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1.
Artigo em Inglês | MEDLINE | ID: mdl-31427294

RESUMO

Posaconazole diffusion has been documented in various organs, contrasting with scarce data available for the human central nervous system (CNS). We analyzed posaconazole concentrations in plasma and multiple CNS specimens taken from a patient who received posaconazole because of cerebral phaeohyphomycosis. Low posaconazole concentrations were obtained in CNS specimens, with sample to plasma ratio between 5% and 22%. This case highlights the role of neurosurgery during cerebral phaeohyphomycosis, even those caused by posaconazole-susceptible black fungi.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31405852

RESUMO

We report cases of a 39-year-old woman with chronic lymphocytic leukemia and of 21-year-old man with chronic granulomatous disease treated for cerebral aspergillosis. Patients required radical surgery respectively for infection progression despite adequate isavuconazole plasma concentration or neurological complication. We thus decided to measure brain isavuconazole concentration. These results suggest that the concentrations of isavuconazole obtained clearly differ in the infected brain tissue from those obtained in the normal brain tissue and the cerebrospinal fluid.

3.
J Clin Immunol ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401750

RESUMO

PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.

4.
Transpl Infect Dis ; : e13141, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31283872

RESUMO

BACKGROUND: Scedosporium species and Lomentospora prolificans (S/L) are the second most common causes of invasive mold infections following Aspergillus in lung transplant recipients. METHODS: We assessed the current practices on management of S/L colonization/infection of the lower respiratory tract before and after lung transplantation in a large number of lung transplant centers through an international practice survey from October 2016 to March 2017. RESULTS: A total of 51 respondents from 45 lung transplant centers (17 countries, 4 continents) answered the survey (response rate 58%). S/L colonization was estimated to be detected in candidates by 48% of centers. Only 18% of the centers used a specific medium to detect S/L colonization. Scedosporium spp. colonization was a contraindication to transplantation in 10% of centers whereas L prolificans was a contraindication in 31%; 22% of centers declared having had 1-5 recipients infected with S/L in the past 5 years. CONCLUSIONS: This survey gives an overview of the current practices regarding S/L colonization and infection in lung transplant centers worldwide and underscores the need of S/L culture procedure standardization before implementing prospective studies.

5.
Proc Natl Acad Sci U S A ; 116(33): 16463-16472, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31346092

RESUMO

Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients' primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

6.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31275560

RESUMO

The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated cryptococcal meningitis within minutes. However, diagnostic advances have not been matched by new antifungal drugs and treatment still relies on old off-patent drugs: amphotericin B, flucytosine and fluconazole. Cryptococcal meningitis treatment is divided in three phases: induction, consolidation and maintenance. The induction phase, aimed at drastically reducing cerebrospinal fluid fungal burden, is key for patient survival. The major challenge in cryptococcal meningitis management has been the optimisation of induction phase treatment using the limited number of available medications, and major progress has recently been made. In this review, we summarise data from key trials which form the basis of current treatment recommendations for HIV-associated cryptococcal meningitis.

7.
Clin Infect Dis ; 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31155650

RESUMO

In Malawi, 236 participants from the ACTA cryptococcal meningitis treatment trial were followed-up for 12 months. The trial outcomes reported at 10 weeks were sustained to 1 year. One-week amphotericinB plus flucytosine was associated with the lowest 1 year mortality (27.5% [95%CI: 16.3 to 44.1]).

8.
J Antimicrob Chemother ; 74(Supplement_2): ii16-ii20, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31222312

RESUMO

Fungal infection in solid organ transplant (SOT) recipients is a challenge for physicians. Our aim was to review progress made within the past decade in managing the most important invasive fungal diseases in SOT recipients. Standards of care for candidosis, aspergillosis, mucormycosis and cryptococcosis in this special population are summarized.

10.
BMJ Open ; 9(4): e026288, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940760

RESUMO

INTRODUCTION: Cryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation. METHODS AND ANALYSIS: Country-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial. ETHICS AND DISSEMINATION: The AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings. TRIAL REGISTRATION: ISRCTN 7250 9687; Pre-results.

11.
BMC Infect Dis ; 19(1): 302, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943907

RESUMO

BACKGROUND: Staphylococcus aureus has emerged as a leading cause of invasive severe diseases with a high rate of morbidity and mortality worldwide. The wide spectrum of clinical manifestations and outcome observed in staphylococcal illness may be a consequence of both microbial factors and variability of the host immune response. CASE PRESENTATION: A 14-years old child developed limb ischemia with gangrene following S. aureus bloodstream infection. Histopathology revealed medium-sized arterial vasculitis. The causing strain belonged to the emerging clone CC1-MSSA and numerous pathogenesis-related genes were identified. Patient's genotyping revealed functional variants associated with severe infections. A combination of virulence and host factors might explain this unique severe form of staphylococcal disease. CONCLUSION: A combination of virulence and genetic host factors might explain this unique severe form of staphylococcal disease.


Assuntos
Infecções Estafilocócicas/diagnóstico , Staphylococcus aureus/genética , Vasculite/diagnóstico , Adolescente , Amputação , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Encéfalo/diagnóstico por imagem , Cefotaxima/farmacologia , Cefotaxima/uso terapêutico , Clindamicina/farmacologia , Clindamicina/uso terapêutico , Humanos , Perna (Membro)/cirurgia , Imagem por Ressonância Magnética , Masculino , Meticilina/farmacologia , Choque Séptico/diagnóstico , Choque Séptico/tratamento farmacológico , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação , Vasculite/complicações , Vasculite/microbiologia
12.
J Allergy Clin Immunol Pract ; 7(7): 2387-2395.e3, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30954641

RESUMO

BACKGROUND: Patients with mast cell diseases may suffer from various distressing symptoms, which can be insufficiently controlled with available therapies, severely affecting their quality of life. There is a need for new and safe treatment options for these patients. OBJECTIVES: We aimed to evaluate safety and efficacy of omalizumab administration in patients with a symptomatic mast cell disorder. METHODS: We included 55 patients with a mast cell disorder associated with debilitating symptoms who received omalizumab treatment between January 2015 and December 2017, after a multidisciplinary team meeting at the French National Reference Center for Mastocytosis. RESULTS: A complete response was achieved for 1 patient (1.8%), a major response for 30 patients (54.5%), and a partial response for 12 patients (21.8%), resulting in an overall best response rate of 78.2% (43 of 55 patients). The response was persistent at least 3 months in 33 of 43 responding patients (76.7%). At the last follow-up, the final overall response rate was 58.2% (32 of 55 patients). Median time to first response was 2 months and median time to best response was 6 months. Omalizumab was dramatically effective on all superficial and general vasomotor symptoms and on most gastrointestinal or urinary symptoms, and partially effective on most neuropsychiatric symptoms. Safety profile was acceptable, except for one severe adverse event (edema of the larynx and dyspnea after the first injection of omalizumab). Side effects were reported in 16 patients (29%), mainly of low to mild intensity, yet causing interruption of treatment in 5 patients (9%). CONCLUSION: Omalizumab seems to be a useful therapeutic option to control mast cell-mediator symptoms and displays a favorable safety profile.

13.
Clin Infect Dis ; 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816418

RESUMO

BACKGROUND: Mortality from cryptococcal meningitis remains very high in Africa. In the ACTA trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2-week amphotericin-based regimens. However, many African settings treat with FLU monotherapy and the cost effectiveness of adding 5FC to FLU is uncertain. METHODS: Effectiveness and costs of FLU+5FC were taken from ACTA, which included costing analysis at the Zambian site. Effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtraction of 5FC drug and monitoring costs.Cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity analysis assessed uncertainties, and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. RESULTS: Mean costs per patient were US$847 (95%CI:776-927) for FLU+5FC, and US$628 (95%CI:557-709) for FLU. 10 week mortality was 35.1% (95%CI 28.9-41.7) with FLU+5FC and 53.8% (95%CI: 43.1-64.1) with FLU. At the current 5FC price of $US1.30 per 500mg tablet, the ICER of 5FC+FLU versus FLU alone was US$65 (95%CI: 28-208) per life year saved. Reducing 5FC cost to between US$0.80 and US$0.40 per 500mg resulted in an ICER between US$44 and US$28 per life year saved. CONCLUSIONS: Addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and if made available widely could substantially reduce mortality rates among HIV-infected persons in Africa.

14.
Med Mycol ; 57(Supplement_2): S94-S103, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30816963

RESUMO

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.


Assuntos
Testes Diagnósticos de Rotina/métodos , Hospedeiro Imunocomprometido , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/epidemiologia , França/epidemiologia , Humanos , Incidência , Fatores de Risco
15.
Clin Infect Dis ; 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30863852

RESUMO

BACKGROUND: Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. METHODS: Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. RESULTS: Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91-1210) per life-year saved. CONCLUSIONS: Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments.

16.
J Allergy Clin Immunol Pract ; 7(6): 1986-1995.e3, 2019 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30878710

RESUMO

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.

17.
Nephrol Dial Transplant ; 34(9): 1597-1604, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608553

RESUMO

BACKGROUND: Diarrhoea is one of the most frequent complications after kidney transplantation (KT). Non-infectious diarrhoea has been associated with reduced graft survival in kidney transplant recipients. However, the risk factors for renal allograft loss following diarrhoea remain largely unknown. METHODS: Between January 2010 and August 2011, 195 consecutive KT recipients who underwent standardized microbiological workups for diarrhoea at a single centre were enrolled in this retrospective study. RESULTS: An enteric pathogen was readily identified in 91 patients (47%), while extensive microbiological investigations failed to find any pathogen in the other 104. Norovirus was the leading cause of diarrhoea in these patients, accounting for 30% of the total diarrhoea episodes. The baseline characteristics were remarkably similar between non-infectious and infectious diarrhoea patients, with the exception that the non-infectious group had significantly lower graft function before diarrhoea (P = 0.039). Infectious diarrhoea was associated with a longer duration of symptoms (P = 0.001) and higher rates of acute kidney injury (P = 0.029) and hospitalization (P < 0.001) than non-infectious diarrhoea. However, the non-infectious group had lower death-censored graft survival than the infectious group (Gehan-Wilcoxon test, P = 0.038). Multivariate analysis retained three independent predictors of graft failure after diarrhoea: diarrhoea occurring ≥5 years after KT [hazard ratio (HR) 4.82; P < 0.001], re-transplantation (HR 2.38; P = 0.001) and baseline estimated glomerular filtration rate <30 mL/min/1.73 m2 (HR 11.02; P < 0.001). CONCLUSION: Our study shows that pre-existing conditions (re-transplantation, chronic graft dysfunction and late occurrence) determine the primary functional long-term consequences of post-transplant diarrhoea.

18.
J Clin Immunol ; 39(1): 55-64, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30552536

RESUMO

PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a rare but severe demyelinating disease caused by the polyomavirus JC (JCV) in immunocompromised patients. We report a series of patients with primary immune deficiencies (PIDs) who developed PML. METHODS: Retrospective observational study including PID patients with PML. Clinical, immunological, imaging features, and outcome are provided for each patient. RESULTS: Eleven unrelated patients with PIDs developed PML. PIDs were characterized by a wide range of syndromic or genetically defined defects, mostly with combined B and T cell impairment. Genetic diagnosis was made in 7 patients. Before the development of PML, 10 patients had recurrent infections, 7 had autoimmune and/or inflammatory manifestations, and 3 had a history of malignancies. Immunologic investigations showed CD4+ lymphopenia (median 265, range 50-344) in all cases. Six patients received immunosuppressive therapy in the year before PML onset, including prolonged steroid therapy in 3 cases, rituximab in 5 cases, anti-TNF-α therapy, and azathioprine in 1 case each. Despite various treatments, all but 1 patient died after a median of 8 months following PML diagnosis. CONCLUSION: PML is a rare but fatal complication of PIDs. Many cases are secondary to immunosuppressive therapy warranting careful evaluation before initiation subsequent immunosuppression during PIDs.

19.
Artigo em Inglês | MEDLINE | ID: mdl-30416055

RESUMO

Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future.

20.
Emerg Infect Dis ; 24(12): 2382-2386, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30457541

RESUMO

We report a disseminated infection caused by Spiroplasma apis, a honeybee pathogen, in a patient in France who had X-linked agammaglobulinemia. Identification was challenging because initial bacterial cultures and direct examination by Gram staining were negative. Unexplained sepsis in patients with agammaglobulinemia warrants specific investigation to identify fastidious bacteria such as Spiroplasma spp.

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