Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV

Farr, Katherine; Ravindran, Resmi; Strnad, L; Chang, Emily; Chaisson, Lelia H.; Yoon, Christina; Worodria, William; Andama, Alfred; Ayakaka, Irene; Nalwanga, Priscilla Bbosa; Byanyima, Patrick; Kalema, Nelson; Kaswabuli, Sylvia; Katagira, Winceslaus; Aman, Kyomugisha; Musisi, Emmanuel; Tumwine, Nuwagaba Wallen; Sanyu, Ingvar; Ssebunya, Robert; Davis, J. Lucian; Huang, Laurence; Khan, Imran; Cattamanchi, Adithya

doi:10.1371/journal.pone.0206119

Cited by 14 publications

(13 citation statements)

References 30 publications

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“…The plasma level of CRP, an activator of the classical complement pathway, increases during an inflammatory state and is widely used as a biomarker for pulmonary infections (35). Previous studies have shown that TB patients display higher CRP levels than healthy controls (36, 37), but in our study, no significant differences in serum CRP levels were observed between M. bovis-infected cattle and NC by iTRAQ analysis.…”

Section: Discussioncontrasting

confidence: 95%

Interleukin 8 and Pentaxin (C-Reactive Protein) as Potential New Biomarkers of Bovine Tuberculosis

Gao

Guo

et al. 2019

J Clin Microbiol

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Bovine tuberculosis (bTB) is caused by Mycobacterium bovis. During the early stage of infection, greater than 15% of M. bovis-infected cattle shed mycobacteria through nasal secretions, which can be detected by nested PCR. To compare the differences in the protein profiles of M. bovis-infected cattle that were nested PCR positive (bTBPCR-P) and M. bovis-infected cattle that were nested PCR negative (bTBPCR-N) and to screen for biomarkers that will facilitate the early and accurate detection of bTB, we investigated the protein expression profiles of serum and bovine purified protein derivative (PPD-B)-stimulated plasma among bTBPCR-P (n = 20), bTBPCR-N (n = 20), and uninfected cattle (NC; n = 20) by iTRAQ labeling coupled with two-dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2D LC-MS/MS). After comprehensive analysis, we selected 15 putative differentially expressed serum proteins and 15 plasma proteins for validation by parallel reaction monitoring (PRM) with the same cohort used in the iTRAQ analysis. Four serum and five PPD-B-stimulated proteins were confirmed in follow-up enzyme-linked immunosorbent assays. PPD-B-stimulated interleukin 8 (IL-8) displayed the potential to differentiate M. bovis-infected cattle from NC, with an area under the curve (AUC) value of 0.9662, while PPD-B-stimulated C-reactive protein (CRP) displayed the potential to differentiate bTBPCR-P from bTBPCR-N, with an AUC value of 1.00. Finally, double-blind testing with 244 cattle indicated that the PPD-B-stimulated IL-8 test exhibited good agreement with traditional tests (κ > 0.877) with a >90% relative sensitivity and a >98% relative specificity; the PPD-B-stimulated CRP test displayed good agreement with nested PCR (κ = 0.9117), with an observed 94% relative sensitivity and 97% relative specificity. Therefore, the PPD-B-stimulated IL-8 and CRP tests could be used to detect bTB and to differentiate bTBPCR-P from bTBPCR-N.

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Section: Discussioncontrasting

confidence: 95%

Interleukin 8 and Pentaxin (C-Reactive Protein) as Potential New Biomarkers of Bovine Tuberculosis

Gao

Guo

et al. 2019

J Clin Microbiol

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“…Other individual serum markers identified in our work included IL-6 and TGFα, both showing a good performance differentiating active TB from uninfected contacts. Our results agree with previous studies [12][13][14]16] that had reported diagnostic potential of IL-6, which indicates the robustness of this biomarker in different geographical settings. However, we have not found in the literature previous references of TGFα as a potential TB biomarker, which suggests that further research is required to investigate this new candidate.…”

Section: Discussionsupporting

confidence: 93%

“…Moreover, we showed that accuracy of IP-10 as an individual biomarker can be improved when combined with IL-7 for discrimination between active TB and NoTBI contacts, or combined with BCA-1 to differentiate active TB and LTBI. Although previous studies have analysed an array of biomarkers in serum or plasma samples for TB diagnosis [10][11][12][13][14][15][16], none of them have proposed IL-7 or BCA-1 as potential biomarkers before. Our results suggest that they could not only be used in combination with IP-10, but they showed a good performance PLOS ONE differentiating active TB from both NoTBI and LTBI contacts when used individually, based on their respective AUCs.…”

Section: Discussionmentioning

confidence: 99%

“…Identification of host biomarkers in serum and saliva that help to discriminate between groups is key for the development of improved diagnostic tools. Previous investigations have been done using serum, plasma [10][11][12][13][14][15][16][17][18][19] and saliva [16,20,21] samples, that identified some candidate TB biomarkers. However, there is still a lack of consensus of which are the most powerful ones to differentiate active and latent TB infection or between healthy people with or without infection.…”

Section: Introductionmentioning

confidence: 99%

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Identification of candidate host serum and saliva biomarkers for a better diagnosis of active and latent tuberculosis infection

et al. 2020

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In our work, we aim to identify new candidate host biomarkers to discriminate between active TB patients (n = 28), latent infection (LTBI; n = 27) and uninfected (NoTBI; n = 42) individuals. For that, active TB patients and their contacts were recruited that donated serum and saliva samples. A multiplex assay was performed to study the concentration of different cytokines, chemokines and growth factors. Proteins with significant differences between groups were selected and logistic regression and the area under the ROC curve (AUC) was used to assess the diagnostic accuracy. The best marker combinations that discriminate active TB from NoTBI contacts were [IP-10 + IL-7] in serum and [Fractalkine + IP-10 + IL-1α + VEGF] in saliva. Best discrimination between active TB and LTBI was achieved using [IP-10 + BCA-1] in serum (AUC = 0.83) and IP-10 in saliva (p = 0.0007; AUC = 0.78). The levels of TNFα (p = 0.003; AUC = 0.73) in serum and the combination of [Fractalkine +IL-12p40] (AUC = 0.83) in saliva, were able to differentiate between NoTBI and LTBI contacts. In conclusion, different individual and combined protein markers could help to discriminate between active TB and both uninfected and latently-infected contacts. The most promising ones include [IP-10 + IL-7], [IP-10 + BCA-1] and TNFα in serum and [Fractalkine + IP-10 + IL-1α + VEGF], IP-10 and [Fractalkine+IL-12p40] in saliva.

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“…The immunological and inflammatory environments of granulomas change due to the recirculation of immune cells and the release of cytokines that reach the periphery. Therefore, evaluations of cytokine/chemokine profiles in the blood are promising for the differentiation of infectious states in TB [6–8].…”

Section: Introductionmentioning

confidence: 99%

IL-18/IL-37/IP-10 signalling complex as a potential biomarker for discriminating active and latent TB

et al. 2019

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BackgroundCurrently, there are serious limitations in the direct diagnosis of active tuberculosis (ATB). We evaluated the levels of the IL-18/IL-37/IP-10 signalling complex proteins in Mycobacterium tuberculosis (M.tb)-specific antigen-stimulated QuantiFERON® Gold In-Tube (QFT) cultures and in serum samples from ATB patients, healthy individuals with latent M.tb infection (LTBI) and healthy controls (HC) to examine whether combined analyses of these proteins were useful in the differentiation of M.tb states.MethodsThe concentrations of IL-18, IL-18BP, IFN-γ, IL-37 and IP-10 in the serum and QFT supernatants were measured using specific enzyme-linked immunosorbent assay (ELISA) kits. Free IL-18 levels were calculated using the law of mass action.ResultsIncreased concentrations of total and free IL-18, IL-18BP, IFN-γ and IP-10 in the sera of ATB patients were detected. These increases were not counterbalanced by the overproduction of IL-37. Complex co-expression of serum IL-18BP and IL-37, IP-10 and IFN-γ was identified as the highest discriminative biomarker set for the diagnosis of ATB.ConclusionsOur results suggest that the IL-18 signalling complex might be exploited by M. tuberculosis to expand the clinical manifestations of pulmonary TB. Therefore, direct analysis of the serum components of the IL-18/IL-37 signalling complex and IP-10 may be applicable in designing novel diagnostic tests for ATB.

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Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV

Cited by 14 publications

References 30 publications

Interleukin 8 and Pentaxin (C-Reactive Protein) as Potential New Biomarkers of Bovine Tuberculosis

Interleukin 8 and Pentaxin (C-Reactive Protein) as Potential New Biomarkers of Bovine Tuberculosis

Identification of candidate host serum and saliva biomarkers for a better diagnosis of active and latent tuberculosis infection

IL-18/IL-37/IP-10 signalling complex as a potential biomarker for discriminating active and latent TB

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