Recent advances in the understanding and management of mucormycosis [version 1; referees: 2 approved]

Mucormycoses were difficult-to-manage infections owing to limited diagnostic tools and therapeutic options. We review here advances in pathology understanding, diagnostic tools including computed tomography, and serum polymerase chain reaction and therapeutic options

Phenotypic and genotypic characteristics of mastocytosis according to the age of onset.

International audienceAdult's mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutation, while pediatrics disease is mostly limited to the skin and often resolves spontaneously. We prospectively included 142 adult patients with histologically proven mastocytosis. We compared phenotypic and genotypic features of adults patients whose disease started during childhood (Group 1, n = 28) with those of patients whose disease started at adult's age (Group 2, n = 114). Genotypic analysis was performed on skin biopsy by sequencing of c-kit exons 17 and 8 to 13. According to WHO classification, the percentage of systemic disease was similar (75 vs. 73%) in 2 groups. C-kit 816 mutation was found in 42% and 77% of patients in groups 1 and 2, respectively (p<0.001). 816 c-kit mutation was associated with systemic mastocytosis in group 2 (87% of patients with systemic mastocytosis vs. 45% with cutaneous mastocytosis, p = 0.0001). Other c-kit activating mutations were found in 23% of patients with mastocytosis' onset before the age of 5, 0% between 6 and 15 years and 2% at adults' age (p<0.001). In conclusion, pathogenesis of mastocytosis significantly differs according to the age of disease's onset. Our data may have major therapeutic relevance when considering c-kit-targeted therapy

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Performance of the beta-glucan test for the diagnosis of invasive fusariosis and scedosporiosis: a meta-analysis

The (1→3)-β-D-glucan (BDG) is a component of the fungal cell wall that can be detected in serum and used as an adjunctive tool for the diagnosis of invasive mold infections (IMI) in patients with hematologic cancer or other immunosuppressive conditions. However, its use is limited by modest sensitivity/specificity, inability to differentiate between fungal pathogens, and lack of detection of mucormycosis. Data about BDG performance for other relevant IMI, such as invasive fusariosis (IF) and invasive scedosporiosis/lomentosporiosis (IS) are scarce. The objective of this study was to assess the sensitivity of BDG for the diagnosis of IF and IS through systematic literature review and meta-analysis. Immunosuppressed patients diagnosed with proven or probable IF and IS, with interpretable BDG data were eligible. A total of 73 IF and 27 IS cases were included. The sensitivity of BDG for IF and IS diagnosis was 76.7% and 81.5%, respectively. In comparison, the sensitivity of serum galactomannan for IF was 27%. Importantly, BDG positivity preceded the diagnosis by conventional methods (culture or histopathology) in 73% and 94% of IF and IS cases, respectively. Specificity was not assessed because of lacking data. In conclusion, BDG testing may be useful in patients with suspected IF or IS. Combining BDG and galactomannan testing may also help differentiating between the different types of IMI

Guideline adherence and survival of patients with candidaemia in Europe: results from the ECMM Candida III multinational European observational cohort study

© 2022 Elsevier Ltd. All rights reserved.[Background] The European Confederation of Medical Mycology (ECMM) collected data on epidemiology, risk factors, treatment, and outcomes of patients with culture-proven candidaemia across Europe to assess how adherence to guideline recommendations is associated with outcomes.[Methods] In this observational cohort study, 64 participating hospitals located in 20 European countries, with the number of eligible hospitals per country determined by population size, included the first ten consecutive adults with culture-proven candidaemia after July 1, 2018, and entered data into the ECMM Candida Registry (FungiScope CandiReg). We assessed ECMM Quality of Clinical Candidaemia Management (EQUAL Candida) scores reflecting adherence to recommendations of the European Society of Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of America guidelines.[Findings] 632 patients with candidaemia were included from 64 institutions. Overall 90-day mortality was 43% (265/617), and increasing age, intensive care unit admission, point increases in the Charlson comorbidity index score, and Candida tropicalis as causative pathogen were independent baseline predictors of mortality in Cox regression analysis. EQUAL Candida score remained an independent predictor of mortality in the multivariable Cox regression analyses after adjusting for the baseline predictors, even after restricting the analysis to patients who survived for more than 7 days after diagnosis (adjusted hazard ratio 1·08 [95% CI 1·04–1·11; p<0·0001] in patients with a central venous catheter and 1·09 [1·05–1·13; p<0·0001] in those without one, per one score point decrease). Median duration of hospital stay was 15 days (IQR 4–30) after diagnosis of candidaemia and was extended specifically for completion of parenteral therapy in 100 (16%) of 621 patients. Initial echinocandin treatment was associated with lower overall mortality and longer duration of hospital stay among survivors than treatment with other antifungals.[Interpretation] Although overall mortality in patients with candidaemia was high, our study indicates that adherence to clinical guideline recommendations, reflected by higher EQUAL Candida scores, might increase survival. New antifungals, with similar activity as current echinocandins but with longer half-lives or oral bioavailability, are needed to reduce duration of hospital stay.Scynexis.Peer reviewe

Infections fongiques invasives et déficit en CARD9

Les infections fongiques invasives, sont des infections sévères grevées d’une lourde mortalité. Elles sont actuellement un problème majeur de santé publique et leur incidence augmente. Les candidémies représentent la quatrième cause d’infection hématogène nosocomiale aux Etats-Unis, les cryptococcoses sont responsables de 600 000 décès chaque année en Afrique et l’aspergillose invasive infecte 10% des patients transplantés de cellules souches. La mortalité de ces infections reste élevée avec des taux de mortalité de 50, 15 et 40% respectivement. L’augmentation de leur incidence est due à l’accroissement des populations immunodéprimées à risque de développer des infections fongiques en raison de l’augmentation des thérapeutiques immunosuppressives et de l’allongement de la durée de vie des patients immunodéprimés. Les infections fongiques invasives surviennent chez des patients immunodéprimés, majoritairement dans un contexte d’immunodépression acquise (neutropénie, chimiothérapie, greffe de cellules souches périphériques ou transplantation d’organe solide, diabète, infection par le virus de l’immunodéficience humaine), mais également secondairement à un déficit immunitaire héréditaire (granulomatose septique chronique, déficit immunitaire combiné, neutropénie congénitale, défaut de l’axe IFNγ-IL12). Cependant certains patients développent des infections fongiques invasives sans immunodépression ou facteurs de risques identifiés. Nous avons donc émis l’hypothèse que ces infections avaient possiblement une origine génétique non identifiée. Au cours de ma thèse, j’ai étudié une cohorte de patients présentant des infections fongiques invasives sans facteur favorisant identifié afin de rechercher une étiologie génétique à ces infections. Le premier groupe de patients que j’ai étudié présentait une dermatophytose invasive ou dermatophytose profonde sans immunodépression. Contrairement à la dermatophytose superficielle, en général bénigne et fréquente dans la population générale; la dermatophytose profonde est une infection rare, invasive et sévère, dans laquelle les dermatophytes (qui sont des champignons filamenteux) envahissent les tissus dermiques et hypodermiques, les ganglions et parfois les organes profonds. Les patients que j’ai étudié étaient tous originaires d’Afrique du Nord, pour la plupart issus de familles consanguines, dont certains avec des cas multiples. Ces observations suggéraient une origine génétique de la dermatophytose profonde avec une hérédité probablement récessive. Au cours de ma thèse, j’ai étudié les caractéristiques cliniques, immunologiques et génétiques de 18 patients atteints d’une dermatophytose profonde, issus de neuf familles Marocaines, Algériennes, Tunisiennes ou Egyptiennes. En parallèle, j’ai étudié des patients ayant présenté des infections fongiques avec localisations cérébrales. L’une de ces patients a présenté des abcès cérébraux suite à une infection disséminée à Exophiala dermatitidis et trois patients ont développé des infections du système nerveux central à Candida spp.. Les infections invasives à Exophiala dermatitidis sont des infections rares, avec de fréquentes atteintes du système nerveux central, survenant majoritairement chez des patients sans déficit immunitaire identifié suggérant l’existence d’une origine génétique probable méconnue chez ces patients. Les candidoses invasives surviennent habituellement chez des patients neutropéniques, ayant récemment subi une intervention chirurgicale ou étant porteurs d’un cathéter intraveineux. Parmi les candidoses invasives, les localisations au système nerveux central sont rares, et classiquement rapportées chez des nouveau-nés prématurés ou suite à une intervention neurochirurgicale. J’ai par ailleurs étudié une patiente ayant développé des infections invasives des tissus sous-cutanés et des adénopathies dues à un champignon filamenteux. (...)Invasive fungal diseases are a major health problem as they are severe infections complicated with high mortality rates and with rising incidence. Invasive fungal diseases occur mainly in patients with acquired immunodeficiencies, but also with primary immunodeficiencies (chronic granulomatous disease, defect in IFN-ϒ/IL-12 axis, congenital neutropenia). However, few patients develop invasive fungal disease without known risk factor. We therefore hypothesized that these infections probably have an unidentified genetic etiology. I studied a cohort of patients who developed invasive fungal diseases without risk factors and searched for a genetic etiology to their infections. The first group of patients presented with deep dermatophytosis without known immunodeficiency. Deep dermatophytosis is a rare, invasive and severe infection where dermatophytes invade dermis, hypodermis, lymph nodes and sometimes deep organs. I could study clinical, immunological and genetic characteristics of 18 patients from nine families who presented deep dermatophytosis. I also studied patients who developed central nervous system (CNS) fungal infections; one patient with CNS Exophiala dermatitidis infection and three patients with CNS Candida spp. infection. Invasive E. dermatitidis infections are rare, with frequent CNS location, mainly reported in patients without known immunodeficiencies, suggesting a potential unknown genetic etiology in these patients. CNS candidiasis are also rare infections usually occuring in preterm neonates or following neurosurgery. Based on literature data previously reporting a large consanguineous Iranian family with CARD9 deficiency that developed chronic mucocutaneous and central nervous system candidiasis; according to candidate gene approach, I sequenced CARD9 in all patients. CARD9 is an adaptor protein expressed by myeloid cells that signals downstream Dectin-1 and Dectin2 that are the main Pattern Recognotion Receptor implicated in antifungal immunity. I identified in all studied patients homozygous CARD9 mutations. Among 18 patients with deep dermatophytosis, 16 had homozygous nonsense Q289X and two homozygous missense R101C mutation in CARD9. I identified R18W, R35Q and R70W homozygous missense mutations in the patients who developed E. dermatitidis and two patients who developed CNS candidiasis, respectively. Transmission was autosomal recessive for all patients, except for the one with E. dermatitidis infection who had an uniparental disomy. In contrast with controls, CARD9 expression is abolished in Q289X, reduced in R70W and normal in R18W patients’ myeloid cells. CARD9 deficient patients whole blood and dendritic cells display a selective response defect to Candida albicans and Saccharomyces cerevisiae ; with IL-6 and TNF-α production impairment after Candida albicans and Saccharomyces cerevisiae stimulation. This defect can explain elective fungal susceptibility of CARD9 deficient patients to invasive fungal infections. This work evidenced that CARD9 deficiency was the main genetic etiology of deep dermatophytosis. It also could evidence that CARD9 deficiency is associated with Exophiala dermatitidis and Candida spp. CNS infections. This susceptibility is associated with proinflammatory cytokines defect by dendritic cells and whole blood to fungal agents. Various fungal clinical phenotypes in CARD9 deficient patients assess CARD9 central role in skin and central nervous system antifungal immunity

Mucormycoses rhino-orbito-cérébrales (survie, facteurs pronostiques, place du traitement chirurgical pour le contrôle local)

Les mucormycoses Rhino-Orbito-Cérébrales (ROC) sont une infection potentiellement mortelle, rapidement évolutive et survenant chez des immunodéprimés. Nous avons réalisé une étude rétrospective nationale, comportant 22 cas de mucormycose ROC. Le taux de survie global est de 57%. La survie actuarielle est de 80% pour les patients ayant reçu un traitement chirurgical radical. En analyse uni variée, le taux de survie variait significativement de 76,4% à 0% pour les patients avec une hémopathie maligne, de 66,7% à 25% si ils présentaient un chemosis et de 71,4% à 37,5% si ils présentaient une paralysie du VI. Deux classifications radiologiques ont été suggérées et comparées. La survie diminue en fonction du stade radiologique pour les deux mais sans différence significative. Les taux de survie semblent indiquer que le traitement chirurgical radical est une composante majeure du traitement. Des études supplémentaires permettront de montrer son rôle dans l'amélioration de la survie des patients.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF

Mucormycosis in Organ and Stem Cell Transplant Recipients

Mucormycosis is a devastating invasive fungal disease whose incidence has increased during the past decade. Mucormycosis now represents a major threat in transplant recipients, accounting for 2% and 8% of invasive fungal infections in recent cohorts of solid-organ and allogeneic stem-cell transplant recipients, respectively. Mucormycosis most often occurs late, &gt;3 months after transplantation, although cases occurring early have been observed, especially among liver transplant recipients and in cases of graft-transmitted infection. Recent guidelines have emphasized the direct examination of the involved fluid or tissue and culture from a sterile site as the most appropriate diagnostic strategy and the use of lipid formulations of amphotericin B and major surgery when feasible as the most appropriate first-line therapeutic strategy for mucormycosis in organ and stem cell transplant recipients

Grippe aviaire en décembre 2007

International audienc