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Improved detection of invasive pulmonary aspergillosis arising during leukemia treatment using a panel of host response proteins and fungal antigens

Brasier, AR and Zhao, Y and Spratt, HM and Wiktorowicz, JE and Ju, H and Wheat, LJ and Baden, L and Stafford, S and Wu, Z and Issa, N and Caliendo, AM and Denning, DW and Soman, K and Clancy, CJ and Nguyen, MH and Sugrue, MW and Alexander, BD and Wingard, JR (2015) Improved detection of invasive pulmonary aspergillosis arising during leukemia treatment using a panel of host response proteins and fungal antigens. PLoS ONE, 10 (11).

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Abstract

© 2015 Copyright Brasier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Brasier, AR
Zhao, Y
Spratt, HM
Wiktorowicz, JE
Ju, H
Wheat, LJ
Baden, L
Stafford, S
Wu, Z
Issa, N
Caliendo, AM
Denning, DW
Soman, K
Clancy, CJcjc76@pitt.eduCJC76
Nguyen, MH
Sugrue, MW
Alexander, BD
Wingard, JR
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorJacobsen, Ilse D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 November 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 11
DOI or Unique Handle: 10.1371/journal.pone.0143165
Institution: University of Pittsburgh
Refereed: Yes
Date Deposited: 23 Aug 2016 14:52
Last Modified: 13 Oct 2017 19:55
URI: http://d-scholarship.pitt.edu/id/eprint/28350

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