Elevated Plasma Matrix Metalloproteinases Are Associated With Mycobacterium tuberculosis Bloodstream Infection and Mortality in Human Immunodeficiency Virus-Associated Tuberculosis

Abstract

Mortality from human immunodeficiency virus (HIV)-associated tuberculosis (TB) is high, particularly among hospitalized patients. In 433 people with HIV hospitalized with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality, and Mycobacterium tuberculosis (Mtb) bloodstream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10, and PIIINP were associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB.

Keywords: HIV; biomarker; matrix degradation product; matrix metalloproteinase; mortality; procollagen III N-terminal propeptide; tuberculosis.

Figure 1.

Elevated matrix metalloproteinase-8 in human immunodeficiency virus (HIV)-associated tuberculosis (TB), Mycobacterium tuberculosis bloodstream infection (Mtb-BSI), and TB mortality. Plasma matrix metalloproteinase (MMP)-8 (A) and Col4α1 (B) were elevated in hospitalized participants with HIV infection and microbiologically confirmed TB, compared to hospitalized HIV-positive participants with symptoms due to other diagnoses (no TB). Differences between confirmed TB and TB diagnosed clinically were not statistically significant. Plasma MMP-8 was increased in participants with confirmed TB and Mtb-BSI compared to those without (C) and in those who had died compared to those who had survived at 12 weeks (D). Col4α1 was measured in a subset of 73 participants. *P < .05, **P < .01, ***P < .001.

Figure 2.

Plasma matrix metalloproteinase (MMP) and procollagen III N-terminal propeptide (PIIINP) are associated with Mycobacterium tuberculosis bloodstream infection (Mtb-BSI) and mortality in human immunodeficiency virus–associated tuberculosis. Probability (dependent variable, y-axis) of Mtb-BSI (A and C) and mortality (B and D) by analyte log concentration (predictor variable, x-axis). Loess fit to data (colored lines with shaded 95% confidence intervals [CI]) demonstrates the functional relationship, with measured concentrations shown as a jittered scatterplot at 0 (survived/no Mtb-BSI) or 1 (died/Mtb-BSI) on the y-axis. Odds ratios (OR) and 95% CIs are from logistic regression models, with adjustment for random effects by plate. In A and B, log MMP or PIIINP concentrations are in pg/mL. In C and D, log neutrophil count is ×10⁹/L and log procalcitonin concentration is in μg/L.