Publications by authors named "Raoul Herbrecht"

159 Publications

Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia.

Leukemia 2021 May 8;35(5):1463-1474. Epub 2021 Apr 8.

Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

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.
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http://dx.doi.org/10.1038/s41375-021-01221-5DOI Listing
May 2021

Factors associated with coinfections in invasive aspergillosis: a retrospective cohort study.

Clin Microbiol Infect 2021 Mar 2. Epub 2021 Mar 2.

Department of Haematology, Institut de Cancérologie de Strasbourg (ICANS), Strasbourg, France.

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.
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http://dx.doi.org/10.1016/j.cmi.2021.02.021DOI Listing
March 2021

Antifungal Stewardship in Hematology: Reflection of a Multidisciplinary Group of Experts.

Clin Lymphoma Myeloma Leuk 2021 Jan 18;21(1):35-45. Epub 2020 Aug 18.

Department of Oncology and Hematology, Strasbourg University Hospitals and Strasbourg University, Strasbourg, France.

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.
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http://dx.doi.org/10.1016/j.clml.2020.08.010DOI Listing
January 2021

Needles in a haystack: Extremely rare invasive fungal infections reported in FungiScope-Global Registry for Emerging Fungal Infections.

J Infect 2020 11 13;81(5):802-815. Epub 2020 Aug 13.

Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.

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.
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http://dx.doi.org/10.1016/j.jinf.2020.08.015DOI Listing
November 2020

Real-world non-interventional long-term post-authorisation safety study of ruxolitinib in myelofibrosis.

Br J Haematol 2020 12 24;191(5):764-774. Epub 2020 Jun 24.

Department of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria.

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.
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http://dx.doi.org/10.1111/bjh.16729DOI Listing
December 2020

Incidental Discovery of a COVID-19 Infection on a Reevaluation FDG PET/CT in a Patient Treated for Hodgkin Lymphoma.

Clin Nucl Med 2020 Aug;45(8):644-646

Intermediate Care Unit, Institut de Cancérologie Strasbourg, Europe (ICANS), Strasbourg, France.

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.
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http://dx.doi.org/10.1097/RLU.0000000000003144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315839PMC
August 2020

Severe Neutropenia and Agranulocytosis Related to Antithyroid Drugs: A Study of 30 Cases Managed in A Single Reference Center.

Medicines (Basel) 2020 Mar 19;7(3). Epub 2020 Mar 19.

Departments of Internal Medicine, Strasbourg University Hospitals, 67000 Strasbourg, France.

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. 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. 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/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/L) was seen at 8.3 days (range: 2-24), but faster in those receiving hematopoietic growth factors (4.9 days, = 0.046). Two patients died during hospitalization, and the rest had a favorable clinical outcome. 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.
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http://dx.doi.org/10.3390/medicines7030015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151575PMC
March 2020

Clinical characteristics and outcomes of invasive Lomentospora prolificans infections: Analysis of patients in the FungiScope registry.

Mycoses 2020 May 15;63(5):437-442. Epub 2020 Apr 15.

Department of Medicine, University of California San Diego, San Diego, CA, USA.

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.
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http://dx.doi.org/10.1111/myc.13067DOI Listing
May 2020

Invasive pulmonary aspergillosis treatment duration in haematology patients in Europe: An EFISG, IDWP-EBMT, EORTC-IDG and SEIFEM survey.

Mycoses 2020 May 4;63(5):420-429. Epub 2020 Mar 4.

Service de Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Université de Paris, Paris, France.

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.
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http://dx.doi.org/10.1111/myc.13056DOI Listing
May 2020

Antifungal Therapy: New and Evolving Therapies.

Semin Respir Crit Care Med 2020 02 30;41(1):158-174. Epub 2020 Jan 30.

Department of Oncology and Hematology, Strasbourg University Hospital, Strasbourg, France.

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 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.
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http://dx.doi.org/10.1055/s-0039-3400291DOI Listing
February 2020

Invasive Pulmonary Aspergillosis.

Semin Respir Crit Care Med 2020 02 30;41(1):80-98. Epub 2020 Jan 30.

Department of Oncology and Hematology, University Hospital of Strasbourg, Strasbourg, France.

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 F-fludeoxyglucose positron emission tomography with computed tomography (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 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 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.
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http://dx.doi.org/10.1055/s-0039-3401990DOI Listing
February 2020

Invasive Scedosporium spp. and Lomentospora prolificans infections in pediatric patients: Analysis of 55 cases from FungiScope® and the literature.

Int J Infect Dis 2020 Mar 19;92:114-122. Epub 2019 Dec 19.

Pediatric Hematology and Oncology, Hospital for Children and Adolescents, University Hospital, Goethe University, Frankfurt, Germany.

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.
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http://dx.doi.org/10.1016/j.ijid.2019.12.017DOI Listing
March 2020

Risk factors and mortality in invasive Rasamsonia spp. infection: Analysis of cases in the FungiScope registry and from the literature.

Mycoses 2020 Mar 10;63(3):265-274. Epub 2019 Dec 10.

Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), European Diamond Excellence Center for Medical Mycology (ECMM), University of Cologne, Cologne, Germany.

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.
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http://dx.doi.org/10.1111/myc.13039DOI Listing
March 2020

Amotosalen-inactivated fresh frozen plasma is comparable to solvent-detergent inactivated plasma to treat thrombotic thrombocytopenic purpura.

Transfus Apher Sci 2019 Dec 5;58(6):102665. Epub 2019 Nov 5.

Reference Center for Thrombotic Microangiopathies, Assistance Publique des Hôpitaux de Paris, Paris, France; Service d'Hématologie, Hôpital Saint-Antoine, Assistance Publique des Hôpitaux de Paris, Paris, France; Sorbonne Universités, Paris, France. Electronic address:

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/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.
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http://dx.doi.org/10.1016/j.transci.2019.10.007DOI Listing
December 2019

Isavuconazole for the treatment of patients with invasive fungal diseases involving the central nervous system.

Med Mycol 2020 Jun;58(4):417-424

Weiden Clinic, Weiden; and University Medical Center, Würzburg, Germany.

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.
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http://dx.doi.org/10.1093/mmy/myz103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261609PMC
June 2020

Methylprednisolone-induced immune thrombocytopenia.

Am J Hematol 2020 01 31;95(1):E13-E16. Epub 2019 Oct 31.

Etablissement Français du Sang, Service d'Immunologie plaquettaire, Hôpital Henri Mondor, Créteil, France.

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http://dx.doi.org/10.1002/ajh.25645DOI Listing
January 2020

Matched-paired analysis of patients treated for invasive mucormycosis: standard treatment versus posaconazole new formulations (MoveOn).

J Antimicrob Chemother 2019 11;74(11):3315-3327

University of Cologne, Faculty of Medicine and University Hospital of Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), European Diamond Excellence Center for Medical Mycology (ECMM), Cologne, Germany.

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.
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http://dx.doi.org/10.1093/jac/dkz344DOI Listing
November 2019

An atypical cause of dyspnea.

Eur J Intern Med 2019 Oct 5;68:e5-e6. Epub 2019 Jun 5.

Department of Oncology and Hematology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Université de Strasbourg, Inserm, UMR-S1113 / IRFAC, Strasbourg, France.

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http://dx.doi.org/10.1016/j.ejim.2019.05.004DOI Listing
October 2019

Micafungin prophylaxis in routine medical practice in adult and pediatric patients with hematological malignancy: a prospective, observational study in France.

Diagn Microbiol Infect Dis 2019 Jul 26;94(3):268-273. Epub 2019 Jan 26.

Hôpitaux Universitaires de Strasbourg and Université de Strasbourg, Inserm, UMR-S1113/IRFAC, Strasbourg, France.

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.
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http://dx.doi.org/10.1016/j.diagmicrobio.2019.01.011DOI Listing
July 2019

Evaluation of Mass Spectrometry-Based Detection of Panfungal Serum Disaccharide for Diagnosis of Invasive Fungal Infections: Results from a Collaborative Study Involving Six European Clinical Centers.

J Clin Microbiol 2019 05 26;57(5). Epub 2019 Apr 26.

Laboratoire de Parasitologie Mycologie, CHU Lille, Université Lille, INSERM U995-LIRIC (Lille Inflammation Research International Centre), Lille, France

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;  = 26 patients), invasive aspergillosis (IA;  = 19), and mucormycosis (MM;  = 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 ( ≤ 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 ( ≤ 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.
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http://dx.doi.org/10.1128/JCM.01867-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498025PMC
May 2019

Multi-omics dataset to decipher the complexity of drug resistance in diffuse large B-cell lymphoma.

Sci Rep 2019 01 29;9(1):895. Epub 2019 Jan 29.

Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, Université de Strasbourg, CNRS UMR 7178, Strasbourg, France.

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.
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http://dx.doi.org/10.1038/s41598-018-37273-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351558PMC
January 2019

BCR-associated factors driving chronic lymphocytic leukemia cells proliferation ex vivo.

Sci Rep 2019 01 24;9(1):701. Epub 2019 Jan 24.

Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

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.
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http://dx.doi.org/10.1038/s41598-018-36853-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345919PMC
January 2019

Tuberculosis and atypical mycobacterial infections in ruxolitinib-treated patients with primary or secondary myelofibrosis or polycythemia vera.

Int J Infect Dis 2019 Mar 11;80:134-136. Epub 2019 Jan 11.

Department of Oncology and Haematology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Université de Strasbourg, Inserm UMR-S1113/IRFAC, Strasbourg, France.

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.
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http://dx.doi.org/10.1016/j.ijid.2019.01.002DOI Listing
March 2019

Prognostic factors in 264 adults with invasive Scedosporium spp. and Lomentospora prolificans infection reported in the literature and FungiScope.

Crit Rev Microbiol 2019 Feb 10;45(1):1-21. Epub 2019 Jan 10.

a Department I of Internal Medicine , University Hospital of Cologne , Cologne , Germany.

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.
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http://dx.doi.org/10.1080/1040841X.2018.1514366DOI Listing
February 2019

Isavuconazole Versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial.

Clin Infect Dis 2019 05;68(12):1981-1989

Department of Medicine, University of California Davis.

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.
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http://dx.doi.org/10.1093/cid/ciy827DOI Listing
May 2019

Treatment outcomes in patients with proven/probable vs possible invasive mould disease in a phase III trial comparing isavuconazole vs voriconazole.

Mycoses 2018 Nov 13;61(11):868-876. Epub 2018 Aug 13.

University of Würzburg Medical Center, Würzburg, Germany.

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.
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http://dx.doi.org/10.1111/myc.12831DOI Listing
November 2018