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

Allan R. Brasier, Yingxin Zhao, Heidi Spratt, John E. Wiktorowicz, Hyunsu Ju, L. Joseph Wheat, Lindsey Baden, Susan Stafford, Zheng Wu, Nicolas Issa, Angela M. Caliendo, David W. Denning, Kizhake Soman, Cornelius J. Clancy, M. Hong Nguyen, Michele W. Sugrue, Barbara D. Alexander, John R. Wingard

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article number0143165
JournalPLoS One
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2015

Fingerprint

fungal antigens
Fungal Antigens
Invasive Pulmonary Aspergillosis
aspergillosis
leukemia
Leukemia
lungs
Proteins
blood proteins
Blood Proteins
Chemotherapy
peptides
Hematologic Neoplasms
Stem cells
proteins
Peptides
drug therapy
Fungal Polysaccharides
Patient treatment
Therapeutics

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Improved detection of invasive pulmonary aspergillosis arising during leukemia treatment using a panel of host response proteins and fungal antigens. / Brasier, Allan R.; Zhao, Yingxin; Spratt, Heidi; Wiktorowicz, John E.; Ju, Hyunsu; Wheat, L. Joseph; Baden, Lindsey; Stafford, Susan; Wu, Zheng; Issa, Nicolas; Caliendo, Angela M.; Denning, David W.; Soman, Kizhake; Clancy, Cornelius J.; Nguyen, M. Hong; Sugrue, Michele W.; Alexander, Barbara D.; Wingard, John R.

In: PLoS One, Vol. 10, No. 11, 0143165, 01.11.2015.

Research output: Contribution to journalArticle

Brasier, AR, Zhao, Y, Spratt, H, Wiktorowicz, JE, Ju, H, Wheat, LJ, Baden, L, Stafford, S, Wu, Z, Issa, N, Caliendo, AM, Denning, DW, Soman, K, Clancy, CJ, Nguyen, MH, Sugrue, MW, Alexander, BD & 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, vol. 10, no. 11, 0143165. https://doi.org/10.1371/journal.pone.0143165
Brasier, Allan R. ; Zhao, Yingxin ; Spratt, Heidi ; Wiktorowicz, John E. ; Ju, Hyunsu ; Wheat, L. Joseph ; Baden, Lindsey ; Stafford, Susan ; Wu, Zheng ; Issa, Nicolas ; Caliendo, Angela M. ; Denning, David W. ; Soman, Kizhake ; Clancy, Cornelius J. ; Nguyen, M. Hong ; Sugrue, Michele W. ; Alexander, Barbara D. ; Wingard, John R. / Improved detection of invasive pulmonary aspergillosis arising during leukemia treatment using a panel of host response proteins and fungal antigens. In: PLoS One. 2015 ; Vol. 10, No. 11.
@article{782c77c5ea4b4a76a220cd3c3a9cd2ee,
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.",
author = "Brasier, {Allan R.} and Yingxin Zhao and Heidi Spratt and Wiktorowicz, {John E.} and Hyunsu Ju and Wheat, {L. Joseph} and Lindsey Baden and Susan Stafford and Zheng Wu and Nicolas Issa and Caliendo, {Angela M.} and Denning, {David W.} and Kizhake Soman and Clancy, {Cornelius J.} and Nguyen, {M. Hong} and Sugrue, {Michele W.} and Alexander, {Barbara D.} and Wingard, {John R.}",
year = "2015",
month = "11",
day = "1",
doi = "10.1371/journal.pone.0143165",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - Improved detection of invasive pulmonary aspergillosis arising during leukemia treatment using a panel of host response proteins and fungal antigens

AU - Brasier, Allan R.

AU - Zhao, Yingxin

AU - Spratt, Heidi

AU - Wiktorowicz, John E.

AU - Ju, Hyunsu

AU - Wheat, L. Joseph

AU - Baden, Lindsey

AU - Stafford, Susan

AU - Wu, Zheng

AU - Issa, Nicolas

AU - Caliendo, Angela M.

AU - Denning, David W.

AU - Soman, Kizhake

AU - Clancy, Cornelius J.

AU - Nguyen, M. Hong

AU - Sugrue, Michele W.

AU - Alexander, Barbara D.

AU - Wingard, John R.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84958093495&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958093495&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0143165

DO - 10.1371/journal.pone.0143165

M3 - Article

C2 - 26581097

AN - SCOPUS:84958093495

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 11

M1 - 0143165

ER -