Plasma Profiles of Inflammatory Markers Associated With Active Tuberculosis in Antiretroviral Therapy-Naive Human Immunodeficiency Virus-Positive Individuals

Abstract

Background: Diagnosis of tuberculosis (TB) in human immunodeficiency virus (HIV)-coinfected individuals is challenging. We hypothesized that combinations of inflammatory markers could facilitate identification of active TB in HIV-positive individuals.

Methods: Participants were HIV-positive, treatment-naive adults systematically investigated for TB at Ethiopian health centers. Plasma samples from 130 subjects with TB (HIV⁺/TB⁺) and 130 subjects without TB (HIV⁺/TB^-) were tested for concentration of the following markers: CCL5, C-reactive protein (CRP), interleukin (IL)-6, IL12-p70, IL-18, IL-27, interferon-γ-induced protein-10 (IP-10), procalcitonin (PCT), and soluble urokinase-type plasminogen activator receptor (suPAR). Analyzed markers were then assessed, either individually or in combination, with regard to infection status, CD4 cell count, and HIV ribonucleic acid (RNA) levels.

Results: The HIV⁺/TB⁺ subjects had higher levels of all markers, except IL12p70, compared with HIV⁺/TB^- subjects. The CRP showed the best performance for TB identification (median 27.9 vs 1.8 mg/L for HIV⁺/TB⁺ and HIV⁺/TB^-, respectively; area under the curve [AUC]: 0.80). Performance was increased when CRP was combined with suPAR analysis (AUC, 0.83 [0.93 for subjects with CD4 cell count <200 cells/mm³]). Irrespective of TB status, IP-10 concentrations correlated with HIV RNA levels, and both IP-10 and IL-18 were inversely correlated to CD4 cell counts.

Conclusions: Although CRP showed the best single marker discriminatory potential, combining CRP and suPAR analyses increased performance for TB identification.

Keywords: CRP; HIV; Mycobacterium tuberculosis; biomarker; sub-Saharan Africa.

Figure 1.

Levels of 9 markers of inflammation in plasma from 130 human immunodeficiency virus (HIV)⁺/tuberculosis (TB)⁺ and 130 HIV⁺TB⁻ subjects. Boxes represent median and interquartile range. Whiskers have been graphically cut for soluble urokinase-type plasminogen activator receptor (suPAR), interleukin (IL)-6, and procalcitonin (PCT). Mann-Whitney U test P values are indicated in each graph. All markers remained significantly associated with TB after Holm-Bonferroni correction, except IL-12p70. For IL-12p70 and IL-27, the graphs represent mean fluorescence intensity (MFI) due to unreliable conversions to concentrations.

Figure 2.

C-reactive protein levels (mg/L) subjects with human immunodeficiency virus and tuberculosis coinfection, note that the highest detectable level in our assay was 50 mg/L.

Figure 3.

(A) Receiver operating characteristics (ROC) curves for C-reactive protein (CRP) (area under the curve [AUC], 0.80; 95% confidence interval [CI], 0.75–0.86), soluble urokinase-type plasminogen activator receptor (suPAR) (AUC, 0.77; 95% CI, 0.71–0.83), interleukin (IL)-6 (AUC, 0.76; 95% CI, 0.71–0.82), and IL-18 (AUC, 0.71; 95% CI, 0.65–0.78). (B) The ROC curve for the combination of CRP and suPAR in all subjects (n = 260; AUC, 0.83; 95% CI, 0.78–0.88). (C) The ROC curve for the combination of CRP and suPAR in subjects with CD4 cell count <200 cells/mm³ (n = 132; AUC, 0.93; 95% CI, 0.89–0.97).