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

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background Approaches to screening for active tuberculosis (TB) among people living with HIV are inadequate, leading to missed diagnoses and poor implementation of preventive therapy. Methods Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between June 2011 and July 2013 with a cough 2 weeks were enrolled. Patients underwent extensive evaluation for pulmonary TB. Concentrations of 43 cytokines/chemokines were measured at the same time point as C-reactive protein (CRP) in banked plasma samples using commercially-available multiplex kits. Advanced classification algorithms were used to rank cytokines/chemokines for their ability to identify TB, and to model the specificityof the top-ranked cytokines/chemokines individually and in combination with sensitivity constrained to ? 90% as recommended for TB screening. Results The median plasma level of 5 biomarkers (IL-6, INF-?, MIG, CRP, IL-18) was significantly different between patients with and without TB. With sensitivity constrained to 90%, all had low specificity with IL-6 showing the highest specificity (44%; 95% CI 37.4-49.5). Biomarker panels were found to be more valuable than any biomarker alone. A panel combining IFN-? and IL-6 had the highest specificity (50%; 95% CI 46.7-53.3). Sensitivity remained high (>85%) for all panels among sputum smear-negative TB patients. Conclusions Direct measurement of unstimulated plasma cytokines/chemokines in peripheral blood is a promising approach to TB screening. Cytokine/chemokine panels retained high sensitivity for smear-negative TB and achieved improved specificity compared to individual cytokines/chemokines. These markers should be further evaluated in outpatient settings where most TB screening occurs and where other illnesses associated with systematic inflammation are less common.

Original languageEnglish (US)
Article numbere0206119
JournalPloS one
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Chemokines
tuberculosis
Screening
Tuberculosis
Blood
HIV
chemokines
Cytokines
screening
blood
Biomarkers
cytokines
Interleukin-6
Plasmas
interleukin-6
C-Reactive Protein
biomarkers
C-reactive protein
Interleukin-18
Uganda

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Farr, K., Ravindran, R., Strnad, L., Chang, E., Chaisson, L. H., Yoon, C., ... Cattamanchi, A. (2018). Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV. PloS one, 13(10), [e0206119]. https://doi.org/10.1371/journal.pone.0206119

Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV. / Farr, Katherine; Ravindran, Resmi; Strnad, Luke; 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 Denise; Musisi, Emmanuel; Tumwine, Nuwagaba Wallen; Sanyu, Ingvar; Ssebunya, Robert; Davis, J. Lucian; Huang, Laurence; Khan, Imran H.; Cattamanchi, Adithya.

In: PloS one, Vol. 13, No. 10, e0206119, 01.10.2018.

Research output: Contribution to journalArticle

Farr, K, Ravindran, R, Strnad, L, Chang, E, Chaisson, LH, Yoon, C, Worodria, W, Andama, A, Ayakaka, I, Nalwanga, PB, Byanyima, P, Kalema, N, Kaswabuli, S, Katagira, W, Aman, KD, Musisi, E, Tumwine, NW, Sanyu, I, Ssebunya, R, Davis, JL, Huang, L, Khan, IH & Cattamanchi, A 2018, 'Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV', PloS one, vol. 13, no. 10, e0206119. https://doi.org/10.1371/journal.pone.0206119
Farr, Katherine ; Ravindran, Resmi ; Strnad, Luke ; 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 Denise ; Musisi, Emmanuel ; Tumwine, Nuwagaba Wallen ; Sanyu, Ingvar ; Ssebunya, Robert ; Davis, J. Lucian ; Huang, Laurence ; Khan, Imran H. ; Cattamanchi, Adithya. / Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV. In: PloS one. 2018 ; Vol. 13, No. 10.
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abstract = "Background Approaches to screening for active tuberculosis (TB) among people living with HIV are inadequate, leading to missed diagnoses and poor implementation of preventive therapy. Methods Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between June 2011 and July 2013 with a cough 2 weeks were enrolled. Patients underwent extensive evaluation for pulmonary TB. Concentrations of 43 cytokines/chemokines were measured at the same time point as C-reactive protein (CRP) in banked plasma samples using commercially-available multiplex kits. Advanced classification algorithms were used to rank cytokines/chemokines for their ability to identify TB, and to model the specificityof the top-ranked cytokines/chemokines individually and in combination with sensitivity constrained to ? 90{\%} as recommended for TB screening. Results The median plasma level of 5 biomarkers (IL-6, INF-?, MIG, CRP, IL-18) was significantly different between patients with and without TB. With sensitivity constrained to 90{\%}, all had low specificity with IL-6 showing the highest specificity (44{\%}; 95{\%} CI 37.4-49.5). Biomarker panels were found to be more valuable than any biomarker alone. A panel combining IFN-? and IL-6 had the highest specificity (50{\%}; 95{\%} CI 46.7-53.3). Sensitivity remained high (>85{\%}) for all panels among sputum smear-negative TB patients. Conclusions Direct measurement of unstimulated plasma cytokines/chemokines in peripheral blood is a promising approach to TB screening. Cytokine/chemokine panels retained high sensitivity for smear-negative TB and achieved improved specificity compared to individual cytokines/chemokines. These markers should be further evaluated in outpatient settings where most TB screening occurs and where other illnesses associated with systematic inflammation are less common.",
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T1 - Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV

AU - Farr, Katherine

AU - Ravindran, Resmi

AU - Strnad, Luke

AU - Chang, Emily

AU - Chaisson, Lelia H.

AU - Yoon, Christina

AU - Worodria, William

AU - Andama, Alfred

AU - Ayakaka, Irene

AU - Nalwanga, Priscilla Bbosa

AU - Byanyima, Patrick

AU - Kalema, Nelson

AU - Kaswabuli, Sylvia

AU - Katagira, Winceslaus

AU - Aman, Kyomugisha Denise

AU - Musisi, Emmanuel

AU - Tumwine, Nuwagaba Wallen

AU - Sanyu, Ingvar

AU - Ssebunya, Robert

AU - Davis, J. Lucian

AU - Huang, Laurence

AU - Khan, Imran H.

AU - Cattamanchi, Adithya

PY - 2018/10/1

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N2 - Background Approaches to screening for active tuberculosis (TB) among people living with HIV are inadequate, leading to missed diagnoses and poor implementation of preventive therapy. Methods Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between June 2011 and July 2013 with a cough 2 weeks were enrolled. Patients underwent extensive evaluation for pulmonary TB. Concentrations of 43 cytokines/chemokines were measured at the same time point as C-reactive protein (CRP) in banked plasma samples using commercially-available multiplex kits. Advanced classification algorithms were used to rank cytokines/chemokines for their ability to identify TB, and to model the specificityof the top-ranked cytokines/chemokines individually and in combination with sensitivity constrained to ? 90% as recommended for TB screening. Results The median plasma level of 5 biomarkers (IL-6, INF-?, MIG, CRP, IL-18) was significantly different between patients with and without TB. With sensitivity constrained to 90%, all had low specificity with IL-6 showing the highest specificity (44%; 95% CI 37.4-49.5). Biomarker panels were found to be more valuable than any biomarker alone. A panel combining IFN-? and IL-6 had the highest specificity (50%; 95% CI 46.7-53.3). Sensitivity remained high (>85%) for all panels among sputum smear-negative TB patients. Conclusions Direct measurement of unstimulated plasma cytokines/chemokines in peripheral blood is a promising approach to TB screening. Cytokine/chemokine panels retained high sensitivity for smear-negative TB and achieved improved specificity compared to individual cytokines/chemokines. These markers should be further evaluated in outpatient settings where most TB screening occurs and where other illnesses associated with systematic inflammation are less common.

AB - Background Approaches to screening for active tuberculosis (TB) among people living with HIV are inadequate, leading to missed diagnoses and poor implementation of preventive therapy. Methods Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between June 2011 and July 2013 with a cough 2 weeks were enrolled. Patients underwent extensive evaluation for pulmonary TB. Concentrations of 43 cytokines/chemokines were measured at the same time point as C-reactive protein (CRP) in banked plasma samples using commercially-available multiplex kits. Advanced classification algorithms were used to rank cytokines/chemokines for their ability to identify TB, and to model the specificityof the top-ranked cytokines/chemokines individually and in combination with sensitivity constrained to ? 90% as recommended for TB screening. Results The median plasma level of 5 biomarkers (IL-6, INF-?, MIG, CRP, IL-18) was significantly different between patients with and without TB. With sensitivity constrained to 90%, all had low specificity with IL-6 showing the highest specificity (44%; 95% CI 37.4-49.5). Biomarker panels were found to be more valuable than any biomarker alone. A panel combining IFN-? and IL-6 had the highest specificity (50%; 95% CI 46.7-53.3). Sensitivity remained high (>85%) for all panels among sputum smear-negative TB patients. Conclusions Direct measurement of unstimulated plasma cytokines/chemokines in peripheral blood is a promising approach to TB screening. Cytokine/chemokine panels retained high sensitivity for smear-negative TB and achieved improved specificity compared to individual cytokines/chemokines. These markers should be further evaluated in outpatient settings where most TB screening occurs and where other illnesses associated with systematic inflammation are less common.

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