The Utility of a Three-gene Host Response to Discriminate Tuberculous Meningitis From Other Infections in Children.
| Title: | The Utility of a Three-gene Host Response to Discriminate Tuberculous Meningitis From Other Infections in Children. |
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| Authors: | Huynh J; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, Oxford University.; Le NHT; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Le Nguyen BH; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Hoang HT; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; La Ngoc V; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Ensor S; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; NOTSSCaN Division, Oxford University Hospital NHS Trust, Oxford.; Phan KQN; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Tran NHT; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Pham TN; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Dang Do TA; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Tram TTB; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Vu DTM; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Dinh Do V; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Griffiths A; Institute of Clinical Trials and Methodology, Medical Research Council Clinical Trials Unit at University College of London, High Holborn, United Kingdom.; Anderson S; Institute of Clinical Trials and Methodology, Medical Research Council Clinical Trials Unit at University College of London, High Holborn, United Kingdom.; Gibb D; Institute of Clinical Trials and Methodology, Medical Research Council Clinical Trials Unit at University College of London, High Holborn, United Kingdom.; Ha DMT; Department of Paediatrics, Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease.; Tung TH; Department of Infectious Diseases, Children's Hospital 2, Ho Chi Minh City, Vietnam.; Qui ND; Department of Infectious Diseases, Children's Hospital 2, Ho Chi Minh City, Vietnam.; Nhung NHT; Department of Paediatrics, Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease.; Thwaites GE; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, Oxford University.; Thuong NTT; From the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, Oxford University. |
| Corporate Authors: | SURE trial team |
| Source: | The Pediatric infectious disease journal [Pediatr Infect Dis J] 2026 May 01; Vol. 45 (5), pp. 466-474. Date of Electronic Publication: 2025 Dec 23. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Williams & Wilkins Country of Publication: United States NLM ID: 8701858 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-0987 (Electronic) Linking ISSN: 08913668 NLM ISO Abbreviation: Pediatr Infect Dis J Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Baltimore, Md. : Williams & Wilkins, c1987- |
| MeSH Terms: | Tuberculosis, Meningeal*/diagnosis ; Tuberculosis, Meningeal*/genetics ; Tuberculosis, Meningeal*/blood; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/blood ; Humans ; Male ; Female ; Child ; Child, Preschool ; Infant ; Adolescent ; Gene Expression Profiling ; Diagnosis, Differential |
| Abstract: | Background: Early diagnosis of tuberculous meningitis (TBM) is critical to favorable outcomes. We investigated whether a 3-gene host response signature in whole blood can distinguish TBM from symptomatic controls in children.; Methods: Whole-blood RNA sequencing was performed in children with TBM and controls. Expression of the 3-gene signature, [guanylate-binding protein (GBP5), dual specificity phosphatase 3 (DUSP3) and Krupple-like factor 2 (KLF2)] was quantified and a tuberculosis (TB) score was calculated using (GBP5+DUSP3)/2-KLF2. Discriminatory performance was obtained using receiver-operator characteristic curve analysis against microbiologic and composite reference standards. TB score and 3-gene expression in children were compared against adults with TBM. In parallel, an exploratory transcriptome-wide analysis was performed, applying bootstrapped least absolute shrinkage and selection operator regression to identify additional genes associated with TBM.; Results: Forty-two children had TBM and 41 were controls. KLF2 was upregulated in TBM compared to controls ( P = 0.043); while GBP5, DUSP3 and TB score showed no difference. The diagnostic performance of GBP5 alone (area under the curves: 0.64; 95% confidence interval: 0.46-0.83) and TB score (area under the curves: 0.59; 95% confidence interval: 0.41-0.77) was poor against the reference standard of definite TBM. GBP5 in children with TBM was lower than in adults without HIV (median 13.04; interquartile ranges: 11.91-14.29 vs. median 13.72; interquartile ranges: 12.58-14.53, P = 0.036), and expression was nonlinear across the age spectrum; lowest in young children. Exploratory transcriptomic analysis suggests that novel genes may contribute a discriminatory signal.; Conclusion: The 3-gene host response signature does not discriminate TBM from controls in children and was much less discriminative compared to adults. An alternative set of pediatric-specific signatures may exist, but further discovery and validation are required.; (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.) |
| Competing Interests: | The authors have no conflicts of interest to disclose. |
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| Contributed Indexing: | Keywords: child; diagnostic; transcriptomic; tuberculous meningitis |
| Substance Nomenclature: | 0 (Kruppel-Like Transcription Factors); 0 (KLF2 protein, human) |
| Entry Date(s): | Date Created: 20251223 Date Completed: 20260410 Latest Revision: 20260411 |
| Update Code: | 20260411 |
| PubMed Central ID: | PMC13064836 |
| DOI: | 10.1097/INF.0000000000005105 |
| PMID: | 41430759 |
| Database: | MEDLINE |
Journal Article