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.

OBJECTIVES: To determine the frequency and prognosis of invasive pulmonary aspergillosis in critically ill patients with severe influenza pneumonia. DESIGN: Retrospective multicenter cohort study. SETTING: Five French ICUs. PATIENTS: Patients with influenza admitted to ICU between 2009 and 2018. MEASUREMENTS AND MAIN RESULTS: Of the 524 patients admitted for severe influenza diagnosed with a positive airway reverse-transcriptase polymerase chain reaction test, 450 (86%) required mechanical ventilation. A lower respiratory tract sample yielded with Aspergillus (Asp+) in 28 patients (5.3%). Ten patients (1.9%) were diagnosed with putative or proven invasive pulmonary aspergillosis, based on the validated AspICU algorithm. A multivariate model was built to identify independent risk factors for Aspergillus-positive pulmonary culture. Factors independently associated with Aspergillus-positive culture were liver cirrhosis (odds ratio = 6.7 [2.1–19.4]; p < 0.01), hematologic malignancy (odds ratio = 3.3 [1.2–8.5]; p = 0.02), Influenza A(H1N1)pdm09 subtype (odds ratio = 3.9 [1.6–9.1]; p < 0.01), and vasopressor requirement (odds ratio = 4.1 [1.6–12.7]; p < 0.01). In-hospital mortality of Asp+ patients was 36% versus 21% in patients without Aspergillus-positive pulmonary culture (p = 0.09). CONCLUSIONS: In this large retrospective multicenter cohort of critically ill patients, putative invasive pulmonary aspergillosis according to AspICU algorithm was a relatively rare complication of influenza. Patients at higher risk of Aspergillus pulmonary colonization included those with liver cirrhosis, hematologic malignancy, H1N1pdm09 influenza A virus, and requiring vasopressors. Our results provide additional data on the controversial association between severe influenza and invasive pulmonary aspergillosis. Reaching a consensual definition of invasive pulmonary aspergillosis becomes mandatory and confers further prospective research.

Objective: To evaluate the incidence of the abscopal response (AR) in patients with metastatic melanoma requiring palliative radiotherapy (RT). Patients and methods: Patients treated for metastatic melanoma between January 1998 and February 2020 in four oncology departments were screened. Patients with progression under immune checkpoint inhibitors or without ongoing systemic treatment, and requiring palliative RT were considered. The AR was defined as an objective response according to RECIST and/or iRECIST for at least one non-irradiated metastasis at distance (≥10 cm) from the irradiated lesion. Primary endpoint was the rate of AR. Secondary endpoints were overall survival (OS), progression-free survival (PFS), local control (LC) of the irradiated lesion, and toxicity as assessed by CTCAE v5. Results: Over the period considered, 118 patients were included and analyzed. Fifteen patients (12.7%) had an AR. With a median follow-up of 7.7 months (range, 0.2–242.2), median OS and PFS after RT were significantly longer in patients with an AR compared to those without: 28 vs. 6.6 months (p < 0.01) and not reached vs. 3.2 months, respectively. No grade ≥2 toxicity was reported. Patients who developed an AR were more likely to be treated with immunotherapy (93.3% vs. 55.9%, p = 0.02). In multivariate analysis, they had a higher number of irradiated metastases treated concomitantly (HR = 16.9, p < 0.01) and a higher rate of mild infections during RT (HR = 403.5, p < 0.01). Conclusions: AR in metastatic melanoma seems to be highly prognostic of overall survival, although it is a rare phenomenon. It may be promoted by multiple concomitant treatments with RT and immunotherapy and by acute inflammatory events such as infection.

Model-informed precision dosing is being increasingly used to improve therapeutic drug monitoring. To meet this need, several tools have been developed, but open-source software remains uncommon. Posologyr is a free and open-source R package developed to enable Bayesian individual parameter estimation and dose individualization. Before using it for clinical practice, performance validation is mandatory. The estimation functions implemented in posologyr were benchmarked against reference software products on a wide variety of models and pharmacokinetic profiles: 35 population pharmacokinetic models, with 4.000 simulated subjects by model. Maximum A Posteriori (MAP) estimates were compared to NONMEM post hoc estimates, and full posterior distributions were compared to Monolix conditional distribution estimates. The performance of MAP estimation was excellent in 98.7% of the cases. Considering the full posterior distributions of individual parameters, the bias on dosage adjustment proposals was acceptable in 97% of cases with a median bias of 0.65%. These results confirmed the ability of posologyr to serve as a basis for the development of future Bayesian dose individualization tools.

Cladophialophora bantiana is one of the most virulent phaeohyphomycetes, typically causes non-angiogenic single (or sometimes multiple) cystic brain lesions, and has resulted in a mortality rate of up to 70%. Most C bantiana cases are described either in a series of isolated reports or in very small cohorts. The aim of this retrospective nation-based study was to share the data on C bantiana phaeohyphomycosis cases reported in France and French overseas territories over the past two decades to improve understanding of this disease. Patients with C bantiana infection were processed through the active surveillance programme of invasive fungal infections launched by the National Reference Center for Mycoses and Antifungals, Institut Pasteur (Paris, France), and the French Surveillance Network of Invasive Fungal Infections, which involved 29 hospitals from mainland France and overseas French territories. Only proven and probable cases of infection, according to the revised and updated consensus definitions from the European Organization for Research and Treatment of Cancer and Mycoses Study Group, were included in the study. Patients were diagnosed or confirmed, or both, using a polyphasic approach at the Institut Pasteur between 2002 and 2022. Patients were separated into two groups: those with CNS involvement and those with no CNS involvement. The primary outcome was the survival rate. A total of 23 patients with a C bantiana invasive infection were included during the study period (Jan 1, 2002, to Dec 31, 2022). The median age was 56 years in the CNS involvement group and 65 years in the non-CNS involvement group. Until 2021, the annual number of cases varied between zero and two, with six cases observed in 2022, the warmest year recorded in France since 1900. CNS involvement was observed in 15 (65%) patients, including three disseminated cases; skin and soft tissue involvement in seven (30%) patients and an isolated lung infection in one case. Diabetes was observed in five patients, and any immunodepression factor was observed in 14 (61%) of 23 patients. When considering only patients with CNS involvement, 9-month survival appeared higher in patients who underwent exeresis or large drainage (three [75%] of four patients vs three [27%] of 11 patients; p=0·24) and significantly higher in those treated for 2 or more weeks with triple antifungal therapy (liposomal amphotericin B plus posaconazole and flucytosine; seven [78%] of nine patients vs one [17%] of six patients; p=0·040). Two patients were treated with excision surgery alone (one patient with success, and the other patient lost to follow-up). This study shows that the clinical presentations and underlying medical conditions of C bantiana infections are more diverse than previously described. It also emphasises a significant difference in mortality rate between those with and without CNS involvement. The prognosis improved when surgery was performed and triple antifungal therapy was administered. Such rare and devastating invasive fungal infections should be managed by a multidisciplinary team. Santé Publique France.