CXCL9, a promising biomarker in the diagnosis of chronic Q fever

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Abstract

Background

In the aftermath of the largest Q fever outbreak in the world, diagnosing the potentially lethal complication chronic Q fever remains challenging. PCR, Coxiella burnetii IgG phase I antibodies, CRP and ¹⁸F–FDG-PET/CT scan are used for diagnosis and monitoring in clinical practice. We aimed to identify and test biomarkers in order to improve discriminative power of the diagnostic tests and monitoring of chronic Q fever.

Methods

We performed a transcriptome analysis on C. burnetii stimulated PBMCs of 4 healthy controls and 6 chronic Q fever patients and identified genes that were most differentially expressed. The gene products were determined using Luminex technology in whole blood samples stimulated with heat-killed C. burnetii and serum samples from chronic Q fever patients and control subjects.

Results

Gene expression of the chemokines CXCL9, CXCL10, CXCL11 and CCL8 was strongly up-regulated in C. burnetii stimulated PBMCs of chronic Q fever patients, in contrast to healthy controls. In whole blood cultures of chronic Q fever patients, production of all four chemokines was increased upon C. burnetii stimulation, but also healthy controls and past Q fever individuals showed increased production of CXCL9, CXCL10 and CCL8. However, CXCL9 and CXCL11 production was significantly higher for chronic Q fever patients compared to past Q fever individuals. In addition, CXCL9 serum concentrations in chronic Q fever patients were higher than in past Q fever individuals.

Conclusion

CXCL9 protein, measured in serum or as C. burnetii stimulated production, is a promising biomarker for the diagnosis of chronic Q fever.

Electronic supplementary material

The online version of this article (doi:10.1186/s12879-017-2656-6) contains supplementary material, which is available to authorized users.

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Most cited references 25

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CXCR3 ligands in disease and therapy.

Katrien Van Raemdonck, Philippe Van den Steen, Sandra Liekens … (2015)

Chemokines, binding their various G protein-coupled receptors, lead the way for leukocytes in health and inflammation. Yet chemokine receptor expression is not limited to leukocytes. Accordingly, chemokines are remarkably pleiotropic molecules involved in a range of physiological as well as pathological processes. For example, the CXCR3 chemokine receptor is expressed on activated T lymphocytes, dendritic cells and natural killer cells, but also fibroblasts and smooth muscle, epithelial and endothelial cells. In men, these cells express either CXCR3A, its splice variant CXCR3B or a balanced combination of both. The CXCR3 ligands, activating both receptor variants, include CXCL4, CXCL4L1, CXCL9, CXCL10 and CXCL11. Upon CXCR3A activation these ELR-negative CXC chemokines mediate chemotactic and proliferative responses, for example in leukocytes. In contrast, CXCR3B induces anti-proliferative and anti-migratory effects, as exemplified by angiostatic effects on endothelial cells. Taken together, the unusual and versatile characteristics of CXCR3 and its ligands form the basis for their pertinent involvement in a myriad of diseases. In this review, we discuss the presence and function of all CXCR3 ligands in various malignant, angiogenic, infectious, inflammatory and other disorders. By extension, we have also elaborated on the potential therapeutic applicability of CXCR3 ligand administration or blockade, as well as their additional value as predictive or prognostic biomarkers. This review illustrates the multifunctional, intriguing character of the various CXCR3-binding chemokines. Copyright © 2014 Elsevier Ltd. All rights reserved.

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Beyond the IFN-γ horizon: biomarkers for immunodiagnosis of infection with Mycobacterium tuberculosis.

Novel N Chegou, Jan Heyckendorf, Morten Ruhwald … (2014)

Latent infection with Mycobacterium tuberculosis (LTBI) is defined by the presence of M. tuberculosis-specific immunity in the absence of active tuberculosis. LTBI is detected using interferon-γ release assays (IGRAs) or the tuberculin-skin-test (TST). In clinical practice, IGRAs and the TSTs have failed to distinguish between active tuberculosis and LTBI and their predictive value to identify individuals at risk for the future development of tuberculosis is limited. There is an urgent need to identify biomarkers that improve the clinical performance of current immunodiagnostic methods for tuberculosis prevention, diagnosis and treatment monitoring. Here, we review the landscape of potential alternative biomarkers useful for detection of infection with M. tuberculosis. We describe what individual markers add in terms of specificity for active/latent infection, prediction of progression to active tuberculosis and immunodiagnostic potential in high-risk groups' such as HIV-infected individuals and children.

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Long-term outcome of Q fever endocarditis: a 26-year personal survey.

Didier Raoult, Hervé Richet, Matthieu Million … (2010)

Q fever endocarditis caused by Coxiella burnetii is a potentially fatal disease characterised by a chronic evolution. To assess the long-term outcome and identify prognostic factors for mortality, surgical treatment, and serological changes in Q fever endocarditis, we did a retrospective study in the French National Referral Centre. Patients included were diagnosed with Q fever endocarditis at our centre from May, 1983, to June, 2006, and followed up for a minimum of 3 years for each patient, history and clinical characteristics were recorded with a standardised questionnaire. Prognostic factors associated with death, surgery, serological cure, and serological relapse were assessed by Cox regression analysis. Excised heart valve analysis was assessed according to duration of treatment. 104 patients were identified for inclusion in the study, although one was lost to follow-up; median follow-up was 100 months (range 37-310 months). 18 months of treatment was sufficient to sterilise the valves of all the patients except three, and 2 years of treatment sterilised all valves except one. In a multivariate Cox regression analysis, the major determinants associated with mortality were age (hazard ratio 1.11, 95% CI 1.05-1.18, p=0.003), stroke at diagnosis (7.09, 2.00-25.10, p=0.001), endocarditis on a prosthetic valve (6.04, 1.47-24.80, p=0.044), an absence of a four-times decrease of phase I IgG and IgA at 1 year (5.69, 1.00-32.22, p=0.049), or the presence of phase II IgM at 1 year (12.08, 3.11-46.85, p=0.005). Surgery was associated with heart failure (2.68, 1.21-5.94, p=0.015) or a cardiac abscess (4.71, 1.64-13.50, p=0.004). The determinants of poor serological outcome were male sex (0.47, 0.26-0.86, p=0.014), a high level of phase I IgG (0.65, 0.45-0.95, p=0.027), and a delay in the start of treatment with hydroxychloroquine (0.20, 0.04-0.91, p=0.037). Factors associated with relapse were endocarditis on a prosthetic valve (21.3, 2.05-221.86, p=0.01) or treatment duration less than 18 months (9.69, 1.08-86.72, p=0.042). The optimum duration of treatment with doxycycline and hydroxychloroquine in Q fever endocarditis is 18 months for native valves and 24 months for prosthetic valves. This duration should be extended only in the absence of favourable serological outcomes. Patients should be serologically monitored for at least 5 years because of the risk of relapse. French National Referral Centre for Q Fever. 2010 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Anne F. M. Jansen: 0031-24-3618819 , Anne.FM.Jansen@radboudumc.nl

Marcel van Deuren: 0031-24-3618819 , Marcel.vanDeuren@radboudumc.nl

Journal

Journal ID (nlm-ta): BMC Infect Dis

Journal ID (iso-abbrev): BMC Infect. Dis

Title: BMC Infectious Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2334

Publication date (Electronic): 9 August 2017

Publication date PMC-release: 9 August 2017

Publication date Collection: 2017

Volume: 17

Electronic Location Identifier: 556

Affiliations

[1 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Internal Medicine 463, Radboud center for Infectious Diseases (RCI), , Radboud University Medical Center, ; P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

[2 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Radboud Expert Center for Q fever, , Radboud University Medical Center, ; P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

[3 ]ISNI 0000 0001 2198 4166, GRID grid.412180.e, , Université Claude Bernard Lyon 1, Hospices Civils de Lyon, bioMérieux; EA7426 “Pathophysiology of injury induced immunosuppression (PI3)”, Hôpital E. Herriot, ; Lyon, France

[4 ]ISNI 0000 0001 2176 4817, GRID grid.5399.6, , URMITE, Aix-Marseille University, ; Marseille, France

[5 ]ISNI 0000 0004 0444 9008, GRID grid.413327.0, Department of Medical Microbiology and Infectious Diseases, , Canisius Wilhelmina Hospital, ; Nijmegen, The Netherlands

Article

Publisher ID: 2656

DOI: 10.1186/s12879-017-2656-6

PMC ID: 5551022

PubMed ID: 28793883

SO-VID: 58a36a91-47cf-4423-9c36-365117c9c44f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 14 April 2017

Date accepted : 31 July 2017

Funding

Funded by: Q-support Foundation

Funded by: ERC Consolidator Grant

Award ID: 3310372

Award Recipient : Mihai G. Netea

Funded by: Spinoza Grant of the Netherlands Organization for Scientific Research

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: chronic q fever,coxiella burnetii,chemokines,biomarker,cxcl9

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: chronic q fever, coxiella burnetii, chemokines, biomarker, cxcl9

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CXCL9, a promising biomarker in the diagnosis of chronic Q fever

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Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

Related collections

CHAIN Network Collection

Most cited references 25

CXCR3 ligands in disease and therapy.

Beyond the IFN-γ horizon: biomarkers for immunodiagnosis of infection with Mycobacterium tuberculosis.

Long-term outcome of Q fever endocarditis: a 26-year personal survey.

Author and article information

Contributors

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Article

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Funding

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Cited by 3

Most referenced authors 255