Abstract

BackgroundRecent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Recent data confirmed the hypothesis in cattle and in adults infected with HIV.MethodsWe tested this hypothesis in 1,336 infants (540 HIV-infected, 796 HIV-exposed, uninfected (HEU)) prospectively followed in a randomized controlled trial of isoniazid prophylaxis in Southern Africa, the IMPAACT P1041 study. We modeled the relationship between ML ratio at enrollment (91 to 120 days after birth) and TB disease or death in HIV-infected children and latent Mycobacterium tuberculosis (MTB) infection, TB disease or death in HEU children within 96 weeks (with 12 week window) of randomization. Infants were followed-up prospectively and routinely assessed for MTB exposure and outcomes. Cox proportional hazards models allowing for non-linear associations were used; in all cases linear models were the most parsimonious.ResultsIncreasing ML ratio at baseline was significantly associated with TB disease/death within two years (adjusted hazard ratio (HR) 1.17 per unit increase in ML ratio; 95% confidence interval (CI) 1.01 to 1.34; P = 0.03). Neither monocyte count nor lymphocyte counts alone were associated with TB disease. The association was not statistically dissimilar between HIV infected and HEU children. Baseline ML ratio was associated with composite endpoints of TB disease and death and/or TB infection. It was strongest when restricted to probable and definite TB disease (HR 1.50; 95% CI 1.19 to 1.89; P = 0.006). Therefore, per 0.1 unit increase in the ML ratio at three to four months of age, the hazard of probable or definite TB disease before two years was increased by roughly 4% (95% CI 1.7% to 6.6%).ConclusionElevated ML ratio at three- to four-months old is associated with increased hazards of TB disease before two years among children in Southern Africa. While significant, the modest effect size suggests that the ML ratio plays a modest role in predicting TB disease-free survival; its utility may, therefore, be limited to combination with existing tools to stratify TB risk, or to inform underlying pathophysiologic determinants of TB disease.

Highlights

  • Recent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease

  • We recently reported that the ratio of monocytes: lymphocytes (ML) in HIV-infected South African adults prior to combination antiretroviral therapy initiation was predictive of TB disease during the subsequent five years on cART [12]

  • We found that the ML ratio in peripheral blood at around three months of age was associated with TB disease or Mycobacterium tuberculosis (MTB) infection-free survival in South African children, notwithstanding conventional risk factors

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Summary

Introduction

Recent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Mycobacterium tuberculosis (MTB) infects about 2 billion people, causing 10 million active cases, of whom about 500,000 cases are children [1]. It is a leading cause of death in sub-Saharan Africa, yet practical methods to stratify risk in this population are lacking [2,3]. The current tools to identify children with MTB infection are tuberculin skin testing (TST) or interferongamma release assay (IGRA). Isoniazid (INH) preventive therapy (IPT) is more effective in HIV-infected individuals with a positive TST result [4], neither TST nor IGRA are sufficiently good at predicting TB disease. Predictors of TB may offer new insight into pathogenesis

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