Publications by authors named "Anne-Pauline Bellanger"

59 Publications

COVID-19-Associated Pulmonary Aspergillosis, Fungemia, and Pneumocystosis in the Intensive Care Unit: a Retrospective Multicenter Observational Cohort during the First French Pandemic Wave.

Microbiol Spectr 2021 10 20;9(2):e0113821. Epub 2021 Oct 20.

Laboratoire de Microbiologie, Centre Hospitalier de Saint-Denis, Saint-Denis, France.

The aim of this study was to evaluate diagnostic means, host factors, delay of occurrence, and outcome of patients with COVID-19 pneumonia and fungal coinfections in the intensive care unit (ICU). From 1 February to 31 May 2020, we anonymously recorded COVID-19-associated pulmonary aspergillosis (CAPA), fungemia (CA-fungemia), and pneumocystosis (CA-PCP) from 36 centers, including results on fungal biomarkers in respiratory specimens and serum. We collected data from 154 episodes of CAPA, 81 of CA-fungemia, 17 of CA-PCP, and 5 of other mold infections from 244 patients (male/female [M/F] ratio = 3.5; mean age, 64.7 ± 10.8 years). CA-PCP occurred first after ICU admission (median, 1 day; interquartile range [IQR], 0 to 3 days), followed by CAPA (9 days; IQR, 5 to 13 days), and then CA-fungemia (16 days; IQR, 12 to 23 days) ( < 10). For CAPA, the presence of several mycological criteria was associated with death ( < 10). Serum galactomannan was rarely positive (<20%). The mortality rates were 76.7% (23/30) in patients with host factors for invasive fungal disease, 45.2% (14/31) in those with a preexisting pulmonary condition, and 36.6% (34/93) in the remaining patients ( = 0.001). Antimold treatment did not alter prognosis ( = 0.370). Candida albicans was responsible for 59.3% of CA-fungemias, with a global mortality of 45.7%. For CA-PCP, 58.8% of the episodes occurred in patients with known host factors of PCP, and the mortality rate was 29.5%. CAPA may be in part hospital acquired and could benefit from antifungal prescription at the first positive biomarker result. CA-fungemia appeared linked to ICU stay without COVID-19 specificity, while CA-PCP may not really be a concern in the ICU. Improved diagnostic strategy for fungal markers in ICU patients with COVID-19 should support these hypotheses. To diagnose fungal coinfections in patients with COVID-19 in the intensive care unit, it is necessary to implement the correct treatment and to prevent them if possible. For COVID-19-associated pulmonary aspergillosis (CAPA), respiratory specimens remain the best approach since serum biomarkers are rarely positive. Timing of occurrence suggests that CAPA could be hospital acquired. The associated mortality varies from 36.6% to 76.7% when no host factors or host factors of invasive fungal diseases are present, respectively. Fungemias occurred after 2 weeks in ICUs and are associated with a mortality rate of 45.7%. Candida albicans is the first yeast species recovered, with no specificity linked to COVID-19. Pneumocystosis was mainly found in patients with known immunodepression. The diagnosis occurred at the entry in ICUs and not afterwards, suggesting that if Pneumocystis jirovecii plays a role, it is upstream of the hospitalization in the ICU.
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http://dx.doi.org/10.1128/Spectrum.01138-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528108PMC
October 2021

Knowledge and vaccination practices among family physicians in northeastern France regarding tick-borne encephalitis virus.

Ticks Tick Borne Dis 2021 09 17;12(5):101774. Epub 2021 Jun 17.

Emergency Department, Pontarlier Regional Hospital, 25300 Pontarlier, France.

Tick-borne encephalitis (TBE) cases have been emerging in Europe. The Franche-Comte area, in northeastern France, borders Switzerland, but the two countries differ in their approach to TBE surveillance and prevention. Because family physicians (FPs) are in direct contact with the local population, at-risk of infected tick bites, they need to be well aware of TBE epidemiology and management. An observational survey was performed in 2019 in order to investigate Franche-Comte physicians' knowledge and vaccination practices with regard to TBE. Standardized online questionnaires were sent to a list of FPs practicing in Franche-Comte. The questionnaires included socio-demographic details, questions about TBE knowledge, symptomatology and vaccination. The response rate was 14.7%. FPs practicing in rural areas reported a significantly higher frequency of consultations for tick bites. While 81% of FPs indicated that they had some knowledge about TBE, only 20% were at ease with its clinical symptomatology. Thirty-one % of the FP participants performed TBE vaccinations. A general lack of knowledge about TBE and its clinical symptoms was observed in this survey. FPs play an essential role in screening and preventing TBE, especially those practicing in rural areas and in areas bordering Switzerland.
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http://dx.doi.org/10.1016/j.ttbdis.2021.101774DOI Listing
September 2021

Birds of a Feather Precipitate Together.

Arch Bronconeumol (Engl Ed) 2021 May 26. Epub 2021 May 26.

Department of Parasitology-Mycology, University Hospital of Besancon, Besancon, France.

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http://dx.doi.org/10.1016/j.arbres.2021.05.012DOI Listing
May 2021

Microsporidiosis after liver transplantation: A French nationwide retrospective study.

Transpl Infect Dis 2021 Aug 22;23(4):e13665. Epub 2021 Jun 22.

Hospices civils de Lyon, Hôpital Edouard Herriot, Unité de transplantation hépatique, et Université Claude Bernard Lyon 1, Lyon, France.

Background: Microsporidiosis has been largely reported in patients with acquired immunodeficiency syndrome, but emerged as a cause of persistent diarrhea in solid organ transplant patients.

Methods: Through the French Microsporidiosis Network and the Groupe français de recherche en greffe de foie, we collected all microsporidiosis cases identified in liver transplant patients between 1995 and 2020 in France.

Results: We identified 24 liver transplant recipients with microsporidiosis. Sex ratio was balanced and median age was 58.8 (3.5-83.5) years (there were 4 children). Microsporidiosis occurred at a median time of 3.9 (0.1-18.9) years post-transplant. Median duration of diarrhea before diagnosis was 22 days (12-45). Therapeutic care included immunosuppressive therapy changes in 20 patients, as follows: stop cyclosporine or tacrolimus (n = 2), dose reduction of cyclosporine or tacrolimus (n = 12), stop MMF (n = 5), and dose reduction of corticosteroids (n = 1). In addition, 15 patients received specific therapy against microsporidiosis: fumagillin (n = 11) or albendazole (n = 4). Median duration of treatment was 14 days (8-45 days). Finally, 7 patients had immunosuppressive treatment tapering only. Microsporidiosis was complicated by renal failure in 15 patients, requiring dialysis in one case. Two patients had infection relapse. No patient presented proven rejection within the 3 months after microsporidiosis. None of the patients died within the 3 months after microsporidiosis.

Conclusions: Microsporidiosis is a very rare infection after liver transplantation but can induce severe dehydration and renal failure. Therefore, it must be systematically sought in any case of persistent diarrhea after first line screening of frequent infectious causes.
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http://dx.doi.org/10.1111/tid.13665DOI Listing
August 2021

Innate and adaptive immune responses following PD-L1 blockade in treating chronic murine alveolar echinococcosis.

Parasite Immunol 2021 08 7;43(8):e12834. Epub 2021 May 7.

Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland.

Background: Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) immune checkpoint blockade are efficacious in certain cancer therapies.

Objectives: The present study aimed to provide a picture about the development of innate and adaptive immune responses upon PD-L1 blockade in treating chronic murine AE.

Methods: Immune treatment started at 6 weeks post-E. multilocularis infection, and was maintained for 8 weeks with twice per week anti-PD-L1 administration (intraperitoneal). The study included an outgroup-control with mice perorally medicated with albendazole 5 d/wk, and another one with both treatments combined. Assessment of treatment efficacy was based on determining parasite weight, innate and adaptive immune cell profiles, histopathology and liver tissue cytokine levels.

Results/conclusions: Findings showed that the parasite load was significantly reduced in response to PD-L1 blockade, and this blockade (a) contributed to T-cell activity by increasing CD4 /CD8 effector T cells, and decreasing Tregs; (b) had the capacity to restore DCs and Kupffer cells/Macrophages; (c) suppressed NKT and NK cells; and thus (d) lead to an improved control of E. multilocularis infection in mice. This study suggests that the PD-L1 pathway plays an important role by regulating adaptive and innate immune cells against E. multilocularis infection, with significant modulation of tissue inflammation.
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http://dx.doi.org/10.1111/pim.12834DOI Listing
August 2021

New clinical algorithm including fungal biomarkers to better diagnose probable invasive pulmonary aspergillosis in ICU.

Ann Intensive Care 2021 Mar 8;11(1):41. Epub 2021 Mar 8.

Parasitology-Mycology Department, University Hospital of Besançon, 25000, Besançon, France.

Background: The classification of invasive pulmonary aspergillosis (IPA) issued by the European Organization for the Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) is used for immunocompromised patients. An alternative algorithm adapted to the intensive care unit (ICU) population has been proposed (AspICU), but this algorithm did not include microbial biomarkers such as the galactomannan antigen and the Aspergillus quantitative PCR. The objective of the present pilot study was to evaluate a new algorithm that includes fungal biomarkers (BM-AspICU) for the diagnosis of probable IPA in an ICU population.

Patients And Methods: Data from 35 patients with pathology-proven IPA according to European Organization for the Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSGERC)-2008 criteria were extracted from the French multicenter database of the Invasive Fungal Infections Surveillance Network (RESSIF). The patients were investigated according to the AspICU algorithm, and the BM-AspICU algorithm in analyzing the clinical, imaging, and biomarker data available in the records, without taking into account the pathology findings.

Results: Eight patients had to be excluded because no imaging data were recorded in the database. Among the 27 proven IPAs with complete data, 16 would have been considered as putative IPA with the AspICU algorithm and 24 would have been considered as probable IPA using the new algorithm BM-AspICU. Seven out of the 8 patients with probable BM-AspICU IPA (and not classified with the AspICU algorithm) had no host factors and no Aspergillus-positive broncho-alveolar lavage fluid (BALF) culture. Three patients were non-classifiable with any of the two algorithms, because they did not have any microbial criteria during the course of the infection, and diagnosis of proven aspergillosis was done using autopsy samples.

Conclusion: Inclusion of biomarkers could be effective to identify probable IPA in the ICU population. A prospective study is needed to validate the routine application of the BM-AspICU algorithm in the ICU population.
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http://dx.doi.org/10.1186/s13613-021-00827-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938267PMC
March 2021

Investigating new serological and tissue markers for the follow-up of patients operated for alveolar echinococcosis.

Parasite Immunol 2021 06 18;43(6):e12827. Epub 2021 Mar 18.

Visceral Surgery Department, Inselspital, University Hospital of Bern, Bern, Switzerland.

Aims: Alveolar echinococcosis (AE) is characterized by a chronically progressing hepatic injury caused by Echinococcus multilocularis. Surgery presently remains the best curative option. Currently, biological predictive features derived from the resected specimens are not suitable to assess surgery efficacy. The present study was designed to investigate whether a selection of markers measured on the resected specimens exhibits predictive features related to parasite viability, or to a total elimination of the parasite, in addition to serological markers.

Methods And Results: In a collaboration between two centres, one in France (Besançon), and one in Switzerland (Bern), samples from 40 AE patients were analysed by microarray and serology techniques, individually. Paired serum samples before and after surgery were obtained for 26 patients. In the sera, a significant decrease in PD-L1 levels was observed after surgery, in addition to anti-Em18 levels. In the liver tissue, low levels of Cluster of Differentiation (CD)-3 were correlated with the absence of serum anti-Em18 after surgery.

Conclusion: This study showed PD-L1 is promising as a potential serological marker and further confirmed the performance of anti-Em18 serology. Further studies on a larger cohort are needed to confirm the utility of performing systematically microarray on resected liver tissue.
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http://dx.doi.org/10.1111/pim.12827DOI Listing
June 2021

Characteristics and outcome according to underlying disease in non-AIDS patients with acute respiratory failure due to Pneumocystis pneumonia.

Eur J Clin Microbiol Infect Dis 2021 Jun 7;40(6):1191-1198. Epub 2021 Jan 7.

AP-HP, Hôpital Saint-Louis, Medical ICU, Paris, France.

In the non-AIDS group, several underlying conditions and immune defects could lead to different PCP presentations. This study compared PCP presentation and outcome according to the underlying disease. A secondary analysis of a previously published prospective observational study including 544 PCP patients was done. Only non-AIDS patients were included. Underlying disease was defined as chronic lymphocytic leukemia (CLL), organ transplantation, solid cancer, allogeneic hematopoietic stem cell transplant (AHSCT), other hematological diseases, and immunosuppressive treatment. Clinical characteristics and outcomes were compared between groups. Multiple correspondent analyses compared clinical characteristics at diagnosis. Day 30 mortality was analyzed. Three hundred and twenty-one patients were included in the study. The underlying diseases were hematological malignancy (n = 75), AHSCT (n = 14), CLL (n = 19), solid organ transplant (n = 94), solid tumor (n = 39), and immunosuppressive treatment (n = 57). Compared with other underlying diseases, PCP related to CLL was closer to PCP related to AIDS presentation (long duration of symptoms before diagnosis, high level of dyspnea, and low oxygen saturation at diagnosis). Day 30 mortality was associated with underlying disease, oxygen flow, and shock at ICU admission. PCP presentations may vary according to the underlying reason for immunosuppression. Response to treatment and adjuvant steroid therapy should be analyzed regarding this result.
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http://dx.doi.org/10.1007/s10096-020-04118-wDOI Listing
June 2021

Exposure Assessment Tools for Hypersensitivity Pneumonitis. An Official American Thoracic Society Workshop Report.

Ann Am Thorac Soc 2020 12;17(12):1501-1509

This report is based on proceedings from the Exposure Assessment Tools for Hypersensitivity Pneumonitis (HP) Workshop, sponsored by the American Thoracic Society, that took place on May 18, 2019, in Dallas, Texas. The workshop was initiated by members from the Environmental, Occupational, and Population Health and Clinical Problems Assemblies of the American Thoracic Society. Participants included international experts from pulmonary medicine, occupational medicine, radiology, pathology, and exposure science. The meeting objectives were to ) define currently available tools for exposure assessment in evaluation of HP, ) describe the evidence base supporting the role for these exposure assessment tools in HP evaluation, ) identify limitations and barriers to each tool's implementation in clinical practice, ) determine which exposure assessment tools demonstrate the best performance characteristics and applicability, and ) identify research needs for improving exposure assessment tools for HP. Specific discussion topics included history-taking and exposure questionnaires, antigen avoidance, environmental assessment, specific inhalational challenge, serum-specific IgG testing, skin testing, lymphocyte proliferation testing, and a multidisciplinary team approach. Priorities for research in this area were identified.
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http://dx.doi.org/10.1513/AnnalsATS.202008-942STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706597PMC
December 2020

Soluble programmed death-1 (sPD-1) as predictor of early surgical outcomes of paediatric cystic echinococcosis.

Parasite Immunol 2021 03 1;43(3):e12809. Epub 2020 Dec 1.

Department of Parasitology Mycology, University Hospital of Besançon, UMR/CNRS 6249 Chrono-Environnement Research Team, University of Bourgogne, Franche-Comté, France.

Aims: Following treatment, cystic echinococcosis (CE) exhibits a relatively high relapse rate. Here, we evaluated the value of soluble programmed death-1 (sPD-1), sPD-1 ligand (sPD-L1) and anti-recP29 antibody concentrations, as predictors of early surgical treatment outcomes in young CE-affected patients.

Methods And Results: This prospective study included 59 Tunisian children (177 plasmas), where CE was surgically treated and monitored for 3 post-operative years. Based on CE post-surgical development, patients were clustered into a 'No relapsed' CE (NRCE; n = 39) and a 'Relapsed' CE (RCE; n = 20) group. Plasma levels of sPD-1, sPD-L1 and anti-recP29 IgG were measured using ELISA. In the NRCE group, sPD-1, sPD-L1 and anti-recP29 IgG concentrations were significantly lower at D365 than at D30. By contrast, in the RCE group, no significant difference was observed between D0, D30 and D365. When considering individual variations, the probability to be 'relapse-free' was 67% and 73% when anti-recP29 IgG and sPD-L1 level, respectively, decreased between D30 and D365. The probability to be 'relapse-free' was 86% when the sPD-1 level decreased between D30 and D365 (P = .003; chi-square test).

Conclusion: sPD-1 may be a useful biomaker for the early evaluation of surgical procedure efficacy in paediatric CE cases.
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http://dx.doi.org/10.1111/pim.12809DOI Listing
March 2021

Studying smoking benefit in farmer's lung to understand Covid-19.

Occup Med (Lond) 2020 12;70(9):620-621

Chrono-Environment Research Team UMR/CNRS-6249, University of Bourgogne Franche-Comté, Besançon, France.

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http://dx.doi.org/10.1093/occmed/kqaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454784PMC
December 2020

Echinococcus multilocularis vesicular fluid induces the expression of immune checkpoint proteins in vitro.

Parasite Immunol 2020 06;42(6):e12711

Parasitology Mycology Department, Jean Minjoz University Hospital, Besancon, France.

Aims: Alveolar echinococcosis is a severe chronic helminthic infection that mimics a tumour-like disease. This study aimed at investigating in vitro interactions between Echinococcus multilocularis vesicular fluid (VF) and different immune checkpoints (PD-1/PD-L1, CTLA-4, LAG-3 and TIM-3).

Methods And Results: Peripheral blood mononuclear cells (PBMC) from healthy blood donors were isolated by Ficoll. Natural killer (NK) cells were selected. Each type of cell was stimulated individually with E. multilocularis-VF. Expression of the different immune checkpoints was measured by flow cytometry on day 3 and day 6; all supernatants were used for immunoassays. Cells and supernatants from 22 healthy donors were analysed. A significant increase of PD-1, PD-L1, LAG-3 and TIM-3 was observed upon E. multilocularis-VF exposure for NK cells on day 3 (P < .05, Wilcoxon signed-rank test). A significant increase of PD-L1 and CTLA-4 was observed upon E. multilocularis-VF exposure for T cells on day 6 (P < .05, Wilcoxon signed-rank test), which was associated with increased levels of Th1 and Th2 cytokines P < .05, Wilcoxon signed-rank test).

Conclusion: These preliminary data suggest that immune checkpoints could be a way for E. multilocularis to modulate the host immune response during alveolar echinococcosis.
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http://dx.doi.org/10.1111/pim.12711DOI Listing
June 2020

Invasive Aspergillosis Due to Aspergillus Section Usti: A Multicenter Retrospective Study.

Clin Infect Dis 2021 04;72(8):1379-1385

Department of Infectious Diseases, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Background: Aspergillus spp. of section Usti (A. ustus) represent a rare cause of invasive aspergillosis (IA). This multicenter study describes the epidemiology and outcome of A. ustus infections.

Methods: Patients with A. ustus isolated from any clinical specimen were retrospectively identified in 22 hospitals from 8 countries. When available, isolates were sent for species identification (BenA/CaM sequencing) and antifungal susceptibility testing. Additional cases were identified by review of the literature. Cases were classified as proven/probable IA or no infection, according to standard international criteria.

Results: Clinical report forms were obtained for 90 patients, of whom 27 had proven/probable IA. An additional 45 cases were identified from literature review for a total of 72 cases of proven/probable IA. Hematopoietic cell and solid-organ transplant recipients accounted for 47% and 33% cases, respectively. Only 8% patients were neutropenic at time of diagnosis. Ongoing antimold prophylaxis was present in 47% of cases. Pulmonary IA represented 67% of cases. Primary or secondary extrapulmonary sites of infection were observed in 46% of cases, with skin being affected in 28% of cases. Multiple antifungal drugs were used (consecutively or in combination) in 67% of cases. The 24-week mortality rate was 58%. A. calidoustus was the most frequent causal agent. Minimal inhibitory concentrations encompassing 90% isolates (MIC90) were 1, 8, >16, and 4 µg/mL for amphotericin B, voriconazole, posaconazole, and isavuconazole, respectively.

Conclusions: Aspergillus ustus IA mainly occurred in nonneutropenic transplant patients and was frequently associated with extrapulmonary sites of infection. Mortality rate was high and optimal antifungal therapy remains to be defined.
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http://dx.doi.org/10.1093/cid/ciaa230DOI Listing
April 2021

Positive quantitative PCR detecting Fusarium solani in a case of mixed invasive fungal disease due to Mucorales and Fusarium solani.

Bone Marrow Transplant 2020 05 5;55(5):873-876. Epub 2020 Feb 5.

Chrono-Environnement CNRS 6249 Research Team, Franche-Comté University, Besançon, France.

We present a case of invasive fungal co-infection in a young patient treated for an acute myeloid leukemia and having undergone a twice-haploid matched unrelated donor hematopoietic stem cell transplantation (HSCT) with two different donors. A mucormycosis diagnosis was made shortly after the patient's admission using imagery and specific Mucorales qPCR which was treated with liposomal amphotericin B and posaconazole. Twenty days later, a blood culture was positive for Fusarium solani, and disseminated cutaneous lesions appeared. The antifungal treatment was changed to liposomal amphotericin B and voriconazole. Thanks to a complete hematological reconstitution and despite a co-infection with two aggressive filamentous opportunistic fungi, the patient recovered. We took advantage of this clinical case to test a specific Fusarium solani qPCR, which proved to be promising when performed retrospectively on some of the patient samples.
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http://dx.doi.org/10.1038/s41409-020-0819-3DOI Listing
May 2020

A survey investigating the current practice of French health professionals regarding infection risk after monkey bites.

Zoonoses Public Health 2020 03 12;67(2):193-197. Epub 2019 Dec 12.

Emergency Department, Regional Hospital of Pontarlier, Pontarlier, France.

International tourism is steadily increasing, with 15% of travellers reporting health problems when they come back. Animal bites represent 2% of consulting causes, of which 20% are due to monkey bites. The Monkey B virus (Macacine alphaherpesvirus 1) is an alphaherpesvirus (Herpesviridae, genus Simplexvirus) enzootic in macaques (Genus Macaca). Zoonotic infections with the Monkey B virus following exposure to macaques are exceptionally rare, but can cause fatal encephalomyelitis in humans. An observational survey was undertaken in 2018 to assess the practice of French health professionals regarding infection risk after monkey bites. French health professionals practicing in vaccination and rabies centres were specifically targeted for this study. Standardized questionnaires were sent by email to a sample of French health professionals. They were asked to participate on a voluntary and anonymous basis. The questionnaires requested epidemiological details and included multiple-choice questions about the infection management of monkey bites. The response rate was 33.5%. The frequency of monkey bites in 2017 was variable with a minority of centres managing more than 6 per year (12%), 46% managing 1-5 monkey bites and 42% none. Most of the monkey bites were described as occurring in South Asia at tourist sites, on naked upper limbs, shortly after the travellers arrived at their destination. Tetanus status verification, rabies post-exposure prophylaxis and antibiotic therapy were said to be prescribed in most cases. Knowledge about the Monkey B virus was reported as scarce for 38% of the participants. The number of monkey bites managed per year per centre varied greatly but practices regarding infectious risk after monkey bites were generally homogeneous. The risk of Monkey B virus transmission did not readily come to mind in the differential diagnosis of infection risk for many French health professionals.
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http://dx.doi.org/10.1111/zph.12665DOI Listing
March 2020

Invasive Fungal Disease, Isavuconazole Treatment Failure, and Death in Acute Myeloid Leukemia Patients.

Emerg Infect Dis 2019 09;25(9):1778-1779

We present 2 fatal cases of invasive fungal disease with isavuconazole treatment failure in immunocompromised patients: one with a TR34-L98H azole-resistant Aspergillus fumigatus isolate and the other a Rhizomucor-A. fumigatus co-infection. Such patients probably require surveillance by galactomannan antigen detection and quantitative PCRs for A. fumigatus and Mucorales fungi.
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http://dx.doi.org/10.3201/eid2509.190598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711214PMC
September 2019

Hypersensitivity pneumonitis: A new strategy for serodiagnosis and environmental surveys.

Respir Med 2019 04 5;150:101-106. Epub 2019 Mar 5.

Department of Parasitology Mycology, University Hospital of Besançon, UMR/CNRS 6249 Chrono-Environnement Research Team, University of Bourgogne- Franche-Comté, France.

We propose a strategy for serodiagnosis of hypersensitivity pneumonitis (HP): 1) question patients about their private or occupational activity, or visit him on site; 2) select panels of six somatic specific antigens appropriate for each type of exposure; 3) and use ELISA to test concomitantly two recombinant antigens highly specific to Farmer's lung, Metalworking-fluid HP, and for Bird fancier's lung. The serodiagnosis provides an immunological argument that may complete radiological, functional lung exploration and clinical features; 4) If the serodiagnosis is negative but the suspicion of HP is strong, a microbial analysis of the patient's specific exposure is conducted; 5) "A la carte" antigens are produced from the microorganisms isolated in the patient's environment sample and tested; 6) Finally, the patient may be asked to undergo a specific inhalation challenge with the offending antigens in a safety cabin, or to avoid his usual environment for a few days.
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http://dx.doi.org/10.1016/j.rmed.2019.02.019DOI Listing
April 2019

Molecular Strategies to Diagnose Mucormycosis.

J Fungi (Basel) 2019 Mar 20;5(1). Epub 2019 Mar 20.

Parasitology Mycology Department, University Hospital, 25000 Besancon, France.

Molecular techniques have provided a new understanding of the epidemiology of mucormycosis and improved the diagnosis and therapeutic management of this life-threatening disease. PCR amplification and sequencing were first applied to better identify isolates that were grown from cultures of biopsies or bronchalveolar lavage samples that were collected in patients with Mucorales infection. Subsequently, molecular techniques were used to identify the fungus directly from the infected tissues or from bronchalveolar lavage, and they helped to accurately identify Mucorales fungi in tissue samples when the cultures were negative. However, these tools require invasive sampling (biospsy, bronchalveolar lavage), which is not feasible in patients in poor condition in Hematology or Intensive Care units. Very recently, PCR-based procedures to detect Mucorales DNA in non-invasive samples, such as plasma or serum, have proved successful in diagnosing mucormycosis early in all patients, whatever the clinical status, and these procedures are becoming essential to improving patient outcome.
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http://dx.doi.org/10.3390/jof5010024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463105PMC
March 2019

Rapid identification of Candida sp. by MALDI-TOF mass spectrometry subsequent to short-term incubation on a solid medium.

APMIS 2019 Apr;127(4):217-221

Parasitology Mycology Department, Jean Minjoz University Hospital, Besancon, France.

Rapid identification of Candida species is important for appropriate antifungal therapy of fungemia. The matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) system is a useful tool to identify bacteria and yeasts. In this study, we evaluated the feasibility of identifying yeasts after a short-term incubation on a solid medium. We tested 24 strains of eight Candida species. Blood culture bottles were spiked with a calibrated suspension of each Candida strain. Three different culture media, two types of blood culture bottles and three different incubation time points were tested. A multivariable random-effects logistic regression analysis was performed for determining factors independently associated with a successful MALDI-TOF MS identification. One-hundred and thirty-one out of 432 MALDI-TOF MS analyses (30%) exhibited a score ≥ 1.7. The performance of the technique varied across Candida species. Factors associated with a successful identification were the use of a chromogenic Candida medium and the time points 4 and 5 h. Using the factors 'chromogenic Candida medium' and time point 5 h the global performance of identification reached 60% and a mean MALDI-TOF score of 1.78. Identifying yeasts after a short-term incubation on a solid medium seems possible, especially when using a chromogenic Candida medium and respecting at least 5 h of incubation. This assay was a first step and needs to be completed using more strains, various chromogenic Candida medium and maybe also testing a longer culture time such as 6 h.
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http://dx.doi.org/10.1111/apm.12936DOI Listing
April 2019

Microbial exposure to dairy farmers' dwellings and COPD occurrence.

Int J Environ Health Res 2019 Aug 21;29(4):387-399. Epub 2018 Nov 21.

a UMR/CNRS 6249 Chrono-Environnement, UFR Sciences médicales et pharmaceutiques , University of Bourgogne Franche-Comté , Besançon , France.

Dairy farming is a risk factor for chronic obstructive pulmonary disease (COPD). The aim was to determine predictive markers either in blood samples or in dwelling dust samples by comparing COPD and healthy controls with or without farming activity. Dust was collected and analyzed by real-time quantitative PCR. ELISA and DELFIA® were performed to assay the level of specific IgG and IgE of 10 targeted microorganisms. The dwelling exposure of farmers was higher than in the non-farmers (Especially and ). The IgG response against and was more often higher in the farmers than the non-farmers. However, exposure and sensitization to the microorganisms tested cannot explain the occurrence of COPD in the dairy farmers' population. COPD development is probably caused by multiple factors associated with exposure over a period of several years.
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http://dx.doi.org/10.1080/09603123.2018.1545900DOI Listing
August 2019

Immunotherapy of alveolar echinococcosis via PD-1/PD-L1 immune checkpoint blockade in mice.

Parasite Immunol 2018 Dec 4;40(12):e12596. Epub 2018 Nov 4.

Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland.

The growth potential of the tumour-like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly dependent upon the nature/function of the periparasitic adaptive host immune-mediated processes. PD-1/PD-L1 pathway (programmed cell death 1), which inhibits lymphocytic proliferation in tumour development, is over-expressed at the chronic stage of AE. We tested the impact of a PD-1/PD-L1 pathway blockade on the outcome of both chronic AE (intraperitoneal metacestode inoculation, secondary AE and SAE) and acute AE (peroral egg infection, primary AE and PAE). To assess the parasite proliferation potential, we measured parasite mass weight for SAE and liver lesion number for PAE. In both models, the parasite load was significantly decreased in response to anti-PD-L1 antibody treatment. In SAE, anti-PDL1 administration was associated with increased Th1 response parameters and decreased Treg responses, while in PAE anti-PDL1 administration was associated with fewer lesions in the liver and decreased Treg/Th2 responses. Our findings highly suggested that a PD-1/PD-L1 pathway blockade triggered the host immune responses in favour of an immune-mediated control of E. multilocularis proliferation. Based on this, future studies that combine PD-1/PD-L1 blockade with a parasitostatic albendazole medication may yield in a putatively curative therapeutic approach to control alveolar echinococcosis.
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http://dx.doi.org/10.1111/pim.12596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587932PMC
December 2018

Quantitative PCR (qPCR) Detection of Mucorales DNA in Bronchoalveolar Lavage Fluid To Diagnose Pulmonary Mucormycosis.

J Clin Microbiol 2018 08 26;56(8). Epub 2018 Jul 26.

Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Besançon, France

Early diagnosis and treatment are essential to improving the outcome of mucormycosis. The aim of this retrospective study was to assess the contribution of quantitative PCR detection of Mucorales DNA in bronchoalveolar lavage fluids for early diagnosis of pulmonary mucormycosis. Bronchoalveolar lavage fluid samples ( = 450) from 374 patients with pneumonia and immunosuppressive conditions were analyzed using a combination of 3 quantitative PCR assays targeting the main genera involved in mucormycosis in France (, , and ). Among these 374 patients, 24 patients had at least one bronchoalveolar lavage fluid sample with a positive PCR; 23/24 patients had radiological criteria for invasive fungal infections according to consensual criteria; 10 patients had probable or proven mucormycosis, and 13 additional patients had other invasive fungal infections (4 probable aspergillosis, 1 proven fusariosis, and 8 possible invasive fungal infections). Only 2/24 patients with a positive PCR result on a bronchoalveolar lavage fluid sample had a positive Mucorales culture. PCR was also positive on serum in 17/24 patients. In most cases, a positive PCR result was first detected using sera (15/17). However, a positive PCR on bronchoalveolar lavage fluid was the earliest and/or the only biological test revealing mucormycosis in 4 patients with a final diagnosis of probable or proven mucormycosis, 3 patients with probable aspergillosis, and one patient with a possible invasive fungal infection. Mucorales PCR performed on bronchoalveolar lavage fluid could provide additional support for earlier administration of Mucorales-directed antifungal therapy, thus improving the outcome of lung mucormycosis cases.
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http://dx.doi.org/10.1128/JCM.00289-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062785PMC
August 2018

Local retrospective analysis of galactomannan cut-off values in bronchoalveolar lavage fluids for diagnosis of invasive aspergillosis.

Folia Microbiol (Praha) 2018 Nov 30;63(6):757-761. Epub 2018 May 30.

Department of Parasitology-Mycology, Besançon University Hospital, Besançon, France.

Galactomannan antigen (GM) testing has been used for decades to screen immunocompromised patients for invasive aspergillosis (IA). Recent publications suggested that using a higher cut-off value than 0.5 in bronchoalveolar lavage fluid (BALF) could be more discriminant for hematology patients. We retrospectively analyzed the values of GM in BALF over 7 years (from 2010 to 2016). Performance indicators of the GM in BALF, according to three different cut-off values (0.5, 0.8, 1.5), were calculated using Stata 14.1. IA classification for hematology patients was based on European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria, as defined in 2008. A number of 716 GM were performed on BALF from 2010 to 2016 (597 patients) and 66 were positive (> 0.5). Among these 597 patients, 27 IA were diagnosed, 13 with a positive GM in BALF, 9 with a negative GM in BALF, and 5 unclassified IA (ICU patients). The analysis of performance indicators, based on our local data, did not demonstrate any significant difference using a higher cut-off value of GM in BALF. This result may be explained by the local recruitment of patients and by pre-analytic variations during BALF realization.
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http://dx.doi.org/10.1007/s12223-018-0618-zDOI Listing
November 2018

Development of a quantitative PCR detecting Cunninghamella bertholletiae to help in diagnosing this rare and aggressive mucormycosis.

Bone Marrow Transplant 2018 09 30;53(9):1180-1183. Epub 2018 Apr 30.

Chrono-Environnement CNRS 6249 Research Team, Franche-Comté University, Besançon, France.

Mucormycosis is an invasive mold infection, frequently fatal in immunocompromised patients. We report the case of a patient with chronic lymphocytic leukemia admitted to the hematology unit for febrile aplasia. Pulmonary lesions suggesting a fungal infection expanded/increased despite a combination of posaconazole and liposomal amphotericin B. The fungal biomarkers performed repeatedly were negative. At D65 after chemotherapy a bronchial biopsy was positive for Cunninghamella bertholletiae. The patient died despite appropriate antifungal management. A qPCR targeting Cunninghamella was developed a posteriori, and a retrospective analysis showed that a sample was positive more than 30 days before culture-based identification could be made.
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http://dx.doi.org/10.1038/s41409-018-0194-5DOI Listing
September 2018

Echinococcus multilocularis vesicular fluid inhibits activation and proliferation of natural killer cells.

Folia Parasitol (Praha) 2017 08 25;64. Epub 2017 Aug 25.

Parasitology-Mycology Department, University Hospital, Besancon, France.

Alveolar echinococcosis is a severe chronic helminthic disease that mimics slow-growing liver cancer. The immune evasion strategy of Echinococcus multilocularis Leuckart, 1863 remains poorly understood. The aim of this study was to investigate in vitro the impact of E. multilocularis vesicular fluid (Em-VF) on peripheral blood mononuclear cells (PBMC) and on natural killer (NK) cells. PBMC and NK cells were exposed to Em-VF (1 µg/ml) during six days. The effect of Em-VF was assessed on CD69, viability and proliferation, and on and transforming growth factor β (TGF-β), interferon γ (IFN-γ), interleukin 17 (IL-17) and interleukin 10, using flow cytometry and ELISA, respectively. Exposure to Em-VF had no bearing on PBMC's viability, proliferation and expression of CD69. In contrast, higher levels of IL-17 at day three and of TGF-β at day six were observed in PBMC supernatant after exposure to Em-VF (p < 0.05, Wilcoxon signed-rank test). Exposure to Em-VF induced a significant decrease of CD69 expression of NK cells at day three and a significant decrease of proliferation of NK cells at day six (p < 0.05, Wilcoxon signed-rank test). In contrast, NK cells viability and levels of cytokines did not vary significantly over Em-VF stimulation. Exposure to Em-VF had a significant bearing on activation and proliferation of NK cells. NK cells may play an important role in the immune response of the host against E. multilocularis.
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http://dx.doi.org/10.14411/fp.2017.029DOI Listing
August 2017

Fungal aerocontamination exposure risk for patients in 3 successive locations of a pediatric hematology unit department: Influence of air equipment and building structure on air quality.

Am J Infect Control 2017 Oct 8;45(10):e109-e113. Epub 2017 Jun 8.

Chrono-Environnement UMR 6249 Research Team, Bourgogne-Franche-Comté University, Besançon, Doubs, France; Parasitology-Mycology Department, Besançon University Hospital, Besançon, Doubs, France.

Background: Invasive fungal infections (IFIs) play an important role in the mortality of immunocompromised patients. The pediatric hematology department (PHD) at Besançon University Hospital has relocated 3 times: (1) from a building without an air filtration system (B1), (2) to a renovated building with low air pressure (B2), and (3) to a new building with high air pressure and high-efficiency particulate air filters (B3). This study aimed to investigate how these relocations influenced the fungal exposure risk for the PHD's patients.

Methods: Air samples were taken monthly in patient rooms and weekly in corridors. The detection of opportunistic fungi species was used to assess IFI risk. Data were analyzed using univariate and multivariate random-effects negative binomial regression.

Results: A total of 1,074 samples from 29 rooms over a 10-year period showed that renovation of an old building with a basic ventilation system did not lead to a significant improvement of air quality (P = .004, multivariate analysis). Among factors linked to higher risk of patient rooms mold contamination was fungal contamination of the corridors (P <.001).

Conclusions: This study demonstrates that corridors can be used as reliable sentinel to prevent fungal contamination in patient rooms. Only relocation in building B3, equipped with laminar air flow, achieved adequate air quality.
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http://dx.doi.org/10.1016/j.ajic.2017.04.283DOI Listing
October 2017

Fungal peptides from pneumonitis hypersensitivity etiologic agents are able to induce specific cellular immune response.

J Immunol Methods 2017 01 20;440:67-73. Epub 2016 Nov 20.

Chrono-Environnement CNRS 6249 Research Team, Franche-Comté University, Besançon, France; Parasitology-Mycology Department, Besançon University Hospital, Besançon, France.

Purpose: Hypersensitivity pneumonitis (HP) is an immunoallergic disease due to chronic exposure to high quantities of different microorganisms such as Mycobacterium immunogenum (Mi), a mycobacterium, and Lichtheimia corymbifera (Lc), a filamentous fungus. It has recently been demonstrated that the protein DLDH (dihydrolipoyl dehydrogenase), is common to these microorganisms. This study aimed to investigate the immune potential of overlapping peptide pools covering the MiDLDH and LcDLDH.

Experimental Design: A selection of 34 peptides, from the MiDLDH and LcDLDH, able to interact with Major Histocompatibility Complex (MHC) 1 and MHC 2, was obtained using three different epitope prediction websites. By means of ELISPOT assays, we compared the frequency of Interferon gamma (IFNγ) secreting peripheral blood mononuclear cells (PBMC) after stimulation with overlapping peptide pools. Tests were performed using cells from 35 healthy blood donors.

Results: One peptide pool containing five peptides from MiDLDH and able to interact with MHC 2 induced a marked IFNγ specific immune response (Pool F, p<0.001, Wilcoxon signed-rank test).

Conclusion: This study demonstrated that peptides from microorganisms involved in HP were able to induce a high IFNγ specific immune response after stimulation of PBMCs from healthy blood donors which could be useful to develop an effective prevention strategy.
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http://dx.doi.org/10.1016/j.jim.2016.11.009DOI Listing
January 2017

Prevalence, risk factors for infection and subtype distribution of the intestinal parasite Blastocystis sp. from a large-scale multi-center study in France.

BMC Infect Dis 2016 Aug 26;16(1):451. Epub 2016 Aug 26.

Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, 1 rue du Professeur Calmette, BP 245, 59019, Lille cedex, France.

Background: Blastocystis sp. is the most common intestinal parasite of humans. Despite its potential public health impact, epidemiological data regarding the prevalence and molecular subtype distribution of Blastocystis sp. in Europe are rarely reported. Therefore, the first multi-center epidemiological survey performed in Europe was conducted in France to diagnose and subtype Blastocystis sp. and to identify risk factors for infection.

Methods: Stool samples from 788 patients were collected either in summer or winter in 11 hospitals throughout France together with patient data. All stool samples were tested for the presence of Blastocystis sp. by quantitative PCR targeting the SSU rDNA gene. Positive samples were sequenced to determine the distribution of the subtypes in our cohort. Statistical analyses were performed to identify potential risk factors for infection.

Results: Using quantitative PCR, the overall prevalence of Blastocystis sp. was shown to reach 18.1 %. The prevalence was significantly higher in summer (23.2 %) than in winter (13.7 %). Travellers or subjects infected with other enteric parasites were significantly more infected by Blastocystis sp. than non-travellers or subjects free of other enteric parasites, respectively. Different age-related epidemiological patterns were also highlighted from our data. The prevalence of Blastocystis sp. was not significantly higher in patients with digestive symptoms or diagnosed with chronic bowel diseases. Among symptomatic patients, Blastocystis sp. infection was significantly associated with abdominal pain. Gender, socioeconomic status, and immune status were not identified as potential risk factors associated with infection. Among a total of 141 subtyped isolates, subtype 3 was predominant (43.3 %), followed by subtype 1 and subtype 4 (20 %), subtype 2 (12.8 %), subtype 6 and subtype 7 (2.1 %). No association between ST and clinical symptoms was statistically evidenced.

Conclusions: A high prevalence of Blastocystis sp. infection was found in our French patient population. Seasonal impact on the prevalence of Blastocystis sp. was highlighted and recent travels and age were identified as main risk factors for infection. Most cases were caused by subtypes 1 to 4, with a predominance of subtype 3. Large variations in both prevalence and ST distribution between hospitals were also observed, suggesting distinct reservoirs and transmission sources of the parasite.
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http://dx.doi.org/10.1186/s12879-016-1776-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002209PMC
August 2016

Common peptide epitopes induce cross-reactivity in hypersensitivity pneumonitis serodiagnosis.

J Allergy Clin Immunol 2016 12 4;138(6):1738-1741.e6. Epub 2016 Aug 4.

CNRS, University of Bourgogne-Franche-Comté, Chrono-Environnement, Besançon, France; Department of Parasitology-Mycology, University Hospital of Besançon, Besançon, France.

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http://dx.doi.org/10.1016/j.jaci.2016.06.037DOI Listing
December 2016
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