David Navarro

Fundación de Investigación del Hospital Clínico Universitario de Valencia INCLIVA, Valenza, Valencia, Spain

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Publications (115)358.06 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Currently, a lack of consensus exists on how to manage a hepatitis C virus (HCV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ribavirin alone, or in combination with interferon, has been the mainstream therapy for HCV infection after transplantation. However, very few patients have been regularly treated owing to concerns about poor tolerability, frequent side effects, and limited efficacy. The present case illustrates the striking efficacy of the combination therapy of sofosbuvir with simeprevir, early after transplantation, as it was able to completely eliminate viral replication within 1 month of initiation of treatment. Moreover, tolerance was good, with only minor interactions between the immunosuppressive drugs. This case report supports the feasibility of using this combination therapy early after allo-HSCT for patients with HCV infection. This article is protected by copyright. All rights reserved.
    Transplant Infectious Disease 10/2015; DOI:10.1111/tid.12474 · 2.06 Impact Factor
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    ABSTRACT: Background Invasive candidiasis (IC) is a frequent and life-threatening infection in critically ill patients. The aim of this study was to evaluate the epidemiology of IC and the antifungal susceptibility of etiological agents in patients admitted to our surgical intensive care unit (SICU) in Spain. Methods We designed a prospective, observational, single center, population-based study in a SICU. We included all consecutive adult patients (≥18 years old) who had documented IC, either on admission or during their stay, between January 2012 and December 2013. Results There were a total of 22 episodes of IC in the 1149 patients admitted during the 24-month study. The overall IC incidence was 19.1 cases per 1000 admissions. Thirteen cases of IC (59.1 %) were intra-abdominal candidiasis (IAC) and 9 (40.9 %) were candidemias. All cases of IAC were patients with secondary peritonitis and severe sepsis or septic shock. The overall crude mortality rate was 13.6 %; while, it was 33 % in patients with candidemia. All patients with IAC survived, including one patient with concomitant candidemia. The most common species causing IC was Candida albicans (13; 59.1 %) followed by Candida parapsilosis (5; 22.7 %), and Candida glabrata (2; 9.1 %). There was also one case each (4.5 %) of Candida krusei and Candida tropicalis. Thus, the ratio of non-C. albicans (9) to C. albicans (13) was 1:1.4. There was resistance to fluconazole and itraconazole in 13.6 % of cases. Resistance to other antifungals was uncommon. Conclusions Candida parapsilosis was the second most common species after C. albicans, indicating the high prevalence of non-C. albicans species in the SICU. Resistance to azoles, particularly fluconazole, should be considered when starting an empirical treatment. Although IAC is a very frequent form of IC in critically ill surgical patients, prompt antifungal therapy and adequate source control appears to lead to a good outcome. However, our results are closely related to our ICU and any generalization must be taken with caution. Therefore, further investigations are needed.
    BMC Research Notes 09/2015; 8(1). DOI:10.1186/s13104-015-1458-4
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    ABSTRACT: A bidirectional interaction between active cytomegalovirus (CMV) infection and acute graft versus host disease (aGvHD) is pathogenetically feasible given the pro-inflammatory nature of CMV and the immunosuppressive effect directly attributable to aGvHD [1]. Contradictory data have been published on this issue [2-5]. The use of methods for CMV surveillance displaying different sensitivities (pp65 antigenemia assay-AG- vs. real-time PCR assays) may account in part for these discrepancies [6]. In this single-center retrospective study we reexamined this potential association using highly sensitive real-time PCR assays (limit of detection: approximately 20 copies/ml-[6-8]) (CMV PCR Kit and the New CMV RealTime PCR assay; Abbott Molecular, Des Plaines, IL) in plasma specimens. We included 92 non-consecutive patients undergoing Allo-SCT (January 2010-August 2014) for hematological malignancy. This article is protected by copyright. All rights reserved.
    Transplant International 09/2015; DOI:10.1111/tri.12689 · 2.60 Impact Factor
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    ABSTRACT: Metabolomics analysis of biofluids is being increasingly recognized as a useful tool for the diagnosis and management of a number of infectious diseases. Here we showed that plasma metabolomics profiling by untargeted 1H nuclear magnetic resonance may allow the anticipation of the occurrence of CMV DNAemia in allogeneic stem cell transplant (Allo-SCT). For this purpose, key discriminatory metabolites were total glutathione, taurine, methylamine, trimethylamine N-oxide and lactate, all of which were upregulated in patients eventually developing CMV DNAemia. The overall classification accuracy (predictability) of the projection to latent structure discriminant analysis (PLS-DA) model in cross-validation technical replicates was 73%. Increased levels of alanine, lactate and total fatty acids, and a shift in the fatty acid profile towards unsaturated species were observed in patients with detectable CMV DNA in plasma. The classification accuracy of this PLS-DA model in cross-validation technical replicates was 81%. Plasma metabolomics profiling may prove useful for identifying patients at highest risk for CMV DNAemia thus allowing early inception of antiviral therapy.
    Journal of General Virology 09/2015; DOI:10.1099/jgv.0.000275 · 3.18 Impact Factor
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    ABSTRACT: HIV-1 CRF19_cpx, is a recombinant variant found almost exclusively in Cuba and recently associated to a faster AIDS onset. Infection with this variant leads to higher viral loads and levels of RANTES and CXCR4 co-receptor use. The goal of this study was to assess the presence of CRF19_cpx in the Spanish province of Valencia, given its high pathogenicity. 1294 HIV-1 protease-reverse transcriptase (PR/RT) sequences were obtained in Valencia (Spain), between 2005 and 2014. After subtyping, the detected CRF19_cpx sequences were aligned with 201 CRF19_cpx and 66 subtype D sequences retrieved from LANL, and subjected to maximum-likelihood phylogenetic analyses and Bayesian coalescent reconstructions. The presence of resistance mutations in the PR/RT region of these sequences was also analyzed. Among the 9 CRF19_cpx sequences from different patients found (prevalence <0.1%), 7 grouped in two well-supported clades (groups A, n=4, and B, n=3), suggesting the existence of at least two independent introductions which subsequently started to expand in the studied Spanish region. Unprotected sex between men was the only known transmission route. Coalescent analyses suggested that the introductions in Valencia occurred between 2008 and 2010. Resistance mutations in the RT region were found in all sequences from group A (V139D) and in two sequences from group B (E138A). This study reports for the first time the recent expansion of CRF19_cpx outside Cuba. Our results suggest that CRF19_cpx might become an emerging HIV variant in Spain, affecting Spanish native MSM and not only Cuban migrants. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 08/2015; 69:146-149. DOI:10.1016/j.jcv.2015.06.094 · 3.02 Impact Factor

  • Clinical Infectious Diseases 07/2015; 61(9). DOI:10.1093/cid/civ583 · 8.89 Impact Factor
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    ABSTRACT: Evaluate the protective effect against late CMV disease of delaying antiviral prophylaxis initiation in D+/R-patients receiving solid organ transplant (SOT). Prospective multicenter study in D+/R- SOT recipients in Spain (Sept/09 -Sept/12). Whole blood specimens were prospectively collected after Tx for CMV-specific cell-mediated immunity (CMI) determination. Two prophylaxis strategies were compared: early prophylaxis (EP; starting within the first 3 days after Tx) and delayed prophylaxis (DP; starting 14 days after Tx). Risk factors for the occurrence of CMV disease were determined by survival analysis and proportional risk Cox regression models. We included 95 patients (50 EP Vs 45 DP). Twenty six patients (27.4%) developed CMV disease: 32.7% EP vs. 20% DP; (p=0.2). No cases of CMV disease were reported previously to beginning delayed prophylaxis. The percentage of individuals with detectable CMI response was higher in patients with DP although differences did not reach statistic significance (42% vs 29.6% at day 200 after Tx; p=0.4). There was a clear trend towards less end-organ CMV disease in patients receiving DP (18.2% EP Vs 5% DP; p=0.09) and DP was the only protective factor in the multivariate analysis (HR: 0.26; CI: 0.05-1.2; p=0.09). A 14-day delay in CMV prophylaxis in D+/R- SOT recipients is safe and may reduce the incidence of late CMV end-organ disease although correlation of this effect with CMI responses was not complete. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
    The Journal of infection 07/2015; 71(5). DOI:10.1016/j.jinf.2015.06.013 · 4.44 Impact Factor
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    ABSTRACT: The current study aimed to characterize the dynamics of acquisition of cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) in CMV donor positive/recipient negative solid organ transplant (SOT) patients receiving long-term antiviral prophylaxis, and to determine whether development of CMI confers protection against CMV disease. A prospective multicenter study was conducted in Spain from September 2009 to September 2012. Whole blood specimens were prospectively collected at 30, 90, 120, 200, and 365 days after SOT, and CMI was determined by enumeration of CMV pp65 and IE-1-specific CD69(+) /interferon-γ-producing CD8(+) and CD4(+) T cells by flow cytometry for intracellular cytokine staining. As part of a simultaneous clinical trial, patients received either early prophylaxis (in the first 3 days after transplantation) in the first period of the study or delayed prophylaxis (initiated at day 14) during the second period of the study. The impact of the dynamics of acquisition of CMV-specific CMI on the incidence of CMV disease was evaluated by Kaplan-Meier survival analysis. A total of 95 SOT recipients were recruited. CMV infection and disease occurred in 38 (40%) and 26 (27.4%) patients, respectively. The proportion of patients achieving any detectable CMV-specific CMI response at each of the different monitoring points was higher in liver transplant recipients, as compared to kidney or heart transplant recipients. The presence of any detectable response at day 120 or 200 was protective against the development of CMV disease (positive predictive values 92% and 93% respectively). The rate of acquisition of CMV-specific CMI in SOT recipients undergoing antiviral prophylaxis differed significantly between different SOT populations. Patients developing any detectable CMI response were protected against the occurrence of CMV disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Transplant Infectious Disease 07/2015; 17(5). DOI:10.1111/tid.12417 · 2.06 Impact Factor

  • American Journal of Transplantation 07/2015; 15(9). DOI:10.1111/ajt.13370 · 5.68 Impact Factor
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    ABSTRACT: The current study gathered information about current practices of cytomegalovirus (CMV) infection management in allogeneic stem cell transplant recipients (Allo-SCT) in Spanish centers. A wide variety of pre-emptive antiviral therapy strategies for CMV infection guided by real-time PCR assays was observed, yet the incidence of CMV disease was low (<3%). Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of clinical microbiology 06/2015; 53(8). DOI:10.1128/JCM.01057-15 · 3.99 Impact Factor
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    ABSTRACT: The role cytomegalovirus (CMV)-specific polyfunctional CD8+ T cells and that of antibodies neutralizing virus epithelial infection (AbNEI) in the control of CMV DNAemia was investigated in 39 CMV-seropositive allogeneic stem cell transplant recipients (Allo-SCT) with (n=24) or without (n=15) CMV DNAemia. AbNEI levels were prospectively monitored by means of a neutralization assay employing retinal epithelial cells (ARPE-19) and the recombinant CMV strain BADrUL131-Y4. Quantification of CMV-specific polyfunctional CD8+ T cells (expressing 2 or 3 of the following markers: IFN-γ, TNF-α, CD107a) in whole blood was performed by flow cytometry for intracellular cytokine staining. We found no differences in the dynamic pattern of AbNEI in patients with or without subsequent CMV DNAemia. Baseline and peak AbNEI titers were not predictive of the dynamics of CMV replication within episodes. No correlation was found between CMV DNA loads and AbNEI levels during episodes of CMV DNAemia (rho=0.09; 95% C.I. -0.52-0.64; P=0.78). The detection of pp65/IE-1 CMV-specific polyfunctional CD8+ T cells was associated with low level viral replication within subsequent episodes of CMV DNAemia. Interestingly, the presence of AbNEI titers (inverse) >4.7 log2 was predictive of the occurrence of CMV DNAemia (sensitivity, 83%; Specificity, 80%). Our findings should add insights to the role of humoral and cellular immunity in the control of CMV infection in the Allo-SCT setting.
    Journal of General Virology 05/2015; 96(9). DOI:10.1099/vir.0.000203 · 3.18 Impact Factor
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    ABSTRACT: The functional profile of cytomegalovirus (CMV)-specific CD8(+) T cells that associate with protection from and control of CMV DNAemia in allogeneic stem cell transplant (allo-SCT) recipients remains incompletely characterized. We enumerated pp65 and immediate early (IE)-1-specific CD8(+) T cells expressing interferon-gamma, tumor necrosis factor-alpha, and CD107a, by flow cytometry in 94 patients at days +30 and +60 after allo-SCT. Fifty out of 94 patients had CMV DNAemia within the first 100 days after transplant. CMV-specific CD8(+) T-cell responses (of any functional type) were more likely to be detected in patients who did not display CMV DNAemia than in those who did (P = 0.04). Qualitatively, no major differences in the functional signature of CMV-specific CD8(+) T cells were noted between patients who had or did not have CMV DNAemia. Patients displaying levels of polyfunctional CD8(+) T cells at day +30 >0.30 cell/μL had a lower risk of CMV DNAemia (positive predictive value 76%, and negative predictive value 43%). The presence of polyfunctional CD8(+) T cells (either expressing CD107a or not) was associated with lower levels of CMV replication, and higher frequency of self-resolved episodes. The data reported further clarify the role of polyfunctional CD8(+) T cells in control of CMV DNAemia in allo-SCT recipients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Transplant Infectious Disease 04/2015; 17(3). DOI:10.1111/tid.12391 · 2.06 Impact Factor
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    ABSTRACT: There is notable heterogeneity in the implementation of cytomegalovirus (CMV) prevention practices among CMV-seropositive (R+) kidney transplant (KT) recipients. In this prospective observational study, we included 387 CMV R+ KT recipients from 25 Spanish centers. Prevention strategies (antiviral prophylaxis or preemptive therapy) were applied according to institutional protocols at each site. The impact on the 12-month incidence of CMV disease was assessed by Cox regression. Asymptomatic CMV infection, acute rejection, graft function, non-CMV infection, graft loss and all-cause mortality were also analyzed (secondary outcomes). Models were adjusted for a propensity score (PS) analysis for receiving antiviral prophylaxis. Overall, 190 patients (49.1%) received preemptive therapy, 185 (47.8%) antiviral prophylaxis, and 12 (3.1%) no specific intervention. Twelve-month cumulative incidences of CMV disease and asymptomatic infection were 3.6% and 39.3%, respectively. Patients on prophylaxis had lower incidence of CMV disease (PS-adjusted HR [aHR]: 0.10; 95% confidence interval [CI]: 0.01-0.79) and asymptomatic infection (aHR: 0.46; 95% CI: 0.29-0.72) than those managed preemptively, with no significant differences according to the duration of prophylaxis. All cases of CMV disease in the prophylaxis group occurred after prophylaxis discontinuation. There were no differences in any of the secondary outcomes. In conclusion, antiviral prophylaxis was associated with a lower occurrence of CMV disease in CMV R+ KT recipients, although such benefit should be balanced with the risk of late-onset disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Transplant International 04/2015; 28(9). DOI:10.1111/tri.12586 · 2.60 Impact Factor
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    ABSTRACT: The role of Natural killer (NK) cells in the control of cytomegalovirus (CMV) infection in allogeneic stem cell transplant recipients has not been precisely characterized. The current study is aimed at investigating the potential role of NK cells expressing the activating receptor NKG2C in affording protection against the development of CMV DNAemia in patients exhibiting detectable CMV-specific CD8(+) T-cell responses early following transplantation. A total of 61 nonconsecutive patients were included in the study. Peripheral levels of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK cells and CMV pp65/IE-1-specific IFN-γ-producing CD8(+) T-cells were enumerated by flow cytometry at days +30 and +60 after transplant. Neither the absolute number of NKG2C(+) NK cells, nor that of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK-cell subsets at day 30 differed significantly between patients with or without subsequent CMV DNAemia. No significant correlation was found between levels of both NKG2C(+) NK-cell populations and the peak CMV DNA load within subsequent episodes of CMV DNAemia. The data indicate that enumeration of NKG2C(+) NK cells early after transplant is unlikely to be helpful in identifying those patients at highest risk of developing CMV DNAemia. Moreover, the data do not support a direct implication of NKG2C(+) NK cells in preventing the development of CMV DNAemia. J. Med. Virol. 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Medical Virology 03/2015; 87(9). DOI:10.1002/jmv.24198 · 2.35 Impact Factor
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    ABSTRACT: In this study, we assessed the association between single-nucleotide polymorphisms (SNPs) in seven candidate genes involved in orchestrating the immune response against cytomegalovirus (CMV) and the 12-month incidence of CMV infection in 315 CMV-seropositive kidney transplant (KT) recipients. Patients were managed either by antiviral prophylaxis or preemptive therapy. CMV infection occurred in 140 patients (44.4%), including 13 episodes of disease. After adjusting for various clinical covariates, patients harboring T-allele genotypes of interleukin-28B (IL28B) (rs12979860) SNP had lower incidence of CMV infection (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.46-0.96; p-value = 0.029). In the analysis restricted to patients not receiving prophylaxis, carriers of the TT genotype of toll-like receptor 9 (TLR9) (rs5743836) SNP had lower incidence of infection (aHR: 0.61; 95% CI: 0.38-0.96; p-value = 0.035), whereas the GG genotype of dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN) (rs735240) SNP exerted the opposite effect (aHR: 1.86; 95% CI: 1.18-2.94; p-value = 0.008). An independent association was found between the number of unfavorable SNP genotypes carried by the patient and the incidence of CMV infection. In conclusion, specific SNPs in IL28B, TLR9 and DC-SIGN genes may play a role in modulating the susceptibility to CMV infection in CMV-seropositive KT recipients. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
    American Journal of Transplantation 03/2015; 15(5). DOI:10.1111/ajt.13107 · 5.68 Impact Factor
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    ABSTRACT: The performance of the CLART® PneumoVir system with that of the Luminex xTAG RVP Fast v1 assay for detection of most common respiratory viruses in upper and lower tract respiratory specimens (n=183) from unique patients with influenza-like syndrome or lower tract respiratory infection. Nested PCR coupled to automated sequencing was used for resolution of discrepancies. Fully concordant results were obtained for a total of 122 specimens, whereas 56 specimens gave partially (n=21) or fully discordant (n=35) results (Kappa coefficient, 0.62). The overall specificity of the Luminex xTAG RVP Fast v1 assay was slightly higher than that of the CLART® PneumoVir assay for human bocavirus, influenza A virus/H3N2, influenza B virus, human metapneumovirus, and parainfluenza virus, whereas the sensitivity of the latter was higher for most targeted viruses except, notably, for picornaviruses. This was irrespective of either the origin of the respiratory specimen or the age group to which the patients belonged. Copyright © 2015 Elsevier Inc. All rights reserved.
    Diagnostic Microbiology and Infectious Disease 02/2015; 82(1). DOI:10.1016/j.diagmicrobio.2015.02.004 · 2.46 Impact Factor
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in genes involved in the activation or regulation of innate and adaptive immune responses may modulate the susceptibility to and the natural history of certain chronic viral infections. The current study aimed to investigate whether donor and recipient SNPs in the chemokine receptor 5 (rs1800023), monocyte chemoattractant protein 1 (rs13900), interleukin-10 (rs1878672), and Toll-like receptor 9 (rs352140) genes would exert any influence on the rate of incidence and features of CMV DNAemia in the allogeneic stem cell transplantation setting. This was a retrospective observational multicenter study. The cohort consisted of 102 non-consecutive allogeneic stem cell transplant recipients. SNP genotyping was performed by allele-specific real-time PCR. CMV surveillance was performed by the pp65 antigenemia assay/and or by real-time PCR. Seventy-three patients developed CMV DNAemia within the first 100 days after transplantation (71.5%). Neither donor nor recipient SNPs were associated significantly with the rate of incidence of active CMV infection, nor with the need for pre-emptive antiviral therapy. Both the duration of CMV DNAemia and the plasma CMV DNA peak load during episodes were significantly higher in patients harboring the donor (but not the recipient) chemokine receptor 5 A/A genotype, than in their A/G and G/G counterparts (P = 0.022 and P = 0.045, respectively). The data reported suggest that SNPs in chemokine receptor 5 may influence the dynamics of CMV infection in the Allo-SCT setting. J. Med. Virol. 9999: XX–XX, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 02/2015; 87(2). DOI:10.1002/jmv.24050 · 2.35 Impact Factor
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    ABSTRACT: A significant progress has been made in deciphering critical aspects of the biology and immunology of CMV infection in the allogeneic stem cell transplantation setting. Genetic traits predisposing to active CMV infection and CMV end-organ disease have begun to be delineated. Reliable molecular assays for CMV DNA load quantitation in body fluids have been developed. Elucidation of immune mechanisms affording control of CMV infection will help to improve the management of active CMV infection. Finally, the advent of new CMV-specific antivirals and promising vaccine prototypes as well as the development of fine procedures for large-scale ex vivo generation of functional CMV-specific T cells for adoptive T cell transfer therapies will certainly minimize the negative impact of CMV on survival in these patients.
    Future Virology 02/2015; 10(2):113-134. DOI:10.2217/fvl.14.102 · 1.01 Impact Factor
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    ABSTRACT: Microbiological documentation of peritoneal candidiasis (PC) is hampered by the low numbers of yeasts observable by direct microscopic examination and recoverable by culture methods. The performance of a polymerase chain reaction (PCR) DNA Low-Density Microarray System (CLART STIs B) was compared to that of BACTEC FX automated culture method for the detection of Candida spp. in 161 peritoneal fluids (PF) from patients with peritonitis. The clinical utility of (1-3)-β-d-glucan (BDG) antigenemia in the diagnosis of PC was evaluated in 42 of these patients. The overall agreement between the PCR assay and the culture method was good (κ = 0.790), and their sensitivities were 93.5% and 74.19%, respectively. Serum BDG levels in patients with Candida spp. in PFs (median, 200.3 pg/mL; Range, 22.0-523.4 pg/mL) was significantly higher (P = 0.002) than those found in patients without the yeast (median, 25.3 pg/mL; Range, 0-523.4 pg/mL). Our study demonstrates the potential clinical utility of molecular methods and the measurement of serum BDG levels for the diagnosis of PC. © The Author 2014. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Medical Mycology 12/2014; 53(2). DOI:10.1093/mmy/myu075 · 2.34 Impact Factor

Publication Stats

2k Citations
358.06 Total Impact Points


  • 2013-2015
    • Fundación de Investigación del Hospital Clínico Universitario de Valencia INCLIVA
      Valenza, Valencia, Spain
  • 2000-2015
    • University of Valencia
      • • Department of Medicin
      • • Department of Microbiology and Ecology
      Valenza, Valencia, Spain
  • 1996-2015
    • Hospital Clínico Universitario de Valencia
      Valenza, Valencia, Spain
  • 2012
    • Polytechnical University of Valencia
      • Centre of Biomaterial and Tissue Engineering (CBIT)
      Valenza, Valencia, Spain
  • 1998
    • Hospital San Francisco de Borja
      Gandía, Valencia, Spain
  • 1990-1997
    • University of California, San Francisco
      • • School of Dentistry
      • • Division of Hospital Medicine
      San Francisco, California, United States