Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022

The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced.Peer reviewe

Étude rétrospective multicentrique nationale des aspergilloses cérébrales en France

Introduction : l’aspergillose cérébrale (AC) est une infection fongique rare associée à une mortalité et une morbidité importante. L’objectif de ce travail est de décrire la présentation clinico-mycologique au diagnostic, la prise en charge, l’évolution et le pronostic de l’AC selon le terrain sous-jacent. Matériels et méthodes : nous avons mené une étude rétrospective nationale multicentrique recueillant des données épidémiologiques, cliniques, mycologiques, radiologiques ainsi que des données sur le traitement et l’évolution. Les cas inclus ont été classés en aspergillose invasive prouvée ou probable selon les critères EORTC/MSG publiés en 2008 modifiés par l’ajout du diabète dans les critères d’hôte. L’atteinte cérébrale a été également classée en prouvée ou probable selon des critères histologiques, mycologiques et radiologiques adaptés des critères EORTS/MSG. Résultats : vingt-six patients ayant eu une AC prouvée (73,1%) ou probable (26,9%) entre janvier 2006 et juillet 2017 dans 7 centres français ont été inclus. L’âge médian était de 58 ans [50-71] et 73% des patients étaient des hommes. Les pathologies sous-jacentes étaient les suivantes : hémopathie maligne (19.2%), transplantation d’organe solide (34,6%), diabète (23,1%), pathologie auto-immune sous immunosuppresseurs (3,8%) et granulomatose septique chronique (3,8%). Deux patients avaient comme seul facteur de risque une chirurgie sinusienne récente. Aucun facteur prédisposant n’était retrouvé chez 2 patients. La sensibilité du ß-D-glucane, de l’antigène galactomannane et de la PCR Aspergillus sp sériques était de 87,5%, 50% et 30%, respectivement. L’AC survenait par dissémination hématogène chez 38,5% des patients et par contiguïté à partir d’un foyer de la base du crâne chez 57,7%. Elle était isolée chez 1 patient. L’atteinte par contiguïté était associée à une moins bonne sensibilité de l’antigénémie galactomannane (20% vs 77,8%, p = 0,02) et une plus grande fréquence des complications vasculaires (40% vs 0%, p = 0,02), sans différence en terme de survie. La survie globale était de 76,9% à 3 mois, de 69,2% à 12 mois et de 57,7% aux dernières nouvelles. L’absence d’hémopathie maligne était associée à une meilleure survie à 3 mois. Discussion : bien que moins importante que celle rapportée dans des études précédentes, la mortalité de l’AC reste élevée dans notre série en partie en raison de la difficulté du diagnostic et de la sévérité des pathologies sous-jacentes. L’AC touche des patients présentant une immunodépression d’intensité variable et parfois des patients sans facteur de risque connu. Les modalités optimales de la prise en charge médico-chirurgicale restent à définir

Vaccinologie structurale anti-bunyavirus

Les hantavirus, transmis par contact avec des rongeurs infectés, sont des virus émergents responsables de deux syndromes potentiellement mortels et pour lesquels il n'existe pas de traitement. Connaître l'organisation précise des glycoprotéines à la surface des virions ainsi que les bases moléculaires du mécanisme d'action des anticorps neutralisants est essentiel pour le développement de futurs vaccins et/ou traitements. A la surface des virions, les deux protéines d'enveloppe, Gn et Gc, s'associent en spikes tétramétriques, formant ainsi un maillage carré caractéristique. Ces glycoprotéines, qui sont les seules cibles des anticorps neutralisants, permettent l'entrée du virus dans les cellules cibles par endocytose après interaction avec un récepteur et contrôlent la fusion membranaire. Grâce à une approche combinant la cristallographie aux rayons X et des données issues de la microscopie électronique, nous avons pu obtenir la structure de l'hétérodimère Gn/Gc et construire un modèle de la surface antigénique des virions à une résolution atomique. En raison de l'important degré de conservation des glycoprotéines, nous supposons notre modèle applicable à l'ensemble des hantavirus. Nos résultats révèlent un mécanisme original par lequel Gn contrôle l'insertion de Gc dans la membrane-cible, empêchant ainsi toute fusion prématurée. Dans la deuxième partie du projet, nous avons étudié les structures cristallines de trois anticorps neutralisants humains en complexe avec les glycoprotéines virales. L'analyse de ces structures permet d'identifier des sites de vulnérabilité à la surface des virions et de comprendre le mécanisme de neutralisation de ces anticorps. De plus, nos résultats sont en faveur de l'existence d'un phénomène dynamique de « breathing » des spikes, similaire à celui décrit pour le virus de la dengue. Ces résultats pourront servir au développement de nouvelles stratégies vaccinales ainsi qu'à l'optimisation d'anticorps thérapeutiques.Present worldwide, hantaviruses are rodent-borne emerging viruses associated with two life-threatening syndromes for which no specific treatment is available. To develop them and be ready for future outbreaks, it is essential to have a detailed picture of the virus organization and to understand the molecular mechanism of antibody neutralization, paving the way to develop innovative vaccines. At the surface of the viral particle, the envelope glycoproteins, Gn and Gc, associate in tetrameric spikes forming a characteristic square lattice. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry via receptor-mediated endocytosis and endosomal membrane fusion. Using a hybrid approach combining high resolution X-ray structures of the viral glycoproteins and low-resolution cryo-electron tomography data, we have obtained the structure of the heterodimer Gn/Gc and fitted it into a 11 Å resolution cET map of Tula hantavirus, thus producing an atomic model of the complete surface lattice. Given the high amino acid sequence similarity between the envelope glycoproteins, we expect our model to be valid for all hantaviruses. Our results reveal an in-built mechanism controlling Gc membrane-insertion for fusion, that has not been previously described for other viral fusion proteins. In a second part of the project, we studied the crystal structures of three of neutralizing human antibodies in complex with the viral glycoproteins. Analysis of these structures allowed us to identify vulnerability sites on the spike and provided key information to elucidate the neutralization mechanism of these antibodies. Furthermore, our data support the hypothesis of a "breathing" phenomenon, such as described for dengue virus, and suggest the existence of an original neutralization mechanism where an antibody could capture the spike in an open conformation. These results can be useful for the optimization of therapeutic antibodies and the rational design a pan-hantaviral vaccine

Disease Entities in Mucormycosis

Mucormycosis is an emerging life-threatening fungal infection caused by Mucorales. This infection occurs mainly in immunocompromised patients, especially with hematological malignancy, transplantation, or diabetes mellitus. Rhino-orbito-cerebral and pulmonary mucormycosis are the predominant forms. Interestingly, location is associated with the underlying disease as pulmonary mucormycosis is more frequent in hematological malignancy patients whereas rhino-orbito-cerebral mucormycosis is associated with diabetes. Cutaneous mucormycosis results from direct inoculation, mainly after trauma or surgery. Gastro-intestinal mucormycosis occurs after ingestion of contaminated food or with contaminated device and involves the stomach or colon. Disseminated disease is the most severe form and is associated with profound immunosuppression. Uncommon presentations with endocarditis, osteoarticluar or isolated cerebral infections are also described. Finally, health-care associated mucormycosis is a matter of concern in premature newborns and burn units. Clinical symptoms and CT scan findings are not specific, only the early reversed halo sign is associated with pulmonary mucormycosis. Circulating Mucorales DNA detection is a recent promising diagnostic tool that may lead to improving the diagnosis and prompting therapeutic initiation that should include antifungal treatment, correction of the underlying disease and surgery when feasible

The Hantavirus Surface Glycoprotein Lattice and Its Fusion Control Mechanism

Hantaviruses are rodent-borne viruses causing serious zoonotic outbreaks worldwide for which no treatment is available. Hantavirus particles are pleomorphic and display a characteristic square surface lattice. The envelope glycoproteins Gn and Gc form heterodimers that further assemble into tetrameric spikes, the lattice building blocks. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry via receptor-mediated endocytosis and endosomal membrane fusion. Here we describe the high-resolution X-ray structures of the heterodimer of Gc and the Gn head and of the homotetrameric Gn base. Docking them into an 11.4-angstrom-resolution cryoelectron tomography map of the hantavirus surface accounted for the complete extramembrane portion of the viral glycoprotein shell and allowed a detailed description of the surface organization of these pleomorphic virions. Our results, which further revealed a built-in mechanism controlling Gc membrane insertion for fusion, pave the way for immunogen design to protect against pathogenic hantaviruses.Peer reviewe

Case Report: Immune Checkpoint Blockade Plus Interferon-Γ Add-On Antifungal Therapy in the Treatment of Refractory Covid-Associated Pulmonary Aspergillosis and Cerebral Mucormycosis

Invasive fungal diseases (IFD) still cause substantial morbidity and mortality, and new therapeutic approaches are urgently needed. Recent data suggest a benefit of checkpoint inhibitors (ICI). We report the case of a diabetic patient with refractory IFD following a SARSCoV-2 infection treated by ICI and interferon-gamma associated with antifungal treatment

Histoplasmosis of the Central Nervous System: A Case Series between 1990 and 2019 in French Guiana

International audienceDisseminated histoplasmosis is the most frequent acquired immunodeficiency syndrome-defining illness in French Guiana. Paradoxically, central nervous system (CNS) involvement has been scarcely described. We aimed to identify CNS histoplasmosis in our territory. We conducted an observational, multicentric, descriptive, and retrospective study including patients with proven or probable CNS histoplasmosis according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MGS). The study population consisted of patients admitted in one of the hospitals of French Guiana between January 1, 1990 and December 31, 2019. During the study period, 390 cases of HIV-associated histoplasmosis were recorded, in which six of them had CNS infections with Histoplasma capsulatum. The male to female sex ratio was 0.25, and the median age at diagnosis was 37.5 years. The median CD4 count was 42 cells/mm 3 ([IQR: 29-60]). All patients had disseminated histoplasmosis. Usual signs of meningitis were observed in three patients and focal signs in four patients. One patient had no neurological signs. The median time between the first cerebral symptoms and diagnosis was 22.4 days (IQR 9.5-36.2). Two patients died within a month after diagnosis. In conclusion, few proven CNS localizations of histoplasmosis were observed on 30-year study in French Guiana. This low proportion suggests that the documentation of CNS involvement is often not ascertained for lack of awareness of this particular presentation, and for lack of rapid and sensitive diagnostic tools

European Study of Cerebral Aspergillosis treated with Isavuconazole: an EFISG study

Introduction: Cerebral aspergillosis (CA) is associated with high mortality. According to ECIL-6 and ESCMID guidelines, the recommended first-line treatment for all forms of aspergillosis is voriconazole or isavuconazole. However, little is known about the efficacy and safety of isavuconazole in CA. Methods: We conducted a European multi-centre retrospective study of patients treated with isavuconazole for proven or probable CA between 2014 and 2022 and compared the outcomes to those of weighted control groups from the previously published French national cohort of CA, the Cerebral Aspergillosis Lesional Study. Results: Forty patients from 10 countries were included. The main underlying conditions were hematological malignancies (53%) and solid organ transplantation (20%). Isavuconazole was administered as a first-line treatment to 10 patients, primarily in combination therapy, resulting in control of CA in 70% of these cases. Thirty patients received isavuconazole after a median of 65 days on another therapy, mostly because of side effects (50%) or therapeutic failure (23%) of the previous treatment. Predominantly given as monotherapy, it achieved control of CA in 73% of the patients. Seventeen patients (43%) undergone neurosurgery. When measured, isavuconazole levels were low in cerebrospinal fluid but adequate in serum and brain tissue. Isavuconazole toxicity led to treatment interruption in 7.5% of the patients. Twelve-week mortality was 18%. Comparison with the CEREALS cohort showed a comparable survival in patients receiving isavuconazole or voriconazole as a first line treatment. Conclusion: Isavuconazole appears to be a well-tolerated treatment. Mortality of CA treated with isavuconazole is similar to that reported with voriconazole

New Approaches to Manage Infections in Transplant Recipients: Report From the 2023 GTI (Infection and Transplantation Group) Annual Meeting

International audienceThis year’s GTI (“Groupe Transplantation and Infection”) annual meeting was held in Paris, France in February 2023. This meeting focused on new approaches to manage infectious complications in solid organ and stem cell transplant recipients. In this meeting report, we summarize the presentations and discussions from this annual meeting. Covered topics included new anti-infective agents and non-antibiotic approaches to manage infections due to multidrug-resistant Gram-negative bacteria, staphylococci, and fungal infections, as well as new approaches to manage symptomatic urinary tract infections and asymptomatic bacteriuria in kidney transplant recipients. Innovative approaches are needed to manage infectious complications in transplant recipients, who are at high risk of difficult-to-treat infections and side effects associated with the use of anti-infective agents.No abstract availabl