Inflammatory markers in the cerebrospinal fluid linked to mortality in tuberculous meningitis

Sofiati Dian; Valerie A C M Koeken; Edwin Ardiansyah; Ahmad R Ganiem; Kirsten van Abeelen; Raul Aguirre-Gamboa; Feby Purnama; Sofia Imaculata; Jessi Annisa; Lidya Chaidir; Rovina Ruslami; Leo A B Joosten; Mihai G Netea; Bachti Alisjahbana; Reinout van Crevel; Arjan van Laarhoven; Vinod Kumar

doi:10.1093/braincomms/fcaf273

journal article Open Access Jan 01, 2025

Inflammatory markers in the cerebrospinal fluid linked to mortality in tuberculous meningitis

Sofiati Dian

Valerie A C M Koeken Edwin Ardiansyah

Ahmad R Ganiem Kirsten van Abeelen Raul Aguirre-Gamboa Feby Purnama Sofia Imaculata Jessi Annisa Lidya Chaidir Rovina Ruslami

Leo A B Joosten Mihai G Netea Bachti Alisjahbana

Reinout van Crevel

Arjan van Laarhoven

Vinod Kumar

Brain Communications Vol. 7 No. 4 · Oxford University Press (OUP)

View at Publisher Save 10.1093/braincomms/fcaf273

Abstract

Abstract
This study examines the role of host inflammation in the high mortality of tuberculous meningitis (TBM) and identifies potential biomarkers associated with improved survival. We conducted a case-control study involving 131 patients in a discovery cohort, 81 TBM patients in a validation cohort, and 43 non-infected controls from a referral hospital in Indonesia. We measured 94 inflammation-related proteins in cerebrospinal fluid (CSF) and performed genome-wide quantitative trait loci (QTL) mapping. Sixty-seven proteins were found to be differentially expressed between TBM patients and controls, with 64 proteins elevated in patients. Five proteins, including vascular endothelial growth factor (VEGF) and matrix metalloproteinase-10 (MMP-10), were identified as predictors of 180-day mortality in TBM patients. The validation cohort confirmed that MMP-10, but not VEGF, was predictive of mortality. Genome-wide QTL mapping identified two genome-wide significant and four suggestive genetic loci associated with CSF MMP-10, which also predicted survival in an additional cohort of 218 patients. High CSF concentrations of MMP-10, along with specific genetic loci, may be associated with survival in TBM patients, suggesting a potential role for MMP-10 in disease pathogenesis and warranting further investigation into its utility in host-directed therapies.

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References

24

[1]

Thwaites "Tuberculous meningitis: More questions, still too few answers" Lancet Neurol (2013) 10.1016/s1474-4422(13)70168-6

[2]

Tuberculous meningitis

Robert J. Wilkinson, Ursula Rohlwink, Usha Kant Misra et al.

Nature Reviews Neurology 2017 10.1038/nrneurol.2017.120

[3]

Prasad "Corticosteroids for managing tuberculous meningitis" Cochrane Database Syst Rev (2016)

[4]

Thuong "Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis" J Infect Dis (2017) 10.1093/infdis/jix050

[5]

Simmons "Pretreatment intracerebral and peripheral blood immune responses in Vietnamese adults with tuberculous meningitis: Diagnostic value and relationship to disease severity and outcome" J Immunol (2006) 10.4049/jimmunol.176.3.2007

[6]

Van Laarhoven "Clinical parameters, routine inflammatory markers, and LTA4H genotype as predictors of mortality among 608 patients with tuberculous meningitis in Indonesia" J Infect Dis (2017) 10.1093/infdis/jix051

[7]

Rohlwink "Standardized approaches for clinical sampling and endpoint ascertainment in tuberculous meningitis studies" Wellcome Open Res (2020) 10.12688/wellcomeopenres.15497.2

[8]

Homogenous 96-Plex PEA Immunoassay Exhibiting High Sensitivity, Specificity, and Excellent Scalability

Erika Assarsson, Martin Lundberg, Göran Holmquist et al.

PLoS ONE 2014 10.1371/journal.pone.0095192

[9]

van Laarhoven "Cerebral tryptophan metabolism and outcome of tuberculous meningitis: An observational cohort study" Lancet Infect Dis (2018) 10.1016/s1473-3099(18)30053-7

[10]

Ardiansyah "Sequencing whole genomes of the West Javanese population in Indonesia reveals novel variants and improves imputation accuracy" Front Genet (2025) 10.3389/fgene.2024.1492602

[11]

Rohlwink "Biomarkers of brain injury in cerebral infections" Clin Chem (2014) 10.1373/clinchem.2013.212472

[12]

Svensson "Model-based meta-analysis of rifampicin exposure and mortality in Indonesian tuberculous meningitis trials" Clin Infect Dis (2020) 10.1093/cid/ciz1071

[13]

Ward "HaploReg v4: Systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease" Nucleic Acids Res (2016) 10.1093/nar/gkv1340

[14]

Rodriguez "Metalloproteinases and atherothrombosis: MMP-10 mediates vascular remodeling promoted by inflammatory stimuli" Front Biosci (2008) 10.2741/2896

[15]

Brilha "Early secretory antigenic target-6 drives matrix metalloproteinase-10 gene expression and secretion in Tuberculosis" Am J Respir Cell Mol Biol (2017) 10.1165/rcmb.2016-0162oc

[16]

Jenner "Insights into host responses against pathogens from transcriptional profiling" Nat Rev Microbiol (2005) 10.1038/nrmicro1126

[17]

Marais "Neutrophil-associated central nervous system inflammation in tuberculous meningitis immune reconstitution inflammatory syndrome" Clin Infect Dis (2014) 10.1093/cid/ciu641

[18]

Rohlwink "Matrix metalloproteinases in pulmonary and central nervous system Tuberculosis-A review" Int J Mol Sci (2019) 10.3390/ijms20061350

[19]

Brilha "Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis" Sci Rep (2017) 10.1038/s41598-017-16250-3

[20]

Green "Mycobacterium tuberculosis upregulates microglial matrix metalloproteinase-1 and -3 expression and secretion via NF-kappaB- and Activator Protein-1-dependent monocyte networks" J Immunol (2010) 10.4049/jimmunol.0903811

[21]

Green "Dexamethasone, cerebrospinal fluid matrix metalloproteinase concentrations and clinical outcomes in tuberculous meningitis" PLoS One (2009) 10.1371/journal.pone.0007277

[22]

Figaji "The neurosurgical and acute care management of tuberculous meningitis: Evidence and current practice" Tuberculosis (Edinb) (2010) 10.1016/j.tube.2010.09.005

[23]

Te Brake "Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis" Int J Antimicrob Agents (2015) 10.1016/j.ijantimicag.2014.12.027

[24]

Ruslami "Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: An open-label, randomised controlled phase 2 trial" Lancet Infect Dis (2013) 10.1016/s1473-3099(12)70264-5

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Details

Published: Jan 01, 2025
Vol/Issue: 7(4)
License: View

Authors

S

Sofiati Dian

Research Centre for Care and Control of Infectious Diseases (RC3ID), Faculty of Medicine, Universitas Padjadjaran , 40161 Bandung ,; Department of Neurology, Faculty of Medicine, Hasan Sadikin General Hospital, Universitas Padjadjaran , 40161 Bandung, West Java Province ,

V

Valerie A C M Koeken

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , 6525 GA Nijmegen ,

E

Edwin Ardiansyah

Research Centre for Care and Control of Infectious Diseases (RC3ID), Faculty of Medicine, Universitas Padjadjaran , 40161 Bandung ,

A

Ahmad R Ganiem

Research Centre for Care and Control of Infectious Diseases (RC3ID), Faculty of Medicine, Universitas Padjadjaran , 40161 Bandung ,; Department of Neurology, Faculty of Medicine, Hasan Sadikin General Hospital, Universitas Padjadjaran , 40161 Bandung, West Java Province ,

K

Kirsten van Abeelen

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , 6525 GA Nijmegen ,

R

Raul Aguirre-Gamboa

Department of Genetics, University Medical Center Groningen, University of Groningen , 9700 RB Groningen ,

F

Feby Purnama

Research Centre for Care and Control of Infectious Diseases (RC3ID), Faculty of Medicine, Universitas Padjadjaran , 40161 Bandung ,

S

Sofia Imaculata

Research Centre for Care and Control of Infectious Diseases (RC3ID), Faculty of Medicine, Universitas Padjadjaran , 40161 Bandung ,

J

Jessi Annisa

Research Centre for Care and Control of Infectious Diseases (RC3ID), Faculty of Medicine, Universitas Padjadjaran , 40161 Bandung ,

L

Lidya Chaidir

Research Centre for Care and Control of Infectious Diseases (RC3ID), Faculty of Medicine, Universitas Padjadjaran , 40161 Bandung ,

R

Rovina Ruslami

Research Centre for Care and Control of Infectious Diseases (RC3ID), Faculty of Medicine, Universitas Padjadjaran , 40161 Bandung ,

L

Leo A B Joosten

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , 6525 GA Nijmegen ,

M

Mihai G Netea

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , 6525 GA Nijmegen ,; Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn , Bonn 53115 ,

B

Bachti Alisjahbana

Research Centre for Care and Control of Infectious Diseases (RC3ID), Faculty of Medicine, Universitas Padjadjaran , 40161 Bandung ,; Department of Neurology, Faculty of Medicine, Hasan Sadikin General Hospital, Universitas Padjadjaran , 40161 Bandung, West Java Province ,

R

Reinout van Crevel

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , 6525 GA Nijmegen ,; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford , OX3 7LG Oxford ,

A

Arjan van Laarhoven

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , 6525 GA Nijmegen ,

V

Vinod Kumar

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , 6525 GA Nijmegen ,; Department of Genetics, University Medical Center Groningen, University of Groningen , 9700 RB Groningen ,

Funding

National Institutes of Health

European Research Council Award: #833247

United States Agency for International Development

Direktorat Jenderal Pendidikan Tinggi

Netherlands Foundation for Scientific Research Award: 017.106.310

Using Tryptophan Metabolism and Response to Corticosteroids to Define New Therapeutic Targets for Tuberculosis Meningitis: Integration of Large Scale Clinical, Metabolomic, and Genomic Data Award: R01AI145781

INtegrative omics and aspirin response to define ThERapeutiC targEts for Pediatric Tbm Award: R01AI165721

Cite This Article

Sofiati Dian, Valerie A C M Koeken, Edwin Ardiansyah, et al. (2025). Inflammatory markers in the cerebrospinal fluid linked to mortality in tuberculous meningitis. Brain Communications, 7(4). https://doi.org/10.1093/braincomms/fcaf273

Inflammatory markers in the cerebrospinal fluid linked to mortality in tuberculous meningitis

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