criteria, developed for use in hematology/oncology, still applied to only half the cases diagnosed among HIV-infected patients. A rapid diagnosis of IA is paramount to improve survival. For patients who do not fulfill the EORTC definition, we suggest that the addition of "HIV infected with a CD4 count \textless100 cells/µL" to the EORTC host criteria be validate