title: Improved Detection of Invasive Pulmonary Aspergillosis Arising during Leukemia Treatment Using a Panel of Host Response Proteins and Fungal Antigens.
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.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX, United States of America.|Institute for Translational Sciences, UTMB, Galveston, TX, United States of America.|Sealy Center for Molecular Medicine, UTMB, Galveston, TX, United States of America.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX, United States of America.|Institute for Translational Sciences, UTMB, Galveston, TX, United States of America.|Sealy Center for Molecular Medicine, UTMB, Galveston, TX, United States of America.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute for Translational Sciences, UTMB, Galveston, TX, United States of America.|Sealy Center for Molecular Medicine, UTMB, Galveston, TX, United States of America.|Department of Preventive Medicine and Community Health, UTMB, Galveston, TX, United States of America.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Spratt
authors.affiliation: Institute for Translational Sciences, UTMB, Galveston, TX, United States of America.|Sealy Center for Molecular Medicine, UTMB, Galveston, TX, United States of America.|Department of Biochemistry and Molecular Biology, UTMB, Galveston, TX, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Wiktorowicz
authors.affiliation: Institute for Translational Sciences, UTMB, Galveston, TX, United States of America.|Department of Preventive Medicine and Community Health, UTMB, Galveston, TX, United States of America.
authors.forename: Hyunsu
authors.initials: H
authors.lastname: Ju
authors.affiliation: MiraVista Laboratories, Indianapolis, IN, United States of America.
authors.forename: L Joseph
authors.initials: LJ
authors.lastname: Wheat
authors.affiliation: Harvard University, Boston, MA, United States of America.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Baden
authors.affiliation: Biomolecular Resource Facility, UTMB, Galveston, TX, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Stafford
authors.affiliation: Biomolecular Resource Facility, UTMB, Galveston, TX, United States of America.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Harvard University, Boston, MA, United States of America.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Issa
authors.affiliation: Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Caliendo
authors.affiliation: University of Manchester, Manchester, United Kingdom.
authors.forename: David W
authors.initials: DW
authors.lastname: Denning
authors.affiliation: Sealy Center for Molecular Medicine, UTMB, Galveston, TX, United States of America.|Department of Biochemistry and Molecular Biology, UTMB, Galveston, TX, United States of America.
authors.forename: Kizhake
authors.initials: K
authors.lastname: Soman
authors.affiliation: University of Pittsburgh, Pittsburgh, United States of America.
authors.forename: Cornelius J
authors.initials: CJ
authors.lastname: Clancy
authors.affiliation: University of Florida, Gainesville, FLA, United States of America.
authors.forename: M Hong
authors.initials: MH
authors.lastname: Nguyen
authors.affiliation: University of Florida, Gainesville, FLA, United States of America.
authors.forename: Michele W
authors.initials: MW
authors.lastname: Sugrue
authors.affiliation: Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Alexander
authors.affiliation: University of Florida, Gainesville, FLA, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Wingard
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000946:Antigens, Fungal / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000175:diagnosis* / Q000209:etiology*; D007938:Leukemia / Q000150:complications* / Q000188:drug therapy*; D000069550:Machine Learning; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D008954:Models, Biological; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D012372:ROC Curve; D015203:Reproducibility of Results
chemical_list: D000946:Antigens, Fungal; D015415:Biomarkers; D001798:Blood Proteins; D010455:Peptides