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1.  Multicenter Outbreak of Infections by Saprochaete clavata, an Unrecognized Opportunistic Fungal Pathogen 
Vaux, Sophie | Criscuolo, Alexis | Desnos-Ollivier, Marie | Diancourt, Laure | Tarnaud, Chloé | Vandenbogaert, Matthias | Brisse, Sylvain | Coignard, Bruno | Dromer, Françoise | Garcia-Hermoso, Dea | Blanc, Catherine | Hoinard, Damien | Lortholary, Olivier | Bretagne, Stéphane | Thiolet, Jean-Michel | de Valk, Henriette | Courbil, Rémi | Chabanel, Anne | Simonet, Marion | Maire, Francoise | Jbilou, Saadia | Tiberghien, Pierre | Blanchard, Hervé | Venier, Anne-Gaëlle | Bernet, Claude | Simon, Loïc | Sénéchal, Hélène | Pouchol, Elodie | Angot, Christiane | Ribaud, Patricia | Socié, G. | Flèche, M. | Brieu, Nathalie | Lagier, Evelyne | Chartier, Vanessa | Allegre, Thierry | Maulin, Laurence | Lanic, Hélène | Tilly, Hervé | Bouchara, Jean-Philippe | Pihet, Marc | Schmidt, Aline | Kouatchet, Achille | Vandamme, Yves-Marie | Ifrah, Norbert | Mercat, Alain | Accoceberry, Isabelle | Albert, Olivier | Leguay, Thibaut | Rogues, Anne-Marie | Bonhomme, Julie | Reman, Oumédaly | Lesteven, Claire | Poirier, Philippe | Chabrot, Cécile Molucon | Calvet, Laure | Baud, Olivier | Cambon, Monique | Farkas, Jean Chistophe | Lafon, Bruno | Dalle, Frédéric | Caillot, Denis | Lazzarotti, Aline | Aho, Serge | Combret, Sandrine | Facon, Thierry | Sendid, Boualem | Loridant, Séverine | Louis, Terriou | Cazin, Bruno | Grandbastien, Bruno | Bourgeois, Nathalie | Lotthé, Anne | Cartron, Guillaume | Ravel, Christophe | Colson, Pascal | Gaudard, Philippe | Bonmati, Caroline | Simon, Loic | Rabaud, Christian | Machouart, Marie | Poisson, Didier | Carp, Diana | Meunier, Jérôme | Gaschet, Anne | Miquel, Chantal | Sanhes, Laurence | Ferreyra, Milagros | Leibinger, Franck | Geudet, Philippe | Toubas, Dominique | Himberlin, Chantal | Bureau-Chalot, Florence | Delmer, Alain | Favennec, Loïc | Gargala, Gilles | Michot, Jean-Baptiste | Girault, Christophe | David, Marion | Leprêtre, Stéphane | Jardin, Fabrice | Honderlick, Pierre | Caille, Vincent | Cerf, Charles | Cassaing, Sophie | Recher, Christian | Picard, Muriel | Protin, Caroline | Huguet, Françoise | Huynh, Anne | Ruiz, Jean | Riu-Poulenc, Béatrice | Letocart, Philippe | Marchou, Bruno | Verdeil, Xavier | Cavalié, Laurent | Chauvin, Pamela | Iriart, Xavier | Valentin, Alexis | Bouvet, Emmanuelle | Delmas-Marsalet, Béatrice | Jeblaoui, Asma | Kassis-Chikhani, Najiby | Mühlethaler, Konrad | Zimmerli, Stefan | Zalar, Polona | Sánchez-Reus, Ferran | Gurgui, Merce
mBio  2014;5(6):e02309-14.
ABSTRACT
Rapidly fatal cases of invasive fungal infections due to a fungus later identified as Saprochaete clavata were reported in France in May 2012. The objectives of this study were to determine the clonal relatedness of the isolates and to investigate possible sources of contamination. A nationwide alert was launched to collect cases. Molecular identification methods, whole-genome sequencing (WGS), and clone-specific genotyping were used to analyze recent and historical isolates, and a case-case study was performed. Isolates from thirty cases (26 fungemias, 22 associated deaths at day 30) were collected between September 2011 and October 2012. Eighteen cases occurred within 8 weeks (outbreak) in 10 health care facilities, suggesting a common source of contamination, with potential secondary cases. Phylogenetic analysis identified one clade (clade A), which accounted for 16/18 outbreak cases. Results of microbiological investigations of environmental, drug, or food sources were negative. Analysis of exposures pointed to a medical device used for storage and infusion of blood products, but no fungal contamination was detected in the unused devices. Molecular identification of isolates from previous studies demonstrated that S. clavata can be found in dairy products and has already been involved in monocentric outbreaks in hematology wards. The possibility that S. clavata may transmit through contaminated medical devices or can be associated with dairy products as seen in previous European outbreaks is highly relevant for the management of future outbreaks due to this newly recognized pathogen. This report also underlines further the potential of WGS for investigation of outbreaks due to uncommon fungal pathogens.
IMPORTANCE
Several cases of rapidly fatal infections due to the fungus Saprochaete clavata were reported in France within a short period of time in three health care facilities, suggesting a common source of contamination. A nationwide alert collected 30 cases over 1 year, including an outbreak of 18 cases over 8 weeks. Whole-genome sequencing (WGS) was used to analyze recent and historical isolates and to design a clade-specific genotyping method that uncovered a clone associated with the outbreak, thus allowing a case-case study to analyze the risk factors associated with infection by the clone. The possibility that S. clavata may transmit through contaminated medical devices or can be associated with dairy products as seen in previous European outbreaks is highly relevant for the management of future outbreaks due to this newly recognized pathogen.
doi:10.1128/mBio.02309-14
PMCID: PMC4271555  PMID: 25516620
2.  Primary immunodeficiencies underlying fungal infections 
Current opinion in pediatrics  2013;25(6):736-747.
Purpose of review
We review the primary immunodeficiencies underlying an increasing variety of superficial and invasive fungal infections. We also stress that the occurrence of such fungal infections should lead physicians to search for the corresponding single-gene inborn errors of immunity. Finally, we suggest that other fungal infections may also result from hitherto unknown inborn errors of immunity, at least in some patients with no known risk factors.
Recent findings
An increasing number of primary immunodeficiencies are being shown to underlie fungal infectious diseases in children and young adults. Inborn errors of the phagocyte NADPH oxidase complex (chronic granulomatous disease), severe congenital neutropenia and leukocyte adhesion deficiency type I confer a predisposition to invasive aspergillosis and candidiasis. More rarely, inborn errors of IFN-γ immunity underlie endemic mycoses. Inborn errors of IL-17 immunity have recently been shown to underlie chronic mucocutaneous candidiasis, whereas inborn errors of CARD9 immunity underlie deep dermatophytosis and invasive candidiasis.
Summary
Chronic mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, deep dermatophytosis, pneumocystosis, and endemic mycoses can all be caused by primary immunodeficiencies. Each type of infection is highly suggestive of a specific type of primary immunodeficiency. In the absence of overt risk factors, single-gene inborn errors of immunity should be sought in children and young adults with these and other fungal diseases.
doi:10.1097/MOP.0000000000000031
PMCID: PMC4098727  PMID: 24240293
primary immunodeficiencies (PIDs); superficial and invasive fungal diseases; chronic mucocutaneous candidiasis; invasive aspergillosis; candidiasis; Candida central nervous system infection; deep dermatophytosis; endemic mycosis; pneumocystosis; IL-17; NADPH oxidase complex; CARD9; STAT1; IFN-γ/IL-12; autoantibodies against GM-CSF; autoantibodies against IFN-γ; X-linked CD40L deficiency
3.  Bacterial Pathogens Associated with Hidradenitis Suppurativa, France 
Emerging Infectious Diseases  2014;20(12):1990-1998.
Staphylococcus lugdunensis and anaerobic actinomycetes are associated with this skin infection.
Hidradenitis suppurativa (HS) is a skin disease characterized by recurrent nodules or abscesses and chronic suppurating lesions. In the absence of clear pathophysiology, HS is considered to be an inflammatory disease and has no satisfactory medical treatment. Recently, prolonged antimicrobial treatments were shown to improve or resolve HS lesions. We prospectively studied the microbiology of 102 HS lesions sampled from 82 patients using prolonged bacterial cultures and bacterial metagenomics on 6 samples. Staphylococcus lugdunensis was cultured as a unique or predominant isolate from 58% of HS nodules and abscesses, and a polymicrobial anaerobic microflora comprising strict anaerobes, milleri group streptococci, and actinomycetes was found in 24% of abscesses or nodules and in 87% of chronic suppurating lesions. These data show that bacteria known to cause soft tissue and skin infections are associated with HS lesions. Whether these pathogens are the cause of the lesions or are secondary infectious agents, these findings support targeted antimicrobial treatment of HS.
doi:10.3201/eid2012.140064
PMCID: PMC4257786  PMID: 25418454
Hidradenitis suppurativa; Staphylococcus lugdunensis; Actinomyces; Streptococcus milleri group; anaerobic bacteria; Prevotella; infectious skin diseases; microbiota; opportunistic infections; antibiotic; antibacterial; antimicrobial; acne inversa; Verneuil disease; France; skin and soft tissue infections; bacteria
4.  Aspergillus Osteomyelitis: Epidemiology, Clinical Manifestations, Management, and Outcome 
The Journal of infection  2013;68(5):478-493.
Background
The epidemiology, pathogenesis, diagnosis, and management of Aspergillus osteomyelitis are not well understood.
Methods
Protocol-defined cases of Aspergillus osteomyelitis published in the English literature were reviewed for comorbidities, microbiology, mechanisms of infection, clinical manifestations, radiological findings, inflammatory biomarkers, antifungal therapy, and outcome.
Results
Among 180 evaluable patients, 127 (71%) were males. Possible predisposing medical conditions in 103 (57%) included pharmacological immunosuppression, primary immunodeficiency, and neutropenia. Seventy-three others (41%) had prior open fracture, trauma or surgery. Eighty (44%) followed a hematogenous mechanism, 58 (32%) contiguous infections, and 42 (23%) direct inoculation. Aspergillus osteomyelitis was the first manifestation of aspergillosis in 77%. Pain and tenderness were present in 80%. The most frequently infected sites were vertebrae (46%), cranium (23%), ribs (16%), and long bones (13%). Patients with vertebral Aspergillus osteomyelitis had more previous orthopedic surgery (19% vs 0%; P=0.02), while those with cranial osteomyelitis had more diabetes mellitus (32% vs 8%; P=0.002) and prior head/neck surgery (12% vs 0%; P=0.02). Radiologic findings included osteolysis, soft-tissue extension, and uptake on T2-weighted images. Vertebral body Aspergillus osteomyelitis was complicated by spinal-cord compression in 47% and neurological deficits in 41%. Forty-four patients (24%) received only antifungal therapy, while 121(67%) were managed with surgery and antifungal therapy. Overall mortality was 25%. Median duration of therapy was 90 days (range, 10–772 days). There were fewer relapses in patients managed with surgery plus antifungal therapy in comparison to those managed with antifungal therapy alone (8% vs 30%; P=0.006).
Conclusions
Aspergillus osteomyelitis is a debilitating infection affecting both immunocompromised and immunocompetent patients. The most common sites are vertebrae, ribs, and cranium. Based upon this comprehensive review, management of Aspergillus osteomyelitis optimally includes antifungal therapy and selective surgery to avoid relapse and to achieve a complete response.
doi:10.1016/j.jinf.2013.12.008
PMCID: PMC4214682  PMID: 24378282
5.  Last Generation Triazoles for Imported Eumycetoma in Eleven Consecutive Adults 
Background
Optimal management of eumycetoma, a severely debilitating chronic progressive fungal infection of skin, disseminating to bone and viscera, remains challenging. Especially, optimal antifungal treatment and duration are ill defined.
Methodology/Principal Findings
We conducted a monocentric retrospective study of 11 imported cases of eumycetoma treated by voriconazole or posaconazole for at least 6 months. Response to treatment was assessed through evolution of clinical and magnetic resonance imaging (MRI). (1→3) ß-D-glucan (BG) and positron emission tomography using [18F] fluorodeoxyglucose (PET/CT) results were also assessed. Identified species were Fusarium solani complex (n = 3); Madurella mycetomatis, (n = 3), and Exophiala jeanselmei, (n = 1). Moreover, two coelomycetes and one phaeohyphomycetes strains without species identification were retrieved. Serum BG and PET/CT were abnormal in 7/8 and 6/6 patients tested, respectively. Patients received last generation azoles for a mean duration of 25.9±18 months. Complete response (major clinical and MRI improvement) was observed in 5/11 patients, partial response (minor MRI improvement or stable MRI findings) in 5 and failure (MRI evidence of disease progression) in one, with a 73±39 [6–132] months mean follow-up. Relapse occurred in 2 patients after treatment discontinuation. Optimal outcome was associated with fungal species, initiation of last generation triazole therapy (<65 months since first symptoms), negative serum BG and PET/CT normalization.
Conclusions/Significance
MRI, PET/CT and serum BG appear as promising tools to assess optimal time of antifungal treatment for eumycetoma.
Author Summary
Eumycetoma is a severe chronic progressive fungal infection of skin and ultimately bone or viscera that affect mainly people with low economic status. Optimal treatment of this condition relies on medical and often surgical therapy and remains challenging because of lack of gold standard therapy and high rate of relapse after treatment discontinuation. In this retrospective study we assessed whether modern triazoles (voriconazole and posaconazole) suited to eumycetoma treatment and if tailored treatment duration, based on serial evaluation of a serum biomarker of fungal infection (Serum (1→3) ß-D-Glucan, (BD)), magnetic resonance imaging (MRI) or positron emission tomography using [18F] fluorodeoxyglucose (PET/CT) would be useful. We found that modern triazoles were efficient treatments of eumycetoma, allowing complete or partial response in 10/11 of patients, without significant side effects. Moreover, patients with treatment discontinuation based on normalization of BD, MRI or PET/CT seemed to have better long-term outcome than those with clinical cure but still abnormal BD or imaging results.
doi:10.1371/journal.pntd.0003232
PMCID: PMC4191942  PMID: 25299610
6.  Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002–2010) 
Intensive Care Medicine  2014;40(9):1303-1312.
Purpose
To analyze trends in incidence and mortality of candidemia in intensive care units (ICUs) vs. non-ICU hospitalized patients and to determine risk factors for infection by specific species and for death.
Methods
Active hospital-based surveillance program of incident episodes of candidemia due to common species in 24 tertiary care hospitals in the Paris area, France between October 2002 and September 2010.
Results
Among 2,507 adult cases included, 2,571 Candida isolates were collected and species were C. albicans (56 %), C. glabrata (18.6 %), C. parapsilosis (11.5 %), C. tropicalis (9.3 %), C. krusei (2.9 %), and C. kefyr (1.8 %). Candidemia occurred in ICU in 1,206 patients (48.1 %). When comparing ICU vs. non-ICU patients, the former had significantly more frequent surgery during the past 30 days, were more often preexposed to fluconazole and treated with echinocandin, and were less frequently infected with C. parapsilosis. Risk factors and age remained unchanged during the study period. A significant increased incidence in the overall population and ICU was found. The odds of being infected with a given species in ICU was influenced by risk factors and preexposure to fluconazole and caspofungin. Echinocandins initial therapy increased over time in ICU (4.6 % first year of study, to 48.5 % last year of study, p < 0.0001). ICU patients had a higher day-30 death rate than non-ICU patients (odds ratio [OR] 2.12; 95 % confidence interval [CI] 1.66–2.72; p < 0.0001). The day-30 and early (
Conclusions
The availability of new antifungals and the publication of numerous guidelines did not prevent an increase of candidemia and death in ICU patients in the Paris area.
doi:10.1007/s00134-014-3408-3
PMCID: PMC4147247  PMID: 25097069
Candida; Echinocandins; Fluconazole; Hematological malignancy; Intensive care unit; Epidemiology; Risk factors; Non-albicans species
Solid organ transplant recipients are at risk for invasive fungal diseases, and are also exposed to healthcare-associated mucormycosis. Mainly causing localized cutaneous mucormycosis, Mucor irregularis infection is reported for the first time in a kidney-transplant recipient. A healthcare-associated origin was highly suspected in this case. We performed a literature review and highlight the characteristics of this very rare fungus.
doi:10.1016/j.mmcr.2014.07.005
PMCID: PMC4216332  PMID: 25379401
Invasive fungal disease; Mucorales; Solid organ transplantation; Mucormycoses; Amphotericin B
The New England journal of medicine  2013;369(18):1704-1714.
BACKGROUND
Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause.
METHODS
We studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain–containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients.
RESULTS
Four patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance.
CONCLUSIONS
All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.)
doi:10.1056/NEJMoa1208487
PMCID: PMC4084693  PMID: 24131138
Emerging Infectious Diseases  2014;20(7):1163-1169.
These infections are underrecognized as a cause of death in the general population and high-risk groups.
To determine the epidemiology and trends of invasive fungal infections (IFIs) in France, we analyzed incidence, risk factors, and in-hospital death rates related to the most frequent IFIs registered in the national hospital discharge database during 2001–2010. The identified 35,876 IFI cases included candidemia (43.4%), Pneumocystis jirovecii pneumonia (26.1%), invasive aspergillosis (IA, 23.9%), cryptococcosis (5.2%), and mucormycosis (1.5%). The overall incidence was 5.9/100,000 cases/year and the mortality rate was 27.6%; both increased over the period (+1.5%, +2.9%/year, respectively). Incidences substantially increased for candidemia, IA, and mucormycosis. Pneumocystis jirovecii pneumonia incidence decreased among AIDS patients (−14.3%/year) but increased in non-HIV–infected patients (+13.3%/year). Candidemia and IA incidence was increased among patients with hematologic malignancies (>+4%/year) and those with chronic renal failure (>+10%/year). In-hospital deaths substantially increased in some groups, e.g., in those with hematologic malignancies. IFIs occur among a broad spectrum of non–HIV-infected patients and should be a major public health priority.
doi:10.3201/eid2007.140087
PMCID: PMC4073874  PMID: 24960557
Invasive mycosis; candidemia; Pneumocystis jirovecii; aspergillosis; cryptococcosis; mucormycosis
BMC Infectious Diseases  2014;14:241.
Background
Yeasts, mostly Candida, are important causes of bloodstream infections (BSI), responsible for significant mortality and morbidity among hospitalized patients. The epidemiology and species distribution vary from different regions. The goals of this study were to report the current epidemiology of Candida BSI in a Shanghai Teaching Hospital and estimate the impact of appropriate antifungal therapy on the outcome.
Methods
From January 2008 to December 2012, all consecutive patients who developed Candida BSI at Ruijin University Hospital were enrolled. Underlying diseases, clinical severity, species distribution, antifungal therapy and its impact on the outcome were analyzed.
Results
A total of 121 episodes of Candida BSI were identified, with an incidence of 0.32 episodes/1,000 admissions (0.21 in 2008 and 0.42 in 2012) The proportion of candidemia caused by non-albicans species (62.8%), including C. parapsilosis (19.8%), C. tropicalis (14.9%), C. glabrata (7.4%), C. guilliermondii (5.8%), C. sake (5.0%) was higher than that of candidemia caused by C. albicans (37.2%). The overall crude 28-day mortality was 28.1% and significantly reduced with appropriate empiric antifungal therapy administered within 5 days (P = 0.006). Advanced age (OR 1.04; P = 0.014), neutropenia < 500/mm3 (OR 17.44; P < 0.001) were independent risk factors for 28-day mortality, while appropriate empiric antifungal therapy (OR 0.369; P = 0.035) was protective against 28-day mortality.
Conclusion
The epidemiology of candidemia in Shanghai differed from that observed in Western countries. Appropriate empiric antifungal therapy influenced the short-term survival.
doi:10.1186/1471-2334-14-241
PMCID: PMC4033490  PMID: 24886130
Candida spp; Bloodstream infection; Appropriate antifungal therapy; Survival
Antimicrobial Agents and Chemotherapy  2013;57(11):5727-5728.
Iatrogenic Cushing's syndrome is an undesirable outcome of glucocorticoids treatment. It can be increased by pharmacologic interactions. Glucocorticoid therapy, given in association with ritonavir, and some azole treatments are causes of iatrogenic Cushing's syndrome. We present a patient with common-variable immunodeficiency who received 7 years of itraconazole therapy for bronchial colonization with Aspergillus in combination with inhaled fluticasone without any Cushingoid symptoms. After a switch to posaconazole, the patient developed Cushingoid symptoms.
doi:10.1128/AAC.00416-13
PMCID: PMC3811248  PMID: 23979730
PLoS ONE  2014;9(4):e94183.
Objective
To describe characteristics and outcomes of HIV-infected patients with Pneumocystis jirovecii pneumonia (PCP) over 2004–2011 in France, in particular in those previously enrolled (PE) in the French Hospital Database on HIV (FHDH).
Methods
PE patients with an incident PCP were compared with patients with an inaugural PCP revealing HIV infection (reference). Adequate adherence to care was defined as a CD4 measurement at least every 6 months. Immune reconstitution (CD4≥200/mm3) and risk of death were studied using Kaplan-Meier estimates and multivariable Cox proportional hazards models.
Results
In a context of a decreasing incidence of PCP, 1259 HIV-infected patients had a PCP diagnosis, and 593 (47%) were PE patients of whom 161 (27%) have had a prior history of AIDS-defining clinical illness (prior ADI). Median time since enrolment was 8 years for PE patients; 74% had received cART. Median proportion of time with adequate adherence to care was 85% (IQR, 66–96) for all FHDH enrollees, but only 45% (IQR, 1–81) for PE patients during the 2 years before PCP. Median CD4 cell count (38/mm3) and HIV viral load (5.2 log10 copies/ml) at PCP diagnosis did not differ between PE patients and the reference group. Three year mortality rate of 25% was observed for PE prior ADI group, higher than in PE non-prior ADI group (8%) and the reference group (9%) (p<0.0001). In the PE prior ADI group, poor prognosis remained even after adjustment for virological control and immune reconstitution (HR, 2.4 [95%CI, 1.5–3.7]).
Conclusion
Almost 50% of PCP diagnoses in HIV-infected patients occurred presently in patients already in care, mainly with a previous cART prescription but with waning adherence to care. Having repeated ADI is contributing to the risk of death beyond its impact on immune reconstitution and viral suppression: special efforts must be undertaken to maintain those patients in care.
doi:10.1371/journal.pone.0094183
PMCID: PMC3984113  PMID: 24727746
Diverse aetiologies of viral and bacterial encephalitis are widely recognized as significant yet neglected public health issues in the Mekong region. A robust analysis of the corresponding health burden is lacking. We retrieved 75 articles on encephalitis in the region published in English or in French from 1965 through 2011. Review of available data demonstrated that they are sparse and often derived from hospital-based studies with significant recruitment bias. Almost half (35 of 75) of articles were on Japanese encephalitis virus (JEV) alone or associated with dengue. In the Western Pacific region the WHO reported 30,000–50,000 annual JEV cases (15,000 deaths) between 1966 and 1996 and 4,633 cases (200 deaths) in 2008, a decline likely related to the introduction of JEV vaccination in China, Vietnam, or Thailand since the 1980s. Data on dengue, scrub typhus and rabies encephalitis, among other aetiologies, are also reviewed and discussed.
Countries of the Mekong region are undergoing profound demographic, economic and ecological change. As the epidemiological aspects of Japanese encephalitis (JE) are transformed by vaccination in some countries, highly integrated expert collaborative research and objective data are needed to identify and prioritize the human health, animal health and economic burden due to JE and other pathogens associated with encephalitides.
doi:10.1371/journal.pntd.0002533
PMCID: PMC3907313  PMID: 24498443
PLoS ONE  2014;9(1):e85362.
Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) is a rare and heterogeneous subtype of SM and few studies on this specific entity have been reported. Sixty two patients with Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) were presented. Myeloid AHNMD was the most frequent (82%) cases. This subset of patients were older, had more cutaneous lesions, splenomegaly, liver enlargement, ascites; lower bone mineral density and hemoglobin levels and higher tryptase level than lymphoid AHNMD. Defects in KIT, TET2, ASXL1 and CBL were positive in 87%, 27%, 14%, and 11% of cases respectively. The overall survival of patients with SM-AHNMD was 85.2 months. Within the myeloid group, SM-MPN fared better than SM-MDS or SM-AML (p = 0.044,). In univariate analysis, the presence of C-findings, the AHNMD subtypes (SM-MDS/CMML/AML versus SM-MPN/hypereosinophilia) (p = 0.044), Neutropenia (p = 0.015), high monocyte level (p = 0.015) and the presence of ASXL1 mutation had detrimental effects on OS (p = 0.007). In multivariate analysis and penalized Cox model, only the presence of ASXL1 mutation remained an independent prognostic factor that negatively affected OS (p = 0.035). SM-AHNMD is heterogeneous with variable prognosis according to the type of the AHNMD. ASXL1 is mutated in a subset of myeloid AHNMD and adversely impact on OS.
doi:10.1371/journal.pone.0085362
PMCID: PMC3897447  PMID: 24465546
Scientifica  2014;2014:821969.
Invasive mold infections represent an increasing source of morbidity and mortality in solid organ transplant recipients. Whereas there is a large literature regarding invasive molds infections in hematopoietic stem cell transplants, data in solid organ transplants are scarcer. In this comprehensive review, we focused on invasive mold infection in the specific population of solid organ transplant. We highlighted epidemiology and specific risk factors for these infections and we assessed the main clinical and imaging findings by fungi and by type of solid organ transplant. Finally, we attempted to summarize the diagnostic strategy for detection of these fungi and tried to give an overview of the current prophylaxis treatments and outcomes of these infections in solid organ transplant recipients.
doi:10.1155/2014/821969
PMCID: PMC4261198  PMID: 25525551
Disseminated histoplasmosis is an emerging infection in patients with cellular immune deficiency in non-endemic countries, caused by the migration from endemic regions and the development of travels. Diagnosis can be challenging in this context because rapid diagnostic tools such as Histoplasma antigen detection or appropriate molecular tools are generally unavailable, serology is often negative in immunosuppressed patients, and isolation of the fungus from cultures often takes several weeks. Here, we report the contribution of galactomannan serum detection for the management of an HIV-infected patient with disseminated histoplasmosis.
doi:10.4269/ajtmh.2012.12-0119
PMCID: PMC3414568  PMID: 22855762
Medicine  2012;91(4):e1-19.
Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.
doi:10.1097/MD.0b013e31825f95b9
PMCID: PMC3680355  PMID: 22751495
Journal of Antimicrobial Chemotherapy  2013;68(11):2435-2444.
Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.
doi:10.1093/jac/dkt221
PMCID: PMC3797641  PMID: 23788479
5-FC; cryptococcal meningitis; cryptococcal meningitis treatment guidelines; access to essential antifungals for cryptococcal meningitis; 5-FC safety; combination antifungal therapy; opportunistic infection
BMC Infectious Diseases  2013;13:245.
Background
Fluoroquinolones are used with increasing frequency in children with a major risk of increasing the emergence of FQ resistance. FQ use has expanded off-label for primary antibacterial prophylaxis or treatment of infections in immune-compromised children and life-threatening multi-resistant bacteria infections. Here we assessed the prescriptions of ciprofloxacin in a pediatric cohort and their appropriateness.
Methods
A monocenter audit of ciprofloxacin prescription was conducted for six months in a University hospital in Paris. Infected site, bacteriological findings and indication, were evaluated in children receiving ciprofloxacin in hospital independently by 3 infectious diseases consultants and 1 hospital pharmacist.
Results
Ninety-eight ciprofloxacin prescriptions in children, among which 52 (53.1%) were oral and 46 (46.9%) parenteral, were collected. 45 children had an underlying condition, cystic fibrosis (CF) (21) or an innate or acquired immune deficiency (24). Among CF patients, the most frequent indication was a broncho-pulmonary Pseudomonas aeruginosa infection (20). In non-CF patient, the major indications were broncho-pulmonary (25), urinary (8), intra-abdominal (7), operative site infection (5) and bloodstream/catheter (2/4) infection. 62.2% were microbiologically documented. Twenty-three (23.4%) were considered “mandatory”, 48 (49.0%) “alternative” and 27 (27.6%) “unjustified”.
Conclusion
In our university hospital, only 23.4% of fluoroquinolones prescriptions were mandatory in children, especially in Pseudomonas aeruginosa healthcare associated infection. Looking to the ecological risk of fluoroquinolones and the increase consumption in children population we think that a control program should be developed to control FQ use in children. It could be done with the help of an antimicrobial stewardship team.
doi:10.1186/1471-2334-13-245
PMCID: PMC3668209  PMID: 23710669
Ciprofloxacin; Children; Cystic fibrosis; Appropriate prescription
In vitro interaction of anidulafungin with voriconazole was tested by a microdilution broth checkerboard technique and an agar diffusion method against 30 Aspergillus clinical isolates belonging to five different species. By using a complete inhibition endpoint, indifferent interactions were observed for 97% of the isolates by the checkerboard technique (FIC index from 0.5 to 2) and for 100% of the isolates by the agar diffusion method (variation of −2 to +1 log2 dilutions).
doi:10.1128/AAC.00045-12
PMCID: PMC3421560  PMID: 22615296
PLoS ONE  2013;8(1):e55570.
Idiopathic CD4 lymphocytopenia (ICL) is a rare immune deficiency characterized by a protracted CD4+ T cell loss of unknown etiology and by the occurrence of opportunistic infections similar to those seen in AIDS. We investigated whether a defect in responses to cytokines that control CD4+ T cell homeostasis could play a role in ICL. Immunophenotype and signaling responses to interleukin-7 (IL-7), IL-2, and thymic stromal lymphopoietin (TSLP) were analyzed by flow cytometry in CD4+ T cells from 15 ICL patients and 15 healthy blood donors. The induction of phospho-STAT5 after IL-7 stimulation was decreased in memory CD4+ T cells of some ICL patients, which correlated with a decreased expression of the IL-7Rα receptor chain (R = 0.74, p<0.005) and with lower CD4+ T cell counts (R = 0.69, p<0.005). IL-2 responses were also impaired, both in the Treg and conventional memory subsets. Decreased IL-2 responses correlated with decreased IL-7 responses (R = 0.75, p<0.005), pointing to combined defects that may significantly perturb CD4+ T cell homeostasis in a subset of ICL patients. Unexpectedly, responses to the IL-7-related cytokine TSLP were increased in ICL patients, while they remained barely detectable in healthy controls. TSLP responses correlated inversely with IL-7 responses (R = −0.41; p<0.05), suggesting a cross-regulation between the two cytokine systems. In conclusion, IL-7 and IL-2 signaling are impaired in ICL, which may account for the loss of CD4+ T cell homeostasis. Increased TSLP responses point to a compensatory homeostatic mechanism that may mitigate defects in γc cytokine responses.
doi:10.1371/journal.pone.0055570
PMCID: PMC3559496  PMID: 23383227
Journal of Clinical Microbiology  2012;50(7):2330-2336.
The monitoring and prediction of treatment responses to invasive aspergillosis (IA) are difficult. We determined whether serum galactomannan index (GMI) trends early in the course of disease may be useful in predicting eventual clinical outcomes. For the subjects recruited into the multicenter Global Aspergillosis Study, serial GMIs were measured at baseline and at weeks 1, 2, and 4 following antifungal treatment. Clinical response and survival at 12 weeks were the outcome measures. GMI trends were analyzed by using the generalized estimation equation approach. GMI cutoffs were evaluated by using receiver-operating curve analyses incorporating pre- and posttest probabilities. Of the 202 study patients diagnosed with IA, 71 (35.1%) had a baseline GMI of ≥0.5. Week 1 GMI was significantly lower for the eventual responders to treatment at week 12 than for the nonresponders (GMIs of 0.62 ± 0.12 and 1.15 ± 0.22, respectively; P = 0.035). A GMI reduction of >35% between baseline and week 1 predicted a probability of a satisfactory clinical response. For IA patients with pretreatment GMIs of <0.5 (n = 131; 64.9%), GMI ought to remain low during treatment, and a rising absolute GMI to >0.5 at week 2 despite antifungal treatment heralded a poor clinical outcome. Here, every 0.1-unit increase in the GMI between baseline and week 2 increased the likelihood of an unsatisfactory clinical response by 21.6% (P = 0.018). In summary, clinical outcomes may be anticipated by charting early GMI trends during the first 2 weeks of antifungal therapy. These findings have significant implications for the management of IA.
doi:10.1128/JCM.06513-11
PMCID: PMC3405588  PMID: 22553232
Histoplasma capsulatum var. capsulatum infection is rare outside disease-endemic areas. Clinical presentation and outcome of acquired immunodeficiency syndrome–related histoplasmosis are unknown in non-endemic areas with wide access to highly active anti-retroviral therapy (HAART). Retrospective analysis of cases recorded at the French National Reference Center for Mycoses and Antifungals during two decades: pre-HAART (1985–1994) and HAART (1997–2006). Clinical features and outcome of all adults with proven acquired immunodeficiency syndrome–related histoplasmosis were compared between the two periods. One hundred four patients were included (40 during the pre-HAART era and 64 during the HAART era). Diagnosis was established a mean of 62 days after onset of symptoms. One-year overall mortality rates decreased from 53% (pre-HAART era) to 22% (HAART era). Diagnosis during the pre-HAART era and an older age were the only independent factors associated with death. Histoplasmosis is a rare invasive fungal infection outside disease-endemic areas. Its prognosis improved significantly during the HAART era.
doi:10.4269/ajtmh.2011.11-0224
PMCID: PMC3205645  PMID: 22049053
Emerging Infectious Diseases  2012;18(11):1817-1824.
Outbreaks are spatiotemporally associated with litchi harvest, but the causative agent remains unknown.
Since the end of the 1990s, unexplained outbreaks of acute encephalitis in children coinciding with litchi harvesting (May–July) have been documented in the Bac Giang Province in northern Vietnam. A retrospective ecologic analysis of data for 2004–2009 involving environmental, agronomic, and climatic factors was conducted to investigate the suspected association between the outbreaks and litchi harvesting. The clinical, biological, and immunologic characteristics of the patients suggested a viral etiology. The ecologic study revealed an independent association between litchi plantation surface proportion and acute encephalitis incidence: Incidence rate ratios were 1.52 (95% CI 0.90–2.57), 2.94 (95% CI 1.88–4.60), and 2.76 (95% CI 1.76–4.32) for second, third, and fourth quartiles, respectively, compared with the lowest quartile. This ecologic study confirmed the suspected association between incidence of acute encephalitis and litchi plantations and should be followed by other studies to identify the causative agent for this syndrome.
doi:10.3201/eid1811.111761
PMCID: PMC3559149  PMID: 23092599
Encephalitis; epidemics; disease outbreaks; epidemiology; risk factors; litchi; retrospective studies; Vietnam; Asia; viruses; vector-borne infections

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