Ratio of monocytes to lymphocytes in peripheral blood identifies adults at risk of incident tuberculosis among HIV-infected adults initiating antiretroviral therapy

Abstract

Background: Eight decades ago, the ratio of monocytes to lymphocytes (hereafter, the "ML ratio") was noted to affect outcomes of mycobacterial infection in rabbits. Recent transcriptomic studies support a role for relative proportions of myeloid and lymphoid transcripts in tuberculosis outcomes. The ML ratio in peripheral blood is known to be governed by hematopoietic stem cells with distinct biases.

Methods: The predictive value of the baseline ML ratio was modeled in 2 prospective cohorts of HIV-infected adults starting cART in South Africa (primary cohort, 1862 participants; replication cohort, 345 participants). Incident tuberculosis was diagnosed with clinical, radiographic, and microbiologic methods per contemporary guidelines. Kaplan-Meier survival analyses and Cox proportional hazards modeling were conducted.

Results: The incidence rate of tuberculosis differed significantly by baseline ML ratio: 32.61 (95% confidence interval [CI], 15.38-61.54), 16.36 (95% CI, 12.39-21.23), and 51.80 (95% CI, 23.10-101.71) per 1000 patient-years for ML ratios of less than the 5th percentile, between the 5th and 95th percentiles, and greater than the 95th percentile, respectively (P = .007). Neither monocyte counts nor lymphocyte counts alone were associated with tuberculosis. After adjustment for sex, World Health Organization human immunodeficiency virus disease stage, CD4(+) T-cell counts, and previous history of tuberculosis, hazards of disease were significantly higher for patients with ML ratios of less than the 5th percentile or greater than the 95th percentile (adjusted hazard ratio, 2.47; 95% CI, 1.39-4.40; P = .002).

Conclusions: The ML ratio may be a useful, readily available tool to stratify the risk of tuberculosis and suggests involvement of hematopoietic stem cell bias in tuberculosis pathogenesis.

Keywords: HIV; ML ratio; combination antiretroviral therapy; lymphocytes; monocytes; tuberculosis.

Figures

Figure 1.

Kaplan-Meier estimates of probability of tuberculosis-free survival for individuals commencing combination antiretroviral therapy (cART), by category of baseline ratio of monocytes to lymphocytes (ML ratio; A). Bootstrapped hazard ratio (HR) estimates of tuberculosis across the ML ratio continuum (B). HRs are adjusted for age, World Health Organization human immunodeficiency virus infection and disease stage, and past history of tuberculosis. Each dot denotes 1 estimate, with the locally weighted scatterplot smoothing curve overplotted.

Figure 2.

Ratios of monocytes to lymphocytes (ML ratios), monocyte counts, and lymphocyte counts among healthy human immunodeficiency virus–uninfected woman. A, The correlation between the ML ratio at enrollment and 3, 12, and 24 months after enrollment among 790 participants. Results of Spearman rank correlation are shown as rho and P values in the top right of each correlation plot. B, The overall stability of ML ratios in healthy individuals, shown as box plots at each time point. The dotted horizontal lines denote the overall population 5th and 95th percentiles. Boxes show the 25th, 50th (median), and 75th percentiles, whiskers denote the 25th percentile – [1.5 × interquartile range] and the 75th percentile + [1.5 × interquartile range], and outliers are plotted as dots. C, ML ratios may be abnormal even if the monocyte or lymphocyte counts are normal. Monocyte and lymphocyte counts are plotted on the x-axes and y-axes, respectively. Colors of data points denote the corresponding category of the ML ratio (5th–95th percentiles, >95th percentile, and < 5th percentile). Dotted horizontal lines denote the 5th and 95th percentiles for lymphocyte counts. Dotted vertical lines denote the 5th and 95th percentiles for monocyte counts. Abbreviation: NS, not significant.

Figure 3.

The impact of human immunodeficiency virus (HIV) acquisition and disease progression on ratios of monocytes to lymphocytes (ML ratios). A, The ML ratio is stable before infection among 160 women who acquired HIV but is significantly increased by HIV acquisition. Boxes show the 25th, 50th (median), and 75th percentiles, whiskers denote the 25th percentile – [1.5 × interquartile range] and the 75th percentile + [1.5 × interquartile range], and outliers are plotted as dots. B, The distribution of ML ratios is broadened by HIV acquisition. C, ML ratios over the course of HIV acquisition are variable but increase overall. Data are shown as a scatterplot showing all ML measures over time among HIV acquirers. The black line is a smoothed curve computed by locally weighted scatterplot smoothing. Horizontal lines denote the 5th and 95th percentile for ML ratios in HIV-uninfected healthy individuals in red and blue, respectively. D, ML ratios over the course of HIV infection increase significantly with disease progression. Boxes show the 25th, 50th (median), and 75th percentiles, whiskers denote the 25th percentile – [1.5 × interquartile range] and the 75th percentile + [1.5 × interquartile range], and outliers are plotted as dots. Horizontal lines denote the 5th and 95th percentile for ML ratios in HIV-uninfected healthy individuals in red and blue, respectively.

Figure 4.

The impact of combination antiretroviral therapy (cART) on the ratio of monocytes to lymphocytes (ML ratio). A, The ML ratio is reduced significantly over the first 2 years of cART and stabilizes within the normal range for human immunodeficiency virus (HIV)–uninfected individuals until up to 7 years after cART commencement. Box plots show the ML ratio before and during 7 years of cART. Boxes show the 25th, 50th (median), and 75th percentiles, whiskers denote the 25th percentile – [1.5 × interquartile range] and the 75th percentile + [1.5 × interquartile range], and outliers are plotted as dots. Horizontal lines denote the 5th and 95th percentile for ML ratios in HIV-uninfected healthy individuals in red and blue, respectively. B, The distribution of ML ratios becomes narrower over time.