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Purpose: We evaluated the interest of systematic screening of serum fungal markers in patients hospitalized in a medical ward., Methods: We retrospectively analyzed all patients hospitalized in our infectious disease department from October 1st to October 31st, 2020 for COVID-19 without prior ICU admission, and for whom systematic screening of serum fungal markers was performed., Results: Thirty patients were included. The majority of patients received corticosteroids (96.7%). The galactomannan antigen assay was positive for 1/30 patients at D0, and 0/24, 0/16, 0/13 and 0/2 at D4, D7, D10 and D14 respectively. 1,3-ß-D-glucan was positive for 0/30, 1/24, 1/12, 0/12, 0/2 at D0, D4, D7, D10 and D14 respectively. No Aspergillus fumigatus PCR was positive. No cases of aspergillosis were retained., Conclusion: Our study does not support the interest of systematic screening of fungal markers in immunocompetent patients with COVID-19 in a conventional unit., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Invasive mold infections (IMD) are an emerging concern due to the growing prevalence of patients at risk, encompassing but not limited to allogeneic hematopoietic stem cell transplant recipients, hematological malignancies patients, solid organ transplant recipients and intensive care unit patients. In contrast with invasive aspergillosis and mucormycosis, other hyalohyphomycoses and phaeohyphomycoses remain poorly known. We conducted a retrospective analysis of the clinical, biological, microbiological and evolutive features of 92 IMD having occurred in patients in our tertiary-care center over more than 25 years. A quarter of these infections were due to multiple molds. Molds involved were Fusarium spp. (36.2% of IMD with a single agent, 43.5% of IMD with multiple agents), followed by Scedosporium spp. (respectively 14.5% and 26.1%) and Alternaria spp. (respectively 13.0% and 8.7%). Mortality at day 84 was higher for Fusarium spp., Scedosporium spp. or multiple pathogens IMD compared with Alternaria or other pathogens (51.7% vs. 17.6%, p < 0.05). Mortality at day 84 was also influenced by host factor: higher among hematology and alloHSCT patients than in other patients (30.6% vs. 20.9% at day 42 and 50.0% vs. 27.9% at day 84, p = 0.041). Better awareness, understanding and treatments are awaited to improve patient prognosis.

ZAP70 has a prognostic value in chronic lymphocytic leukemia (CLL), through altered B-cell receptor signaling, which is important in CLL pathogenesis. A good correlation between ZAP70 expression in CLL cells and the occurrence of autoimmune phenomena has been reported. Yet, the great majority of CLL-associated autoimmune cytopenia is due to polyclonal immunoglobulin (Ig) G synthesized by nonmalignant B cells, and this phenomenon is poorly understood. Here, we show, using flow cytometry, that a substantial percentage of CD5- nonmalignant B cells from CLL patients expresses ZAP70 compared with CD5- B cells from healthy subjects. This ZAP70 expression in normal B cells from CLL patients was also evidenced by the detection of ZAP70 mRNA at single-cell level with polyclonal Ig heavy- and light-chain gene transcripts. ZAP70+ normal B cells belong to various B-cell subsets and their presence in the naïve B-cell subset suggests that ZAP70 expression may occur during early B-cell development in CLL patients and potentially before malignant transformation. The presence of ZAP70+ normal B cells is associated with autoimmune cytopenia in CLL patients in our cohort of patients, and recombinant antibodies produced from these ZAP70+ nonmalignant B cells were frequently autoreactive including anti-platelet reactivity. These results provide a better understanding of the implication of ZAP70 in CLL leukemogenesis and the mechanisms of autoimmune complications of CLL., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Pulmonary mucormycosis (PM) is a life-threatening invasive mold infection. Diagnosis of mucormycosis is challenging and often delayed, resulting in higher mortality., Research Question: Are the disease presentation of PM and contribution of diagnosis tools influenced by the patient's underlying condition?, Study Design and Methods: All PM cases from six French teaching hospitals between 2008 and 2019 were retrospectively reviewed. Cases were defined according to updated European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria with the addition of diabetes and trauma as host factors and positive serum or tissue PCR as mycologic evidence. Thoracic CT scans were reviewed centrally., Results: A total of 114 cases of PM were recorded, including 40% with disseminated forms. Main underlying conditions were hematologic malignancy (49%), allogeneic hematopoietic stem cell transplantation (21%), and solid organ transplantation (17%). When disseminated, main dissemination sites were the liver (48%), spleen (48%), brain (44%), and kidneys (37%). Radiologic presentation included consolidation (58%), pleural effusion (52%), reversed halo sign (26%), halo sign (24%), vascular abnormalities (26%), and cavity (23%). Serum quantitative polymerase chain reaction (qPCR) was positive in 42 (79%) of 53 patients and BAL in 46 (50%) of 96 patients. Results of transthoracic lung biopsy were diagnostic in 8 (73%) of 11 patients with noncontributive BAL. Overall 90-day mortality was 59%. Patients with neutropenia more frequently displayed an angioinvasive presentation, including reversed halo sign and disseminated disease (P < .05). Serum qPCR was more contributive in patients with neutropenia (91% vs 62%; P = .02), and BAL was more contributive in patients without neutropenia (69% vs 41%; P = .02). Serum qPCR was more frequently positive in patients with a > 3 cm main lesion (91% vs 62%; P = .02). Overall, positive qPCR was associated with an early diagnosis (P = .03) and treatment onset (P = .01)., Interpretation: Neutropenia and radiologic findings influence disease presentation and contribution of diagnostic tools during PM. Serum qPCR is more contributive in patients with neutropenia and BAL examination in patients without neutropenia. Results of lung biopsies are highly contributive in cases of noncontributive BAL., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. Coste has received a travel grant from the association Marie-Bertille. O. L. has received speaker's fees from MSD, Gilead, Astellas, Pfizer, and F2G, and is consultant for Gilead. F. L. has received personal fees from Gilead, F2G and Pfizer. R. H. has received a grant from Gilead and personal honoraria from Pfizer, Gilead, and Mundipharma. L. M. has received travel grants from Gilead and Pfizer. F. D. has received personal fees from Gilead, outside the submitted work. None declared (A. Conrad, R. P., S. P., P. P., C. D., V. L.-B., F. M., T. G., M.-E. B., F. S., G. N., D. D., F. A., C. H.-D., S. D.-L., F. B., G. G., S. A., D. B., M.-P. L., J.-E. H., C. R., G. M., E. B., O. P., D. G.-H.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Invasive pulmonary aspergillosis is growing in incidence, as patients at risk are growing in diversity. Outside the classical context of neutropenia, new risk factors are emerging or newly identified, such as new anticancer drugs, viral pneumonias and hepatic dysfunctions. Clinical signs remain unspecific in these populations and the diagnostic work-up has considerably expanded. Computed tomography is key to assess the pulmonary lesions of aspergillosis, whose various features must be acknowledged. Positron-emission tomography can bring additional information for diagnosis and follow-up. The mycological argument for diagnosis is rarely fully conclusive, as biopsy from a sterile site is challenging in most clinical contexts. In patients with a risk and suggestive radiological findings, probable invasive aspergillosis is diagnosed through blood and bronchoalveolar lavage fluid samples by detecting galactomannan or DNA, or by direct microscopy and culture for the latter. Diagnosis is considered possible with mold infection in lack of mycological criterion. Nevertheless, the therapeutic decision should not be hindered by these research-oriented categories, that have been completed by better adapted ones in specific settings. Survival has been improved over the past decades with the development of relevant antifungals, including lipid formulations of amphotericin B and new azoles. New antifungals, including first-in-class molecules, are awaited.

Background: Early diagnosis and prompt initiation of specific antifungal treatment are essential for improving the prognosis of mucormycosis. We aimed to assess the performance of serum Mucorales quantitative polymerase chain reaction (qPCR) for the early diagnosis and follow-up of mucormycosis., Methods: We prospectively enrolled 232 patients with suspicion of invasive mold disease, evaluated using standard imaging and mycological procedures. Thirteen additional patients with proven or probable mucormycosis were included to analyze DNA load kinetics. Serum samples were collected twice-a-week for Mucorales qPCR tests targeting the Mucorales genera Lichtheimia, Rhizomucor, and Mucor/Rhizopus., Results: The sensitivity was 85.2%, specificity 89.8%, and positive and negative likelihood ratios 8.3 and 0.17, respectively in this prospective study. The first Mucorales qPCR-positive serum was observed a median of 4 days (interquartile range [IQR], 0-9) before sampling of the first mycological or histological positive specimen and a median of one day (IQR, -2 to 6) before the first imaging was performed. Negativity of Mucorales qPCR within seven days after liposomal-amphotericin B initiation was associated with an 85% lower 30-day mortality rate (adjusted hazard ratio = 0·15, 95% confidence interval [.03-.73], P = .02)., Conclusions: Our study argues for the inclusion of qPCR for the detection of circulating Mucorales DNA for mucormycosis diagnosis and follow-up after treatment initiation. Positive results should be added to the criteria for the consensual definitions from the European Organization for the Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC), as already done for Aspergillus PCR., Competing Interests: Potential conflicts of interests. L. M. reports personal fees outside the submitted work and travel grants from Gilead and Pfizer. S. B. reports personal fees outside the submitted work and travel grants from Gilead. F. L. reports personal fees from Airnspace, Gilead, and F2G outside the submitted work. A. A. reports personal fees form Gilead and Pfizer outside the submitted work, consulting fees from Pfizer for serving on an Advisory Board; travel grants from Gilead and Pfizer; and patent licensed for Pneumocystis PCR and patent issued for Histoplasma PCR. F. D. reports travel grants from Pfizer to attend Trend in Medical Mycology congress, Aberdeen, 2021 and is Vice President for French Society of Medical Mycology. R. H. reports research grant from Gilead, personal fees form Gilead and Pfizer outside the submitted work, and travel grants from Gilead and Pfizer. A. P. B. reports support for attending meetings and/or travel from Gilead. BD reports fees for travel and as a speaker at 2 national congresses in 2021 from Gilead and consultancy fees at an expert meeting planned in 01/2022 from Pfizer. F. B. reports consulting fees, payment or honoraria, and support for attending meetings and/or travel from Gilead and support for attending meetings and/or travel from Pfizer and leadership or fiduciary role from the Society of French Medical Mycology. S. B. reports honorarium from Gilead to attend an educational workshop and support for attending meetings and/or travel from Gilead travel grant for TIMM congress Aberdeen UK. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy., (© 2022. The Author(s).)

Background: Invasive fungal diseases (IFD) remain a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) and are associated with high mortality rates in patients receiving alloHSCT. Antifungal prophylaxis is increasingly being used in the management of IFDs in patients receiving alloHSCT., Methods: A post-hoc analysis of the cross-sectional observational AFHEM study was carried out to describe the use of antifungal drugs in real-life clinical practice in alloHSCT recipients hospitalized in French hematological units., Results: A total of 147 alloHSCT recipients were enrolled; most were adults (n = 135; 92%) and had received alloHSCT < 6 months prior to enrollment (n = 123; 84%). Overall, 119 (81%) patients received a systemic antifungal therapy; of these, 95 (80%) patients received antifungal prophylaxis. Rates of patients receiving systemic antifungal treatment were similar irrespective of transplant time, neutropenic, and graft-versus-host disease status. Among patients on systemic antifungal treatment, 83 (70%) received an azole, 22 (18%) received an echinocandin, and 16 (13%) received a polyene., Conclusions: This work provides evidence of the antifungal strategies used in alloHSCT recipients hospitalized in French hematological units. Unlike earlier studies, the AFHEM study showed that prophylaxis appears to be the leading antifungal strategy used in alloHSCT recipients in France., (© 2022. The Author(s).)

Introduction: Mucormycosis are infections caused by molds of the order Mucorales. These opportunistic infections are rare, difficult to diagnose, and have a poor prognosis. We aimed to describe common radiographic patterns that may help to diagnose cerebral mucormycosis and search for histopathological correlations with imaging data., Methods: We studied the radiological findings (CT and MRI) of 18 patients with cerebral mucormycosis and four patients' histopathological findings., Results: All patients were immunocompromised and/or diabetic. The type of lesions depended on the infection's dissemination pathway. Hematogenous dissemination lesions were most frequently abscesses (59 lesions), cortical, cortical-subcortical, or in the basal ganglia, with a halo aspect on DWI for lesions larger than 1.6 cm. Only seven lesions were enhanced after contrast injection, with different presentations depending on patients' immune status. Ischemia and hemorrhagic areas were also seen. Vascular lesions were represented by stenosis and thrombosis. Direct posterior extension lesions were bi-fronto basal hypodensities on CT and restricted diffusion without enhancement on MRI. A particular extension, perineural spread, was seen along the trigeminal nerve. Histopathological analysis found endovascular lesions with destruction of vessel walls by Mucorales, microbleeds around vessels, as well as acute and chronic inflammation., Conclusions: MRI is the critical exam for cerebral mucormycosis. Weak ring enhancement and reduced halo diffusion suggest the diagnosis of fungal infections. Involvement of the frontal lobes should raise suspicion of mucormycosis (along with aspergillosis). The perineural spread can be considered a more specific extension pathway of mucormycosis., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Because of chronic anemia, hypogonadotropic hypogonadism, and iron chelation, pregnancy in homozygous and heterozygous compound beta-thalassemia patients stays a challenge. Pregnancies of transfused beta-thalassemia women registered in the French National Registry, conducted between 1995 and 2015, are described. These pregnancies were compared with pregnancies in healthy women and to data previously published in the literature. Fifty-six pregnancies of 37 women were studied. There were 5 twin pregnancies. Assisted reproductive technologies (ART) were used in 9 pregnancies. Median term at delivery was 39 amenorrhea weeks, and median weight at birth was 2780 g. Cesarean section was performed in 53.6% of the pregnancies. There were 6 thromboembolic events, 6 serious infections, 6 pregnancy-induced hypertensions (PIH), 6 intrauterine growth retardations (IUGR), 5 severe hemorrhages, 4 gestational diabetes, 3 alloimmunizations, 2 heart diseases, and 1 pre-eclampsia. There were 5 infections and 4 osteoporosis in the first year of post-partum. ART and cesarean sections were more often used in the beta-thalassemia group, compared to control subjects. Thromboembolic events, PIH, hemorrhage at delivery, and IUGR were more frequent in the beta-thalassemia group. Time to delivery was not different, but infant weight at birth was significantly smaller in the beta-thalassemia group. In the post-partum period, global maternal complications were more frequent in the beta-thalassemia group. Pregnancy in transfused beta-thalassemia women is safe with rare obstetrical and fetal complications. Cesarean section remains often chosen, and infant weight at birth remains smaller than that in the general population, despite delivery at full term., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rare fungal pathogens are emerging as agents of invasive fungal infections. We analyzed 13 cases of fungal infections caused by Kazachstania (Arxiozyma) spp. in Strasbourg University Hospital, Strasbourg, France. Among the cases, 4 patients had proven fungal disease (3 cases of invasive fungal disease and 1 mucocutaneous infection) and 9 were colonized by Kazachstania (Arxiozyma) spp. Candida albicans was also isolated from 11 of the 13 patients. None of the patients with proven invasive fungal disease met host criteria, but most had underlying diseases. All strains were identified as K. telluris by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and 3 were confirmed as K. bovina by internal transcribed spacer sequencing. For all tested strains, the MICs for fluconazole were >2 μg/mL. Emergence of this rare fungal infection might be explained by the increasing number of patients with immunocompromised conditions and gastroesophageal diseases.

Objectives: To describe the coinfections in invasive aspergillosis (IA), to identify factors associated with coinfections, and to evaluate the impact of coinfection on mortality., Patients and Methods: We conducted a monocentric retrospective study of consecutive putative, probable, or proven IA that occurred between 1997 and 2017. All coinfections, with an onset within 7 days before or after the first sign of aspergillosis, were identified. Factors associated with coinfections and mortality were analysed by multivariable analysis., Results: Among the 690 patients with IA included in the study, the median age was 57 years (range 7 days to 90 years). A coinfection was diagnosed in 272/690 patients (39.4%, 95%CI 35.8-43.2). The location of this coinfection was pulmonary only in 131/272 patients (48%), bloodstream only in 66/272 patients (24%) and other/multiple sites in 75/272 patients (28%). Coinfections were bacterial (110/272 patients, 40%), viral (58/272, 21%), fungal (57/272, 21%), parasitic (5/272, 2%) or due to multiple types of pathogens (42/272, 15%). Factors associated with a coinfection in adjusted analysis were: allogeneic haematopoietic stem-cell transplantation (OR 2.3 (1.2-4.4)), other haematological malignancies (OR 2.1 (1.2-3.8)), other underlying diseases (OR 4.3 (1.4-13.6)), lymphopenia (OR 1.7 (1.1-2.5)), C-reactive protein >180 mg/L (OR 1.9 (1.2-3.0)), fever (OR 2.4 (1.5-4.1)), tracheal intubation (OR 2.6 (1.5-4.7)), isolation of two or more different Aspergillus species (OR 2.7 (1.1-6.3)), and the presence of non-nodular lesions on chest computed tomography (OR 2.2 (1.3-3.7) and OR 2.2 (1.2-4.0)). Coinfections were independently associated with a higher mortality at week 12 (adjusted HR 1.5 (1.1-1.9), p < 0.01)., Conclusions: Coinfections are frequent in IA patients and are associated with higher mortality., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality., Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020., Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases., Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases., (© 2021. The Author(s).)

B-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand-receptor interactions.

We have presented a practical guide developed by a working group of experts in infectious diseases and hematology to summarize the different recommendations issued by the different international groups on antifungal agents used for hematology patients. In addition, a working group of experts in the domains of nephrology, hepatology, and drug interactions have reported their different recommendations when administering antifungal agents, including dose adjustments, monitoring, and management of their side effects. This guide will enable prescribers to have a document available that will allow for better and optimal use of antifungal agents for hematology patients with consideration of the toxicity and interactions adjusted to each indication., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Primary objective of this non-interventional, post-authorisation safety study was to provide real-world safety data [incidence of adverse drug reactions (ADRs)/serious adverse events (SAEs)] on adult patients with myelofibrosis exposed/or not exposed to ruxolitinib. Key secondary objectives included the incidence/outcome of events of special interest (bleeding events, serious/opportunistic infections, second primary malignancies, and deaths). Overall, 462 patients were included [prevalent users = 260, new users = 32, non-exposed = 170 (inclusive of ruxolitinib-switch, n = 57)]. The exposure-adjusted incidence rates (per 100 patient-years) of ADRs (19·3 vs. 19·6) and SAEs (25·2 vs. 25·0) were comparable amongst new-users versus prevalent-users cohorts, respectively; most frequent ADRs across all cohorts included thrombocytopenia, anaemia, epistaxis, urinary tract infection, and herpes zoster. Anaemia, pneumonia, general physical health deterioration, sepsis, and death were the most frequent SAEs across all cohorts. Incidence rates of bleeding events (21·6) and serious/opportunistic infections (34·5) were higher in ruxolitinib-switch cohort versus other cohorts. The incidence rate of second primary malignancies was higher in the prevalent-users cohort (10·1) versus other cohorts. The observed safety profile of ruxolitinib in the present study along with the safety findings from the COMFORT/JUMP/EXPAND studies support the use of ruxolitinib for long-term treatment of patients with myelofibrosis., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: Emerging invasive fungal infections (IFI) have become a notable challenge. Apart from the more frequently described fusariosis, lomentosporiosis, mucormycosis, scedosporiosis, and certain dematiaceae or yeasts, little is known about extremely rare IFI., Methods: Extremely rare IFI collected in the FungiScope Ⓡ registry were grouped as Dematiaceae, Hypocreales, Saccharomycetales, Eurotiales, Dermatomycetes, Agaricales, and Mucorales., Results: Between 2003 and June 2019, 186 extremely rare IFI were documented in FungiScope Ⓡ . Dematiaceae (35.5%), Hypocreales (23.1%), Mucorales (11.8%), and Saccharomycetales (11.3%) caused most IFI. Most patients had an underlying malignancy (38.7%) with acute leukemia accounting for 50% of cancers. Dissemination was observed in 26.9% of the patients. Complete or partial clinical response rate was 68.3%, being highest in Eurotiales (82.4%) and in Agaricales (80.0%). Overall mortality rate was 29.3%, ranging from 11.8% in Eurotiales to 50.0% in Mucorales., Conclusions: Physicians are confronted with a complex variety of fungal pathogens, for which treatment recommendations are lacking and successful outcome might be incidental. Through an international consortium of physicians and scientists, these cases of extremely rare IFI can be collected to further investigate their epidemiology and eventually identify effective treatment regimens., Competing Interests: Declaration of Competing Interest PK reports personal fees from Astellas Pharma GmbH, Gilead Sciences GmbH, Akademie für Infektionsmedizin e.V., MSD Sharp & Dohme GmbH, and University Hospital, LMU Munich; non-financial support from Miltenyi Biotec GmbH; and other support from Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany, outside the submitted work. SCAC reports grants from MSD Australia, outside the submitted work. NK reports personal fees from Astellas, Gilead, MSD, and Pfizer, outside the submitted work. DCS reports grants from Merck and personal fees from Merck, Astellas, and AVIR, outside the submitted work. MH reports grants from Gilead, outside the submitted work. SCM reports personal fees from Octapharma, outside the submitted work. RH reports grants from Gilead, Novartis, and Pfizer and personal fees from Astellas, Basilea, Gilead, MSD, Novartis, and Pfizer, outside the submitted work. GK reports personal fees from Astellas Pharma, Gilead Sciences, Merck Sharp and Dohme, Pfizer, and Sandoz outside the submitted work. CLF reports grants from Astellas Pharma and Gilead Sciences; personal fees from Angelini, Basilea, Biomerieux, Gilead Sciences, and Merck Sharp and Dohme; and other support from Astellas Pharma, Basilea, Biomerieux, Gilead Sciences, and Merck Sharp and Dohme, outside the submitted work. KM reports grants as a clinical trial investigator from Gilead Sciences, Inc., clinical research grants from Ansun, Astellas, Merck, Rebiotix, Scynexis, and Shire; and consultant fees/honoraria from Chimerix, GlaxoSmithKline, Merck, and Scynexis outside the submitted work. DCV reports support from Avir Pharma, Cidara Therapeutics, CSL Behring, and Fonds de la Recherche en Santé du Quebec, during the conduct of the study (salary support), outside the submitted work. OAC reports grants from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, Medicines Company, MedPace, Melinta Therapeutics, Merck/MSD, Pfizer, and Scynexis and personal fees from Actelion, Allecra Therapeutics, Amplyx, Astellas, Basilea, Biosys UK Limited, Cidara, Da Volterra, F2G, Entasis, Gilead, Grupo Biotoscana, Matinas, MedPace, Menarini Ricerche, Merck/MSD, Nabriva Therapeutics Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Roche Diagnostics, Scynexis, Seres Therapeutics, and Tetraphase outside the submitted work. Other authors: none, (Copyright © 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

We report the results of F-FDG PET/CT in an asymptomatic case of COVID-19 infection. A 27-year-old woman underwent FDG PET/CT for revaluation of a stage IIIE B Hodgkin lymphoma after the fourth cycle of chemotherapy. It showed intense avid FDG subpleural mixed ground-glass and consolidative lesions, especially in the left lung. Because of this morpho-metabolic aspect and the epidemic context, a viral pneumopathy was suspected. The patient who was initially asymptomatic was admitted for fever 28 hours after the PET/CT. The nasopharyngeal swab was positive for COVID-19, and the outcome was favorable.

The incidence of invasive fungal diseases (IFDs) with central nervous system (CNS) involvement is increasing due to the rising numbers of immunocompromised individuals, such as patients receiving chemotherapy, transplantation procedures, or immune-modulating therapies. CNS IFDs cause significant morbidity and mortality, and treatments are complicated by difficulties in identifying fungal pathogens and delivering antifungal agents to the CNS. Isavuconazole is a novel triazole with broad-spectrum activity that has shown good blood-brain barrier penetration in animal models. We present a retrospective analysis of isavuconazole in the treatment of patients with CNS IFDs and who either participated in the phase III VITAL or SECURE clinical trials, or were included in a named-patient program. A total of 36 patients were identified, including 27 patients from the clinical trials. Of these patients, 47.2% had hematologic malignancies, while 13.9% had no identifiable underlying conditions. Mucorales, Aspergillus species, and Cryptococcus species accounted for 30.6%, 22.2%, and 13.9% of infections, respectively. The overall survival rate was 80.6% at day 42 and 69.4% at day 84, and at the end of treatment, a complete or partial clinical response was achieved in 58.3% of patients. Isavuconazole exhibited clinical activity in a variety of CNS IFDs., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Invasive pulmonary aspergillosis (IPA) optimal duration of antifungal treatment is not known. In a joint effort, four international scientific societies/groups performed a survey to capture current practices in European haematology centres regarding management of IPA. We conducted a cross-sectional internet-based questionnaire survey in 2017 to assess practices in sixteen European countries concerning IPA management in haematology patients including tools to evaluate treatment response, duration and discontinuation. The following four groups/societies were involved in the project: European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG), Infectious Diseases Working Party-European Society for Blood and Bone Marrow Transplantation (IDWP-EBMT), European Organisation for Research and Treatment-Infectious Disease group (EORTC-IDG) and Sorveglianza Epidemiologica Infezioni nelle Emopatie (SEIFEM). A total of 112 physicians from 14/16 countries answered the survey. Galactomannan antigen was available in serum and bronchoalveolar lavage in most centres (106/112 [95%] and 97/112 [87%], respectively), quantitative Aspergillus PCR in 27/112 (24%) centres, β-D-glucan in 24/112 (21%) and positron emission tomography in 50/112 (45%). Treatment duration differed between haematological malignancies, with a median duration of 6 weeks [IQR 3-12] for patients with AML, 11 [4-12] for patients with allogenic stem cell transplantation and GvHD and 6 [3-12] for patients with lymphoproliferative disease. Treatment duration significantly differed according to country. Essential IPA biomarkers are not available in all European countries, and treatment duration is highly variable according to country. It will be important to provide guidelines to help with IPA treatment cessation with algorithms according to biomarker availability., (© 2020 Blackwell Verlag GmbH.)

Objectives: Invasive fungal infections caused by Lomentospora prolificans are associated with very high mortality rates and can be challenging to treat given pan-drug resistance to available antifungal agents. The objective of this study was to describe the clinical presentation and outcomes in a cohort of patients with invasive L prolificans infections., Methods: We performed a retrospective review of medical records of patients with invasive L prolificans infection in the FungiScope ® registry of rare invasive fungal infections. Patients diagnosed between 01 January 2008 and 09 September 2019 were included in for analysis., Results: The analysis included 41 patients with invasive L prolificans infection from eight different countries. Haematological/oncological malignancies were the most frequent underlying disease (66%), disseminated infection was frequent (61%), and the lung was the most commonly involved organ (44%). Most infections (59%) were breakthrough infections. Progression/deterioration/treatment failure was observed in 23/40 (58%) of patients receiving antifungal therapy. In total, 21/41 (51%) patients, and 77% of patients with underlying haematological/oncological malignancy, had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was frequent (24/40) and associated with improved survival. In particular, treatment regimens including terbinafine were significantly associated with higher treatment success at final assessment (P = .012), with a positive trend observed for treatment regimens that included voriconazole (P = .054)., Conclusions: Lomentospora prolificans infections were associated with mortality rates of 77% and above in patients with underlying haematological/oncological malignancies and those with disseminated infections. While combination therapy is the preferred option for now, the hope lies with novel antifungals currently under development., (© 2020 Blackwell Verlag GmbH.)

Background: The most important series devoted to antithyroid drug-induced severe neutropenia and agranulocytosis are Japanese studies, almost specifically in relation to the intake of methimazole. The clinical data of 30 Caucasian patients followed up for antithyroid drug-induced neutropenia at a third-level hospital are reported. Methods: The data of 30 patients with idiosyncratic antithyroid drug-induced neutropenia and agranulocytosis from a cohort study on drug-induced neutropenia and agranulocytosis conducted at the University Hospital of Strasbourg (France) were retrospectively reviewed. Results: The mean patient age was 61.7 years old (range: 20-87), and the gender ratio (F/M) was 4. Several comorbidities were reported in 23 patients (76.7%), with the mean Charlson comorbidity index of 1. The causative drugs were carbimazole and benzylthiouracil, in 28 (93.3%) and 2 cases, respectively, prescribed primarily for multi-hetero-nodular goiter or thyroid nodule to 18 patients (60%). Sore throat and acute tonsillitis (40%), isolated fever (20%), septicemia (13.3%), documented pneumonia (6.7%), and septic shock (6.7%) were the main clinical features upon admission. The mean neutrophil count at nadir was 0.02 and 0 × 10 9 /L (range: 0-0.3). Regarding the patients' hospital course: 13 cases (43.3%) worsened during hospitalization, severe sepsis was found in 26.7%, systemic inflammatory response syndrome-in 13.3%, and septic shock-in 3.3% of the cases, respectively. Broad-spectrum antibiotics were indicated for all the patients, and 21 (73.3%) of them received hematopoietic growth factors. Hematological recovery (neutrophil count ≥ 1.5 × 10 9 /L) was seen at 8.3 days (range: 2-24), but faster in those receiving hematopoietic growth factors (4.9 days, p = 0.046). Two patients died during hospitalization, and the rest had a favorable clinical outcome. Conclusions: Antithyroid drug-induced neutropenia represents a serious complication resulting from the rates of severe infections especially in those cases severe neutropenia. In this setting, an established procedure for the management of patients seems useful or even indispensable in view of potential mortality., Competing Interests: E.A. is the recipient of several grants from different laboratories: Novartis, BMS, Pfizer, Léo Pharma, Boehringer, Servier, Aspen, Ferring, and Air Liquide but these sponsors have no part in the research or writing of the present manuscript. The other authors declare no conflict of interest.

Background: The new Rasamsonia spp. complex can develop invasive infection in immunosuppression or chronic pulmonary disease. It has potential to be misidentified as other genera due to morphological similarities. Nowadays, there is a gap of knowledge on this fungi., Objectives: To provide knowledge base of risk factors and therapeutic decisions in invasive Rasamsonia spp. complex infection., Patients/methods: Cases of invasive infection due to Rasamsonia spp. (formerly Geosmithia/Penicillium spp.) from FungiScope ® registry and all reported cases from a literature were included., Results: We identified 23 invasive infections due to Rasamsonia spp., six (26.1%) in the FungiScope ® registry. Main risk factors were chronic granulomatous disease (n = 12, 52.2%), immunosuppressive treatment (n = 10, 43.5%), haematopoietic stem cell transplantation (n = 7, 30.4%), graft-versus-host disease and major surgery (n = 4, 17.4%, each). Predominantly affected organs were the lungs (n = 21, 91.3%), disease disseminated in seven cases (30.4%). Fungal misidentification occurred in 47.8% (n = 11), and sequencing was used in 69.6% of the patients (n = 16) to diagnose. Breakthrough infection occurred in 13 patients (56.5%). All patients received antifungal treatment, mostly posaconazole (n = 11), caspofungin (n = 10) or voriconazole (n = 9). Combination therapy was administered in 13 patients (56.5%). Susceptibility testing showed high minimum inhibitory concentrations for azoles and amphotericin B, but not for echinocandins. No preferable treatment influencing favourable outcome was identified. Overall mortality was 39% (n = 9)., Conclusion: Rasamsonia spp. are emerging fungi causing life-threatening infections, especially in immunocompromised and critically ill patients. Mortality is high. Treatment is challenging and clinicians dealing with this patient population should become aware of this infection constituting a medical emergency., (© 2019 The Authors. Mycoses published by Blackwell Verlag GmbH.)

Objectives: Current knowledge on infections caused by Scedosporium spp. and Lomentospora prolificans in children is scarce. We therefore aim to provide an overview of risk groups, clinical manifestation and treatment strategies of these infections., Methods: Pediatric patients (age ≤18 years) with proven/probable Scedosporium spp. or L. prolificans infection were identified in PubMed and the FungiScope® registry. Data on diagnosis, treatment and outcome were collected., Results: Fifty-five children (median age 9 years [IQR: 5-14]) with invasive Scedosporium spp. (n = 33) or L. prolificans (n = 22) infection were identified between 1990 and 2019. Malignancy, trauma and near drowning were the most common risk factors. Infections were frequently disseminated. Most patients received systemic antifungal therapy, mainly voriconazole and amphotericin B, plus surgical treatment. Overall, day 42 mortality was 31%, higher for L. prolificans (50%) compared to Scedosporium spp. (18%). L. prolificans infection was associated with a shorter median survival time compared to Scedosporium spp. (6 days [IQR: 3-28] versus 61 days [IQR: 16-148]). Treatment for malignancy and severe disseminated infection were associated with particularly poor outcome (HR 8.33 [95% CI 1.35-51.40] and HR 6.12 [95% CI 1.52-24.66], respectively). Voriconazole use at any time and surgery for antifungal treatment were associated with improved clinical outcome (HR 0.33 [95% CI 0.11-0.99] and HR 0.09 [95% CI 0.02-0.40], respectively)., Conclusions: Scedosporium spp. and L. prolificans infections in children are associated with high mortality despite comprehensive antifungal therapy. Voriconazole usage and surgical intervention are associated with successful outcome., (Copyright © 2019 University Hospital of Cologne. Published by Elsevier Ltd.. All rights reserved.)

Invasive pulmonary aspergillosis (IPA) remains difficult to diagnose and to treat. Most common risk factors are prolonged neutropenia, hematopoietic stem cell or solid organ transplantation, inherited or acquired immunodeficiency, administration of steroids or other immunosuppressive agents including monoclonal antibodies and new small molecules used for cancer therapy. Critically ill patients are also at high risk of IPA. Clinical signs are unspecific. Early computed tomography (CT)-scan identifies the two main aspects, angioinvasive and airway invasive aspergillosis. Although CT-scan findings are not fully specific they usually allow early initiation of therapy before mycological confirmation of the diagnosis. Role of 18 F-fludeoxyglucose positron emission tomography with computed tomography ( 18 F-FDG PET/CT) is discussed. Confirmation is based on microscopy and culture of respiratory samples, histopathology in case of biopsy, and importantly by detection of Aspergillus galactomannan using an immunoassay in serum and bronchoalveolar lavage fluid. Deoxyribonucleic acid detection by polymerase chain reaction is now standardized and increases the diagnosis yield. Two point of care tests detecting an Aspergillus glycoprotein using a lateral flow assay are also available. Mycological results allow classification into proven (irrespective of underlying condition), probable or possible (for cancer and severely immunosuppressed patients) or putative (for critically ill patients) IPA. New antifungal agents have been developed over the last 2 decades: new azoles (voriconazole, posaconazole, isavuconazole), lipid formulations of amphotericin B (liposomal amphotericin B, amphotericin B lipid complex), echinocandins (caspofungin, micafungin, anidulafungin). Results of main trials assessing these agents in monotherapy or in combination are presented as well as the recommendations for their use according to international guidelines. New agents are under development., Competing Interests: Dr. Ledoux reports personal fees from Gilead, personal fees from Pfizer, personal fees from Daiichi Sankyo, personal fees from Novartis, outside the submitted work.Dr. HERBRECHT reports personal fees from Astellas, personal fees from Basilea, grants and personal fees from Gilead, personal fees from MSD, grants and personal fees from Pfizer, outside the submitted work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Invasive fungal diseases primarily occur in immunocompromised patients. Immunosuppression has become more prevalent due to novel treatments, and this has led to a rise in the incidence of invasive fungal diseases. The antifungal armamentarium has long been insufficient and has taken quite some time to become diverse. Antifungal spectrum, tolerability, and toxicity are critical issues. Amphotericin B and its lipid formulations still have the widest spectrum, but, in spite of the better tolerance of the lipid formulations, toxicity remains a drawback, mostly with regard to renal function. Azoles constitute a heterogeneous antifungal class, in which newer molecules have an improved spectrum of activity. The main concern for the clinician when using azoles relates to the management of their many potential drug-drug interactions in an often fragile patient population. Echinocandins are better tolerated but possess a narrower antifungal spectrum and lack an oral route of administration. Still, their fungicidal activity makes them a weapon of first choice against Candida species. For certain uncommon fungal infections, antifungals such as flucytosine and terbinafine can also be useful. This article will give an overview of the mechanisms of action of currently used antifungals, as well as their spectrum of activity, clinically relevant pharmacological features, drug-drug interactions, and frequent side effects, all of which should drive the clinician's choice of agent when managing invasive fungal infections., Competing Interests: Dr. Ledoux reports personal fees from Gilead, personal fees from Pfizer, personal fees from Daiichi Sankyo, personal fees from Novartis, outside the submitted work. Dr. HERBRECHT reports personal fees from Astellas, personal fees from Basilea, grants and personal fees from Gilead, personal fees from MSD, grants and personal fees from Pfizer, outside the submitted work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Therapeutic Plasma Exchange (TPE) is the primary therapy of immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP). Efficacy and safety data for TPE of iTTP have been assessed with Quarantine and Solvent-Detergent inactivated (SD) plasma. Here, amotosalen-UVA pathogen inactivated (AI) plasma, also in routine use, was evaluated in iTTP., Methods: We conducted a retrospective review of iTTP cases prospectively reported to the French national registry (2010-2013). Cases reviewed underwent TPE with ≥70% of either AI or SD plasma. The primary endpoint was time to platelet count recovery; secondary endpoints were related to follow-up (sustained remission, relapses, flare-ups and refractoriness)., Results: 30 Test patients were identified in the AI group which could be timely matched to 40 Control patients in the SD group. The groups were fairly comparable for clinical presentation. Major findings were: (i) iTTP patients were exposed to lower plasma volumes in the AI group than in the SD group; (ii) Recovery rates were comparable between the groups. Median time to platelet count recovery (>150 × 10 9 /L) trended to be shorter in the AI group though non significantly. Tolerance of AI vs SD plasma was of comparable frequency and severity in either group., Conclusion: TPE with Amotosalen-inactivated plasma demonstrated therapeutic efficacy and tolerability for iTTP patients. In view of the retrospective design, confirmation of these results is required in larger prospective studies., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: First-line antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B. Salvage treatment options are limited and often based on posaconazole oral suspension. With the approval of posaconazole new formulations, patients could benefit from improved pharmacokinetics, safety and tolerability., Objectives: Our aim was to assess the effectiveness of posaconazole new formulations for IM treatment., Methods: We performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. First-line posaconazole new formulations (1st-POSnew) and first-line amphotericin B plus posaconazole new formulations (1st-AMB+POSnew) cases were matched with first-line amphotericin B-based (1st-AMB) treatment controls. Salvage posaconazole new formulations (SAL-POSnew) cases were matched with salvage posaconazole oral suspension (SAL-POSsusp) controls. Each case was matched with up to three controls (based on severity, haematological/oncological malignancy, surgery and/or renal dysfunction)., Results: Five patients receiving 1st-POSnew, 18 receiving 1st-AMB+POSnew and 22 receiving SAL-POSnew were identified. By day 42, a favourable response was reported for 80.0% (n = 4/5) of patients receiving 1st-POSnew, for 27.8% (n = 5/18) receiving 1st-AMB+POSnew and for 50.0% (n = 11/22) receiving SAL-POSnew. Day 42 all-cause mortality of patients receiving posaconazole new formulations was lower compared with controls [20.0% (n = 1/5) in 1st-POSnew versus 53.3% (n = 8/15) in 1st-AMB; 33.3% (n = 6/18) in 1st-AMB+POSnew versus 52.0% (n = 26/50) in 1st-AMB; and 0.0% (n = 0/22) in SAL-POSnew versus 4.4% (n = 2/45) in SAL-POSsusp]., Conclusions: Posaconazole new formulations were effective in terms of treatment response and associated mortality of IM. While posaconazole new formulations may be an alternative for treatment of IM, the limited sample size of our study calls for a cautious interpretation of these observations., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This prospective, observational, multicenter study evaluated the real-world incidence of invasive fungal infection (IFI) during and after micafungin prophylaxis in France. Patients with a hematological malignancy/solid tumor received micafungin prophylaxis according to usual clinical practice and were followed for 3 months. Primary endpoint was breakthrough IFI incidence during prophylaxis. Secondary endpoints included the identification of IFI risk factors, IFI incidence during follow-up, and adverse events (AEs). One hundred and fifty patients (55 children, 95 adults) were enrolled. Micafungin prophylaxis was initiated at 50 mg in adults and at a median 1.01 mg/kg (range: 0.6-2.2) in children. Fifteen patients (10%) experienced an IFI during prophylaxis. IFI breakthrough occurred in 15% children, 7% adults, 3.1% allogeneic transplant patients, 8.7% acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients, 7.0% other patients (never allotransplanted/non-AML/MDS). Nineteen patients (12.7%) experienced an IFI during 3-month follow-up. Micafungin was well tolerated with few treatment-related AEs, supporting its use in this patient population in France., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis., Methods: Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety., Results: Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9--1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups., Conclusions: This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups., Clinical Trials Registration: NCT00413218., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

A mass spectrometry (MS) method that detects a serum disaccharide (DS) (MS-DS) was recently described for the diagnosis of invasive fungal infections (IFI). We carried out a European collaborative study to evaluate this assay. Patients with the following IFI were selected according to the availability of sera obtained at about the time that IFI was documented: invasive candidiasis (IC; n  = 26 patients), invasive aspergillosis (IA; n  = 19), and mucormycosis (MM; n  = 23). Control sera originated from 20 neutropenic patients and 20 patients with bacteremia. MS-DS was carried out in blind manner for the diagnosis of IFI. A diagnosis of IC or IA was confirmed by detection of mannan (Man) or galactomannan (GM), respectively, associated with detection of (1,3)-β-d-glucan (BDG) in both infections. MM was detected by quantitative real-time PCR (qPCR). All tests discriminated sera from patients with IC from sera from control subjects with bacteremia ( P  ≤ 0.0009). For IC, the MS-DS sensitivity and specificity were 51% and 87%, respectively. MS-DS complemented the high specificity of Man monitoring. All tests discriminated sera from IA patients from sera from neutropenic controls ( P  ≤ 0.0009). For IA, MS-DS sensitivity and specificity were 64% and 95%, respectively. Only 13/36 serum samples from patients with MM were concordant by MS-DS and qPCR (6 were positive, and 7 were negative); 14 were positive by MS-DS alone. qPCR and MS-DS made a similar contribution to the diagnosis of MM. In patients undergoing long-term monitoring, the persistent circulation of serum disaccharide was observed, whereas DNA was detected only for a short period after initiation of treatment. MS-DS has an important role to play in the early diagnosis of IFI. Its panfungal nature and complementarity with other tests may justify its use in the management of IFI., (Copyright © 2019 Cornu et al.)

Ruxolitinib is a JAK-1/JAK-2 inhibitor indicated for the treatment of polycythemia vera and primary or secondary myelofibrosis. Only one patient (0.2%) was diagnosed with tuberculosis among the 485 patients receiving ruxolitinib in the four pivotal trials. Fourteen cases of tuberculosis have since been reported. We observed two (3%) mycobacterial infections (one due to Mycobacterium tuberculosis and one due to Mycobacterium avium complex) in our cohort of 65 patients receiving ruxolitinib. This observation suggests that the rate of mycobacterial infection might be higher than that observed in the pivotal trials and that atypical mycobacterial infections can also occur., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Invasive Scedosporium spp. and Lomentospora prolificans infections are an emerging threat in immunocompromised and occasionally in healthy hosts. Scedosporium spp. is intrinsically resistant to most, L. prolificans to all the antifungal drugs currently approved, raising concerns about appropriate treatment decisions. High mortality rates of up to 90% underline the need for comprehensive diagnostic workup and even more for new, effective antifungal drugs to improve patient outcome. For a comprehensive analysis, we identified cases of severe Scedosporium spp. and L. prolificans infections from the literature diagnosed in 2000 or later and the FungiScope ® registry. For 208 Scedosporium spp. infections solid organ transplantation (n = 58, 27.9%) and for 56 L. prolificans infection underlying malignancy (n = 28, 50.0%) were the most prevalent risk factors. L. prolificans infections frequently presented as fungemia (n = 26, 46.4% versus n = 12, 5.8% for Scedosporium spp.). Malignancy, fungemia, CNS and lung involvement predicted worse outcome for scedosporiosis and lomentosporiosis. Patients treated with voriconazole had a better overall outcome in both groups compared to treatment with amphotericin B formulations. This review discusses the epidemiology, prognostic factors, pathogen susceptibility to approved and investigational antifungals, and treatment strategies of severe infections caused by Scedosporium spp. and L. prolificans.

The prognosis of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains unsatisfactory and, despite major advances in genomic studies, the biological mechanisms underlying chemoresistance are still poorly understood. We conducted for the first time a large-scale differential multi-omics investigation on DLBCL patient's samples in order to identify new biomarkers that could early identify patients at risk of R/R disease and to identify new targets that could determine chemorefractoriness. We compared a well-characterized cohort of R/R versus chemosensitive DLBCL patients by combining label-free quantitative proteomics and targeted RNA sequencing performed on the same tissues samples. The cross-section of both data levels allowed extracting a sub-list of 22 transcripts/proteins pairs whose expression levels significantly differed between the two groups of patients. In particular, we identified significant targets related to tumor metabolism (Hexokinase 3), microenvironment (IDO1, CXCL13), cancer cells proliferation, migration and invasion (S100 proteins) or BCR signaling pathway (CD79B). Overall, this study revealed several extremely promising biomarker candidates related to DLBCL chemorefractoriness and highlighted some new potential therapeutic drug targets. The complete datasets have been made publically available and should constitute a valuable resource for the future research.

A chronic antigenic stimulation is believed to sustain the leukemogenic development of chronic lymphocytic leukemia (CLL) and most of lymphoproliferative malignancies developed from mature B cells. Reproducing a proliferative stimulation ex vivo is critical to decipher the mechanisms of leukemogenesis in these malignancies. However, functional studies of CLL cells remains limited since current ex vivo B cell receptor (BCR) stimulation protocols are not sufficient to induce the proliferation of these cells, pointing out the need of mandatory BCR co-factors in this process. Here, we investigated benefits of several BCR co-stimulatory molecules (IL-2, IL-4, IL-15, IL-21 and CD40 ligand) in multiple culture conditions. Our results demonstrated that BCR engagement (anti-IgM ligation) concomitant to CD40 ligand, IL-4 and IL-21 stimulation allowed CLL cells proliferation ex vivo. In addition, we established a proliferative advantage for ZAP70 positive CLL cells, associated to an increased phosphorylation of ZAP70/SYK and STAT6. Moreover, the use of a tri-dimensional matrix of methylcellulose and the addition of TLR9 agonists further increased this proliferative response. This ex vivo model of BCR stimulation with T-derived cytokines is a relevant and efficient model for functional studies of CLL as well as lymphoproliferative malignancies.

Objectives: Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA., Methods: Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model., Results: Four articles were identified that compared L-AmB with AmB-D (Study 1), standard-dose L-AmB (3-5 mg/kg/day) with high-dose L-AmB (10 mg/kg/day; Study 2), voriconazole with AmB-D (Study 3), and isavuconazole with voriconazole (Study 4). In the network meta-analysis, isavuconazole was statistically superior to AmB-D on both ACM (odds ratio [95% credible intervals] shown as natural log, 1.00 [0.26, 1.74]) and overall response (-1.39 [-2.21, -0.63]). Differences between isavuconazole, and standard-dose L-AmB, high-dose L-AmB and voriconazole were not statistically significant for either ACM (0.18 [-1.17, 1.53], 0.50 [-1.11, 2.13] and 0.32 [-0.19, 0.84], respectively) or overall response (-0.99 [-2.21, 0.29], -0.89 [-2.41, 0.65] and 0.06 [-0.43, 0.57], respectively)., Conclusions: This data suggests that the efficacy of isavuconazole for treatment of IA is superior to AmB-D and comparable with both L-AmB and voriconazole.

Treatment outcomes in patients with proven/probable vs possible invasive mould disease (IMD; 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] criteria) needed further assessment. The Phase III SECURE trial compared isavuconazole vs voriconazole for treatment of IMD. This post hoc analysis assessed all-cause mortality (ACM) through day 42 (primary endpoint) and day 84, overall and clinical success at end of treatment (EOT), and drug-related treatment-emergent adverse events (TEAEs) in subgroups with proven/probable or possible IMD. Of 516 randomised patients, 304 (58.9%) had proven/probable IMD and 164 (31.8%) had possible IMD as per EORTC/MSG criteria; 48 did not have IMD. Across treatment groups, day 42 and day 84 ACM were numerically lower for possible vs proven/probable IMD (day 42: 17.1% vs 21.1%; P = 0.3, day 84: 26.2% vs 32.6%; P = 0.15). Overall and clinical success at EOT were significantly higher for possible IMD compared with proven/probable IMD (48.2% vs 36.2%; P = 0.01, 75.0% vs 63.1%; P = 0.01 respectively). Fewer drug-related TEAEs were reported with isavuconazole compared with voriconazole in patients with either proven/probable or possible IMD. Compared with patients with proven/probable IMD, those with possible IMD demonstrated higher overall and clinical success rates, supporting early initiation of antifungal treatment., (© 2018 Blackwell Verlag GmbH.)

Purpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R 2 WLS ) and Copula bivariable ( R 2 Copula ) models. Prespecified criteria for surrogacy required either R 2 WLS or R 2 Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R 2 WLS = 0.83; R 2 Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R 2 WLS = 0.77; R 2 Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature.

Introduction: The frequency of invasive fungal diseases (IFDs) has increased in recent years. Within a context where both treatments and guidelines are fast evolving, we aim to shed new light on IFD management in hematologic departments in France., Methods: A multicenter cross-sectional observational study was prospectively conducted in 24 French centers in September and October 2013., Results: Four hundred ninety-four hospitalized children and adult patients suffering from hematologic malignancy were enrolled: 147 (30%) were allogeneic hematopoietic stem cell transplant (HSCT) recipients, 131 (27%) were patients with acute myeloblastic leukemia or myelodysplastic syndrome (MDS), 71 (14%) were patients with acute lymphoblastic leukemia who did not undergo allogeneic HSCT, and the 145 (29%) remaining patients did not belong to the three above groups. Two hundred forty-six patients (50%) received antifungal treatment, which was prophylactic in 187 (76%) treated patients. These rates were similar across all groups (63-80%). Patients received prophylaxis with an azole (79%), intravenous amphotericin B formulation (10%), echinocandin (9%), or two combination drugs (2%)., Conclusion: Results indicate that prophylaxis is the leading antifungal strategy in French hematology units, regardless of the disease condition, representing 76% of prescriptions for antifungal therapy., Funding: Astellas Pharma France.

Invasive pulmonary aspergillosis (IPA) is a common complication of immunosuppression. Rapid diagnosis using molecular techniques is essential to improve patient survival. PCR techniques are promising in enhancing Aspergillus detection in blood and respiratory samples. We evaluate for the first time the performances of two commercial real-time PCR kits, the A. fumigatus Bio-Evolution and the MycoGENIE A. fumigatus for the detection of A. fumigatus DNA in bronchoalveolar lavage (BAL) from patients with and without IPA. Seventy-three BAL samples were included. Thirty-one of them corresponded to patients with probable IPA, 11 to patients with possible IPA, and 31 to patients without aspergillosis, according to the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. In the probable IPA group, A. fumigatus Bio-Evolution and the MycoGENIE A. fumigatus real-time PCR kits showed a specificity of 100% and a sensitivity of 81% and 71%, respectively. The A. fumigatus Bio-Evolution detected Aspergillus DNA in the 14 BAL samples with a positive Aspergillus culture result, whereas the MycoGENIE A. fumigatus PCR result was positive only for 12. In the possible IPA group, there were no positive real-time PCR or positive Aspergillus culture results. For the patients without aspergillosis, no positive result was observed for real-time PCR kit, despite the presence of various other non-Aspergillus pathogens in this group. Our study demonstrates an excellent specificity and a good sensitivity of A. fumigatus DNA detection in BAL samples with both kits., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Invasive aspergillosis (IA) remains a major cause of morbidity in immunocompromised hosts. This is due to the inability of the host immunity to respond appropriately to Aspergillus. An established risk factor for IA is neutropenia that is encountered by patients undergoing chemotherapy. Herein, we investigate the role of neutrophils in modulating host response to Aspergillus. We found that neutrophils had the propensity to suppress proinflammatory cytokine production but through different mechanisms for specific cytokines. Cellular contact was requisite for the modulation of interleukin-1 beta production by Aspergillus with the involvement of complement receptor 3. On the other hand, inhibition of tumour necrosis factor-alpha production (TNF-α) was cell contact-independent and mediated by secreted myeloperoxidase. Specifically, the inhibition of TNF-α by myeloperoxidase was through the TLR4 pathway and involved interference with the mRNA transcription of TNF receptor-associated factor 6/interferon regulatory factor 5. Our study illustrates the extended immune modulatory role of neutrophils beyond its primary phagocytic function. The absence of neutrophils and loss of its inhibitory effect on cytokine production explains the hypercytokinemia seen in neutropenic patients when infected with Aspergillus., (© 2017 John Wiley & Sons Ltd.)

Cladophialophora bantiana brain abscesses are rare, but are frequently and quickly lethal in transplanted patients. We report the case of a 63-year-old man who had undergone lung transplantation for chronic obstructive pulmonary disease and presented with headaches and a neurological deficit. Magnetic resonance imaging revealed multiple brain abscesses. C. bantiana was identified by DNA sequencing performed directly on cerebral tissue obtained by surgical biopsy. After 6 months of antifungal treatment, the brain abscesses were replaced by ischemic sequelae. The patient died suddenly 2 months later from a pulmonary bacterial infection. This is the second reported case of C. bantiana brain abscesses in a lung transplant recipient, to our knowledge, who experienced a long survival period with medical antifungal treatment alone. We review the literature and discuss our treatment., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)