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Background Nocardiosis is rare after hematopoietic cell transplantation (HCT). Little is known regarding its presentation, management, and outcome in this population. Methods This retrospective international study reviewed nocardiosis episodes in HCT recipients (1/1/2000–31/12/2018; 135 transplant centers; 33 countries) and described their clinical, microbiological, radiological, and outcome characteristics. Results We identified 81 nocardiosis episodes in 74 allo- and 7 auto-HCT recipients. Nocardiosis occurred a median of 8 (IQR: 4–18) months post-HCT. The most frequently involved organs were lungs (70/81; 86%) and brain (30/81; 37%); 29 (36%) patients were afebrile; 46/81 (57%) had disseminated infections. The most common lung imaging findings were consolidations (33/68; 49%) or nodules (32/68; 47%); brain imaging findings were multiple brain abscesses (19/30; 63%). Ten of 30 (33%) patients with brain involvement lacked neurological symptoms. Fourteen of 48 (29%) patients were bacteremic. Nocardia farcinica was the most common among molecularly identified species (27%; 12/44). Highest susceptibility rates were reported to linezolid (45/45; 100%), amikacin (56/57; 98%), trimethoprim-sulfamethoxazole (57/63; 90%), and imipenem (49/57; 86%). One-year and last follow-up (IQR: 4–42.5 months) all-cause mortality were 40% (32/81) and 52% (42/81), respectively. In the multivariable analysis, underlying disease not in complete remission (HR: 2.81; 95% CI: 1.32–5.95) and prior bacterial infection (HR: 3.42; 95% CI: 1.62–7.22) were associated with higher 1-year all-cause mortality. Conclusions Nocardiosis is a late post-HCT infection usually manifesting as a pulmonary disease with frequent dissemination, brain infection, and bacteremia. Brain imaging should be performed in HCT recipients with nocardiosis regardless of neurological symptoms. Overall mortality is high.

BackgroundIntegrase strand transfer inhibitors (INSTIs) are increasingly used in patients living with HIV due to their safety, effectiveness and high genetic barrier. However, an association with weight gain has recently been suggested and several cases of diabetes mellitus have been reported with raltegravir and dolutegravir. The long-time metabolic impact of these recent molecules remains unclear.ObjectivesTo assess if an INSTI as a third agent is statistically associated with new-onset diabetes mellitus compared with an NNRTI or a PI.Patients and methodsPatients undergoing first-line combined ART (cART) without diabetes at baseline were retrospectively included from the Dat’AIDS French cohort study (ClinicalTrials.gov NCT02898987). Incident diabetes mellitus was defined as a notification of new diabetes in the medical history, a glycated haemoglobin (HbA1c) level superior to 7.5% or the start of a diabetes therapy following the initiation of ART.ResultsFrom 2009 to 2017, 19 462 patients were included, among which 265 cases of diabetes mellitus occurred. Multivariate and survival analyses did not highlight an increase in new-onset diabetes in patients undergoing cART with an INSTI as a third agent compared with an NNRTI or a PI. BMI >30 kg/m2, age >37 years old (in survival analysis), black race or Hispanic ethnicity, arterial hypertension and AIDS were associated with a higher proportion of incident diabetes.ConclusionsINSTIs were not statistically associated with new-onset diabetes. However, clinicians should remain aware of this possible metabolic comorbidity, particularly in patients with a high BMI and older patients.

Background In late 2013, France was one of the first countries to recommend initiation of combination antiretroviral therapy (cART) irrespective of CD4 cell count. Methods To assess the impact of achieving the second and third Joint United Nations Programme on HIV/AIDS 90-90-90 targets (ie, 90% of diagnosed people on sustained cART, and, of those, 90% virologically controlled) on human immunodeficiency virus (HIV) incidence, we conducted a longitudinal study to describe the epidemiology of primary HIV infection (PHI) and/or recent HIV infection (patients with CD4 cell count ≥500/mm3 at HIV diagnosis; (PRHI) between 2007 and 2017 in a large French multicenter cohort. To identify changes in trends in PHI and PRHI, we used single breakpoint linear segmented regression analysis. Results During the study period, 61 822 patients were followed in the Dat’AIDS cohort; 2027 (10.0%) had PHI and 7314 (36.1%) had PRHI. The second and third targets were reached in 2014 and 2013, respectively. The median delay between HIV diagnosis and cART initiation decreased from 9.07 (interquartile range [IQR], 1.39–33.47) months in 2007 to 0.77 (IQR, 0.37–1.60) months in 2017. A decrease in PHI (−35.1%) and PRHI (−25.4%) was observed starting in 2013. The breakpoints for PHI and PRHI were 2012.6 (95% confidence interval [CI], 2010.8–2014.4) and 2013.1 (95% CI, 2011.3–2014.8), respectively. Conclusions Our findings show that the achievements of 2 public health targets in France and the early initiation of cART were accompanied by a reduction of about one-third in PHI and PRHI between 2013 and 2017. Clinical Trials Registration NCT02898987.

Introduction. 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. Aim. We describe the emergence of azole-resistant Aspergillus fumigatus infections in STAT3-deficient patients. Methodology. During a retrospective study of 13 pulmonary aspergillosis cases in STAT3-deficient patients conducted in France, we identified patients infected with azole-resistant A. fumigatus isolates. Results. Two out of the 13 STAT3-deficient patients with aspergillosis had azole-resistant A. fumigatus 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 A. fumigatus isolates (TR34/L98). Despite prolonged antifungal treatment, including caspofungin and amphotericin B, the patient was not able to clear the azole-resistant A. fumigatus. The second patient had chronic cavitary pulmonary aspergillosis (CCPA). The A. fumigatus 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 (TR34/L98) in the first case whereas resistance developed under antifungal treatments in the second case. These infections required long-term antifungal treatments and surgery. Conclusions. The emergence of azole-resistant A. fumigatus 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.

International audience; 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.

Comment on Invasive aspergillosis with pulmonary and central nervous system involvement during ibrutinib therapy for relapsed chronic lymphocytic leukaemia: case report. [Clin Microbiol Infect. 2018]; International audience; We read with great interest the article from Peri et al. describing a case report of invasive aspergillosis (IA) with primary pulmonary involvement followed by central nervous system (CNS) involvement in a patient treated for chronic lymphocytic leukaemia (CLL) with ibrutinib [1]. The clinical outcome has been favourable with a combination of voriconazole and liposomal amphotericin B (L-AmB). This case highlights the need for systematic screening of CNS involvement in patients receiving ibrutinib therapy for CLL and concurrent invasive fungal infection, which was not performed during the initial course of pulmonary aspergillosis in the case reported by Peri et al. To complement Peri et al.'s work, we would like to report a case with primary CNS involvement that has benefited from a systematic screening for extra-neurological involvement and additional invasive tissue biopsies. As ibrutinib-associated fungal infections are an emerging syndrome, we would like to describe clinical issues in the management of these infections. A 52-year-old woman presented with a 5-year history of CLL. In 2015 she received a combination of rituximab, fludarabine and cyclophosphamide with complete remission. She relapsed in September 2017 when a treatment with ibrutinib was started. At that time, she experienced neutropenia (between 0.4 and 0.6 G/L). She presented to the hospital on 16 March 2018 with a 2-week history of confusion, behaviour disorders and aggression. The pa-tient's temperature was 38.3 C. Cerebral computed tomography (CT) demonstrated a well-defined rim-enhancing lesion with a hypodense centre surrounded by oedema in the left external capsule region complicated by a mass effect on the left ventricle and a subfalcine herniation (Fig. 1a). A stereotaxic biopsy was performed, and mycological cultures were positive for Aspergillus fumigatus with negative direct examination. Antifungal susceptibility tests showed the following MICs (EUCAST method): vor-iconazole 0.19 mg/L; isavuconazole 0.25 mg/L; posaconazole 0.094 mg/L; itraconazole 0.36 mg/L; caspofungin 0.094 mg/L. Bacterial cultures were also positive for Propionibacterium acnes. No tumour cell was detected on pathological examination. After the biopsy was performed, she subsequently received cefotaxime and metronidazole for 7 days and a single dose of prednisolone of 1 mg/kg. Intravenous voriconazole (400 mg/12 h at day one then 200 mg/12 h) was started after the result of fungal cultures. Serum galactomannan antigen was negative. (1,3)-b-D-glucan serum titres were 84 pg/mL. Aspergillus fumigatus PCR in serum was negative. Sinus and chest CT scans were normal. A systematic abdominal CT scan revealed a lesion of the upper pole of the left kidney and a lesion of the spleen both consistent with abscesses (Fig. 1c). A CT-guided biopsy was performed of the kidney lesion. The histopathological examination showed ischaemic ne-crosis associated with non-septate broad hyphae. Fungal cultures

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.

SCOPUS: le.j, info:eu-repo/semantics/published

International audience; 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 bio-therapies, 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 biomark-ers 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.

Toxocariasis is a zoonotic disease that occurs when humans are infected by the parasites Toxocara canis or Toxocara cati. Toxocariasis is highly prevalent in tropical areas, but can also be found in industrialized countries, particularly in rural areas. Clinical presentation can range from asymptomatic infection to more severe disease. Diagnosis of toxocariasis is based on suggestive clinical findings, eosinophilia and a positive serological testing. Albendazole represents the first-line treatment, associated with corticosteroids in case of severe disease. Here we describe three clinical cases of toxocariasis in order to illustrate the clinical presentation, diagnosis and treatment of this unrecognized disease.La toxocarose est une zoonose liée à l’infection de l’homme par

International audience; Elastin-based side-chain polymers (EBPs) were prepared by the polymerization of a methacrylate derivative of the pentapeptide valine-proline-glycine-valine-glycine (VPGVG) using reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymerizations proceeded in a controlled manner, yielding polymers with a narrow molecular weight distribution (polydispersity indices 1.03-1.23) and molecular weights in good agreement with those predicted from the initial monomer:initiator ratio for the conversion obtained. The dithioester end groups of the resulting polymers were removed by reaction with azo initiator-derived radicals. The lower critical solution temperature (LCST) behavior of the series of EBPs so obtained was investigated in solutions of varying pH (1.5-5.1) and polymer concentration (0.11-0.97 mg/mL) and for polymers of different degrees of polymerization (29-88 repeating units). These EBPs behaved similarly to linear polypeptides, known as elastin-like peptides (ELPs); the transition temperature decreased with increasing polymer concentration and molecular weight. Unlike ELPs, but in common with previously reported EBPs, a strong dependence of transition temperature on pH was observed due to the presence of the carboxylic acid from the C-terminal residue in the peptide side chains. Significant differences between the EBPs described here and those reported earlier were found, however, regarding the transition temperature at a given pH and its variation with molecular weight. These variations are attributed to differences in architecture between the polymers described here (higher molecular weight homopolymers) and those reported earlier (A-B-A triblock copolymers with short EBP A blocks and a PEG B block).

Introduction La sarcoidose est generalement associee a un deficit immunitaire cellulaire et le traitement des sarcoidoses symptomatiques comprend souvent des traitements immunosuppresseurs. Il existe actuellement peu de donnees sur l’incidence, les facteurs pronostiques et l’evolution des infections severes au cours de la sarcoidose. Patients et methodes Etude retrospective d’une cohorte de 585 patients avec un diagnostic de sarcoidose prouvee histologiquement suivis dans le centre hospitalier universitaire de la Pitie-Salpetriere. Seize patients (2,7 %) avec une infection severe non mycobacterienne ont ete compares a un groupe controle de 60 patients avec un diagnostic de sarcoidose, en les appariant sur le sexe, l’origine ethnique, l’âge au diagnostic de sarcoidose et le fait de recevoir une corticotherapie. 19 patients (10 %) avec une infection due a une mycobacterie ont ete exclus de l’etude. Resultats Apres une duree mediane de suivi de 8 ans [IIQ ; 1–46], 22 episodes d’infections severe non mycobacteriennes [infections fongiques (n = 10), bacterienne (n = 8), virales (n = 3) et parasitaire (n = 1)] ont ete observees chez 16 patients. L’incidence d’infections severes etait de 0,43 % personnes-annees (IC 95 % 0,27–0,66). Le taux median de lymphocytes T CD4 etait de 204/mm3 (164–570) chez les patients presentant au moins un episode d’infection severe. Les patients avec infection severe etaient plus souvent des hommes (75 % contre 46 %, p = 0,023) et avaient ete traites plus frequemment par ≥ 3 traitements immunosuppresseurs differents (OR = 6,99, IC 95 % [1,8–26,5], p = 0,004) et par cyclophosphamide (OR = 9,6, IC 95 % [2–47,2], p = 0,005) par rapport aux patients du groupe controle. Deux patients sont decedes dans les 6 mois suivant le diagnostic de l’infection : le premier en rapport avec une leucoencephalopathie multifocale progressive (n = 1) et le second apres un diagnostic de peritonite (n = 1). Conclusions Nous avons observes des infections severes non mycobacteriennes chez 3 % des patients suivis pour une sarcoidose dans notre centre et ces infections etaient souvent associees a une lymphopenie CD4. Les facteurs de risques de developper une infection severe etaient d’avoir recu plus de 3 lignes de traitements immunosuppresseurs et plus particulierement un traitement par cyclophosphamide.

Introduction La principale cause genetique du syndrome hyper-IgE (ex syndrome de Job) est un deficit en Signal Transducer and Activator of Transcription 3 (STAT3). Cette pathologie autosomique dominante se manifeste par un deficit immunitaire Th17 et qualitatif des immunoglobulines associe a des manifestations atopiques, rhumatologiques, cardio-vasculaires, cutanees et respiratoires. L’atteinte respiratoire est la premiere cause de mortalite. Peu de donnees sont disponibles du fait de la faible prevalence de la maladie et d’une heterogeneite clinique importante. Notre objectif etait de decrire les evenements respiratoires aigus et l’atteinte respiratoire chronique a l’âge adulte. Methodes Un recueil retrospectif exhaustif des donnees cliniques, biologiques, radiologiques et fonctionnelles concernant les evenements respiratoires aigus et chroniques des patients de plus de 16 ans ayant un deficit en STAT3 et enregistres dans le registre national du CEREDIH, a ete realise de mai 2015 a decembre 2015. Resultats Cinquante-six patients âgees de 16 a 51 ans, dont 44 % de femmes, ont ete inclus dans 23 centres. Douze patients (21 %) avaient ete diagnostiques a l’âge adulte. Les evenements respiratoires infectieux etaient les plus frequents dans toutes les tranches d’âge et touchaient 95 % des patients, la plupart d’origine bacterienne (30 % etaient documentes a S. aureus) et fungiques (32 infections aspergillaires decrites chez 19 patients (34 %)). Les evenements vasculaires etaient inhabituellement frequents : sept patients (12,5 %) ont presente au moins un evenement thromboembolique dont un cas d’hypertension arterielle pulmonaire severe post-embolique. L’analyse de l’imagerie a identifie des dilatations des bronches ou des pneumatoceles chez 42 patients (75 %), apparus avant l’âge de 16 ans pour 19 d’entre eux. Quatorze patients (25 %) avaient ete operes, la plupart pendant l’enfance, pour pneumothorax persistant apres drainage (29 %) ou traitement d’un aspergillome sur cavite (43 %). Conclusion Cette etude confirme l’importance des atteintes respiratoires infectieuses bacteriennes et fungiques chez ces patients et precise leurs caracteristiques. Elle identifie egalement une frequence elevee de maladie veineuse thromboembolique. Enfin, ces patients developpent des cavites parenchymateuses de tres grande taille difficiles a prendre en charge, avec des suites operatoires complexes.

The synthesis of (2S,2′S)-2,3-bis(aziridin-2-yl)quinoxaline 4 from d -mannitol is reported. Reductive aminocyclization of diazidodiols has been achieved by polymer-supported PPh3 in a suitable manner. The N-Boc and N-Tos aziridines 4b and 4c have been reacted with different nucleophiles either in protic or aprotic media.

The coupling reaction of 1,2:5,6-di- O -isopropylidene- d -mannitol with α,α′-dibromoxylene has been reinvestigated. We found reaction conditions leading to the 3,4- d -mannitol bridged o , o -cyclophane 3 , free of the 3,4- O - o -xylylene protected mannitol 2 . Compound 3 could be converted in 57% yield into tetrakis-epoxide 4 .