Barbara D Alexander

Duke University, Durham, North Carolina, United States

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Publications (127)523.23 Total impact

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    ABSTRACT: Systemic Candida albicans infection causes high morbidity and mortality and is now the leading cause of nosocomial bloodstream infection in the United States. Neutropenia is a major risk factor for poor outcome in infected patients; however, the molecular factors that mediate neutrophil trafficking and effector function during infection are poorly defined. Using a mouse model of systemic candidiasis, we found that the neutrophil-selective CXC chemokine receptor Cxcr1 and its ligand, Cxcl5, are highly induced in the Candida-infected kidney, the target organ in the model. To investigate the role of Cxcr1 in antifungal host defense in vivo, we generated Cxcr1(-/-) mice and analyzed their immune response to Candida. Mice lacking Cxcr1 exhibited decreased survival with enhanced Candida growth in the kidney and renal failure. Increased susceptibility of Cxcr1(-/-) mice to systemic candidiasis was not due to impaired neutrophil trafficking from the blood into the infected kidney but was the result of defective killing of the fungus by neutrophils that exhibited a cell-intrinsic decrease in degranulation. In humans, the mutant CXCR1 allele CXCR1-T276 results in impaired neutrophil degranulation and fungal killing and was associated with increased risk of disseminated candidiasis in infected patients. Together, our data demonstrate a biological function for mouse Cxcr1 in vivo and indicate that CXCR1-dependent neutrophil effector function is a critical innate protective mechanism of fungal clearance and host survival in systemic candidiasis.
    No preview · Article · Jan 2016 · Science translational medicine
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    Full-text · Article · Jan 2016
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    ABSTRACT: Invasive pulmonary aspergillosis (IPA) is an opportunistic fungal infection in patients undergoing chemotherapy for hematological malignancy, hematopoietic stem cell transplant, or other forms of immunosuppression. In this group, Aspergillus infections account for the majority of deaths due to mold pathogens. Although early detection is associated with improved outcomes, current diagnostic regimens lack sensitivity and specificity. Patients undergoing chemotherapy, stem cell transplantation and lung transplantation were enrolled in a multi-site prospective observational trial. Proven and probable IPA cases and matched controls were subjected to discovery proteomics analyses using a biofluid analysis platform, fractionating plasma into reproducible protein and peptide pools. From 556 spots identified by 2D gel electrophoresis, 66 differentially expressed post-translationally modified plasma proteins were identified in the leukemic subgroup only. This protein group was rich in complement components, acute-phase reactants and coagulation factors. Low molecular weight peptides corresponding to abundant plasma proteins were identified. A candidate marker panel of host response (9 plasma proteins, 4 peptides), fungal polysaccharides (galactomannan), and cell wall components (β-D glucan) were selected by statistical filtering for patients with leukemia as a primary underlying diagnosis. Quantitative measurements were developed to qualify the differential expression of the candidate host response proteins using selective reaction monitoring mass spectrometry assays, and then applied to a separate cohort of 57 patients with leukemia. In this verification cohort, a machine learning ensemble-based algorithm, generalized pathseeker (GPS) produced a greater case classification accuracy than galactomannan (GM) or host proteins alone. In conclusion, Integration of host response proteins with GM improves the diagnostic detection of probable IPA in patients undergoing treatment for hematologic malignancy. Upon further validation, early detection of probable IPA in leukemia treatment will provide opportunities for earlier interventions and interventional clinical trials.
    Preview · Article · Nov 2015 · PLoS ONE
  • Frédéric Lamoth · Barbara D Alexander
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    ABSTRACT: Invasive mold infections are life-threatening diseases, for which appropriate antifungal therapy is crucial. Their epidemiology is evolving with the emergence of triazole-resistant Aspergillus spp. and multi-resistant non-Aspergillus molds. Despite the lack of interpretive criteria, antifungal susceptibility testing of molds may be useful in guiding antifungal therapy. The standard broth microdilution method (BMD) is fastidious and requires expertise. We assessed the performance of a commercialized gradient diffusion method (Etest) as an alternative to BMD.Minimal inhibitory concentrations (MIC) or minimal effective concentrations (MEC) of amphotericin B, voriconazole, posaconazole, caspofungin and micafungin were assessed against 290 clinical isolates of the most representative pathogenic molds (154 Aspergillus spp. and 136 non-Aspergillus molds) by BMD and Etest. Essential agreements (EA) within +/-2 dilutions of ≥90% between both methods were considered acceptable.EA for amphotericin B and voriconazole was >90% for most potentially susceptible species. For posaconazole, correlation was acceptable for Mucoromycotina, but Etest MIC values were consistently lower for Aspergillus spp. (EA<90%). Excellent EA was found for echinocandins among highly susceptible (MEC<0.015 μg/ml) or intrinsically resistant (MEC>16 μg/ml) strains. However, MEC determination lacked consistency between methods for strains exhibiting mid-range MECs to echinocandins.We concluded that Etest is an appropriate alternative method to BMD for antifungal susceptibility testing of molds in specific circumstances, including testing amphotericin B or triazoles among non-Aspergillus molds (Mucoromycotina, Fusarium spp.). Additional study of molecularly characterized triazole resistant Aspergillus isolates is required to confirm the ability of Etest to detect voriconazole and posaconazole resistance among Aspergillus spp. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    No preview · Article · Jul 2015 · Journal of clinical microbiology
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    ABSTRACT: Transplant recipients are at a high risk for developing invasive fungal infections. The agents of phaeohyphomycosis are environmental molds found worldwide, and they cause a broad spectrum of disease including skin and subcutaneous lesions, pneumonia, central nervous system disease, fungemia, and disseminated disease. Using data from the Transplant Associated Infection Surveillance Network (TRANSNET), we evaluated patients with proven and probable phaeohyphomycosis. Centers collected data on demographics, co-morbid conditions, clinical features, treatment, and three-month mortality. Fifty-six patients with phaeohyphomycosis were identified from 15 centers, comprising 26 stem cell transplant (SCT) and 30 solid organ transplant (SOT) recipients. Median time to diagnosis post-transplant was 358 days (SCT 100 days; SOT 685 days; P = <.001). The most frequent pathogen was Alternaria species (32%). Disseminated disease was found in 55.4%. Cutaneous infection was more common in SOT (53.3% vs 23.1%; P = .021), while pulmonary disease was more common in SCT (57.7 vs. 26.7; P = .019). Voriconazole (44.6%) and amphotericin B preparations (37.5%) were the most common antifungal therapies. Overall mortality was 25% and was higher in SCT than in SOT (42% vs 10%; P = <.001). A wide variety of organisms encompass phaeohyphomycosis contributing to varying types of infection in transplant recipients. Site of infection, time to disease, and mortality varies significantly between SCT and SOT recipients. Lipid formulations of amphotericin B and voriconazole were the most common antifungals used to treat this disorder. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.
    Full-text · Article · Apr 2015 · Medical mycology: official publication of the International Society for Human and Animal Mycology
  • Frédéric Lamoth · Barbara D Alexander
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    ABSTRACT: The limited armamentarium of active and oral antifungal drugs against emerging non-Aspergillus molds is of particular concern. Current antifungal agents and the new orally available beta-1,3-D-glucan synthase inhibitor, SCY-078, were tested in vitro against 135 clinical non-Aspergillus mold isolates. Akin to echinocandins, SCY-078 showed no or poor activity against Mucoromycotina and Fusarium spp. However, SCY-078 was highly active against Paecilomyces variotii and was the only compound displaying some activity against notoriously pan-resistant Scedosporium prolificans. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    No preview · Article · Apr 2015 · Antimicrobial Agents and Chemotherapy
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    ABSTRACT: Invasive mould infections are associated with a high mortality rate and the emergence of MDR moulds is of particular concern. Calcineurin and its chaperone, the heat shock protein 90 (Hsp90), represent an important pathway for fungal virulence that can be targeted at different levels. We investigated the antifungal activity of compounds directly or indirectly targeting the Hsp90-calcineurin axis against different mould species. The in vitro antifungal activity of the anticalcineurin drug FK506 (tacrolimus), the Hsp90 inhibitor geldanamycin, the lysine deacetylase inhibitor trichostatin A and the Hsp70 inhibitor pifithrin-μ was assessed by the standard broth dilution method against 62 clinical isolates of Aspergillus spp. and non-Aspergillus moulds (Mucoromycotina, Fusarium spp., Scedosporium spp., Purpureocillium/Paecilomyces spp. and Scopulariopsis spp.) RESULTS: FK506 had variable antifungal activity against different Aspergillus spp. and was particularly active against Mucor spp. Geldanamycin had moderate antifungal activity against Fusarium spp. and Paecilomyces variotii. Importantly, trichostatin A had good activity against the triazole-resistant Aspergillus ustus and the amphotericin B-resistant Aspergillus terreus as well as the MDR Scedosporium prolificans. Moreover, trichostatin A exhibited synergistic interactions with caspofungin against A. ustus and with geldanamycin against Rhizopus spp. for which none of the other agents showed activity. Pifithrin-μ exhibited little antifungal activity. Targeting the Hsp90-calcineurin axis at different levels resulted in distinct patterns of susceptibility among different fungal species. Lysine deacetylase inhibition may represent a promising novel antifungal strategy against emerging resistant moulds. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    No preview · Article · Jan 2015 · Journal of Antimicrobial Chemotherapy
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    Preview · Article · Nov 2014 · Journal of Clinical Microbiology
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    ABSTRACT: Background: Risk factors including how changes in immunosuppression influence the occurrence of immune reconstitution syndrome (IRS) in solid organ transplant (SOT) recipients with cryptococcosis have not been fully defined. Methods: SOT recipients with cryptococcosis were identified and followed for 12 months. IRS was defined based on previously proposed criteria. Results: Of 89 SOT recipients, 13 (14%) developed IRS. Central nervous system (CNS) disease (adjusted odds ratio [AOR], 6.23; P = .03) and discontinuation of calcineurin inhibitor (AOR, 5.11; P = .02) were independently associated with IRS. Only 2.6% (1/13) of the patients without these risk factors developed IRS compared with 18.8% (6/32) with 1 risk factor, and 50% (6/12) with both risk factors (χ(2) for trend, P = .0001). Among patients with CNS disease, those with neuroimaging abnormalities (P = .03) were more likely to develop IRS, irrespective of serum or CSF cryptococcal antigen titers and fungemia. Graft rejection after cryptococcosis was observed in 15.4% (2/13) of the patients with IRS compared with 2.6% (2/76) of those without IRS (P = .07). Conclusions: We determined variables that pose a risk for IRS and have shown that discontinuation of calcineurin inhibitors was independently associated with 5-fold increased risk of IRS in transplant recipients with cryptococcosis.
    No preview · Article · Sep 2014 · Clinical Infectious Diseases
  • J. . L. Horan · J. E. Stout · B. D. Alexander
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    ABSTRACT: Hepatitis B virus (HBV) core antibody (HBcAb)-positive donors are increasingly utilized in solid organ transplantation. We report a single center's experience in cardiac transplantation with 18 HBcAb-positive donors. Available follow-up on recipients of cardiac allografts from HBcAb-positive donors, including 2 donors with low-level serum HBV DNA at the time of transplantation, demonstrated no documented donor-derived HBV transmission.
    No preview · Article · Aug 2014 · Transplant Infectious Disease
  • Frédéric Lamoth · Barbara D. Alexander
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    ABSTRACT: Diagnosis of invasive fungal pneumonias by conventional culture methods is difficult to assess and often delayed. Nonmolecular fungal markers have emerged as an important adjunctive tool to support their diagnosis in combination with other clinical, radiologic, and microbiological criteria of invasive fungal diseases. Concerns about the sensitivity and specificity of some tests in different patient populations should lead to warnings about their widespread use. None can identify the emerging and particularly deadly fungal pathogens responsible for mucormycosis. The role of nonmolecular fungal markers should be better defined in combination with other microbiological and radiologic tools in preemptive antifungal strategies.
    No preview · Article · Jun 2014 · Clinics in Laboratory Medicine
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    ABSTRACT: Research to develop and validate novel methods for diagnosis of aspergillosis based on detection of galactomannan requires the use of clinical specimens that have been stored frozen. Data indicating that galactomannan remains stable when frozen are scant. The objective of this study was to determine the stability of galactomannan in clinical specimens stored at −20°C that were positive in the Platelia Aspergillus enzyme immunoassay when initially tested. Prospective real-time testing of serum and bronchoalveolar lavage (BAL) fluid pools from positive and negative patient specimens showed no decline in galactomannan index (GMI) over 11 months at −20°C and no development of positive reactions in the negative-control pool. Retrospective testing of positive specimens that had been stored at −20°C for 5 years showed that 28 of 30 serum (n = 15) or BAL (n = 15) specimens remained positive. These findings support the use of frozen serum or BAL specimens stored for at least 5 years in evaluation of diagnostic tests based on detection of galactomannan.
    Preview · Article · Apr 2014 · Journal of clinical microbiology
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    ABSTRACT: Candida albicans can cause candidemia in neutropenic and critically ill patients and oropharyngeal candidiasis in human immunodeficiency virus (HIV)–positive patients with low CD4+ counts. Because all patients at risk do not develop Candida infections, it is possible that a patient's genetic background might play a role in his or her susceptibility to infection. Autophagy mediates pathogen clearance and modulation of inflammation. Our aim was to assess the effect of genetic variations in the ATG16L1 and IRGM autophagy genes on the susceptibility of patients with candidemia and oropharyngeal candidiasis. We assessed genetic variations in the ATG16L1 and IRGM genes in a cohort of candidemia patients of both African and European origin. In addition, we evaluated the effect of these polymorphisms on the susceptibility to oropharyngeal candidiasis of an HIV-positive cohort from Tanzania. Functional studies have been performed to assess the effect of the ATG16L1 and IRGM genetic variants on both in vitro and in vivo cytokine production. The results indicate that ATG16L1 variants modulate production of tumor necrosis factor-alpha, but not other cytokines, while no effects were seen in the presence of IRGM polymorphisms. In addition, no significant associations between the single-nucleotide polymorphisms in the ATG16L1 and IRGM genetic variants and the incidence of candidemia or oropharyngeal candidiasis were identified. Despite moderate effects on the modulation of proinflammatory cytokine production, genetic variation in the autophagy genes ATG16L1 and IRGM has a minor impact on the susceptibility to both mucosal and systemic Candida infections.
    Full-text · Article · Apr 2014 · Medical mycology: official publication of the International Society for Human and Animal Mycology
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    ABSTRACT: Invasive mold infections (IMIs) are a major source of morbidity and mortality among lung transplant recipients (LTRs), yet information regarding the epidemiology of IMI in this population is limited. From 2001 to 2006, multicenter prospective surveillance for IMIs among LTR was conducted by the Transplant-Associated Infection Surveillance Network. The epidemiology of IMI among all LTRs in the cohort is reported. Twelve percent (143/1173) of LTRs under surveillance at 15 US centers developed IMI infections. The 12-month cumulative incidence of IMIs was 5.5%; 3-month all-cause mortality was 21.7%. Aspergillus caused the majority (72.7%)of IMIs; non-Aspergillus infections (39, 27.3%) included Scedosporium (5, 3.5%), mucormycosis (3, 2.1%) and “unspecified” or “other” mold infections (31, 21.7%). Late-onset IMI was common: 52% occurred within 1 year posttransplant (median 11 months, range 0–162 months). IMIs are common late-onset complications with substantial mortality in LTRs. LTRs should be monitored for late-onset IMIs and prophylactic agents should be optimized based on likely pathogen.
    No preview · Article · Apr 2014 · American Journal of Transplantation
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    ABSTRACT: Paecilomyces species are emerging fungal pathogens. Morphological identifications are complicated by similarities among the members of the P. variotii complex as well as to some Rasamsonia and Hamigera species. The purpose of this study was to compare matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI–TOF MS) with molecular diagnostic standards (i.e., multilocus DNA sequencing of the internal transcribed spacer regions 1 and 2, D1/D2 regions, and part of the β-tubulin gene) for the identification of Paecilomyces spp. encountered in two clinical mycology laboratories. A total of 77 clinical isolates identified morphologically as P. variotii (n = 21), P. lilacinus (n = 52), and Paecilomyces spp. not otherwise specified (n = 4) were included. In accord with the most recent taxonomy, all P. lilacinus isolates were confirmed as Purpureocillium lilacinum by both sequencing and MALDI–TOF MS. Fungi phenotypically resembling P. variotii or Paecilomyces spp. were identified by molecular techniques as P. variotii sensu stricto (n = 12), P. formosus (n = 3), P. dactylethromorphus (n = 3), Rasamsonia argillacea (n = 4), or R. piperina (n = 1) and at the genus level as an isolate of a Hamigera sp. and a Paecilomyces sp. There was 92.2% (71/77) agreement between the molecular and proteomic methods only after supplementation of the MALDI–TOF MS database with type strains. Paecilomyces variotii–like organisms required multilocus DNA interrogations for differentiation and account for all of the fungi whose identification was missed by MALDI–TOF MS. Overall, MALDI–TOF MS was a rapid and reliable alternative to multilocus sequencing. However, significant augmentation of the commercially available database was required to reproducibly identify this group of important human pathogens.
    Preview · Article · Mar 2014 · Medical mycology: official publication of the International Society for Human and Animal Mycology
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    ABSTRACT: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.
    No preview · Article · Mar 2014 · Transplant Infectious Disease
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    ABSTRACT: Systemic Candida albicans infection causes high morbidity and mortality and is associated with neutropenia; however, the roles of other innate immune cells in pathogenesis are poorly defined. Here, using a mouse model of systemic candidiasis, we found that resident macrophages accumulated in the kidney, the main target organ of infection, and formed direct contacts with the fungus in vivo mainly within the first few hours after infection. Macrophage accumulation and contact with Candida were both markedly reduced in mice lacking chemokine receptor CX3CR1, which was found almost exclusively on resident macrophages in uninfected kidneys. Infected Cx3cr1-/- mice uniformly succumbed to Candida-induced renal failure, but exhibited clearance of the fungus in all other organs tested. Renal macrophage deficiency in infected Cx3cr1-/- mice was due to reduced macrophage survival, not impaired proliferation, trafficking, or differentiation. In humans, the dysfunctional CX3CR1 allele CX3CR1-M280 was associated with increased risk of systemic candidiasis. Together, these data indicate that CX3CR1-mediated renal resident macrophage survival is a critical innate mechanism of early fungal control that influences host survival in systemic candidiasis.
    No preview · Article · Nov 2013 · The Journal of clinical investigation
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    ABSTRACT: Twelve laboratories evaluated candidate material for an Aspergillus DNA calibrator. The DNA material was quantified using limiting-dilution analysis; the mean concentration was determined to be 1.73 × 1010 units/ml. The calibrator can be used to standardize aspergillosis diagnostic assays which detect and/or quantify nucleic acid.
    Full-text · Article · Jun 2013 · Journal of Clinical Microbiology
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    ABSTRACT: Background: Fluconazole (FLC) resistance is common in C. glabrata and echinocandins are often used as first-line therapy. Resistance to echinocandin therapy has been associated with FKS1 and FKS2 gene alterations. Methods: We reviewed records of all patients with C. glabrata bloodstream infection at Duke Hospital over the past decade (2001-2010) and correlated treatment outcome with minimum inhibitory concentration (MIC) results and the presence of FKS gene mutations. For each isolate, MICs to FLC and echinocandins (anidulafungin, caspofungin, and micafungin) and FKS1 and FKS2 gene sequences were determined. Results: Two hundred ninety-three episodes (313 isolates) of C. glabrata bloodstream infection were analyzed. Resistance to echinocandins increased from 4.9% to 12.3% and to FLC from 18% to 30% between 2001 and 2010, respectively. Among the 78 FLC resistant isolates, 14.1% were resistant to 1 or more echinocandin. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, odds ratio, 19.647 [95% confidence interval, 7.19-58.1]). Eighty percent (8/10) of patients infected with FKS mutants demonstrating intermediate or resistant MICs to an echinocandin and treated with an echinocandin failed to respond or responded initially but experienced a recurrence. Conclusions: Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.
    Preview · Article · Mar 2013 · Clinical Infectious Diseases
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    ABSTRACT: BK polyomavirus (BKV) infection continues to be a significant source of allograft dysfunction in kidney transplant recipients. The optimal screening method to detect BKV remains undetermined. In this retrospective analysis of 347 consecutive kidney transplant recipients, we compare the diagnostic and screening performance of urine electron microscopy (EM) with plasma polymerase chain reaction (PCR) in testing for BKV, using biopsy-proved polyomavirus-associated nephropathy (PVAN) as the gold standard. Sixty-nine of 347 recipients had a positive screening test for BKV infection. Twenty-nine patients underwent biopsy, and 11 were diagnosed with PVAN. Sensitivity rates of urine EM and plasma PCR were 88% and 100%, respectively. Specificity rates of urine EM and plasma PCR were 91% and 78%. There was no statistical difference in the operating characteristics of the two tests. The majority of both plasma PCR and urine EM tests were positive in the six months prior to a diagnostic biopsy confirming PVAN. In those patients who had evidence of BKV infection but did not have PVAN, the percentage of positive screening tests decreased with aggressive lowering of immunosuppression. We conclude that urine EM and plasma PCR both function well in screening for BKV infection and in the diagnosis of PVAN. There is an opportunity to detect viral replication, lower immunosuppression, and to prevent PVAN in this population.
    No preview · Article · Dec 2012 · Clinical Transplantation

Publication Stats

6k Citations
523.23 Total Impact Points

Institutions

  • 2004-2015
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
  • 2001-2015
    • Duke University Medical Center
      • • Division of Infectious Diseases
      • • Department of Medicine
      Durham, North Carolina, United States
  • 2010
    • Rutgers New Jersey Medical School
      Newark, New Jersey, United States
  • 2007
    • The Children's Hospital of Philadelphia
      • Division of Infectious Diseases
      Philadelphia, Pennsylvania, United States
    • Associates of Cape Cod, Inc.
      East Falmouth, Massachusetts, United States
  • 2005
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Baylor University
      Waco, Texas, United States