Abstract Rationale Tuberculosis is the most prevalent infectious disease in the world and is a leading cause of mortality worldwide. We recently described the Human Immune Dysregulation Evaluation Framework (Hi-DEF), which quantifies myeloid and lymphoid dysregulation associated with disease severity and differential responses to immunomodulatory treatments in sepsis and critical illnesses (Moore et al, Nature Medicine). Given prior research linking T-cell exhaustion with worse outcomes in TB, we investigated whether the cell-specific immune dysregulation quantified by Hi-DEF is associated with worse outcomes in patients with TB. Methods We calculated myeloid and lymphoid dysregulation scores for all subjects in a German n = 121) using blood samples collected at baseline. We applied the Wilcoxon rank-sum test to determine whether myeloid or lymphoid dysregulation scores were associated with microbiologic treatment success. We also assessed the Pearson correlations between the Hi-DEF scores and time to culture conversion. Myeloid and/or lymphoid dysregulation was defined based on an a priori cut-off using median dysregulation scores. Association of dysregulation with treatment outcomes were assessed using Fisher’s Exact Test. Results In the Borstel cohort, patients with unfavorable outcomes (microbiologic failure or death; n = 12) had significantly higher lymphoid (p = 0.026) dysregulation scores, but not myeloid (p = 0.065) dysregulation scores, than those with favorable outcomes (n = 51) (Fig 1A,B). Lymphoid dysregulation score was significantly correlated with increased time to culture conversion (r = 0.31, p = 0.006) (Fig 1C). Patients with lymphoid dysregulation had significantly higher odds of unfavorable outcomes compared to those with balanced lymphoid responses (OR = 6.93, 95% CI: 1.01-157.85, p = 0.048; Fig 1D,E). Notably, all patients who died had both lymphoid and concomitant myeloid dysregulation (Fig 1D). Conclusion Increased lymphoid dysregulation as defined by Hi-DEF is associated with higher risk of unfavorable outcomes in patients with TB. With further refinement, measurement of cell-specific immune dysregulation could allow for more precision-medicine approaches to diagnosis and treatment of this complex, heterogeneous disease. This abstract is funded by: NIAID
Mccann et al. (Fri,) studied this question.