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1.  Imported Pythium insidiosum Keratitis After a Swim in Thailand by a Contact Lens-Wearing Traveler 
A 30-year-old woman with a history of contact lens wear and exposure to swimming pool water in Thailand presented with a non-responsive, progressive corneal ulcer of the right eye. Confocal microscopy evidenced septate linear branching structures, raising suspicion of fungal keratitis. She was promptly treated with topical antibiotics and both topical and intravenous caspofungin plus voriconazole. Worsening of the clinical picture after 1 month of intensive medical therapy led to a large therapeutic penetrating keratoplasty being performed. Corneal cultures grew a mold-like organism, which was identified by sequencing as Pythium insidiosum, an aquatic oomycete. After 4 years of follow-up, the graft exhibits no infection relapse, but graft transparency has been lost after two rejection episodes. Keratoplasty combined with antifungal treatment may offer a cure to P. insidiosum keratitis, although long-term preservation of corneal transparency is difficult to obtain.
doi:10.4269/ajtmh.14-0380
PMCID: PMC4347328  PMID: 25535313
2.  Systemic antifungal therapy for proven or suspected invasive candidiasis: the AmarCAND 2 study 
Background
In the context of recent guidelines on invasive candidiasis (IC), how French intensive care units (ICUs) are managing IC?
Methods
This is a prospective observational multicenter cohort study. During 1 year (2012–2013), 87 French ICUs enrolled consecutive patients with suspected or proven IC (SIC or PIC) and receiving systemic antifungal therapy (SAT). Data were collected up to 28 days after inclusion.
Results
We studied 835 patients, 291 with PIC and 544 with SIC. At SAT initiation, patients with SIC were significantly more severe (SAPS II 50.1 ± 18.7 vs. 46.2 ± 18.0). Severe sepsis or septic shock prompted to initiate empiric SAT in 70 % of SIC. Within 4 days in median, the initial SAT was modified in 49 % of patients with PIC vs. 33 % patients with SIC. Modifications were most often motivated by mycological results, and de-escalation was the most frequent change. Regarding compliance to IC management guidelines, echinocandin was used for 182 (62.5 %) patients with PIC, and 287 (52.7 %) of those with SIC; central venous catheter was removed in 87 (54.3 %) of patients with candidaemia, and 43 of the remaining patients received echinocandin; and de-escalation was undertaken after 5 days of SAT in 142 patients, after 10 days in 13 patients. As 20.6 % of SIC were secondarily documented, 403/835 (48 %) patients had finally a proven IC. Candida albicans was the main pathogen (65.3 %), then Candida glabrata (15.9 %). The 28-day mortality rates were 40.0 % in candidaemia, 25.4 % in cIAI, and 26.7 % in deep-seated candidiasis. In the overall population of patients with proven IC, four independent prognostic factors were identified: immunosuppression (Odds Ratio (OR) = 1.977: 1.03–3.794 95 % confidence interval (CI), p = 0.04), age (OR = 1.035; 1.017–1.053 95 % CI; p < 0.001), SAPS >46 on ICU admission (OR = 2.894; 1.81–4.626 95 % CI; p < 0.001), and surgery just before or during ICU stay (OR = 0.473; 0.29–0.77 95 % CI; p < 0.001).
Conclusion
When SAT is initiated in French ICUs, the IC is ultimately proven for 48 % of patients. Empiric SAT is initiated in severely ill ICU patients. The initial SAT is often adapted, with de-escalation to fluconazole when possible. Mortality rate remains high.
Electronic supplementary material
The online version of this article (doi:10.1186/s13613-015-0103-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13613-015-0103-7
PMCID: PMC4705061  PMID: 26743881
Candida; Intensive care; Cohort study; Candidiasis; Candidaemia; Critically ill
3.  Antimony to Cure Visceral Leishmaniasis Unresponsive to Liposomal Amphotericin B 
PLoS Neglected Tropical Diseases  2016;10(1):e0004304.
We report on 4 patients (1 immunocompetent, 3 immunosuppressed) in whom visceral leishmaniasis had become unresponsive to (or had relapsed after) treatment with appropriate doses of liposomal amphotericin B. Under close follow-up, full courses of pentavalent antimony were administered without life-threatening adverse events and resulted in rapid and sustained clinical and parasitological cure.
Author Summary
Visceral leishmaniasis causes fever, enlargement of internal organs like the liver and the spleen, and leads to death if no treatment is given. It is caused by a microbe called Leishmania and affects children and adults in warm and temperate regions of the world. Antimony in different forms has been used to treat Visceral Leishmaniasis for almost one century and is still in use in several countries despite the fact that it sometimes displays toxic effects, especially in patients with underlying health problems. Because it is better tolerated and at least as effective as antimony, liposomal amphotericin B is now used as the first treatment for Visceral Leishmaniasis in Southern Europe. We observed that a small proportion of patients—especially those with an impaired immune system—do not cure even after several courses of liposomal amphotericin B. In 4 such patients with “unresponsiveness” to liposomal amphotericin B, antimony provided a sustained cure without major side effects. We conclude that when multiple failures or relapses occur after treatment with liposomal amphotericin B, antimony is a reasonable, potentially life-saving treatment option. These observations also suggest that “unresponsiveness” to amphotericin B results from unusual resistance mechanisms.
doi:10.1371/journal.pntd.0004304
PMCID: PMC4703342  PMID: 26735920
4.  Candida Arthritis: Analysis of 112 Pediatric and Adult Cases 
Open Forum Infectious Diseases  2015;3(1):ofv207.
Background. Candida arthritis is a debilitating form of deeply invasive candidiasis. However, its epidemiology, clinical manifestations, management, and outcome are not well understood.
Methods. Cases of Candida arthritis were reviewed from 1967 through 2014. Variables included Candida spp in joint and/or adjacent bone, underlying conditions, clinical manifestations, inflammatory biomarkers, diagnostic imaging, management, and outcome.
Results. Among 112 evaluable cases, 62% were males and 36% were pediatric. Median age was 40 years (range, <1–84 years). Most patients (65%) were not pharmacologically immunosuppressed. Polyarticular infection (≥3 joints) occurred in 31% of cases. Clinical manifestations included pain (82%), edema (71%), limited function (39%), and erythema (22%) with knees (75%) and hips (15%) most commonly infected. Median erythrocyte sedimentation rate was 62 mm/hr (10–141) and C reactive protein 26 mg/dL (0.5–95). Synovial fluid median white blood cell count was 27 500/µL (range, 100–220 000/µL) with 90% polymorphonuclear neutrophils (range, 24–98). Adjacent osteomyelitis was present in 30% of cases. Candida albicans constituted 63%, Candida tropicalis 14%, and Candida parapsilosis 11%. Most cases (66%) arose de novo, whereas 34% emerged during antifungal therapy. Osteolysis occurred in 42%, joint-effusion in 31%, and soft tissue extension in 21%. Amphotericin and fluconazole were the most commonly used agents. Surgical interventions included debridement in 25%, irrigation 10%, and drainage 12%. Complete or partial response was achieved in 96% and relapse in 16%.
Conclusion. Candida arthritis mainly emerges as a de novo infection in usually non-immunosuppressed patients with hips and knees being most commonly infected. Localizing symptoms are frequent, and the most common etiologic agents are C albicans, C tropicalis, and C parapsilosis. Management of Candida arthritis remains challenging with a clear risk of relapse, despite antifungal therapy.
doi:10.1093/ofid/ofv207
PMCID: PMC4742637  PMID: 26858961
antifungal therapy; arthritis; Candida spp; diagnosis; invasive candidiasis
5.  Development of new strategies for early diagnosis of mucormycosis from bench to bedside 
Mycoses  2014;57(0 3):2-7.
Summary
Early diagnosis and initiation of amphotericin B (AmB) for treatment of mucormycosis increases survival from approximately 40% to 80%. The central objective of a new study of the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) Zygomycosis Working Group is to improve the clinical and laboratory diagnosis of mucormycosis. The diagnostic tools generated from this study may help to significantly improve survival from mucormycosis worldwide. The study has three major objectives: to conduct a prospective international registration of patients with mucormycosis using a well-established global network of centres; to construct a predictive risk model for patients at risk for mucormycosis; and to establish an international archive of specimens of tissues, fluids, and organisms linked from the patients enrolled into the registry that will be used for development of leading edge molecular, proteomic, metabolic and antigenic systems for mucormycosis.
doi:10.1111/myc.12249
PMCID: PMC4464811  PMID: 25475924
mucormycosis; zygomycosis; diagnosis; network; epidemiology
6.  Imported African Histoplasmosis in an Immunocompetent Patient 40 Years after Staying in a Disease-Endemic Area 
Histoplasmosis caused by Histoplasma capsulatum var. duboisii is a rare disease outside central and western Africa. In Europe, all cases are imported. We report a case of an African histoplasmosis with isolated pulmonary involvement in a non-immunocompromised patient that occurred 40 years after his stay in a disease-endemic area. The patient was given itraconazole. 18F-fluoro-2-deoxy-d-glucose positron emission tomography–computed tomography was used to assess evolution during treatment. The outcome for the patient was favorable.
doi:10.4269/ajtmh.13-0731
PMCID: PMC4228866  PMID: 25246691
7.  Nocardia Arthritis: 3 Cases and Literature Review 
Medicine  2015;94(42):e1671.
Abstract
Nocardia are Gram-positive filamentous bacteria responsible for infections ranging from opportunistic life-threatening disseminated diseases to chronic skin and soft-tissue infections.
Even if virtually all organs can be infected, articular involvement is rare. Therefore, we report 3 recent cases and performed a literature review of cases of Nocardia arthritis in order to describe clinical features, therapeutic challenges, and outcome of these patients.
Among 34 patients (31 in the literature plus our 3 cases), 21 (62%) were due to hematogenous dissemination, 9 (26%) were due to direct bacterial inoculation through the skin, and in 4 cases, the mechanism of infection was unknown. Four out of these 34 cases occurred on prosthetic joints.
Whereas hematogenous infections mostly occurred in immunocompromised hosts (17 of 21, 81%), direct inoculation was mostly seen in immunocompetent patients.
Eighty-two percent of patients (28 out of 34) received trimethoprim-sulfamethoxazole-containing regimens and median antibiotic treatment duration was 24 weeks (range, 12–120) for hematogenous infections and 12 weeks (range, 6–24) for direct inoculations. Outcome was favorable in 27 cases despite unsystematic surgical management (17 cases) without sequelae in 70% of the cases.
Nocardia arthritis is rare but its management is complex and should rely on a combined approach with rheumatologist, infectious diseases expert, and surgeon.
doi:10.1097/MD.0000000000001671
PMCID: PMC4620750  PMID: 26496274
8.  A French National Survey on Clotting Disorders in Mastocytosis 
Medicine  2015;94(40):e1414.
Abstract
Mastocytosis is characterized by a clonal mast cell proliferation with organ infiltration and uncontrolled degranulation. Although not characteristic and poorly explained, some patients develop clotting abnormalities.
We retrospectively identified patients with established diagnosis of mastocytosis and related clotting abnormalities (clinical and/or biological) using the national French Reference Centre for Mastocytosis database.
From our cohort of 14 adult patients with clotting abnormalities (median age 46 years [range 26–75]), 4 had a presentation suggestive of a primary hemostasis disorder alone (by their symptoms and/or abnormal clotting tests [PFA, von Willebrand's disease [vWD] screening]) and 10 had a laboratory impairment of secondary hemostasis. Among these, 7 had bleeds characteristic of a coagulation cascade disorder (severe/life-threatening in 5 and mild in 2 patients). Clotting abnormalities were of variable severity, typically related to intense crisis of degranulation, such as anaphylactic reactions, and/or to severe organ infiltration by mast cells. Importantly, classical hemostatic management with platelet transfusion, fresh frozen plasma, or vitamin K infusions was unsuccessful, as opposed to the use of agents inhibiting mast cell activity, particularly steroids. This illustrates the crucial role of mast cell mediators such as tryptase and heparin, which interfere both with primary (mainly via inhibition of von Willebrand factor) and secondary hemostasis. There was interestingly an unusually high number of aggressive mastocytosis (particularly mast cell leukemia) and increased mortality in the group with secondary hemostasis disorders (n = 5, 36% of the whole cohort).
Mast cell degranulation and/or high tumoral burden induce both specific biologic antiaggregant and anticoagulant states with a wide clinical spectrum ranging from asymptomatic to life-threatening bleeds. Hemostatic control is achieved by mast cell inhibitors such as steroids.
doi:10.1097/MD.0000000000001414
PMCID: PMC4616764  PMID: 26447996
9.  Cutaneous Invasive Aspergillosis: Retrospective Multicenter Study of the French Invasive-Aspergillosis Registry and Literature Review 
Medicine  2015;94(26):e1018.
Abstract
Invasive aspergillosis (IA) has poor prognosis in immunocompromised patients. Skin manifestations, when present, should contribute to an early diagnosis. The authors aimed to provide prevalence data and a clinical and histologic description of cutaneous manifestations of primary cutaneous IA (PCIA) and secondary CIA (SCIA) in a unique clinical series of IA and present the results of an exhaustive literature review of CIA. Cases of proven and probable IA with cutaneous manifestations were retrospectively extracted from those registered between 2005 and 2010 in a prospective multicenter aspergillosis database held by the National Reference Center for Invasive Mycoses and Antifungals, Pasteur Institute, France. Patients were classified as having PCIA (i.e., CIA without extracutaneous manifestations) or SCIA (i.e., disseminated IA). Among the 1,410 patients with proven or probable IA, 15 had CIA (1.06%), 5 PCIA, and 10 SCIA. Hematological malignancies were the main underlying condition (12/15). Patients with PCIA presented infiltrated and/or suppurative lesions of various localizations not related to a catheter site (4/5), whereas SCIA was mainly characterized by disseminated papules and nodules but sometimes isolated nodules or cellulitis. Histologic data were available for 11 patients, and for 9, similar for PCIA and SCIA, showed a dense dermal polymorphic inflammatory infiltrate, with the epidermis altered in PCIA only. Periodic acid Schiff and Gomori-Grocott methenamine silver nitrate staining for all but 2 biopsies revealed hyphae compatible with Aspergillus. Aspergillus flavus was isolated in all cases of PCIA, with Aspergillus fumigatus being the most frequent species (6/10) in SCIA. Two out 5 PCIA cases were treated surgically. The 3-month survival rate was 100% and 30% for PCIA and SCIA, respectively. Our study is the largest adult series of CIA and provides complete clinical and histologic data for the disease. Primary cutaneous IA should be recognized early, and cases of extensive necrosis should be treated surgically; its prognosis markedly differs from that for SCIA. Any suppurative, necrotic, papulonodular, or infiltrated skin lesion in an immunocompromised patient should lead to immediate biopsy for histologic analysis and mycological skin direct examination and culture.
doi:10.1097/MD.0000000000001018
PMCID: PMC4504535  PMID: 26131805
10.  Cutaneous Invasive Aspergillosis: Retrospective Multicenter Study of the French Invasive-Aspergillosis Registry and Literature Review 
Medicine  2015;94(26):e1018.
Abstract
Invasive aspergillosis (IA) has poor prognosis in immunocompromised patients. Skin manifestations, when present, should contribute to an early diagnosis. The authors aimed to provide prevalence data and a clinical and histologic description of cutaneous manifestations of primary cutaneous IA (PCIA) and secondary CIA (SCIA) in a unique clinical series of IA and present the results of an exhaustive literature review of CIA. Cases of proven and probable IA with cutaneous manifestations were retrospectively extracted from those registered between 2005 and 2010 in a prospective multicenter aspergillosis database held by the National Reference Center for Invasive Mycoses and Antifungals, Pasteur Institute, France. Patients were classified as having PCIA (i.e., CIA without extracutaneous manifestations) or SCIA (i.e., disseminated IA). Among the 1,410 patients with proven or probable IA, 15 had CIA (1.06%), 5 PCIA, and 10 SCIA. Hematological malignancies were the main underlying condition (12/15). Patients with PCIA presented infiltrated and/or suppurative lesions of various localizations not related to a catheter site (4/5), whereas SCIA was mainly characterized by disseminated papules and nodules but sometimes isolated nodules or cellulitis. Histologic data were available for 11 patients, and for 9, similar for PCIA and SCIA, showed a dense dermal polymorphic inflammatory infiltrate, with the epidermis altered in PCIA only. Periodic acid Schiff and Gomori-Grocott methenamine silver nitrate staining for all but 2 biopsies revealed hyphae compatible with Aspergillus. Aspergillus flavus was isolated in all cases of PCIA, with Aspergillus fumigatus being the most frequent species (6/10) in SCIA. Two out 5 PCIA cases were treated surgically. The 3-month survival rate was 100% and 30% for PCIA and SCIA, respectively. Our study is the largest adult series of CIA and provides complete clinical and histologic data for the disease. Primary cutaneous IA should be recognized early, and cases of extensive necrosis should be treated surgically; its prognosis markedly differs from that for SCIA. Any suppurative, necrotic, papulonodular, or infiltrated skin lesion in an immunocompromised patient should lead to immediate biopsy for histologic analysis and mycological skin direct examination and culture.
doi:10.1097/MD.0000000000001018
PMCID: PMC4504535  PMID: 26131805
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
Medicine  2014;93(2):61-72.
Abstract
Idiopathic CD4 T lymphocytopenia (ICL) is a rare and severe condition with limited available data. We conducted a French multicenter study to analyze the clinical and immunologic characteristics of a cohort of patients with ICL according to the Centers for Disease Control criteria.
We recruited 40 patients (24 female) of mean age 44.2 ± 12.2 (19–70) years. Patients underwent T-lymphocyte phenotyping and lymphoproliferation assay at diagnosis, and experiments related to thymic function and interferon (IFN)-γ release by natural killer (NK) cell were performed. Mean follow-up was 6.9 ± 6.7 (0.14–24.3) years. Infectious, autoimmune, and neoplastic events were recorded, as were outcomes of interleukin 2 therapy.
In all, 25 patients had opportunistic infections (12 with human papillomavirus infection), 14 had autoimmune symptoms, 5 had malignancies, and 8 had mild or no symptoms. At the time of diagnosis, the mean cell counts were as follows: mean CD4 cell count: 127/mm3 (range, 4–294); mean CD8: 236/mm3 (range, 1–1293); mean CD19: 113/mm3 (range, 3–547); and mean NK cell count: 122/mm3 (range, 5–416). Most patients had deficiency in CD8, CD19, and/or NK cells. Cytotoxic function of NK cells was normal, and patients with infections had a significantly lower NK cell count than those without (p = 0.01). Patients with autoimmune manifestations had increased CD8 T-cell count. Proliferation of thymic precursors, as assessed by T-cell rearrangement excision circles, was increased. Six patients died (15%). CD4 T-cell count <150/mm3 and NK cell count <100/mm3 were predictors of death.
In conclusion, ICL is a heterogeneous disorder often associated with deficiencies in CD8, CD19, and/or NK cells. Long-term prognosis may be related to initial CD4 and NK cell deficiency.
doi:10.1097/MD.0000000000000017
PMCID: PMC4616307  PMID: 24646462
AIHA = autoimmune hemolytic anemia; CDC = Centers for Disease Control; CMV = cytomegalovirus; cpm = count per minute; CVID = common variable immunodeficiency; CXCR4 = C-X-C chemokine receptor type 4; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; HPV = human papillomavirus; HTLV-1/2 = human T-cell lymphotropic 1/2; ICL = idiopathic CD4 T lymphocytopenia; IFN-γ = interferon-γ; IL = interleukin; JC virus = John Cunningham virus; LPA = lymphocyte proliferation assay; NK = natural killer; P = patient; PBMC = peripheral blood mononuclear cell; Pwd = pokeweed; SI = stimulation index; sj = signal joint; TREC = T-cell rearrangement excision circle
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

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