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Diagnosis, management and outcome of Candida endocarditis

  • Author Footnotes
    * Present address: Université Paris Diderot, AP-HP, Hôpital Beaujon, Service de Médecine Interne, 92110 Clichy Cedex, France
    A. Lefort
    Footnotes
    * Present address: Université Paris Diderot, AP-HP, Hôpital Beaujon, Service de Médecine Interne, 92110 Clichy Cedex, France
    Affiliations
    Université Paris Descartes, AP-HP, Hôpital Necker-Enfants malades, Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Paris
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  • L. Chartier
    Affiliations
    Institut Pasteur, Unité d'Epidémiologie des Maladies Emergentes, Paris
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  • B. Sendid
    Affiliations
    Université Nord de France, INSERM U995, CHRU, Université Lille II, Lille
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  • M. Wolff
    Affiliations
    Université Paris Diderot, AP-HP, Hôpital Bichat, Service de Réanimation Médicale, Paris
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  • J.-L. Mainardi
    Affiliations
    Université Paris Descartes, AP-HP, Hôpital Européen Georges Pompidou, Service de Microbiologie Clinique, Paris

    Université Pierre et Marie Curie, UMR S 872, Paris

    INSERM, U872, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris
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  • I. Podglajen
    Affiliations
    Université Paris Descartes, AP-HP, Hôpital Européen Georges Pompidou, Service de Microbiologie Clinique, Paris
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  • M. Desnos-Ollivier
    Affiliations
    Institut Pasteur, Unité de Mycologie Moléculaire, Centre National de Référence Mycologie et Antifongiques, Paris

    CNRS URA3012, Paris
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  • A. Fontanet
    Affiliations
    Institut Pasteur, Unité d'Epidémiologie des Maladies Emergentes, Paris

    Conservatoire National des Arts et Métiers, Chaire Santé et Développement, Paris
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  • S. Bretagne
    Affiliations
    Institut Pasteur, Unité de Mycologie Moléculaire, Centre National de Référence Mycologie et Antifongiques, Paris

    CNRS URA3012, Paris

    Université Paris 12, AP-HP, Hôpital Henri Mondor, Laboratoire de Mycologie-Parasitologie, Créteil, France
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  • O. Lortholary
    Affiliations
    Université Paris Descartes, AP-HP, Hôpital Necker-Enfants malades, Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Paris

    Institut Pasteur, Unité de Mycologie Moléculaire, Centre National de Référence Mycologie et Antifongiques, Paris

    CNRS URA3012, Paris
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  • for the French Mycosis Study Group
    Author Footnotes
    † Members of the French Mycosis study group are listed in the Appendix. Previous presentation: This work was presented in part at the 49th International Conference on Antimicrobial Agents and Chemotherapy, Clinical Mycology Oral Session, San Francisco, CA, USA, 14 September 2009, presentation number M-1249, and at the 50th International Conference on Antimicrobial Agents and Chemotherapy, Clinical Mycology Poster Session, Boston, MA, USA, 13 September 2010, presentation number M-1073.
    *
  • Author Footnotes
    * Present address: Université Paris Diderot, AP-HP, Hôpital Beaujon, Service de Médecine Interne, 92110 Clichy Cedex, France
    † Members of the French Mycosis study group are listed in the Appendix. Previous presentation: This work was presented in part at the 49th International Conference on Antimicrobial Agents and Chemotherapy, Clinical Mycology Oral Session, San Francisco, CA, USA, 14 September 2009, presentation number M-1249, and at the 50th International Conference on Antimicrobial Agents and Chemotherapy, Clinical Mycology Poster Session, Boston, MA, USA, 13 September 2010, presentation number M-1073.

      Abstract

      Limited data exist on Candida endocarditis (CE) outcome in the era of new antifungals. As early diagnosis of CE remains difficult, non-culture-based tools need to be evaluated. Through the French prospective MYCENDO study (2005–2007), the overall characteristics and risk factors for death from CE were analysed. The contribution of antigen detection (mannan/anti-mannan antibodies and (1,3)-β-D-glucans) and molecular tools was evaluated. Among 30 CE cases, 19 were caused by non-albicans species. Sixteen patients (53%) had a predisposing cardiac disease, which was a valvular prosthesis in ten (33%). Nine patients (30%) were intravenous drug users; none of them had right-sided CE. Among the 21 patients who were not intravenous drug users, 18 (86%) had healthcare-associated CE. Initial therapy consisted of a combination of antifungals in 12 of 30 patients (40%). Thirteen patients (43%) underwent valve replacement. The median follow-up was 1 year after discharge from hospital (range, 5 months to 4 years) and hospital mortality was 37%. On univariate analysis, patients aged ≥60 years had a higher mortality risk (OR 11, 95% CI 1.2–103.9; p 0.024), whereas intravenous drug use was associated with a lower risk of death (OR 0.12, 95% CI 0.02–0.7; p 0.03). Among 18 patients screened for both serum mannan/anti-mannan antibodies and (1,3)-β-D-glucans, all had a positive result with at least one of either test at CE diagnosis. Real-time PCR was performed on blood (SeptiFast) in 12 of 18, and this confirmed the blood culture results. In conclusion, CE prognosis remains poor, with a better outcome among younger patients and intravenous drug users. Detection of serum antigens and molecular tools may contribute to earlier CE diagnosis.

      Keywords

      Introduction

      Candida endocarditis (CE) is rare, accounting for <2% of all infective endocarditis cases [
      • Baddley JW
      • Benjamin Jr, DK
      • Patel M
      • et al.
      Candida infective endocarditis.
      ,
      • Falcone M
      • Barzaghi N
      • Carosi G
      • et al.
      Candida infective endocarditis: report of 15 cases from a prospective multicenter study.
      ,
      • Murdoch DR
      • Corey GR
      • Hoen B
      • et al.
      Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis‐Prospective Cohort Study.
      ], and complicates candidaemia in up to 17.7% of patients when transoesophageal echocardiography (TEE) is systematically performed (Fernandez Cruz et al., 50th ICAAC, 2010, Abstract K-2172). Previously observed predominantly in intravenous drug users, it now occurs in the healthcare-associated setting, affecting patients at risk for invasive fungal infections [
      • Baddley JW
      • Benjamin Jr, DK
      • Patel M
      • et al.
      Candida infective endocarditis.
      ,
      • Falcone M
      • Barzaghi N
      • Carosi G
      • et al.
      Candida infective endocarditis: report of 15 cases from a prospective multicenter study.
      ,
      • Chopra T
      • Bhargava A
      • Kumar S
      • et al.
      Candida kefyr endocarditis in a patient with hypertrophic obstructive cardiomyopathy.
      ,
      • Ellis ME
      • Al‐Abdely H
      • Sandridge A
      • Greer W
      • Ventura W
      Fungal endocarditis: evidence in the world literature, 1965–1995.
      ,
      • Pierrotti LC
      • Baddour LM
      Fungal endocarditis, 1995–2000.
      ,
      • Wang JH
      • Liu YC
      • Lee SS
      Candida endocarditis following percutaneous transluminal coronary angioplasty.
      ]. Recent hospital mortality rates are still as high as 30–47% [
      • Baddley JW
      • Benjamin Jr, DK
      • Patel M
      • et al.
      Candida infective endocarditis.
      ,
      • Falcone M
      • Barzaghi N
      • Carosi G
      • et al.
      Candida infective endocarditis: report of 15 cases from a prospective multicenter study.
      ]. The most recent guidelines for the treatment of CE recommend an amphotericin B-based or echinocandin-based regimen, with or without flucytosine, followed by fluconazole for susceptible organisms, in combination with valve replacement. If surgery is contraindicated, chronic antifungal suppression is recommended. However, data on the long-term outcome of CE are very scarce, as no large prospective study focusing specifically on CE has yet been conducted. Therefore, the guidelines are mainly based on anecdotal case reports, case series, and clinical experience [
      • Pappas PG
      • Kauffman CA
      • Andes D
      • et al.
      Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.
      ]. We conducted a 27-month prospective study in France to determine the current characteristics, risk factors for death and long-term prognosis of CE, in addition to the diagnostic contribution of fungal antigen detection and molecular tools.

      Materials and Methods

       Clinical sample and data collection

      The prospective MYCENDO study on fungal endocarditis was conducted in France between 1 January 2005 and 31 March 2007. Infectious disease, cardiology, internal medicine, intensive-care and paediatric specialists, cardiovascular surgeons and microbiologists of all university and general hospitals were informed about the study by their scientific societies. Anonymous data were collected in centres and then validated by the MYCENDO scientific committee. Diagnostic and therapeutic management of individual cases was performed in each participating hospital according to local recommendations. In addition, all fungal isolates were analysed at the French National Reference Centre for Mycoses and Antifungals (Institut Pasteur, Paris); serum samples were sequentially collected for detection of fungal antigens at the University of Lille, blood samples were collected for detection of fungal DNA at University of East Paris Créteil, and valvular samples were sent to Georges Pompidou Hospital, Paris. Control sera were collected from six patients with definite bacterial endocarditis. The study was approved by the Comité de Protection des Personnes, Hôpital Necker, Paris; #04-10-05, and promoted by the Institut Pasteur.

       Definitions

      All patients who met the criteria for definite or possible CE were enrolled [
      • Li JS
      • Sexton DJ
      • Mick N
      • et al.
      Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis.
      ]. In accordance with previously published criteria [
      • Li JS
      • Sexton DJ
      • Mick N
      • et al.
      Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis.
      ,
      • Ascioglu S
      • Rex JH
      • de Pauw B
      • et al.
      Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus.
      ], CE was definite if culture and/or histology of cardiac material or embolic tissue demonstrated Candida species, or if there was the combination of persistently positive blood cultures for Candida species and evidence of endocardial involvement on echocardiogram; CE was possible in cases where there were positive blood cultures for Candida species and a predisposing heart condition, but no evidence of endocardial involvement on the echocardiogram.
      The date of CE diagnosis was defined as the day of the first echocardiogram suggestive of endocarditis (n = 29) or the first day of blood culture positivity in a patient with ventricular assist device infection. Median time to diagnosis was the number of days elapsed between the first clinical symptoms of CE and diagnosis.
      Cases of CE were classified as either healthcare-associated or community-associated, according to previously defined criteria [
      • Benito N
      • Miro JM
      • de Lazzari E
      • et al.
      Health care‐associated native valve endocarditis: importance of non‐nosocomial acquisition.
      ]. The indications for surgery were classified as ‘infectious', ‘cardiac', or ‘embolic’ [
      • Egeblad H
      • Wennevold A
      • Berning J
      • Lauridsen P
      Mitral valve replacement in infective endocarditis as prophylaxis against embolism. Identification of patients at risk by 2‐dimensional echocardiography.
      ].
      The portal of entry was determined on the basis of compatible clinical, microbiological and/or radiographic features and the isolation of the same Candida species from this presumed source of infection, except for skin, which was considered as the portal of entry in intravenous drug users when no alternative source of infection was found after careful examination. If the clinical data were ambiguous, the portal of entry was categorized as ‘undetermined'. Myocardial abscess and pacemaker lead infection were defined as previously reported [
      • Daniel WG
      • Mugge A
      • Martin RP
      • et al.
      Improvement in the diagnosis of abscesses associated with endocarditis by transesophageal echocardiography.
      ,
      • Klug D
      • Balde M
      • Pavin D
      • et al.
      Risk factors related to infections of implanted pacemakers and cardioverter‐defibrillators: results of a large prospective study.
      ].
      At the time of death, CE was considered to be ‘ongoing’ in the presence of otherwise unexplained fever of ≥38°C, persistent positive blood cultures for Candida species, new vascular phenomena [
      • Li JS
      • Sexton DJ
      • Mick N
      • et al.
      Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis.
      ], and/or the persistence of other major criteria [
      • Li JS
      • Sexton DJ
      • Mick N
      • et al.
      Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis.
      ]. Otherwise, it was considered to be ‘controlled'.

       Mycological methods

      Species identification and antifungal susceptibility determination. All isolates were identified to the species level by the use of carbon assimilation profiles (ID32C; Biomérieux, Marcy-l'Etoile, France). In vitro susceptibility testing was performed according to EUCAST procedures [
      • Subcommittee of Antifungal Susceptibility Testing (AFST)
      • ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST)
      EUCAST definitive document EDef 7.1: method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts.
      ]. Fluconazole, voriconazole, flucytosine, caspofungin [
      • Desnos‐Ollivier M
      • Bretagne S
      • Raoux D
      • Hoinard D
      • Dromer F
      • Dannaoui E
      Mutations in the fks1 gene in Candida albicans, C. tropicalis, and C. krusei correlate with elevated caspofungin MICs uncovered in AM3 medium using the method of the European Committee on Antibiotic Susceptibility Testing.
      ] and amphotericin B were tested as previously described [
      • Dannaoui E
      • Lortholary O
      • Raoux D
      • et al.
      Comparative in vitro activities of caspofungin and micafungin, determined using the method of the European Committee on Antimicrobial Susceptibility Testing, against yeast isolates obtained in France in 2005–2006.
      ,
      • Lortholary O
      • Dannaoui E
      • Raoux D
      • et al.
      In vitro susceptibility to posaconazole of 1903 yeast isolates recovered in France from 2003 to 2006 and tested by the method of the European committee on antimicrobial susceptibility testing.
      ]. The thresholds defined by EUCAST were used for fluconazole [
      EUCAST Technical Note on fluconazole.
      ] and voriconazole [
      EUCAST Technical Note on voriconazole.
      ]. MICs ≥8 mg/L were considered to be high for flucytosine [
      • Desnos‐Ollivier M
      • Bretagne S
      • Bernede C
      • et al.
      Clonal population of flucytosine‐resistant Candida tropicalis from blood cultures, Paris, France.
      ].
      Detection of serum (1,3)-β-D-glucans. Serum samples were diluted in glucan-free reagent-grade water (Fungitell assay; Associates of Cape Cod, Falmouth, MA, USA). Interpretation of (1,3)-β-D-glucan values was as follows: <60 pg/mL, negative; 60–79 pg/mL, indeterminate; >80 pg/mL, positive.
      Detection of serum mannan and anti-mannan antibodies. Mannan and anti-mannan antibodies were measured with commercialized tests (Platelia Candida Ag and Ab; Bio-Rad, Marne-la-Coquette, France) [
      • Sendid B
      • Caillot D
      • Baccouch‐Humbert B
      • et al.
      Contribution of the Platelia Candida‐specific antibody and antigen tests to early diagnosis of systemic Candida tropicalis infection in neutropenic adults.
      ]. The cut-offs were those proposed by the manufacturer: positive value, 0.5 ng/mL for mannan and 10 AU/mL for anti-mannan.
      Detection of fungal DNA in blood samples and in surgical cardiac material. DNA extraction and amplification from blood samples were performed with the SeptiFast Prep Kit and the SeptiFast Kit (Roche Diagnostics, Mannheim, Germany). The results were expressed as cycle threshold values. The higher the cycle threshold, the lower the microbiological DNA burden.
      DNA was extracted from excised cardiac tissue with the QIAmp Tissue kit (Qiagen, Courtaboeuf, France), according to the manufacturer's instructions, with some modifications: grinding of the biopsy specimens was performed with the MagNA Lyser instrument (Roche Diagnostics), and lysis was improved by five successive heat shocks. PCR amplification followed by sequencing was performed with primers ITS1, ITS3, and ITS4 [
      • Playford EG
      • Kong F
      • Sun Y
      • Wang H
      • Halliday C
      • Sorrell TC
      Simultaneous detection and identification of Candida, Aspergillus, and Cryptococcus species by reverse line blot hybridization.
      ,
      • White TJ
      • Burns TD
      • Lee SB
      • Taylor JW
      Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics.
      ], spanning the transcribed intergenic spacers ITS1 and ITS2.

       Statistical analysis

      Characteristics were analysed as medians and range for continuous variables and as percentages for discrete variables. Univariate analysis was based on the chi-square test or Fisher's exact test for discrete variables. Continuous variables were compared by use of the Mann–Whitney test. All significance tests were two-sided, and p-values <0.05 were considered to be significant. The survival time was defined as the interval between diagnosis of CE and death or the last follow-up visit in patients who remained alive. Survival differences were compared by use of the log-rank test, and survival curves were calculated with the Kaplan–Meier method (censoring at 24 months two patients with more than 2 years of follow-up). Data were analysed with STATA software version 11.0 (Stata Corporation, College Station, TX, USA).

      Results

      Overall, 20 hospitals reported at least one case. Among 30 CE cases, 29 were definite and one was possible (patient no. 23, with valvular bioprostheses and eight positive blood cultures but no vegetation at TEE or any septic phlebitis or metastatic complication).

       Patient characteristics, and clinical and biological findings

      Demographic and clinical characteristics of the 30 CE patients are shown in Tables 1 and 2. The median time between the first fungaemic episode and diagnosis of CE was 5 days (range, 1 day to 2 months). The significant differences between intravenous drug users and non-users are shown in Table 3. Only three patients from this latter group had community-acquired endocarditis. Eight patients experienced prior endocarditis; the median intervals between the previous episode and current CE were 1.5 years (range, 15 days to 10 years) for seven of them with prior bacterial endocarditis, and 2 years for patient no. 15, who experienced prior Candida parapsilosis endocarditis. Among ten (33%) patients with prosthetic valve endocarditis, the interval between valve replacement and CE was <1 year for five of ten patients. Eighty-three per cent of patients had an acute presentation, with a duration of symptoms ≤6 weeks. Ten (33%) patients were afebrile. None of the nine drug users had right-sided endocarditis. Among them, five experienced prior left-sided endocarditis and four had no known predisposing cardiopathy. A skin or catheter-related portal of entry was found in eight of ten C. parapsilosis complex cases. Among the 11 of 13 patients with a catheter-related infection in whom the date of insertion was known, the median duration between insertion and CE diagnosis was 46 days (range, 7–540 days). Twenty-two patients (73%) experienced embolic complications, which occurred under medical treatment in three of them. All patients were human immunodeficiency virus-negative.
      TABLE 1Clinical characteristics and outcome in 30 patients with Candida endocarditis (CE)
      CharacteristicsNo. (%)
      Age (years), median (range)57 (6–82)
      Male24 (80)
      Community-acquired CE12 (40)
      Healthcare-associated CE18 (60)
      Host predisposing conditions
      Some patients had more than one predisposing condition.
      30 (100)
       Central venous access16 (53)
       Malnutrition13 (43)
       Intravenous drug addiction9 (30)
       Solid cancer or haematological malignancy6 (20)
       Parenteral nutrition5 (17)
       Diabetes mellitus5 (17)
       Haemodialysis4 (13)
       Chronic respiratory insufficiency4 (13)
       Chronic renal insufficiency4 (13)
       Congestive heart failure4 (13)
       Chronic alcoholism2 (7)
       Prior solid organ transplantation1 (3)
       Antibiotics (>10 days) within 3 months preceding CE
      n = 27.
      13 (48)
       Immunosuppressive and/or corticosteroid treatment6 (20)
      Predisposing cardiac disease
      Some patients had more than one cardiac disease/valve involved.
      16 (53)
       Valvular prosthesis10 (33)
       Previous episode of infective endocarditis8 (27)
       Pacemaker2 (7)
       Artificial heart1 (3)
       Congenital heart disease1 (3)
      Suspected portal of entry
       Central venous access13 (43)
       Skin8 (27)
       Urinary tract2 (7)
       Surgical site infection1 (3)
       Undetermined6 (20)
      Median time to diagnosis (days) (range)11 (1–90)
      Clinical findings
       Fever20 (67)
       Septic shock6 (20)
       Cardiac failure6 (20)
       Embolic complications22 (73)
       Spleen/brain/limb/eye/coronary artery/kidney/liver/lung8/6/6/4/3/3/2/1
      Biology
       C-reactive protein (mg/L), median (range)73 (8–301)
       Neutrophil count (per mm2), median (range)6430 (9–34 780)
      Echocardiographic abnormalities28 (93)
       Cardiac involvement
      Some patients had more than one cardiac disease/valve involved.
        Aortic valve16 (53)
        Mitral valve12 (40)
        Right-sided2 (7)
        Left-sided + right-sided1 (3)
        Pacemaker2 (7)
       Vegetations27 (90)
        Median size (mm) (range)13 (4–30)
        Described as mobile16 (53)
       Annular abscess5 (17)
      Treatment
       Antifungal therapy30 (100)
        Caspofungin23 (77)
        Flucytosine21 (70)
        Fluconazole18 (60)
        Voriconazole9 (30)
        Amphotericin B deoxycholate8 (27)
        Liposomal amphotericin B6 (20)
       Antifungal monotherapy6 (20)
       Antifungal combination24 (80)
       Antifungal therapy alone17 (57)
       Combined medical and surgical therapy13 (43)
        Surgery ≤3 weeks after diagnosis8 (27)
      Outcome
       Death20 (67)
        Median time to death (days) (range)66 (4 days to 6 years)
       Cause of death
        Related to endocarditis14 (70)
        Consequence of comorbidities5 (25)
        Unknown1 (5)
      a Some patients had more than one predisposing condition.
      b n = 27.
      c Some patients had more than one cardiac disease/valve involved.
      TABLE 2Description of cardiac involvement, diagnostic contribution of fungal antigen detection and molecular tools, treatment and outcome in 30 patients with Candida endocarditis
      PatientIVDUSpeciesCardiac involvementMedical treatmentSurgery (time from diagnosis)/fungal result of direct examination (D), culture (C) and PCR of the valveOutcome (duration of follow-up)/cause/ongoing or controlled endocarditisSeptiFast fungal result of the first available sample/time interval between the last positive blood culture and the sampleMannan/anti-mannan and (1,3)-β-d-glucan results: number of positive/total sera
      1NoCandida albicansAo mechanical prosthesisFlu (10 days), Flu + 5FC (7 days), Flu + ABLC (2 months), Flu (2.5 months)Yes (2.5 months)/D−, C−Death (5 years) following several relapses/cardiac failure/controlledNegative/>8 days3/3; 3/3
      2YesC. albicansMi mechanical prosthesisFlu (3 months), Cas + LamB (1 month), Cas (6 months), Vori (2 months)Yes (3 months)/NDDeath (1 year)/Staphylococcus aureus sepsis/controlledND1/1; 1/1
      3YesC. albicansMi homograftCas + 5FC (3 days), LamB + 5FC (14 days), Flu (3.5 months)Yes (1 day)/D+, C+, PCR+Alive (2 years)Positive for C. albicans/1 day3/3; 3/3
      4NoC. albicansAo bioprosthesisCas (7 weeks), AmB + 5FC (15 days), AmB (17 days), Flu life-longNoAlive (2 years)NDND
      5NoC. albicansPM lead, Mi valveFlu (3 weeks), Cas + 5FC (4 weeks), Flu (6 weeks)Yes (1 month)/C−Death (1 year)/bacterial pneumonia/controlledNDND
      6NoC. albicansMi valveCas (1 day), Flu (9 days), Cas (3 days)No/C+ (autopsy)Death (day 12)/C. albicans septic shock/ongoingND5/5; 4/5
      7NoC. albicansMi valveCas (3 weeks), Vori (3 months)NoDeath (4 months)/respiratory insufficiency/controlledNDND
      8NoC. albicansMi valveFlu + 5FC (2 days), Cas + 5FC (4 weeks), Flu + 5FC (2 weeks)NoDeath (6 weeks)/cardiac failure/controlledNegative/2 days5/5; 5/5
      9NoC. albicansAo valveCas (5 weeks), AmB + 5FC (1 month), Flu (3 months), Cas + 5FC (3 weeks), Flu (4 months)Yes (5 months)/C−Death (10 months)/cachexia/controlledNDND
      10YesC. albicansAo valveAmB (3 days), Cas + 5FC (3 weeks), Flu (2.5 months)Yes (3 days)/D+, C+, PCR+Alive (4 years)ND3/3; 3/3
      11NoC. albicansMi valveFlu (2 days), Cas + AmB (3 weeks), Cas + 5FC (1 week), Flu (7 months)NoAlive (8 months)NDND
      12NoCandida parapsilosisPM lead, Ao bioprosthesisAmB (3 weeks), LamB + 5FC (3 weeks), Vori (9 months), Flu (5.5 months)NoDeath (16 months) following a relapse/brain embolism/ongoingND0/2; 2/2
      13NoCandida orthopsilosisMi bioprosthesisCas + 5FC (5 days)NoDeath (5 days)/digestive haemorrhage/ongoingND0/3; 3/3
      14NoC. parapsilosisArtificial heartCas + 5FC (1 day), Cas (13 days), Vori (16 days)Yes (1 year)/NDDeath (1 year) following a relapse/haemodynamic failure during surgery/ongoingNDND
      15YesC. parapsilosisAo homograftCas (5 days), Vori life-longYes (11 days)/D+, C+, PCR+Alive (5 months)NDND
      16NoC. parapsilosisMi valveCas + Flu (3 days), Cas + 5FC (18 days)NoDeath (21 days)/C. parapsilosis septic shock/ongoingNegative/6 days2/2; 2/2
      17YesC. parapsilosisAo valveVori (1 day)Yes (1 day)/D+, C+, PCR NIDeath (4 days)/brain embolism/ongoingNDND
      18NoC. parapsilosisMi valveAmB + 5FC (3 days), Cas + Vori (19 days)NoDeath (22 days)/C. parapsilosis septic shock/ongoingPositive for C. parapsilosis/0 days3/3; 3/3
      19NoC. parapsilosisAo valveCas + 5FC (1 month), Flu + 5FC (6 weeks), Flu (7 months)NoAlive (2 years)Negative/>8 days3/5; 1/5 (4/5 positive for at least one test)
      20NoC. parapsilosisRight atriumCas + Flu (2 months), Flu (10 months)NoAlive (1 year)Negative/>8 days0/6; 6/6
      21YesC. parapsilosisAo valveAmB + 5FC (18 days), Flu + 5FC (5.5 months)Yes (1 day)/D+, C+, PCR+Alive (6 months)Positive for C. parapsilosis/2 days7/7; 7/7
      22NoCandida tropicalisAo valveFlu (4 days), Cas + 5FC (6 days)NoDeath (10 days)/myocardial infarction/ongoingND1/1; 1/1
      23NoC. tropicalisMi, Ao and Pulm bioprosthesisAmB + 5FC (2 days), Cas + AmB (8 days)NoDeath (10 days)/C. tropicalis septic shock/ongoingPositive for C. tropicalis/0 days3/3; 3/3
      24YesC. tropicalisAo valveCas + 5FC (2 weeks), Flu (2.5 months)Yes (1 day)/D+, C+Alive (6 months)Positive for C. tropicalis/7 days5/5; 5/5
      25NoCandida guilliermondiiAo bioprosthesisVori (6 weeks)Yes (3 weeks)/D−, C+Death (6 weeks)/cardiac failure/controlledNDND
      26YesC. guilliermondiiAo mechanical prosthesisFlu (5 days), LamB + 5FC (7 weeks), Flu + 5FC (3 months), Flu life-longNoAlive (12 months)Negative/4 days6/6; 6/6
      27NoCandida glabrataTric valveAmB (11 days), Cas (6 weeks), Vori (6 weeks)NoDeath (3 months)/solid cancer/controlledNDND
      28NoC. glabrataMi valveAmB (4 days), Cas + 5FC (24 days)NoDeath (1 month)/brain embolism/ongoingNegative/3 days5/5, 5/5
      29NoCandida kefyrAo valveFlu (9 days), Cas + LamB (1 month)NoDeath (7 months) following a relapse/brain embolism/ongoingNDND
      30YesCandida pelliculosaAo + Mi valvesAmB + 5FC (1 month), Flu + 5FC (2 months)Yes (1 day)/D+, C+, PCR NIDeath (3 months)/unknownNDND
      ABLC, amphotericin B lipid complex; AmB, amphotericin B deoxycholate; Ao, aortic; Cas, caspofungin; 5FC, flucytosine; Flu, fluconazole; IVDU, intravenous drug user; LamB, liposomal amphotericin B; Mi, mitral; ND, not done; NI, not interpretable (superimposed sequences); PM, pacemaker; Pulm, pulmonary; Tric, tricuspid; Vori, voriconazole.
      TABLE 3Differences in clinical characteristics and outcome between intravenous drug users and non-intravenous drug users with Candida endocarditis
      Intravenous drug users (n = 9)Non-intravenous drug users (n = 21)Total (N = 30)p-Value
      Age (years), median (range)38 (27–42)63 (6–82)57 (6–82)<0.001
      Community-acquired infection, no. (%)9 (100)3 (14)12 (40)<0.001
      Healthcare-associated infection, no. (%)0 (0)18 (86)18 (60)<0.001
      Host predisposing conditions, no. (%)
      Some patients had more than one predisposing condition.
       Central venous access0 (0)16 (76)16 (53)<0.001
       Antibiotics (>10 days) within 3 months preceding endocarditis0 (0)13 (72)
      n = 18.
      13 (48)
      n = 27.
      0.001
       Prior infective endocarditis5 (56)3 (14)8 (27)0.032
      Suspected portal of entry, no (%)
       Central venous access0 (0)13 (62)13 (43)0.003
       Skin8 (89)0 (0)8 (27)<0.001
      Treatment, no. (%)
       Antifungal therapy alone1 (11)16 (76)17 (57)0.002
       Combined medical and surgical therapy8 (89)5 (24)13 (43)0.002
        Surgery ≤3 weeks after diagnosis7 (78)1 (5)8 (27)<0.001
      Death3 (33)17 (81)20 (67)0.03
      a Some patients had more than one predisposing condition.
      b n = 18.
      c n = 27.

       Echocardiographic findings

      TEE was performed in 27 patients (90%); the three remaining patients only had transthoracic echocardiography performed. A description of cardiac involvement is given in Tables 1 and 2. The aortic valve was predominantly involved (n = 16/30 cases; 53%). In half of the cases, the vegetation size was >13 mm.

       Mycological findings

      Susceptibility testing. The Candida species responsible for endocarditis were distributed as follows: 11 Candida albicans, ten C. parapsilosis complex (nine C. parapsilosis and one Candida orthopsilosis), three Candida tropicalis, two Candida guilliermondii, two Candida glabrata, one Candida kefyr, and one Candida pelliculosa. Blood cultures were positive in 28 of 30 (93%) cases. For the remaining two patients (nos. 30 and 5), diagnosis was based on valve or embolic tissue culture results. For all of the isolates tested (n = 29), MIC values were less than or equal to the MIC90 for all species except for one C. parapsilosis isolate with a fluconazole MIC of 8 mg/mL, one C. albicans isolate with a flucytosine MIC of 4 mg/mL, and one C. guilliermondii isolate with a voriconazole MIC of 0.5 mg/mL.
      Diagnostic performances of (1,3)-β-D-glucans, mannan and anti-mannan antibodies, and molecular tools on blood samples. The quantity and quality of blood samples allowed serological investigations in 18 of 30 patients and molecular investigations in 12 of them.
      For serological investigations, 68 sera were available for these 18 patients. Table 2 indicates the number of positive results for each fungal antigen tested. Overall, all patients tested had at least one positive test result: mannan/anti-mannan antibodies and (1,3)-β-D-glucans were detected in 15 of 18 (83%) and 18 of 18 (100%) patients, respectively. False-negative mannan/anti-mannan antibody detection occurred only in patients infected with C. parapsilosis complex. Of 16 of 18 patients who had at least two serum samples collected, all had at least two consecutive positive (1,3)-β-D-glucan results and 13 (81%) had at least two consecutive positive anti-mannan antibody and/or mannanaemia results. (1,3)-β-D-Glucan serum levels were significantly higher in patients infected with C. parapsilosis complex, C. tropicalis and C. guilliermondii than in patients infected with C. albicans (p <0.002) (Fig. 1). In 15 of 18 patients, (1,3)-β-D-glucans persisted for at least 3 weeks after the diagnosis of CE, but no clear relationship between the persistence of (1,3)-β-D-glucans and outcome was established.
      Figure thumbnail gr1
      FIG. 1Distribution of circulating (1,3)-β-D-glucans (O (a)) and anti-mannan antibody levels (O (b)) in 68 serum samples from 18 patients with Candida endocarditis; sera displaying positive mannanaemia are represented in (b) (•). Individual values for the 68 sera are plotted as a function of the category of patients: patients infected with Candida albicans (CAL), Candida glabrata (CGL), Candida tropicalis (CTR), a strain belonging to the Candida parapsilosis complex (CPA), and Candida guilliermondii (CGU). The control group (CTRL) consisted of six patients with bacterial endocarditis. Horizontal bars represent medians, and dotted horizontal lines indicate cut-offs of tests.
      For molecular investigations on blood, 48 samples were available from 12 patients (median, 4; range, 3–6). Quantitative PCR (qPCR) results remained positive in two patients (nos. 23 and 18), but with a slight decrease in the fungal burden over time, whereas blood cultures were persistently positive. For three patients (nos. 3, 21, and 24), only the day 1 sample was qPCR-positive for the same yeast species as blood cultures (Table 2). Those three patients underwent surgery, and the subsequent blood cultures were negative. For five patients, the first sample was obtained after the initiation of treatment (median, 12 days; range, 2–37 days), and all were qPCR-negative. For patient no. 26, the qPCR results were negative, but blood cultures were positive for C. guilliermondii, a yeast species not included in the spectrum of the SeptiFast kit. For the remaining patient (no. 16), the qPCR result was positive for bacteria only.
      Valve investigations. Samples from 13 patients were analysed; 12 were obtained during surgery and one at autopsy. Cultures of the surgical cardiac material were positive in nine of 12 samples, all obtained within the first 3 weeks following diagnosis (Table 2). All three culture-negative samples were obtained from patients who had valvular surgery ≥1 month after diagnosis. A total of eight of 13 samples were submitted for histopathology, and all showed histology compatible with endocarditis, with yeasts being identified in six of eight samples. In three cases, thrombi without valvular tissue were analysed, and consisted mainly of fibrin and leukocytes. The remaining five cases had valvular biopsy specimens that revealed extensive inflammation with neutrophils, ulceration, and necrosis, without fibrosis or calcification. PCR was performed in four cases, and the same species (C. albicans and C. parapsilosis in two cases each) were identified by pan-fungal PCR and culture. In two additional samples, culture performed in the reporting centre was positive (one C. pelliculosa and one C. albicans), but the PCR results were not interpretable, owing to several superimposed sequences. Culture of the arterial embolus was positive in two of two samples studied.

       Treatment and risk factors for death

      The treatment and outcome of the 30 patients are reported in Tables 1 and 2. Death occurred in 67% (n = 20) patients. The median time to death after endocarditis diagnosis was 92 days (range, 4 days to 5 years). Eleven patients (37%) died during the first hospitalization, and nine others died thereafter. For these latter patients, death was attributable to CE relapse in four (nos. 1, 12, 14, and 29), to bacterial infection in two (nos. 2 and 5), and to evolutive underlying disease in two (nos. 9 and 27), and the cause remained unknown in patient no. 30, who died suddenly at home. The median follow-up among survivors at hospital discharge was 1 year (range, 5 months to 4 years). Overall, 13 (43%) patients had valvular surgery; the most frequent indication for surgery was ‘embolic’ (n = 7), followed by ‘infectious’ (n = 5) or ‘cardiac’ (n = 5); four patients had more than one indication. The death rates were 61.5% (8/13) among operated patients and 70.6% (12/17) among unoperated patients (p >0.05).
      Of the ten patients who survived, five (nos. 3, 10, 15, 21, and 24) received antifungals in addition to surgery; all of them were intravenous drug users and had valvular surgery within 11 days following CE diagnosis. Five patients (nos. 4, 11, 19, 20, and 26) received a combination of antifungals without surgery; two of them (nos. 4 and 26) with aortic prostheses are still receiving life-long fluconazole without recurrence after follow-ups of 2 years and 1 year, respectively. Among the 20 patients who died, eight had surgery (five later than 3 weeks following diagnosis). Among the 17 non-operated patients, surgery was contraindicated in 13, owing to poor performance status. Twelve of them died within a median of 42 days (range, 5–210 days) between CE diagnosis and death.
      The mortality rate was significantly lower in patients <60 years old than in those ≥60 years old (4/100 person-months (95% CI 1.9–8.3) and 14.5/100 person-months (95% CI 8.0–26.2), respectively; p 0.018). After univariate analysis, an age ≥60 years increased the risk of death, whereas being an intravenous drug user decreased it. Fig. 2 shows the survival curves according to age (i.e. <60 vs. ≥60 years old) and the intravenous drug user status. No therapeutic option gave a survival benefit (Table 4).
      Figure thumbnail gr2
      FIG. 2Kaplan-Meier survival estimates according to age (i.e. <60 vs. ≥60 years) and intravenous drug use status.
      TABLE 4Risk factors for death identified by univariate analysis in 30 patients with Candida endocarditis; all variables with a p-value of <0.25 are reported
      Risk factorsDead, N = 20Survivors, N = 10Univariate analysis
      No. (%)No. (%)OR (95% CI)p-Value
      Age ≥60 years11 (55)1 (10)11 (1.2–103.9)0.024
      Intravenous drug addiction3 (15)6 (60)0.12 (0.02–0.7)0.03
      Cardiac failure6 (30)00.074
      Septic shock6 (30)00.074
      Diabetes mellitus5 (25)00.14
      Corticosteroid treatment5 (25)00.14
      Caspofungin at initiation of treatment6 (30)6 (60)0.3 (0.06–1.4)0.14

      Discussion

      Our prospective study provides original data on current aspects of 30 CE cases in the era of modern diagnostic tools and new antifungals. Two distinct patient profiles were observed: a group of young intravenous drug users without underlying disease, presenting with ‘non-healthcare-associated’ endocarditis, often having valvular surgery early and having a low mortality rate; and a group of older patients (>60 years) with major comorbidities, developing healthcare-associated endocarditis, often treated with antifungals alone, and having a worse outcome. Although intravenous drug use was a risk factor in as many as 36 of 270 patients with CE [
      • Ellis ME
      • Al‐Abdely H
      • Sandridge A
      • Greer W
      • Ventura W
      Fungal endocarditis: evidence in the world literature, 1965–1995.
      ], this condition has never been identified before as a parameter of better outcome. As no intravenous drug user was older than 60 years, it was not possible to know whether the decreased risk of death associated with drug use was related to their younger age. It is of note that, in contrast to a recent Italian series, we did not find a higher mortality rate among patients with prosthetic valve endocarditis [
      • Falcone M
      • Barzaghi N
      • Carosi G
      • et al.
      Candida infective endocarditis: report of 15 cases from a prospective multicenter study.
      ].
      The classic clinical presentation of CE is a patient with risk factors for invasive candidiasis that rapidly presents symptoms suggestive of embolic complications, leading to the discovery of voluminous left-sided mobile vegetations. The absence of fever and/or cardiac failure does not exclude the diagnosis of CE. Considering the severity of CE and the high frequency of embolic complications, one may wonder whether systematic TEE should be performed for each fungaemic patient, in order to shorten the time for diagnosis (Fernandez Cruz et al., 50th ICAAC, 2010, Abstract K-2172). In addition, as the time between the first fungaemic episode and diagnosis of CE is sometimes very long, CE should be suspected and TEE discussed in cases of recurrence of fever in patients with a past history of fungaemia. Surprisingly, right-sided involvement is currently rare, even among drug users [
      • Ellis ME
      • Al‐Abdely H
      • Sandridge A
      • Greer W
      • Ventura W
      Fungal endocarditis: evidence in the world literature, 1965–1995.
      ,
      • Donal E
      • Abgueguen P
      • Coisne D
      • et al.
      Echocardiographic features of Candida species endocarditis: 12 cases and a review of published reports.
      ]. The outcome is extremely poor [
      • Baddley JW
      • Benjamin Jr, DK
      • Patel M
      • et al.
      Candida infective endocarditis.
      ,
      • Falcone M
      • Barzaghi N
      • Carosi G
      • et al.
      Candida infective endocarditis: report of 15 cases from a prospective multicenter study.
      ,
      • Ellis ME
      • Al‐Abdely H
      • Sandridge A
      • Greer W
      • Ventura W
      Fungal endocarditis: evidence in the world literature, 1965–1995.
      ,
      • Pierrotti LC
      • Baddour LM
      Fungal endocarditis, 1995–2000.
      ,
      • Melgar GR
      • Nasser RM
      • Gordon SM
      • Lytle BW
      • Keys TF
      • Longworth DL
      Fungal prosthetic valve endocarditis in 16 patients. An 11‐year experience in a tertiary care hospital.
      ]. Interpretation of our very high (67%) mortality rate should take into account the long follow-up period as compared with most series, which report only in-hospital mortality. Indeed, only 11 (37%) patients died during the first hospitalization. A meta-analysis reviewing the outcome of 72 CE cases occurring between 1966 and 2002 found a lower proportion of deaths among patients who had valvular surgery [
      • Steinbach WJ
      • Perfect JR
      • Cabell CH
      • et al.
      A meta‐analysis of medical versus surgical therapy for Candida endocarditis.
      ]. Among 33 cases derived from the International Collaboration of Endocarditis-Prospective Cohort Study, the mortality rate was similar whether surgery was performed or not [
      • Baddley JW
      • Benjamin Jr, DK
      • Patel M
      • et al.
      Candida infective endocarditis.
      ]. We did not find any difference in prognosis according to the management (i.e. medical therapy alone vs. combined with surgery) of CE. [
      • Kuhn DM
      • George T
      • Chandra J
      • Mukherjee PK
      • Ghannoum MA
      Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins.
      ]. However, our results suggest that early cardiac surgery during CE should always be attempted, and only patients with very poor medical status might not be operated on. For the latter patients, definitive antifungal therapy can be considered. Overall, 77% of our patients, and 33.3–66.6% of the cases in two recent studies [
      • Baddley JW
      • Benjamin Jr, DK
      • Patel M
      • et al.
      Candida infective endocarditis.
      ,
      • Falcone M
      • Barzaghi N
      • Carosi G
      • et al.
      Candida infective endocarditis: report of 15 cases from a prospective multicenter study.
      ], received caspofungin, in accordance with current guidelines [
      • Pappas PG
      • Kauffman CA
      • Andes D
      • et al.
      Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.
      ]. There was a trend towards better outcome in patients receiving caspofungin at diagnosis, which may be explained by the activity of caspofungin and other echinocandins against Candida species producing biofilms, amphotericin B deoxycholate and azoles not sharing this specificity. In accordance with recent data from France [
      • Leroy O
      • Gangneux JP
      • Montravers P
      • et al.
      Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006).
      ] and elsewhere [
      • Horn DL
      • Neofytos D
      • Anaissie EJ
      • et al.
      Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry.
      ,
      • Dizbay M
      • Fidan I
      • Kalkanci A
      • et al.
      High incidence of Candida parapsilosis candidaemia in non‐neutropenic critically ill patients: epidemiology and antifungal susceptibility.
      ,
      • Sipsas NV
      • Lewis RE
      • Tarrand J
      • et al.
      Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001–2007): stable incidence but changing epidemiology of a still frequently lethal infection.
      ], almost two-thirds of our cases were attributable to non-albicans species.
      As CE diagnosis is often delayed, alternative diagnostic tools needed to be evaluated. We found a positive PCR result in four of six available tissues, in accordance with previous reports [
      • Grijalva M
      • Horvath R
      • Dendis M
      • Erny J
      • Benedik J
      Molecular diagnosis of culture negative infective endocarditis: clinical validation in a group of surgically treated patients.
      ,
      • Vollmer T
      • Stormer M
      • Kleesiek K
      • Dreier J
      Evaluation of novel broad‐range real‐time PCR assay for rapid detection of human pathogenic fungi in various clinical specimens.
      ]. We also investigated the role of fungal DNA detection with a commercially available assay [
      • Fernandez AL
      • Varela E
      • Martinez L
      • et al.
      Evaluation of a multiplex real‐time PCR assay for detecting pathogens in cardiac valve tissue in patients with endocarditis.
      ,
      • Casalta JP
      • Gouriet F
      • Roux V
      • Thuny F
      • Habib G
      • Raoult D
      Evaluation of the LightCycler SeptiFast test in the rapid etiologic diagnostic of infectious endocarditis.
      ,
      • Wallet F
      • Nseir S
      • Baumann L
      • et al.
      Preliminary clinical study using a multiplex real‐time PCR test for the detection of bacterial and fungal DNA directly in blood.
      ]. When positive, the qPCR results correlated with those of blood cultures and the yeast species identification. Whether or not qPCR can provide additional clues for the treatment efficacy evaluation as compared with blood cultures warrants specific study.
      A recent compilation of data regarding the use of mannan/anti-mannan antibody detection showed that it had a high negative predictive value [
      • Mikulska M
      • Calandra T
      • Sanguinetti M
      • Poulain D
      • Viscoli C
      • Third European Conference On Infections In Leukemia Group T
      The use of mannan antigen and anti‐mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia.
      ]. In our study, the classic lack of mannan detection, mainly during C. parapsilosis episodes, was compensated for by the detection of high levels of anti-mannan antibodies. Despite the variability in mannan/anti-mannan antibody and (1,3)-β-D-glucan serum levels between patients, all patients with definite CE had positive results with at least one of the two tests at the time of CE diagnosis. This suggests that, in patients with negative detection of (1,3)-β-D-glucans and mannan/anti-mannan antibodies, the diagnosis of CE is probably unlikely, although we only evaluated patients with positive blood cultures. Interestingly, high levels of (1,3)-β-D-glucans persisted for several weeks. These results mean that (1,3)-β-D-glucan levels increase during the early phase of the disease but do not always return to baseline during the early period of antifungal treatment, as recently observed in haematopoietic stem cell transplantation recipients with candidaemia [
      • Mikulska M
      • Furfaro E
      • Del Bono V
      • et al.
      Persistence of positive (1,3)‐beta‐D‐glucan test after clearance of candidemia in HSCT recipients.
      ]. Complementarity of (1,3)-β-D-glucans, mannan/anti-mannan antibodies and Candida DNAaemia was made apparent here. However, because of the lack of subsequent blood samples, no definite conclusion can be drawn regarding the impact of antifungal treatment on these parameters.
      Although prospective, our study has some limitations. First, the rarity of the disease precludes a multivariate analysis of risk factors for death. Second, complications may be underestimated, as imaging explorations were not performed systematically in the absence of clinical symptoms [
      • Duval X
      • Iung B
      • Klein I
      • et al.
      Effect of early cerebral magnetic resonance imaging on clinical decisions in infective endocarditis: a prospective study.
      ]. Third, all therapeutic decisions were made by the physicians in charge of the patient, which obviously introduces heterogeneity in the management of CE. Finally, we were unable to measure the contribution of serum antigen detection and molecular tools in the diagnosis of CE, as all patients had a diagnosis of endocarditis at inclusion. However, we collected prospective data that provide useful information for accurate clinical decision-making during CE.
      In conclusion, CE remains a severe infection with frequent embolic complications and a high mortality rate. The prognosis in younger patients and intravenous drug users is better than in older patients with healthcare-related infections. Serum markers and molecular tools may help in optimizing the diagnosis and management of CE.

      Acknowledgements

      The authors thank the Direction Médicale de l'Institut Pasteur, Paris, for having promoted the study, and A. Desjardins for her careful review of the manuscript. O. Lortholary had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis.

      Transparency Declaration

      Funding/Support: This study received grants from Pfizer and Merck Sharp & Dohme-Chibret, France. The sponsors had no role in designing or conducting the study, the collection, management, analysis and interpretation of the data, or the preparation, review or approval of the manuscript. Financial disclosure: O. Lortholary has received research grants from Pfizer and Gilead Sciences, is a consultant for Gilead Sciences and Astellas, and is a member of the speaker's bureaus of Pfizer, Merck, Astellas, Gilead Sciences, and Schering Plough. J. L. Mainardi has received a research grant from Novartis. S. Bretagne is a consultant for Gilead Sciences, and has received speaking honoraria from Pfizer and Gilead Sciences and travel grants from Astellas, Pfizer, and Schering-Plough. M. Wolff has received consulting and lecture fees from Astellas, Gilead, Janssen-Cilag, and Aventis. The other authors do not declare any conflicts of interest.

      Appendix: Members of the French Mycosis Study Group

      Principal investigators: A. Lefort (CHU Necker-Enfants malades, Paris), O. Lortholary (Institut Pasteur and CHU Necker-Enfants malades, Paris). Co-investigators: P. de Villartay, F. Ribadeau-Dumas, F. Lanternier, D. Sidi, and M. E. Bougnoux (CHU Necker-Enfants malades, Paris); C. Aznar (CH, Cayenne); M. Wolff, S. Houzé, and C. Chochillon (CHU Bichat, Paris); C. Penot-Rivollet and M. F. Masseyef (Institut Tzank, St-Laurent du Var); P. M. Roger (CHU, Nice); C. Viacroze, F. Tamion, and L. Favennec (CHU, Rouen); A. Combes and A. Datry (CHU Pitié-Salpétrière, Paris); T. Lherm and S. Kubab (CH Sud-Francilien, Corbeil-Essonne); O. Bastien, F. Delahaye, M. Célard, and F. Thivolet-Bejui (CHU Louis-Pradel, Lyon); R. Jospe and A. Raberin (CHU, St-Etienne); E. Hazouard and G. Courouble (CH, Blois); F. Bastides and J. Chandenier (CHU, Tours); H. Nanadoumgar and S. Bouyer (CHU, Poitiers); D. Chauveau and M. D. Linas (CHU Rangueil, Toulouse); L. Tric, J. Cosserat, and Y. Péan (Institut mutualiste Montsouris, Paris); J. P. Gueffet, M. Treilhaud, and F. Gay-Andrieu (CHU, Nantes); J. Cousson, C. Strady, J. Jégou, and D. Toubas (CHU, Reims); D. Bouhour, C. Decouchon, F. Laurent, and H. de Montclos (CH, Bourg-en-Bresse); T. Doco-Lecompte and M. F. Biava (CHU Brabois, Nancy); P. Abgueguen and M. Pihet (CHU, Angers); R. Verdon and C. Duhamel (CHU, Caen); L. Chevret (CHU Bicêtre, Le Kremlin-Bicêtre); B. A. Gauzère and M. C. Jaffar (CHD Guyon, St-Denis de la Réunion); S. Abgrall and C. Bouges-Michel (CHU Avicenne, Bobigny); O. Rogeaux and M. Levast (CH Chambéry); E. Dannaoui (HEGP, Paris); M. A. Hospital (CHU Hôtel-Dieu, Paris). Laboratory studies: M. Desnos-Ollivier (Institut Pasteur, Paris); I. Podglajen, J. L. Mainardi, and P. Bruneval (HEGP, Paris); D. Poulain, B. Sendid, and F. Wallet (CHU, Lille); S. Bretagne (CHU, Créteil). Biostatistics: L. Chartier and A. Fontanet (Institut Pasteur, Paris).

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