A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations

Aditya M. Rao; Stephen J. Popper; Sanjana Gupta; Viengmon Davong; Krista Vaidya; Anisone Chanthongthip; Sabine Dittrich; Matthew T. Robinson; Manivanh Vongsouvath; Mayfong Mayxay; Pruksa Nawtaisong; Biraj Karmacharya; Simone A. Thair; Isaac Bogoch; Timothy E. Sweeney; Paul N. Newton; Jason R. Andrews; David A. Relman; Purvesh Khatri

doi:https://doi.org/10.1016/j.xcrm.2022.100842

A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations

Aditya M. Rao, Stephen J. Popper, Sanjana Gupta, Viengmon Davong, Krista Vaidya, Anisone Chanthongthip, Sabine Dittrich, Matthew T. Robinson, Manivanh Vongsouvath, Mayfong Mayxay, Pruksa Nawtaisong, Biraj Karmacharya, Simone A. Thair, Isaac Bogoch, Timothy E. Sweeney, Paul N. Newton, Jason R. Andrews, David A. Relman, Purvesh Khatri

Research output: Contribution to journal › Article › Academic › peer-review

9 Citations (Scopus)

Abstract

Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries from patients with bacterial or viral infections representing a broad spectrum of biological, clinical, and technical heterogeneity, we show current host-response-based gene signatures have lower accuracy to distinguish intracellular bacterial infections from viral infections than extracellular bacterial infections. Using these 69 datasets, we identify an 8-gene signature to distinguish intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC) > 0.91 (85.9% specificity and 90.2% sensitivity). In prospective cohorts from Nepal and Laos, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity and 91% sensitivity). The 8-gene signature meets the target product profile proposed by the World Health Organization and others for distinguishing bacterial and viral infections.

Original language	English
Article number	100842
Number of pages	23
Journal	Cell Reports Medicine
Volume	3
Issue number	12
DOIs	https://doi.org/10.1016/j.xcrm.2022.100842
Publication status	Published - 20 Dec 2022
Externally published	Yes

Keywords

antimicrobial resistance
bacterial vs. viral diagnosis
gene expression
global health
host response
infectious disease diagnosis
point-of-care diagnostics
public health

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https://doi.org/10.1016/j.xcrm.2022.100842

Cite this

Rao, A. M., Popper, S. J., Gupta, S., Davong, V., Vaidya, K., Chanthongthip, A., Dittrich, S., Robinson, M. T., Vongsouvath, M., Mayxay, M., Nawtaisong, P., Karmacharya, B., Thair, S. A., Bogoch, I., Sweeney, T. E., Newton, P. N., Andrews, J. R., Relman, D. A., & Khatri, P. (2022). A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations. Cell Reports Medicine, 3(12), Article 100842. https://doi.org/10.1016/j.xcrm.2022.100842

@article{9596e03f69394021add791ae9919a1ed,

title = "A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations",

abstract = "Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries from patients with bacterial or viral infections representing a broad spectrum of biological, clinical, and technical heterogeneity, we show current host-response-based gene signatures have lower accuracy to distinguish intracellular bacterial infections from viral infections than extracellular bacterial infections. Using these 69 datasets, we identify an 8-gene signature to distinguish intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC) > 0.91 (85.9% specificity and 90.2% sensitivity). In prospective cohorts from Nepal and Laos, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity and 91% sensitivity). The 8-gene signature meets the target product profile proposed by the World Health Organization and others for distinguishing bacterial and viral infections.",

keywords = "antimicrobial resistance, bacterial vs. viral diagnosis, gene expression, global health, host response, infectious disease diagnosis, point-of-care diagnostics, public health",

author = "Rao, {Aditya M.} and Popper, {Stephen J.} and Sanjana Gupta and Viengmon Davong and Krista Vaidya and Anisone Chanthongthip and Sabine Dittrich and Robinson, {Matthew T.} and Manivanh Vongsouvath and Mayfong Mayxay and Pruksa Nawtaisong and Biraj Karmacharya and Thair, {Simone A.} and Isaac Bogoch and Sweeney, {Timothy E.} and Newton, {Paul N.} and Andrews, {Jason R.} and Relman, {David A.} and Purvesh Khatri",

note = "Funding Information: P.K. is funded in part by the Bill and Melinda Gates Foundation (OPP1113682); the National Institute of Allergy and Infectious Diseases (NIAID) grants 1U19AI167903-01, 5U01AI165527-02, 1U19AI109662, U19AI057229, and 5R01AI125197; Department of Defense contracts W81XWH-18-1-0253 and W81XWH1910235; and the Ralph & Marian Falk Medical Research Trust. D.A.R. is supported by NIH/NIAID U19 AI109761 and the Thomas C. and Joan M. Merigan Endowment at Stanford University. Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit is funded by the Wellcome Trust of Great Britain. A.M.R. is funded by the National Science Foundation Graduate Research Fellowship and the Stanford Graduate Fellowship. This research was funded in whole, or in part, by the Wellcome Trust (grant number 220211). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We are very grateful to the late Dr. Rattanaphone Phetsouvanh, Dr. Vilada Chansamouth, Dr. Sayaphet Rattanavong, Dr. Koukeo Phommasone, the patients, and to Assoc. Prof. Bounthaphany Bounxouei, ex-Director of Mahosot Hospital, and the staff of Mahosot Hospital and the Microbiology Laboratory for their technical help and support. We thank Assoc. Prof. Bounnack Saysanasongkham, the ex-Director of Department of Health Care, Ministry of Health; Assoc. Prof. Bounkong Syhavong, the former Minister of Health, Lao PDR; and Dr. Catrin Moore for their very kind help and support. We thank Stuart Blacksell, Audrey Dubot-P{\'e}r{\`e}s, and Audrey Rachlin for laboratory support. We also thank Veda Khadka for technical assistance. A.M.R. S.J.P. and P.K. conceived the project. A.M.R. collected and curated datasets and performed the primary analysis. S.J.P. and S.G. assisted with analysis. A.M.R. and S.J.P. had full access to the data and verified the data. Patient recruitment, sample collection, and sample processing was done by S.J.P. V.D. K.V. A.C. M.V. M.M. P.N. S.A.T. S.D. M.T.R. B.K. and I.B. and overseen by P.N.N. and J.R.A. S.J.P. A.M.R. and S.A.T. curated patient data. A.M.R. and P.K. wrote and revised the manuscript with input from all authors, who reviewed and approved the final submitted paper. P.K. and D.A.R. supervised the project and were responsible for the decision to submit the paper. P.N. is also an honorary professor at National University of Lao, London School of Hygiene and Tropical Medicine, and Boston University. He receives no salary or other financial support from these institutions. D.R. is a shareholder of Blue Willow Biologics, Cantata Bio, Evelo Biosciences, Karius, Proderm IQ, and Second Genome. D.R. is an advisor to Cantata Bio and Visby Medical. A.M.R. S.J.P. T.E.S. D.A.R. and P.K. are named as inventors on a patent application describing the 8-gene set, which has been licensed to Inflammatix. T.E.S. and P.K. are employees of Inflammatix and are shareholders in Inflammatix. Inflammatix had no role in the design, funding, or reporting of this work. S.D. is currently employed by FIND. Funding Information: P.K. is funded in part by the Bill and Melinda Gates Foundation ( OPP1113682 ); the National Institute of Allergy and Infectious Diseases (NIAID) grants 1U19AI167903-01 , 5U01AI165527-02 , 1U19AI109662 , U19AI057229 , and 5R01AI125197 ; Department of Defense contracts W81XWH-18-1-0253 and W81XWH1910235 ; and the Ralph & Marian Falk Medical Research Trust . D.A.R. is supported by NIH / NIAID U19 AI109761 and the Thomas C. and Joan M. Merigan Endowment at Stanford University. Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit is funded by the Wellcome Trust of Great Britain. A.M.R. is funded by the National Science Foundation Graduate Research Fellowship and the Stanford Graduate Fellowship. This research was funded in whole, or in part, by the Wellcome Trust (grant number 220211 ). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = dec,

day = "20",

doi = "https://doi.org/10.1016/j.xcrm.2022.100842",

language = "English",

volume = "3",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "12",

}

Rao, AM, Popper, SJ, Gupta, S, Davong, V, Vaidya, K, Chanthongthip, A, Dittrich, S, Robinson, MT, Vongsouvath, M, Mayxay, M, Nawtaisong, P, Karmacharya, B, Thair, SA, Bogoch, I, Sweeney, TE, Newton, PN, Andrews, JR, Relman, DA & Khatri, P 2022, 'A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations', Cell Reports Medicine, vol. 3, no. 12, 100842. https://doi.org/10.1016/j.xcrm.2022.100842

TY - JOUR

T1 - A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations

AU - Rao, Aditya M.

AU - Popper, Stephen J.

AU - Gupta, Sanjana

AU - Davong, Viengmon

AU - Vaidya, Krista

AU - Chanthongthip, Anisone

AU - Dittrich, Sabine

AU - Robinson, Matthew T.

AU - Vongsouvath, Manivanh

AU - Mayxay, Mayfong

AU - Nawtaisong, Pruksa

AU - Karmacharya, Biraj

AU - Thair, Simone A.

AU - Bogoch, Isaac

AU - Sweeney, Timothy E.

AU - Newton, Paul N.

AU - Andrews, Jason R.

AU - Relman, David A.

AU - Khatri, Purvesh

N1 - Funding Information: P.K. is funded in part by the Bill and Melinda Gates Foundation (OPP1113682); the National Institute of Allergy and Infectious Diseases (NIAID) grants 1U19AI167903-01, 5U01AI165527-02, 1U19AI109662, U19AI057229, and 5R01AI125197; Department of Defense contracts W81XWH-18-1-0253 and W81XWH1910235; and the Ralph & Marian Falk Medical Research Trust. D.A.R. is supported by NIH/NIAID U19 AI109761 and the Thomas C. and Joan M. Merigan Endowment at Stanford University. Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit is funded by the Wellcome Trust of Great Britain. A.M.R. is funded by the National Science Foundation Graduate Research Fellowship and the Stanford Graduate Fellowship. This research was funded in whole, or in part, by the Wellcome Trust (grant number 220211). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We are very grateful to the late Dr. Rattanaphone Phetsouvanh, Dr. Vilada Chansamouth, Dr. Sayaphet Rattanavong, Dr. Koukeo Phommasone, the patients, and to Assoc. Prof. Bounthaphany Bounxouei, ex-Director of Mahosot Hospital, and the staff of Mahosot Hospital and the Microbiology Laboratory for their technical help and support. We thank Assoc. Prof. Bounnack Saysanasongkham, the ex-Director of Department of Health Care, Ministry of Health; Assoc. Prof. Bounkong Syhavong, the former Minister of Health, Lao PDR; and Dr. Catrin Moore for their very kind help and support. We thank Stuart Blacksell, Audrey Dubot-Pérès, and Audrey Rachlin for laboratory support. We also thank Veda Khadka for technical assistance. A.M.R. S.J.P. and P.K. conceived the project. A.M.R. collected and curated datasets and performed the primary analysis. S.J.P. and S.G. assisted with analysis. A.M.R. and S.J.P. had full access to the data and verified the data. Patient recruitment, sample collection, and sample processing was done by S.J.P. V.D. K.V. A.C. M.V. M.M. P.N. S.A.T. S.D. M.T.R. B.K. and I.B. and overseen by P.N.N. and J.R.A. S.J.P. A.M.R. and S.A.T. curated patient data. A.M.R. and P.K. wrote and revised the manuscript with input from all authors, who reviewed and approved the final submitted paper. P.K. and D.A.R. supervised the project and were responsible for the decision to submit the paper. P.N. is also an honorary professor at National University of Lao, London School of Hygiene and Tropical Medicine, and Boston University. He receives no salary or other financial support from these institutions. D.R. is a shareholder of Blue Willow Biologics, Cantata Bio, Evelo Biosciences, Karius, Proderm IQ, and Second Genome. D.R. is an advisor to Cantata Bio and Visby Medical. A.M.R. S.J.P. T.E.S. D.A.R. and P.K. are named as inventors on a patent application describing the 8-gene set, which has been licensed to Inflammatix. T.E.S. and P.K. are employees of Inflammatix and are shareholders in Inflammatix. Inflammatix had no role in the design, funding, or reporting of this work. S.D. is currently employed by FIND. Funding Information: P.K. is funded in part by the Bill and Melinda Gates Foundation ( OPP1113682 ); the National Institute of Allergy and Infectious Diseases (NIAID) grants 1U19AI167903-01 , 5U01AI165527-02 , 1U19AI109662 , U19AI057229 , and 5R01AI125197 ; Department of Defense contracts W81XWH-18-1-0253 and W81XWH1910235 ; and the Ralph & Marian Falk Medical Research Trust . D.A.R. is supported by NIH / NIAID U19 AI109761 and the Thomas C. and Joan M. Merigan Endowment at Stanford University. Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit is funded by the Wellcome Trust of Great Britain. A.M.R. is funded by the National Science Foundation Graduate Research Fellowship and the Stanford Graduate Fellowship. This research was funded in whole, or in part, by the Wellcome Trust (grant number 220211 ). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © 2022 The Authors

PY - 2022/12/20

Y1 - 2022/12/20

N2 - Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries from patients with bacterial or viral infections representing a broad spectrum of biological, clinical, and technical heterogeneity, we show current host-response-based gene signatures have lower accuracy to distinguish intracellular bacterial infections from viral infections than extracellular bacterial infections. Using these 69 datasets, we identify an 8-gene signature to distinguish intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC) > 0.91 (85.9% specificity and 90.2% sensitivity). In prospective cohorts from Nepal and Laos, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity and 91% sensitivity). The 8-gene signature meets the target product profile proposed by the World Health Organization and others for distinguishing bacterial and viral infections.

AB - Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries from patients with bacterial or viral infections representing a broad spectrum of biological, clinical, and technical heterogeneity, we show current host-response-based gene signatures have lower accuracy to distinguish intracellular bacterial infections from viral infections than extracellular bacterial infections. Using these 69 datasets, we identify an 8-gene signature to distinguish intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC) > 0.91 (85.9% specificity and 90.2% sensitivity). In prospective cohorts from Nepal and Laos, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity and 91% sensitivity). The 8-gene signature meets the target product profile proposed by the World Health Organization and others for distinguishing bacterial and viral infections.

KW - antimicrobial resistance

KW - bacterial vs. viral diagnosis

KW - gene expression

KW - global health

KW - host response

KW - infectious disease diagnosis

KW - point-of-care diagnostics

KW - public health

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U2 - https://doi.org/10.1016/j.xcrm.2022.100842

DO - https://doi.org/10.1016/j.xcrm.2022.100842

M3 - Article

C2 - 36543117

SN - 2666-3791

VL - 3

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 12

M1 - 100842

ER -

A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations

Abstract

Keywords

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