A whole-blood transcriptional signature associated with obstructive post-tuberculosis lung disease.

BACKGROUND

Post-tuberculosis (TB) lung disease (PTLD) affects approximately 50% of persons with pulmonary TB. We recently discovered whole blood transcriptional signatures associated with PTLD. We examined whether a minimum gene signature predicts PTLD as a clinically useful biomarker.

METHODS

We prospectively enrolled 301 treatment naïve adults with newly diagnosed pulmonary TB (PTB) (cohort A). We collected whole blood at 0 and 6-month visits, isolated RNA, and measured a modified MTB Host Response (HR) signature (mHR) based on expression of DUSP3, GBP5, and TMBIM6. We recorded spirometry at 6 (n=216) and 12 months (n=210) after treatment initiation and examined the association of the mHR score with PTLD and Mtb aerosolization. We recruited household contacts of cohort A to compare mHR score with non-PTB participants (cohort B).

FINDINGS: mHR was associated with TB (p=4.15e-66) when compared to HHCs, treatment response (p=1.07e-53), and characteristics including CD4 count (p=0.003), bacillary load (p=3.02e-05), lung cavities (p=1.59e-04), and lung quadrants involved (p=3.87e-06). The mHR score was not associated with Mtb aerosolization. In total, 105 (50%) participants had PTLD at 12 months including 61 with restriction, 26 with obstruction, and 18 with mixed obstruction and restriction. Baseline mHR was associated with obstructive PTLD at both 6 (p=0.003) and 12 months (p=0.012) in bivariate and multivariate analyses. The mHR score was not associated with restrictive lung disease.

INTERPRETATION: Baseline mHR was associated with obstructive PTLD at 6 and 12 months and may have applications in targeting treatment and prognostication.