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Mycobacterium abscessus infection is challenging to treat. Extrapulmonary M. abscessus infections (EP-MAB) are less common than pulmonary M. abscessus infections. To evaluate treatment regimens, we retrospectively analyzed consecutive microbiologically confirmed EP-MAB cases diagnosed in France during 2012–2020. We studied 45 patients with EP-MAB, including 14 bone and joint infections, 10 skin and soft tissue infections, and 8 lymph node infections. Most (62%) patients had no reported immunodeficiency. In 27 patients, EP-MAB followed healthcare-associated (44%) or environmental (16%) injuries. Of the 45 isolates, 25 were subspecies abscessus, 10 bolletii, and 9 massiliense; 1 was unidentified. Cure was achieved for 36 (80%) patients who received a median antimicrobial regimen of 6 months; 22 (55%) also underwent surgery. Four patients died, and 5 were unavailable for follow-up. EP-MAB predominantly affects immunocompetent patients after an injury; outcomes are favorable. We propose a >6-month regimen of antimicrobial therapy with consideration for surgery and regular patient reassessment.

Scedosporium spp. and Lomentospora prolificans are emerging non-Aspergillus filamentous fungi. The Scedosporiosis/lomentosporiosis Observational Study we previously conducted reported frequent fungal vascular involvement, including aortitis and peripheral arteritis. For this article, we reviewed 7 cases of Scedosporium spp. and L. prolificans arteritis from the Scedosporiosis/lomentosporiosis Observational Study and 13 cases from published literature. Underlying immunosuppression was reported in 70% (14/20) of case-patients, mainly those who had solid organ transplants (10/14). Osteoarticular localization of infection was observed in 50% (10/20) of cases; infections were frequently (7/10) contiguous with vascular infection sites. Scedosporium spp./Lomentospora prolificans infections were diagnosed in 9 of 20 patients ≈3 months after completing treatment for nonvascular scedosporiosis/lomentosporiosis. Aneurysms were found in 8/11 aortitis and 6/10 peripheral arteritis cases. Invasive fungal disease­–related deaths were high (12/18 [67%]). The vascular tropism of Scedosporium spp. and L. prolificans indicates vascular imaging, such as computed tomography angiography, is needed to manage infections, especially for osteoarticular locations.

Summary: Background: Mucormycosis is a deadly invasive fungal infection recently included in the WHO priority pathogen list. Here we sought to describe epidemiological trends of mucormycosis in France, and to evaluate factors associated with mortality. Methods: From 2012 to 2022, we implemented a nationwide prospective surveillance programme for mucormycosis in France, focusing on epidemiology, species, seasonal variations. Factors associated with 3-month mortality were studied by univariable and multivariable logistic regression. Findings: Among 550 cases of mucormycosis, the main underlying conditions were haematological malignancy (HM, 65.1%, 358/550), trauma (8%, 44/550), diabetes (7.5%, 41/550) and solid-organ transplants (6.5%, 36/550). Site of infection was pulmonary in 52.4% (288/550), rhinocerebral in 14.5% (80/550), and cutaneo-articular in 17.1% (94/550). Main species identified were Rhizopus arrhizus (21%, 67/316), Rhizopus microsporus (13.6%, 43/316), Lichtheimia corymbifera and Mucor circinelloides (13.3%, 42/316 each), Rhizomucor pusillus (12%, 38/316), and Lichtheimia ramosa (10.8%, 34/316). We found associations between underlying condition, site of infection, and infecting species, including a previously undescribed triad of trauma, cutaneo-articular localisations, and L. ramosa/M. circinelloides. Diagnostic contribution of Polymerase Chain Reaction (PCR) increased from 16% (4/25) in 2012 to 91% (61/67) in 2022, with more than 50% of diagnoses relying solely on PCR in 2022. We also found seasonal variations with relatively more cases in autumn. Ninety-day mortality was 55.8% (276/495). Independent prognostic factors were age, diagnosis in Intensive Care Unit (ICU), and HM while diagnosis after 2015 (i.e. large implementation of PCR) and surgery were associated with reduced mortality. Interpretation: This study reveals major mucormycosis epidemiological changes in France, with a large predominance of HM patients, and a parallel between PCR multicentre implementation and improved prognosis. We also evidence new associations between species, localisations and risk factors, as well as seasonal variations. Funding: Recurrent financial support from Santé Publique France and Institut Pasteur.

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Objectives: Ibrutinib, a first-generation covalent Bruton's tyrosine kinase inhibitor (BTKi) was found to be a risk factor for the occurrence of invasive fungal complications. Acalabrutinib is a second-generation covalent BTKi used to treat B-cell malignancies. Healthy donor neutrophils incubated ex vivo with acalabrutinib lose ability to control Aspergillus conidia germination. In patients receiving acalabrutinib, the potential effect on neutrophil antifungal activity is unknown. Furthermore, only two cases of invasive aspergillosis have been reported during treatment with acalabrutinib, outside of a few cases in a clinical trial. Methods: We describe three new cases of invasive aspergillosis occurring within the first months of acalabrutinib therapy in patients with chronic lymphocytic leukemia. We used videomicroscopy and flow cytometry approaches to investigate the basic functional responses against Aspergillus of neutrophils from acalabrutinib-treated patients. Results: We showed an alteration in the anti-Aspergillus response after 1 month of acalabrutinb therapy: neutrophils lost their capacities of killing Aspergillus fumigatus germinating conidia and decreased their reactive oxygen species production when stimulated by Aspergillus. Conclusions: It is important to follow-up patients treated with acalabrutinib for the risk of aspergillosis as well as those treated with ibrutinib.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in immunocompromised patients with disseminated Mycobacterium genavense. Management relies on high-dose corticosteroids.We describe two cases of late-onset corticosteroid-refractory IRIS related to disseminated infection in a HIV-positive patient and a renal transplant patient who had a favorable outcome with a monoclonal TNF-α blocker.

Abstract Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe -/- mice as well as hematopoietic deletion in Ldlr -/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe -/- Rag2 -/- Card9 -/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1β production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.

We report 3 cases of successful treatment of Microascus spp. bronchopulmonary infection in a multiple-traumatized patient and 2 lung transplant recipients in France. We emphasize the promising use of olorofim antifungal therapy in a rising context of intrinsically less-susceptible respiratory infections caused by mold.

Objectives We aimed to describe patients with autoimmune diseases (AID) developing invasive fungal disease (IFD) and identify factors associated with short-term mortality.Methods We analysed cases of IFD associated with AID from the surveillance network of invasive fungal diseases (Réseau de surveillance des infections fongiques invasives, RESSIF) registry of the French national reference centre for invasive mycoses. We studied association of AID-specific treatments with 30-day mortality. We analysed total lymphocyte and CD4-T cell counts in patients with Pneumocystis jirovecii pneumonia (PCP).Results From 2012 to 2018, 549 individuals with IFD and AID were included, mainly with PCP (n=227, 41.3%), fungemia (n=167, 30.4%) and invasive aspergillosis (n=84, 15.5%). Rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) were the most frequent AID in PCP (n=55 and 25, respectively) and invasive aspergillosis (n=15 and 10, respectively), inflammatory bowel diseases (IBDs) were predominant in fungemia (n=36). At IFD diagnosis, 365 (66.5%) patients received glucocorticoids (GCs), 285 (51.9%) immunosuppressants, 42 (7.7%) tumor necrosis factor (TNF)-α blockers, 75 (13.7%) other biologics. Mortality at 30 days was 28.1% (143/508). Fungemia and high-dose GCs were independently associated with higher 30-day mortality. In PCP patients, lymphopenia

IntroductionThe diagnosis of cutaneous manifestations of deep mycoses relies on both histopathological and direct examinations. Yet, the current diagnostic criteria cannot prevent missed cases, including invasive aspergillosis, which requires the development of a novel diagnostic approach and imaging tools. We recently introduced the use of dynamic full-field optical coherence tomography (D-FF-OCT) in fungal diagnostics with a definition approaching that of conventional microscopy and the ability to return metabolic information regarding different fungal species. The present work focuses on subcellular dynamics and live-cell imaging of Aspergillus fumigatus with D-FF-OCT to follow the fungal growth stages.MethodsThe A. fumigatus ATCC 204305 quality-control strain was used for all imaging experiments, following incubation times varying between 24 and 72 h at 30°C in a humidified chamber on Sabouraud dextrose agar. Fungal growth was subsequently monitored with D-FF-OCT for up to 5 h at room temperature and following the pharmacological stress of either voriconazole, amphotericin B, or caspofungin gradient concentration.ResultsD-FF-OCT images allow not only the visualization of intracellular trafficking of vacuoles but also an evolving dynamic segmentation of conidiophores depending on the chronological development and aging of the hyphae or the effect of antifungal treatment. The same applies to conidial heads, with the most intense D-FF-OCT signal coming from vesicles, revealing a changing dynamic within a few hours only, as well as complete extinction following subsequent drying of the Sabouraud dextrose agar.DiscussionThese results provide additional data on the ability of D-FF-OCT to monitor some of the main life cycle processes, dynamics, and intracellular trafficking of vacuoles in A. fumigatus, with or without the effect of pharmacological stress. Such complementary metabolic information could help both clinicians and microbiologists in either mechanistic studies toward experimental mycology or the development of a potential D-FF-OCT-guided diagnosis of superficial fungal infections.

Abstract is missing (Short communication)

Abstract Background and Aims The coronavirus pandemic challenged countries worldwide in a race against contaminations and variants. Vaccination campaigns were the answer to such an infectious spread. This descriptive study presents the organizational process of the setting up of a Covid‐19 vaccination center in a French University Hospital in January 2021, the issues encountered along the way and assessment of adaptability. Methods Three major stakeholders: SARS CoV‐2 crisis referent, referring vaccination medical doctor and referring vaccination pharmacist retraced key moments and identified issues encountered during the setting up of the vaccination center and its long term maintenance, threw a series of meetings. Records of crisis and periodic meetings that took place threw out the vaccination campaign were consulted. Results A multidisciplinary crisis steering committee with nine different professionals was created January 3. Logistics for the vaccination center opening were discussed: location, informatics, appointment‐scheduling, pharmaceutical circuit, internal circuit, human resources, and information communication. The vaccination center was ready to welcome healthcare workers in less than 24 h on January 4. The first month, 2757 1st shots were administered, leading up to a total of 9167 1st shots during 6 months of activity. From January to June 2021, the multidisciplinary group dealt and adapted its processes to challenging and unexpected situations. Indeed, issues encountered with Pfizer BioNTech's and AstraZeneca's vaccine, were: supply shortages, vaccine manipulation, targeted populations, pharmacovigilance, and general communication. Conclusion This descriptive study provides an exclusive insight on how a hospital vaccination center was organized and adapted during Covid‐19 pandemic to ensure healthcare workers' security and resilience, and to protect high risk patients of severe Covid‐19 infection.

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.

ObjectivesWe describe the clinical, mycological, immunological, and genetic characteristics of six HIV-negative patients presenting with invasive cryptococcosis.MethodsPatients with cryptococcosis without any of the classical risk factors, such as HIV infection, followed at Cayenne Hospital, were prospectively included. An immunologic and genetic assessment was performed.ResultsFive male patients and one female patient, 5 adults and one child, were investigated. All presented a neuromeningeal localization. Cryptococcus neoformans var. gattii and C. neoformans var. grubii were isolated in two and three patients, respectively, whereas one patient could not be investigated. Overall, we did not observe any global leukocyte defect. Two patients were found with high levels of circulating autoantibodies against Granulocyte macrophage-colony stimulating factor (GM-CSF), and none had detectable levels of autoantibodies against Interferon gamma (IFN-γ) Sequencing of STAT1 exons and flanking regions performed for four patients was wild type.ConclusionTo better understand cryptococcosis in patients with cryptococcosis but otherwise healthy, further explorations are needed with repeated immune checkups and strain virulence studies.

Nine new human invasive infections caused by the keratinophilic fungi Nannizziopsis obscura have been reported in France since 2004. The patients had variable clinical manifestations, had frequent dissemination, were mainly T-cell immunocompromised, and all originated from sub-Saharan West Africa. Before collection of the isolates, the etiologies of these infections were often misidentified, underscoring the extent of microscopic and cultural polymorphisms. All isolates but 1 had low MICs for the 8 antifungal drugs tested. When treated, patients received mainly azole therapy. Two of 7 patients with a known outcome died. We performed multilocus sequence analysis of N. obscura clinical strains and several strains of Nannizziopsis spp. isolated from reptiles. The human strains were clearly differentiated from the animal strains. N. obscura might be endemic to West Africa and responsible for undetected infections, which might become reactivated when immunosuppression occurs. N. obscura infection is probably underestimated because only sequencing enables proper identification.

Mucormycosis is a rare but life-threatening fungal infection due to molds of the order Mucorales. The incidence has been increasing over recent decades. Worldwide, pulmonary mucormycosis (PM) presents in the lungs, which are the third main location for the infection after the rhino-orbito-cerebral (ROC) areas and the skin. The main risk factors for PM include hematological malignancies and solid organ transplantation, whereas ROC infections classically are classically favored by diabetes mellitus. The differences between the ROC and pulmonary locations are possibly explained by the activation of different mammalian receptors—GRP78 in nasal epithelial cells and integrin β1 in alveolar epithelial cells—in response to Mucorales. Alveolar macrophages and neutrophils play a key role in the host defense against Mucorales. The diagnosis of PM relies on CT scans, cultures, PCR tests, and histology. The reversed halo sign is an early, but very suggestive, sign of PM in neutropenic patients. Recently, the serum PCR test showed a very encouraging performance for the diagnosis and follow-up of mucormycosis. Liposomal amphotericin B is the drug of choice for first-line therapy, together with correction of underlying disease and surgery when feasible. After a stable or partial response, the step-down treatment includes oral isavuconazole or posaconazole delayed release tablets until a complete response is achieved. Secondary prophylaxis should be discussed when there is any risk of relapse, such as the persistence of neutropenia or the prolonged use of high-dose immunosuppressive therapy. Despite these novelties, the mortality rate from PM remains higher than 50%. Therefore, future research must define the place for combination therapy and adjunctive treatments, while the development of new treatments is necessary.

Abstract Background Bronchiectasis is a heterogeneous disease depending on etiology. It represents the most frequent non-infectious pulmonary complication of primary immunodeficiencies (PID). We investigated whether bronchiectasis associated with PID had a distinct course in comparison to bronchiectasis of other causes. Methods Retrospective single-center study of adult patients diagnosed with non-cystic fibrosis bronchiectasis with more than 5 years of follow-up and at least 4 pulmonary functional tests available at one year apart. They were divided into three groups: PID- related bronchiectasis, idiopathic/post infectious-related bronchiectasis and other causes of bronchiectasis. Respiratory functional data and clinical outcomes were compared. Results Of 329 patients with bronchiectasis diagnosed in Foch Hospital (Suresnes, France), 98 patients fulfilled the selected criteria (20 PID-related cases, 39 idiopathic or post-infectious cases, and 39 cases with other causes). Median time of follow-up was 9.5 years. Groups were similar concerning initial characteristics (female 70.4%, never smokers 59.2%, mild severity bronchiectasis according to the FACED score and median FEV1 at diagnosis 73.5% predicted values [Q1–Q3: 53.75–90.5]), except PID patients who were younger (median age of 51.5 vs 62 years, p = 0.02). Eighty-five percent of PID patients received immunoglobulin substitution (median trough level was measured at 10.5 g/dl [10;10.92]). Global median FEV1 annual decline was 25.03 ml/year [8.16;43.9] and 19.82 ml/year [16.08;48.02] in the PID patients group. Forty-five percent of patients had bacterial colonization, pneumoniae occurred in 56% of patients and median exacerbation annual rate was 0.8 [0.3–1.4]. Hemoptysis occurred in 31.6% of patients. Global mortality rate was 11.2%. We did not record any significant difference for all clinical and functional outcomes between patients with PID and other etiologies. The median decline in FEV1 was similar in the three groups. Conclusions The course of PID-related bronchiectasis was similar to bronchiectasis of other causes. Provided that patients receive immunoglobulin replacement, the course of PID-related bronchiectasis seems to be independent of the underlying immune disorder.

Rhinocladiella mackenziei cerebral phaeohyphomycosis is a rare severe disease that has been typically described in the Middle East. Here, we report 2 cases of R. mackenziei cerebral phaeohyphomycosis in patients from Morocco, diagnosed and treated in France, and raise a concern about the ever-going extension of the area at risk for this devastating invasive fungal infection.

We report a case of Aspergillus felis infection in a patient with chronic granulomatous disease who had overlapping features of invasive pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Identifying the species responsible for aspergillosis by molecular methods can be crucial for directing patient management and selection of appropriate antifungal agents.

Cryptococcosis is the third most common cause of invasive fungal infection in solid organ transplant recipients and cryptococcal meningitis (CM) its main clinical presentation. CM outcomes, as well as its clinical features and radiological characteristics, have not yet been considered on a large scale in the context of kidney transplantation (KT). We performed a nationwide retrospective study of adult patients diagnosed with cryptococcosis after KT between 2002 and 2020 across 30 clinical centers in France. We sought to describe overall and graft survival based on whether KT patients with cryptococcosis developed CM or not. Clinical indicators of CNS involvement and brain radiological characteristics were assessed. Eighty-eight cases of cryptococcosis were diagnosed during the study period, with 61 (69.3%) cases of CM. Mortality was high (32.8%) at 12 months (M12) but not significantly different whether or not patients presented with CM. Baseline hyponatremia and at least one neurological symptom were independently associated with CM (p < 0.001). Positive serum cryptococcal antigen at diagnosis was also significantly associated with CM (p < 0.001). On magnetic resonance imaging (MRI), three patterns of brain injury were identified: parenchymal, meningeal, and vascular lesions. Although CM does not affect graft function directly, it entails a grim prognosis.

Abstract Background The use of isavuconazole is approved for the management of invasive aspergillosis and mucormycosis, only in adults, as no paediatric pharmacology studies have been reported to date. Very few paediatric cases have been published concerning the use of isavuconazole. Amphotericin B is the only antifungal agent recommended in paediatric mucormycosis, but adverse effects and especially nephrotoxicity, even with the liposomal formulation, could be problematic. In this context, the use of other antifungal molecules active on Mucorales becomes needful. Case presentation We describe a case of mucormycosis with rapid onset dissemination in a 3-year-old girl recently diagnosed with acute lymphocytic leukaemia. She was successfully treated with isavuconazole alone and then in combination with liposomal amphotericin B. Isavuconazole therapy was guided by therapeutic drug monitoring. Conclusions This case offers new perspectives on the potential use of isavuconazole in children with mucormycosis, as an alternative or adjunct to liposomal amphotericin B.

We report a disseminated infection caused by Spiroplasma apis, a honeybee pathogen, in a patient in France who had X-linked agammaglobulinemia. Identification was challenging because initial bacterial cultures and direct examination by Gram staining were negative. Unexplained sepsis in patients with agammaglobulinemia warrants specific investigation to identify fastidious bacteria such as Spiroplasma spp.

Background. We sought to determine whether invasive aspergillosis (IA) during the first year after lung transplantation increased the risk of chronic lung allograft dysfunction (CLAD). Methods. We retrospectively reviewed the records of 191 patients who underwent lung transplantation at our institution between January 2013 and December 2017. Screening for Aspergillus was with bronchial aspirates, bronchoalveolar lavage if indicated or during surveillance bronchoscopy, radiography, and computed tomography. We used Fine and Gray multivariable regression to identify potential risk factors for CLAD. Results. During the first posttransplant year, 72 patients had at least 1 deep-airway sample positive for Aspergillus; 63 were classified as having IA and were included in the study. Median number of endoscopies per patient during the first year was 9 (range, 1–44). Median time from transplantation to first Aspergillus-positive sample was 121 d. Bronchial aspirate samples and bronchoalveolar lavage fluid were positive in 71 and 44 patients, respectively. Aspergillus fumigatus (n = 36, 50%) predominated; bacterial samples were also positive in 22 (31%) patients. IA within 4 mo after transplantation was independently associated with CLAD development (subdistribution hazard ratio, 3.75; 95% confidence interval [CI], 1.61-8.73; P < 0.01) by regression analysis. Survival at 3 and 5 y conditional on 1-y CLAD-free survival was 37% (95% CI, 24%-58%), and 24% (95% CI, 11%-52%) in the IA

Phaeohyphomycoses comprise a heterogeneous group of fungal infections caused by dematiaceous fungi and have primarily been reported in patients with underlying acquired immunodeficiencies, such as hematological malignancies or solid-organ transplants. Over the past decade, a growing number of patients with phaeohyphomycosis but otherwise healthy were reported with autosomal recessive (AR) CARD9 deficiency. We report a 28-year-old woman who presented with invasive rhinosinusitis caused by Alternaria infectoria. Following a candidate gene sequencing approach, we identified a biallelic loss-of-function mutation of CARD9, thereby further broadening the spectrum of invasive fungal diseases found in patients with inherited CARD9 deficiency. In addition, we reviewed 17 other cases of phaeohyphomycosis associated with AR CARD9 deficiency. Physicians should maintain a high degree of suspicion for inborn errors of immunity, namely CARD9 deficiency, when caring for previously healthy patients with phaeohyphomycosis, regardless of age at first presentation.

In humans, loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3) gene is frequently associated with susceptibility to bacterial as well as fungal infections including aspergillosis, although its pathogenesis remains largely unknown. In the present study, we investigated the immune responses obtained after stimulation with Aspergillus fumigatus in STAT3-deficient patients. A. fumigatus conidial killing efficiencies of both monocytes and neutrophils isolated from whole blood samples of STAT3-deficient patients were not different compared to those of healthy controls. After stimulation with A. fumigatus conidia, lower concentrations of adaptive cytokines (IFN-γ, IL-17 and IL-22) were secreted by peripheral blood mononuclear cells from STAT3-deficient patients compared to those from healthy controls. Moreover, the frequency of IFN-γ and IL-17 producing CD4+ T cells was lower in STAT3-deficient patients vs. healthy controls. Among the STAT3-deficient patients, those with aspergillosis showed further lower secretion of IFN-γ upon stimulation of their PBMCs with A. fumigatus conidia compared to the patients without aspergillosis. Together, our study indicated that STAT3-deficiency leads to a defective adaptive immune response against A. fumigatus infection, particularly with a lower IFN-γ and IL-17 responses in those with aspergillosis, suggesting potential therapeutic benefit of recombinant IFN-γ in STAT3-deficient patients with aspergillosis.

Mucormycosis is a rare and life-threatening fungal infection of the Mucorales order occurring mainly in immunosuppressed patients. The most common forms are rhinocerebral but pulmonary or disseminated forms may occur. We report the case of a 61-year-old patient in whom pulmonary mucormycosis was diagnosed during his first-ever episode of diabetic ketoacidosis. While receiving liposomal amphotericin B, a sinusal aspergillosis due to Aspergillus fumigatus occurred. Evolution was slowly favorable under antifungal tritherapy by liposomal amphotericin B, posaconazole and caspofungin.

Recent outbreaks of Cryptococcus gattii (CG) infections in North America have sparked renewed interest in the pathogenic potential of CG, and have underscored notable differences with Cryptococcus neoformans in terms of geographic distribution, pathogen virulence, and host susceptibility. While cases of CG are increasingly reported in patients with a wide variety of underlying conditions, only very few have been reported in patients with lymphoid neoplasms. Herein, we report a case of autochthonous CG meningitis in a patient receiving ibrutinib for chronic lymphocytic leukemia in France, and review available data on the clinical epidemiology of CG infections in patients with lymphoid neoplasms. We also summarise recent data on the host responses to CG infection, as well as the potential management pitfalls associated with its treatment in the haematological setting. The clinical epidemiology, clinical presentation, and course of disease during infections caused by CG involve complex interactions between environmental exposure to CG, infecting genotype, pathogen virulence factors, host susceptibility, and host immune responses. Future treatment guidelines should address the challenges associated with the management of antifungal treatments in the onco-haematological setting and the potential drug-drug interactions.

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.

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.

Immune deficiency of diverse etiology, including human immunodeficiency virus (HIV), antineoplastic agents, immunosuppressive agents used in solid organ recipients, immunomodulatory therapy, and other biologics, all promote invasive fungal infections. Subsequent voluntary or unintended immune recovery may induce an exaggerated inflammatory response defining immune reconstitution inflammatory syndrome (IRIS), which causes significant mortality and morbidity. Fungal-associated IRIS raises several diagnostic and management issues. Mostly studied with Cryptococcus, it has also been described with other major fungi implicated in human invasive fungal infections, such as Pneumocystis, Aspergillus, Candida, and Histoplasma. Furthermore, the understanding of IRIS pathogenesis remains in its infancy. This review summarizes current knowledge regarding the clinical characteristics of IRIS depending on fungal species and existing strategies to predict, prevent, and treat IRIS in this patient population, and tries to propose a common immunological background to fungal IRIS.

We report on 4 patients (1 immunocompetent, 3 immunosuppressed) in whom visceral leishmaniasis had become unresponsive to (or had relapsed after) treatment with appropriate doses of liposomal amphotericin B. Under close follow-up, full courses of pentavalent antimony were administered without life-threatening adverse events and resulted in rapid and sustained clinical and parasitological cure.

Summary: Overwhelming post-splenectomy infection (OPSI) remains a long-term risk in asplenic patients, which may be reduced by appropriate preventive measures. Specific guidelines have been developed to lower its incidence. Aims: To assess the implementation of guidelines by specialized physicians of a university hospital and primary care physicians. Methods: A retrospective review of splenectomized patients’ medical files over a six year period was carried out. Patients’ general practitioners were contacted and a questionnaire was sent to them. Results: 154 individuals who underwent splenectomy between 2000 and 2005 were eligible (62 children and 92 adults): 70.8% received pneumococcal vaccine, 44% received vaccine against Haemophilus influenzae type b with a good cover of children population (88.7%), 24% received meningococcal vaccine. Prophylactic antibiotics were prescribed in 74% of patients. Septic events were found in 8.4%, and global mortality was 11.7% during a mean follow-up period of 4.5 years. Conclusions: Management of the infectious risk in asplenic patient has to be improved: some of the patients are not correctly identified as at risk of OPSI, and vaccination against Neisseria meningitidis is insufficient. Hospital specialists should improve the implementation of guidelines and give better information to general practitioners involved. Keywords: Prevention, Infection, Splenectomy, Immunization

We analyzed hospital records to provide a population-based estimate of zygomycosis incidence and trends over a 10-year period at a national level in France. Data showed an increasing incidence from 0.7/million in 1997 to 1.2/million in 2006 (p

BACKGROUND:Optimal management of eumycetoma, a severely debilitating chronic progressive fungal infection of skin, disseminating to bone and viscera, remains challenging. Especially, optimal antifungal treatment and duration are ill defined. METHODOLOGY/PRINCIPAL FINDINGS:We conducted a monocentric retrospective study of 11 imported cases of eumycetoma treated by voriconazole or posaconazole for at least 6 months. Response to treatment was assessed through evolution of clinical and magnetic resonance imaging (MRI). (1→3) ß-D-glucan (BG) and positron emission tomography using [18F] fluorodeoxyglucose (PET/CT) results were also assessed. Identified species were Fusarium solani complex (n = 3); Madurella mycetomatis, (n = 3), and Exophiala jeanselmei, (n = 1). Moreover, two coelomycetes and one phaeohyphomycetes strains without species identification were retrieved. Serum BG and PET/CT were abnormal in 7/8 and 6/6 patients tested, respectively. Patients received last generation azoles for a mean duration of 25.9±18 months. Complete response (major clinical and MRI improvement) was observed in 5/11 patients, partial response (minor MRI improvement or stable MRI findings) in 5 and failure (MRI evidence of disease progression) in one, with a 73±39 [6-132] months mean follow-up. Relapse occurred in 2 patients after treatment discontinuation. Optimal outcome was associated with fungal species, initiation of last generation triazole therapy (

Mucormycosis is an emerging cause of infectious morbidity and mortality in patients with hematologic malignancies. However, there are no recommendations to guide diagnosis and management. The European Conference on Infections in Leukemia assigned experts in hematology and infectious diseases to develop evidence-based recommendations for the diagnosis and treatment of mucormycosis. The guidelines were developed using the evidence criteria set forth by the American Infectious Diseases Society and the key recommendations are summarized here. In the absence of validated biomarkers, the diagnosis of mucormycosis relies on histology and/or detection of the organism by culture from involved sites with identification of the isolate at the species level (no grading). Antifungal chemotherapy, control of the underlying predisposing condition, and surgery are the cornerstones of management (level A II). Options for first-line chemotherapy of mucormycosis include liposomal amphotericin B and amphotericin B lipid complex (level B II). Posaconazole and combination therapy of liposomal amphotericin B or amphotericin B lipid complex with caspofungin are the options for second line-treatment (level B II). Surgery is recommended for rhinocerebral and skin and soft tissue disease (level A II). Reversal of underlying risk factors (diabetes control, reversal of neutropenia, discontinuation/taper of glucocorticosteroids, reduction of immunosuppressants, discontinuation of deferroxamine) is important in the treatment of mucormycosis (level A II). The duration of antifungal chemotherapy is not defined but guided by the resolution of all associated symptoms and findings (no grading). Maintenance therapy/secondary prophylaxis must be considered in persistently immunocompromised patients (no grading).

Dermatophytes are keratinophilic fungi responsible for benign and common forms of infection worldwide. However, they can lead to rare and severe diseases in immunocompromised patients. Severe forms include extensive and/or invasive dermatophytosis, i.e., deep dermatophytosis and Majocchi’s granuloma. They are reported in immunocompromised hosts with primary (autosomal recessive CARD9 deficiency) or acquired (solid organ transplantation, autoimmune diseases requiring immunosuppressive treatments, HIV infection) immunodeficiencies. The clinical manifestations of the infection are not specific. Lymph node and organ involvement may also occur. Diagnosis requires both mycological and histological findings. There is no consensus on treatment. Systemic antifungal agents such as terbinafine and azoles (itraconazole or posaconazole) are effective. However, long-term outcome and treatment management depend on the site and extent of the infection and the nature of the underlying immunodeficiency.

Adult'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