Publications by authors named "François Danion"

29 Publications

  • Page 1 of 1

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; Université de Strasbourg, Inserm UMR-S1113/IRFAC, Strasbourg, France. Electronic address:

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

, One Uninucleate Species with Disparate Offspring.

J Fungi (Basel) 2021 Jan 6;7(1). Epub 2021 Jan 6.

Unité des Aspergillus, Institut Pasteur, 75015 Paris, France.

Establishment of a fungal infection due to relies on the efficient germination of the airborne conidia once they penetrate the respiratory tract. However, the features of conidial germination have been poorly explored and understood in this fungal species as well as in other species of filamentous fungi. We show here that the germination of is asynchronous. If the nutritional environment and extensive gene deletions can modify the germination parameters for , the asynchrony is maintained in all germinative conditions tested. Even though the causes for this asynchrony of conidial germination remain unknown, asynchrony is essential for the completion of the biological cycle of this filamentous fungus.
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http://dx.doi.org/10.3390/jof7010030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825634PMC
January 2021

The BASIC Score: A Useful Tool to Identify Patients at High Risk of Early Progression to Severe Coronavirus Disease 2019.

Open Forum Infect Dis 2020 Oct 1;7(10):ofaa405. Epub 2020 Sep 1.

CHU de Strasbourg, Department of Infectious and Tropical Diseases, Strasbourg, France.

We developed a score, with easily accessible data (age, sex, body mass index, dyspnea, inflammatory parameters), to predict the risk of rapid progression to severe coronavirus disease 2019. Using a cutoff of >6 points, the negative predictive value was 87%.
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http://dx.doi.org/10.1093/ofid/ofaa405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499730PMC
October 2020

Clinical characteristics and risk factors associated with severe COVID-19: prospective analysis of 1,045 hospitalised cases in North-Eastern France, March 2020.

Euro Surveill 2020 12;25(48)

CHU de Strasbourg, Department of Infectious and Tropical Diseases; Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France.

BackgroundIn March 2020, the COVID-19 outbreak was declared a pandemic by the World Health Organization.AimOur objective was to identify risk factors predictive of severe disease and death in France.MethodsIn this prospective cohort study, we included patients ≥ 18 years old with confirmed COVID-19, hospitalised in Strasbourg and Mulhouse hospitals (France), in March 2020. We respectively compared patients who developed severe disease (admission to an intensive care unit (ICU) or death) and patients who died, to those who did not, by day 7 after hospitalisation.ResultsAmong 1,045 patients, 424 (41%) had severe disease, including 335 (32%) who were admitted to ICU, and 115 (11%) who died. Mean age was 66 years (range: 20-100), and 612 (59%) were men. Almost 75% of patients with body mass index (BMI) data (n = 897) had a BMI ≥ 25 kg/m2 (n = 661). Independent risk factors associated with severe disease were advanced age (odds ratio (OR): 1.1 per 10-year increase; 95% CrI (credible interval): 1.0-1.2), male sex (OR: 2.1; 95% CrI: 1.5-2.8), BMI of 25-29.9 kg/m2 (OR: 1.8; 95% CrI: 1.2-2.7) or ≥ 30 (OR: 2.2; 95% CrI: 1.5-3.3), dyspnoea (OR: 2.5; 95% CrI: 1.8-3.4) and inflammatory parameters (elevated C-reactive protein and neutrophil count, low lymphocyte count). Risk factors associated with death were advanced age (OR: 2.7 per 10-year increase; 95% CrI: 2.1-3.4), male sex (OR: 1.7; 95% CrI: 1.1-2.7), immunosuppression (OR: 3.8; 95% CrI: 1.6-7.7), diabetes (OR: 1.7; 95% CrI: 1.0-2.7), chronic kidney disease (OR: 2.3; 95% CrI: 1.3-3.9), dyspnoea (OR: 2.1; 95% CrI: 1.2-3.4) and inflammatory parameters.ConclusionsOverweightedness, obesity, advanced age, male sex, comorbidities, dyspnoea and inflammation are risk factors for severe COVID-19 or death in hospitalised patients. Identifying these features among patients in routine clinical practice might improve COVID-19 management.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.48.2000895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716399PMC
December 2020

Is COVID-19 infection more severe in kidney transplant recipients?

Am J Transplant 2021 03 28;21(3):1295-1303. Epub 2021 Jan 28.

Department of Infectious Diseases, Strasbourg University Hospital, Strasbourg, France.

There are no studies which have compared the risk of severe COVID-19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized for COVID-19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single-center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID-19 or mortality. Severe COVID-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe COVID-19 did not differ between KTR and nontransplant patients; however, 30-day COVID-19-related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe COVID-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID-19-related mortality compared to nontransplant hospitalized patients.
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http://dx.doi.org/10.1111/ajt.16424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753418PMC
March 2021

Prescribing practices of lopinavir/ritonavir, hydroxychloroquine and azithromycin during the COVID-19 epidemic crisis and pharmaceutical interventions in a French teaching hospital.

Eur J Hosp Pharm 2020 Nov 25. Epub 2020 Nov 25.

Service de Pharmacie, Hopitaux universitaires de Strasbourg, Strasbourg, Alsace, France

Objective: The aims of this study were to describe prescribing practices of lopinavir/ritonavir, hydroxychloroquine and azithromycin during the COVID-19 epidemic crisis (primary endpoint), then to characterise pharmaceutical interventions (PIs) targeted to these medications and evaluate the impact of these PIs on prescribers' practices (secondary end-points).

Methods: This retrospective observational study was carried out at the University Hospital of Strasbourg (France) from March to April 2020. The analysed population excluded patients from intensive care units but included all other adult patients with COVID-19 who received at least one dose of lopinavir/ritonavir combination, hydroxychloroquine or azithromycin, while inpatients. Analyses were performed by using data extracted from electronic medical records.

Result: During the study period, 278 patients were included. A rapid decrease in lopinavir/ritonavir prescriptions was observed. This was accompanied by an increase in hydroxychloroquine and azithromycin prescriptions until the end of March, followed by a decrease leading to the disappearance of these two medications in April. The pharmaceutical analysis of the prescriptions resulted in 59 PIs of which 21 were associated with lopinavir/ritonavir, 32 with hydroxychloroquine and 6 with azithromycin. Regarding the medication-related problems, the most frequent ones were incorrect treatment durations (n=32 (54.2%)), drug interactions with potential torsadogenic reactions (n=14 (23.7%)) and incorrect dosing (n=6 (10.2%)). From the 59 PIs, 48 (81.4%) were accepted and physicians adjusted the medication regimens in a timely manner.

Conclusion: This study demonstrated the value-even more meaningful in a crisis situation-of a strong synergy between physicians and pharmacists for patient-safety focused practices.
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http://dx.doi.org/10.1136/ejhpharm-2020-002449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689541PMC
November 2020

Evaluation of the performance of SARS-CoV-2 serological tools and their positioning in COVID-19 diagnostic strategies.

Diagn Microbiol Infect Dis 2020 Dec 21;98(4):115181. Epub 2020 Aug 21.

Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; INSERM, UMR_S1109, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. Electronic address:

Rapid and accurate diagnosis is crucial for successful outbreak containment. During the current coronavirus disease 2019 (COVID-19) public health emergency, the gold standard for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnosis is the detection of viral RNA. Additional diagnostic methods õenabling the detection of current or past SARS-CoV-2 infection would be highly beneficial. We assessed 2 immunochromatographic lateral flow assays (LFA-1, LFA-2) and 2 enzyme-linked immunosorbent assay kits (IgA/IgG ELISA-1, IgM/IgG ELISA-2) using 325 samples: serum samples from polymerase chain reaction-confirmed COVID-19 hospitalized patients (n = 55) and healthcare workers (n = 143) and 127 samples from negative controls. Diagnostic performances were assessed according to days after symptom onset (dso) and the antigenic format used by manufacturers. Clinical sensitivities varied greatly among the assays, showing poor mutual agreement. After 15 dso, ELISA-1 (Euroimmun) and LFA-1 (Biosynex) combining IgM and IgG detection showed the best performances. A thorough selection of serological assays for the detection of ongoing or past infections is advisable.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441068PMC
December 2020

CT lung lesions as predictors of early death or ICU admission in COVID-19 patients.

Clin Microbiol Infect 2020 Oct 24;26(10):1417.e5-1417.e8. Epub 2020 Jul 24.

Department of Infectious Disease, Strasbourg University Hospital, Strasbourg, France.

Objective: The main objective of this study was to investigate the prognostic value of early systematic chest computed tomography (CT) with quantification of lung lesions in coronavirus disease 2019 (COVID-19) patients.

Methods: We studied 572 patients diagnosed with COVID-19 (confirmed using polymerase chain reaction) for whom a chest CT was performed at hospital admission. Visual quantification was used to classify patients as per the percentage of lung parenchyma affected by COVID-19 lesions: normal CT, 0-10%, 11-25%, 26-50%, 51-75% and >75%. The primary endpoint was severe disease, defined by death or admission to the intensive care unit in the 7 days following first admission.

Results: The mean patient age was 66.0 ± 16.0 years, and 343/572 (60.0%) were men. The primary endpoint occurred in 206/572 patients (36.0%). The extent of lesions on initial CT was independently associated with prognosis (odds ratio = 2.35, 95% confidence interval 1.24-4.46; p < 0.01). Most patients with lung involvement >50% (66/95, 69.5%) developed severe disease compared to patients with lung involvement of 26-50% (70/171, 40.9%) and ≤25% (70/306, 22.9%) (p < 0.01 and p < 0.01, respectively). None of the patients with normal CT (0/14) had severe disease.

Conclusion: Chest CT findings at admission are associated with outcome in COVID-19 patients.
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http://dx.doi.org/10.1016/j.cmi.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378475PMC
October 2020

Venous thromboembolism in non-critically ill patients with COVID-19 infection.

Thromb Res 2020 09 17;193:166-169. Epub 2020 Jul 17.

Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, Strasbourg, France; INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, FMTS, Strasbourg, France. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367026PMC
September 2020

Rapid Radiological Worsening and Cytokine Storm Syndrome in COVID-19 Pneumonia.

Eur J Case Rep Intern Med 2020 2;7(7):001822. Epub 2020 Jul 2.

Department of Infectious Diseases, Strasbourg University Hospital, Strasbourg, France.

Background: In June 2020, a large randomised controlled clinical trial in the UK found that dexamethasone was effective in reducing the number of deaths in patients with severe coronavirus disease 2019 (COVID-19).

Case Description: We describe a patient with rapid worsening of COVID-19 pneumonia and its dramatic improvement under corticosteroids.

Discussion: Corticosteroids could be useful in patients with an inflammatory profile, considering that acute respiratory distress syndrome may be the consequence of cytokine storm syndrome.

Learning Points: One of the main pathophysiological hypotheses for severe COVID-19 pneumonia is inappropriate immunological hyperactivation.Corticosteroid therapy may be useful in these patients.
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http://dx.doi.org/10.12890/2020_001822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350974PMC
July 2020

The Good, the Bad, and the Hoax: When Publication Instantaneously Impacts Treatment Strategies for COVID-19.

Antimicrob Agents Chemother 2020 07 22;64(8). Epub 2020 Jul 22.

CHU de Strasbourg, Service de Maladies Infectieuses et Tropicales, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France.

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http://dx.doi.org/10.1128/AAC.01127-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526849PMC
July 2020

Emergence of azole resistant- infections during STAT3-deficiency.

J Med Microbiol 2020 Jun;69(6):844-849

Université de Paris, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.

Signal transducer and activator of transcription 3 (STAT3) deficiency is a rare primary immunodeficiency associated with increased susceptibility to bacterial and fungal infections, notably pulmonary aspergillosis. We describe the emergence of azole-resistant infections in STAT3-deficient patients. During a retrospective study of 13 pulmonary aspergillosis cases in STAT3-deficient patients conducted in France, we identified patients infected with azole-resistant isolates. Two out of the 13 STAT3-deficient patients with aspergillosis had azole-resistant infection, indicating an unexpectedly high prevalence of resistance. The first patient with STAT3 deficiency presented several flares of allergic bronchopulmonary aspergillosis-like episodes. He was chronically infected with two azole-resistant isolates (TR/L98). Despite prolonged antifungal treatment, including caspofungin and amphotericin B, the patient was not able to clear the azole-resistant . The second patient had chronic cavitary pulmonary aspergillosis (CCPA). The isolate was initially azole susceptible but harboured three F46Y, M172V and E427K point mutations. Despite prolonged antifungal therapies, lesions worsened and the isolate became resistant to all azoles. Surgery and caspofungin treatments were then required to cure CCPA. Resistance was probably acquired from the environment (TR/L98) in the first case whereas resistance developed under antifungal treatments in the second case. These infections required long-term antifungal treatments and surgery. The emergence of azole-resistant infections in STAT3-deficiency dramatically impacts both curative and prophylactic antifungal strategies. Physicians following patients with primary immune-deficiencies should be aware of this emerging problem as it complicates management of the patient.
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http://dx.doi.org/10.1099/jmm.0.001200DOI Listing
June 2020

Infection in Humans With STAT3-Deficiency Is Associated With Defective Interferon-Gamma and Th17 Responses.

Front Immunol 2020 28;11:38. Epub 2020 Jan 28.

Unité des Aspergillus, Institut Pasteur, Paris, France.

In humans, loss-of-function mutation in the gene is frequently associated with susceptibility to bacterial as well as fungal infections including aspergillosis, although its pathogenesis remains largely unknown. In the present study, we investigated the immune responses obtained after stimulation with in STAT3-deficient patients. conidial killing efficiencies of both monocytes and neutrophils isolated from whole blood samples of STAT3-deficient patients were not different compared to those of healthy controls. After stimulation with conidia, lower concentrations of adaptive cytokines (IFN-γ, IL-17 and IL-22) were secreted by peripheral blood mononuclear cells from STAT3-deficient patients compared to those from healthy controls. Moreover, the frequency of IFN-γ and IL-17 producing CD4+ T cells was lower in STAT3-deficient patients vs. healthy controls. Among the STAT3-deficient patients, those with aspergillosis showed further lower secretion of IFN-γ upon stimulation of their PBMCs with conidia compared to the patients without aspergillosis. Together, our study indicated that STAT3-deficiency leads to a defective adaptive immune response against infection, particularly with a lower IFN-γ and IL-17 responses in those with aspergillosis, suggesting potential therapeutic benefit of recombinant IFN-γ in STAT3-deficient patients with aspergillosis.
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http://dx.doi.org/10.3389/fimmu.2020.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997434PMC
February 2021

Devastating Gynecological Infections in Women with STAT3 Deficiency.

Clin Infect Dis 2020 Oct;71(7):e186-e190

Paris University, Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, University Hospital Institute (IHU)  Imagine, Paris, France.

We provide the first description of a series of 9 severe gynecological infections (mastitis and pelvic cellulitis) occurring in the French national cohort of women with STAT3 deficiency. Each episode had unique features in terms of clinical presentation, microbial documentation, location, treatment duration, and related persistent esthetic damage.
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http://dx.doi.org/10.1093/cid/ciaa020DOI Listing
October 2020

Isavuconazole Diffusion in Infected Human Brain.

Antimicrob Agents Chemother 2019 10 23;63(10). Epub 2019 Sep 23.

Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris University, Paris, France

We report the cases of a 39-year-old woman with chronic lymphocytic leukemia and a 21-year-old man with chronic granulomatous disease treated for cerebral aspergillosis. The patients required radical surgery for infection progression despite adequate isavuconazole plasma concentration or neurological complication. We thus decided to measure the brain isavuconazole concentration. These results suggest that the concentrations of isavuconazole obtained in the infected brain tissue clearly differ from those obtained in the normal brain tissue and the cerebrospinal fluid.
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http://dx.doi.org/10.1128/AAC.02474-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761565PMC
October 2019

Spectrum of Pulmonary Aspergillosis in Hyper-IgE Syndrome with Autosomal-Dominant STAT3 Deficiency.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):1986-1995.e3. Epub 2019 Mar 13.

Service de Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Université Paris Descartes, Paris, France; Institut Pasteur, CNRS, Centre National de Référence Mycoses Invasives et Antifongiques, Unité de Mycologie Moléculaire, Paris, France. Electronic address:

Background: Autosomal-dominant signal transducer and activator of transcription 3 (STAT3) deficiency predisposes to recurrent bacterial pneumonia, complicated by bronchiectasis and cavitations. Aspergillosis is a major cause of morbidity in these patients. However, its diagnosis, classification, and treatment are challenging.

Objective: We aimed to assess the prevalence and describe the clinical, mycological, and radiological presentation and related therapy and outcome of Aspergillus infections of the respiratory tract in the STAT3-deficient patients of the National French cohort.

Methods: We performed a retrospective study of all pulmonary aspergillosis cases in STAT3-deficient patients (n = 74). Clinical and mycological data were collected up to October 2015 and imaging was centralized.

Results: Twenty-one episodes of pulmonary aspergillosis in 13 (17.5%) STAT3-deficient patients were identified. The median age at first episode was 13 years (interquartile range, 10-26 years). Ninety percent of patients had previous bronchiectasis or cavitations. Infections were classified as follows: 5 single aspergilloma, 9 chronic cavity pulmonary aspergillosis, 5 allergic bronchopulmonary aspergillosis-like disease, and 2 mixed forms of concomitant allergic bronchopulmonary aspergillosis-like disease and chronic cavity pulmonary aspergillosis. No invasive aspergillosis cases were identified. Aspergillus species were isolated in 71% of episodes and anti-Aspergillus antibodies in 93%. Eleven episodes were breakthrough infections. Antifungal treatment was prolonged, with a median of 13 months, and 6 patients (7 episodes) required surgery, with a high rate of postsurgical complications. One patient died and 6 had a relapse.

Conclusions: Chronic and allergic forms of aspergillosis occurred in 17.5% of STAT3-deficient patients, mostly in lung cavities. Almost half had recurrences, despite prolonged antifungal treatment and/or surgery.
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http://dx.doi.org/10.1016/j.jaip.2019.02.041DOI Listing
September 2020

Disease Entities in Mucormycosis.

J Fungi (Basel) 2019 Mar 14;5(1). Epub 2019 Mar 14.

Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), 75015 Paris, France.

Mucormycosis is an emerging life-threatening fungal infection caused by . This infection occurs mainly in immunocompromised patients, especially with hematological malignancy, transplantation, or diabetes mellitus. Rhino-orbito-cerebral and pulmonary mucormycosis are the predominant forms. Interestingly, location is associated with the underlying disease as pulmonary mucormycosis is more frequent in hematological malignancy patients whereas rhino-orbito-cerebral mucormycosis is associated with diabetes. Cutaneous mucormycosis results from direct inoculation, mainly after trauma or surgery. Gastro-intestinal mucormycosis occurs after ingestion of contaminated food or with contaminated device and involves the stomach or colon. Disseminated disease is the most severe form and is associated with profound immunosuppression. Uncommon presentations with endocarditis, osteoarticluar or isolated cerebral infections are also described. Finally, health-care associated mucormycosis is a matter of concern in premature newborns and burn units. Clinical symptoms and CT scan findings are not specific, only the early reversed halo sign is associated with pulmonary mucormycosis. Circulating DNA detection is a recent promising diagnostic tool that may lead to improving the diagnosis and prompting therapeutic initiation that should include antifungal treatment, correction of the underlying disease and surgery when feasible.
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http://dx.doi.org/10.3390/jof5010023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462957PMC
March 2019

Why are so many cases of invasive aspergillosis missed?

Med Mycol 2019 Apr;57(Supplement_2):S94-S103

Department of Infectious Diseases and Tropical Medicine, Necker-Pasteur Infectious Diseases Center, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut Imagine, Paris Descartes University, Paris, France.

Invasive aspergillosis (IA) incidence is increasing in several countries like France, and numerous cases are indeed missed and still only diagnosed at autopsy as evidenced by recently published data. Such missed diagnoses are obviously encountered when appropriate diagnostic tools are not available especially in low resource areas or when biologists have not been trained enough in medical mycology (i.e., microscopic examination and culture in most of those areas). Besides logistical issues, which are indeed critical, IA may not be recognized because clinicians failed to consider that risk factors are evolving with the IA burden now observed among patients with chronic lymphoid malignancies or receiving new biotherapies, with diabetes mellitus or liver cirrhosis and/or acute alcoholic hepatitis, with patients from the intensive care unit (ICU) and among patients with some predisposing primary immune deficiencies now reaching the adult's age. This is also the case for human immunodeficiency virus (HIV)-infected patients who failed to meet the classical definitions of IA. From the radiology perspective, new entities of IA have also emerged which absolutely need to be recognized especially bronchial-based-IA among allogeneic stem cell transplant recipients. Finally, from the laboratory side, contribution and limits of indirect blood biomarkers should be integrated to the clinical life in order not to miss IA cases. To conclude, several diagnostic tools should be combined and a constant dialog between laboratory and clinics is crucial to appropriately diagnose IA.
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http://dx.doi.org/10.1093/mmy/myy081DOI Listing
April 2019

Two KTR Mannosyltransferases Are Responsible for the Biosynthesis of Cell Wall Mannans and Control Polarized Growth in .

mBio 2019 02 12;10(1). Epub 2019 Feb 12.

Aspergillus Unit, Institut Pasteur, Paris, France

Fungal cell wall mannans are complex carbohydrate polysaccharides with different structures in yeasts and molds. In contrast to yeasts, their biosynthetic pathway has been poorly investigated in filamentous fungi. In , the major mannan structure is a galactomannan that is cross-linked to the β-1,3-glucan-chitin cell wall core. This polymer is composed of a linear mannan with a repeating unit composed of four α1,6-linked and α1,2-linked mannoses with side chains of galactofuran. Despite its use as a biomarker to diagnose invasive aspergillosis, its biosynthesis and biological function were unknown. Here, we have investigated the function of three members of the Ktr (also named Kre2/Mnt1) family (Ktr1, Ktr4, and Ktr7) in and show that two of them are required for the biosynthesis of galactomannan. In particular, we describe a newly discovered form of α-1,2-mannosyltransferase activity encoded by the gene. Biochemical analyses showed that deletion of the gene or the gene leads to the absence of cell wall galactomannan. In comparison to parental strains, the and mutants showed a severe growth phenotype with defects in polarized growth and in conidiation, marked alteration of the conidial viability, and reduced virulence in a mouse model of invasive aspergillosis. In yeast, the KTR proteins are involved in protein 0- and N-glycosylation. This study provided another confirmation that orthologous genes can code for proteins that have very different biological functions in yeasts and filamentous fungi. Moreover, in , cell wall mannans are as important structurally as β-glucans and chitin. The fungal cell wall is a complex and dynamic entity essential for the development of fungi. It allows fungal pathogens to survive environmental challenge posed by nutrient stress and host defenses, and it also is central to polarized growth. The cell wall is mainly composed of polysaccharides organized in a three-dimensional network. produces a cell wall galactomannan whose biosynthetic pathway and biological functions remain poorly defined. Here, we described two new mannosyltransferases essential to the synthesis of the cell wall galactomannan. Their absence leads to a growth defect with misregulation of polarization and altered conidiation, with conidia which are bigger and more permeable than the conidia of the parental strain. This study showed that in spite of its low concentration in the cell wall, this polysaccharide is absolutely required for cell wall stability, for apical growth, and for the full virulence of .
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http://dx.doi.org/10.1128/mBio.02647-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372797PMC
February 2019

Intestinal dysbiosis in inflammatory bowel disease associated with primary immunodeficiency.

J Allergy Clin Immunol 2019 02 10;143(2):775-778.e6. Epub 2018 Oct 10.

French National Reference Center for Primary Immune Deficiency (CEREDIH), Necker-Enfants Malades University Hospital, APHP, Paris, France; Paediatric Haematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, APHP, Paris, France; INSERM UMR 1163, Imagine Institute, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France; Collège de France, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.09.021DOI Listing
February 2019

Is It Time for Systematic Voriconazole Pharmacogenomic Investigation for Central Nervous System Aspergillosis?

Antimicrob Agents Chemother 2018 09 27;62(9). Epub 2018 Aug 27.

Paris Descartes University, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris, France

Voriconazole is the standard treatment for invasive aspergillosis but requires therapeutic drug monitoring to optimize therapy. We report two cases of central nervous system aspergillosis treated with voriconazole. Because of low trough plasma concentrations, we identified gain-of-function mutations in CYP2C19 that were partially responsible for the therapeutic failure of voriconazole. We suggest that systematic voriconazole pharmacogenomic investigation of cerebral aspergillosis be performed to avoid effective therapy delay in this life-threatening disease.
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http://dx.doi.org/10.1128/AAC.00705-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125540PMC
September 2018

Long-term efficacy and safety of antitumour necrosis factor alpha treatment in rhupus: an open-label study of 15 patients.

RMD Open 2017 29;3(2):e000555. Epub 2017 Dec 29.

Department of Rheumatology, Centre de référence des maladies rares et auto immunes, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France.

Background: The efficacy of antitumour necrosis factor alpha (anti-TNF-α) treatment is well recognised in rheumatoid arthritis (RA) but remains controversial in systemic lupus erythematosus (SLE). Therefore, the role of anti-TNF-α treatment in 'Rhupus', a disease sharing features of RA and SLE, is still debated.

Objective: To evaluate the efficacy and tolerance of anti-TNF-α in patients with rhupus.

Methods: Fifteen patients with rhupus with Disease Activity Score 28 (DAS 28) >3.2 despite conventional disease-modifying anti-rheumatic drugs were included in an open-label study. Patients were monitored at months (M) 3, 6, 12, 24 and 60 with SLE Disease Activity Index (SLEDAI) and DAS 28. Statistical analyses were performed using Bayesian methods and Prob >97.5% was considered significant.

Results: Twelve patients were treated with etanercept for a median duration of 62.5 (range: 6-112) months and three patients by adalimumab during 36.0 (range: 4-52) months. At baseline, median DAS 28 and SLEDAI were 5.94 (4.83-8.09) and 6 (4-8), respectively. DAS 28 and SLEDAI decreased significantly after 3 months, respectively, to 3.70 (1.80-6.42) and 4 (0-6) (Prob >99.9%, for both). These changes persisted at M6, M12, M24 and M60 (Prob >99.9%, for all). Median prednisone dose decreased significantly from 15 (5-35) mg/day to 5 (0-20) mg/day after 6 months and over the follow-up (Prob >99.9%, for all). Tolerance was acceptable, with a severe infection rate of 3.0 per 100 patient-years.

Conclusion: This pilot study suggests that anti-TNF-α is effective in patients with rhupus with refractive arthritis and has an acceptable safety profile.
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http://dx.doi.org/10.1136/rmdopen-2017-000555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761296PMC
December 2017

Serum Lipids and Lipoproteins During Uncomplicated Malaria: A Cohort Study in Lambaréné, Gabon.

Am J Trop Med Hyg 2017 May;96(5):1205-1214

Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.

AbstractThe serum lipid profile in malaria patients has been found to differ from that of healthy controls. We investigated serum lipid profile changes in malaria patients over time compared with patients with other febrile diseases. In total, 217 patients were included in the study (111 malaria patients and 106 symptomatic controls, defined as malaria-negative febrile patients). Serum lipid levels (mmol/L) were significantly lower in malaria patients compared with those with other febrile diseases (total cholesterol [TC] = 3.26 [standard deviation = 0.94] versus 3.97 [1.22; < 0.001]; high-density lipoprotein cholesterol [HDL-C] = 0.43 [0.47] versus 1.05 [0.67; < 0.001], low-density lipoprotein cholesterol [LDL-C] = 2.05 [0.76] versus 2.42 [0.90; < 0.001]. Triglycerides (TGs) levels were higher in malaria patients (1.81 [1.02] versus 1.11 [0.82; < 0.001]). No significant differences were found for apolipoprotein A1, apolipoprotein B, and lipoprotein(a). Cholesterol levels increased toward reference values on day 28 (TC = 3.26-3.98, < 0.001; HDL-C = 0.43-0.96, < 0.001; LDL-C = 2.05-2.60, < 0.001). TG levels decreased from 1.81 on admission to 1.76 (day 3) and 0.88 (day 28; = 0.130). Lipid profile changes were not correlated with parasitemia or histidine-rich protein 2 levels. This study confirms characteristic temporary lipid profile changes in malaria. Lipid profile changes demonstrated a good accuracy to discriminate between malaria and other febrile diseases (area under the curve = 0.80 (95% confidence interval = 0.742-0.863, < 0.001). Several plausible hypotheses exist regarding the pathophysiology of lipid profile changes in malaria. Further studies to elucidate the precise pathways may lead to improved understanding of the underlying pathophysiology.
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http://dx.doi.org/10.4269/ajtmh.16-0721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417218PMC
May 2017

B cells differentiate in human thymus and express AIRE.

J Allergy Clin Immunol 2017 03 15;139(3):1049-1052.e12. Epub 2016 Nov 15.

CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; UFR Médecine, Université de Strasbourg, Strasbourg, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2016.09.044DOI Listing
March 2017

Mucormycosis: New Developments into a Persistently Devastating Infection.

Semin Respir Crit Care Med 2015 Oct 23;36(5):692-705. Epub 2015 Sep 23.

Service de Maladies Infectieuses et tropicales, APHP-Hôpital Necker-Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, IHU Imagine, Paris, France.

Mucormycosis is a rare, though increasingly prevalent, life-threatening fungal disease caused by Mucorales. The incidence has increased over the last decade and its mortality remains high at around 50%. Mucormycosis occurs mostly in patients with diabetes mellitus and/or in the context of immunosuppression resulting from chemotherapy for hematological malignancy, hematopoietic stem cell transplantation, or solid-organ transplantation. In this situation, lung and rhino-orbito-cerebral infections are the most frequent localizations of the disease. Prompt initiation of an effective treatment is essential to decrease mortality. However, mucormycosis and aspergillosis share close clinical and radiological features. Invasive procedures such as bronchial endoscopy and/or lung biopsy are necessary to confirm diagnosis, as no indirect tests are yet validated. Therefore, the challenge is to minimize the delay in diagnosis. When present, the reversed halo sign on CT scan is suggestive of mucormycosis. Quantitative polymerase chain reaction is a new promising approach to detect Mucorales DNA in serum and new molecular tools are available to detect Mucorales in tissues as well as to specify species. Recommendations from ECIL and ECMM/ESCMID have recently been published on management of mucormycosis. The recommended treatment is an amphotericin B lipid formulation in combination with surgery and modification of risk factors. High-dose (10 mg/kg) of liposomal amphotericin B is recommended in case of neurological involvement and posaconazole for maintenance therapy. Place of isavuconazole as well as posaconazole new formulations (tablets and intravenous) in first line treatment have to be defined. Improved radiologic descriptions of mucormycosis and new molecular tools may be key elements to help with rapid diagnosis in the future. Clinical trials are warranted to improve therapeutic success and hopefully survival.
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http://dx.doi.org/10.1055/s-0035-1562896DOI Listing
October 2015

Streptobacillosis characterised by palmoplantar pustulosis.

Lancet Infect Dis 2013 Jan;13(1):96

Hôpitaux Universitaires de Strasbourg, Department of Internal Medecine, Hôpital de Hautepierre, Université de Strasbourg, Strasbourg, France.

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http://dx.doi.org/10.1016/S1473-3099(12)70141-XDOI Listing
January 2013