The association between the ratio of monocytes:lymphocytes at age 3 months and risk of tuberculosis (TB) in the first two years of life

Vivek Naranbhai, Soyeon Kim, Helen Fletcher, Mark F Cotton, Avy Violari, Charles Mitchell, Sharon Nachman, George McSherry, Helen McShane, Adrian V S Hill, Shabir A Madhi, Vivek Naranbhai, Soyeon Kim, Helen Fletcher, Mark F Cotton, Avy Violari, Charles Mitchell, Sharon Nachman, George McSherry, Helen McShane, Adrian V S Hill, Shabir A Madhi

Abstract

Background: 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. Recent data confirmed the hypothesis in cattle and in adults infected with HIV.

Methods: We 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.

Results: Increasing 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%).

Conclusion: Elevated 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.

Figures

Figure 1
Figure 1
Distribution of monocyte:lymphocyte (ML) ratio at enrollment shown for HEU (n = 796, dashed line) and HIV-positive infants (n = 540, solid line).

References

    1. Lawn SD, Zumla AI. Tuberculosis. Lancet. 2011;378:57–72. doi: 10.1016/S0140-6736(10)62173-3.
    1. Walzl G, Ronacher K, Hanekom W, Scriba TJ, Zumla A. Immunological biomarkers of tuberculosis. Nat Rev Immunol. 2011;11:343–354. doi: 10.1038/nri2960.
    1. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D, Mwansa-Kambafwile J, Fielding K, Wilkinson RJ, Pai M. Predictive value of interferon-gamma release assays for incident active tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12:45–55. doi: 10.1016/S1473-3099(11)70210-9.
    1. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev. 2010;1
    1. WHO: Guidance for national tuberculosis programmes on the management of tuberculosis in children –2nd ed. 2014.
    1. Fletcher H. Correlates of risk of TB disease in infants vaccinated with BCG. Keystone Symposia: Host Response in Tuberculosis (X7) 2013.
    1. Cunningham RS, Sabin FR, Sugiyama S, Kindwall JA. The role of the monocyte in tuberculosis. Bull Johns Hopkins Hosp. 1925;XXXVII:231–280.
    1. Sabin FR, Doan CA, Cunningham RS: Studies of the blood in experimental tuberculosis: the monocyte-lymphocyte ratio; the anemia-leucopenia phase.Transactions of the 22nd Annual Meeting of the National Tuberculosis Association 1926, 252–256.
    1. Doan CA, Sabin FR. The relation of the tubercle and the monocyte:lymphocte ratio to resistance and susceptibility in tuberculosis. J Exp Med. 1930;52:113–152. doi: 10.1084/jem.52.90063.113.
    1. Carpenter E, Fray L, Gormley E. Cellular responses and Mycobacterium bovis BCG growth inhibition by bovine lymphocytes. Immunol Cell Biol. 1997;75:554–560. doi: 10.1038/icb.1997.86.
    1. Denis M, Wedlock DN, Buddle BM. Ability of T cell subsets and their soluble mediators to modulate the replication of Mycobacterium bovis in bovine macrophages. Cell Immunol. 2004;232:1–8. doi: 10.1016/j.cellimm.2005.01.003.
    1. Naranbhai V, Hill AV, Abdool Karim SS, Naidoo K, Abdool Karim Q, Warimwe GM, McShane H, Fletcher H. Ratio of monocytes to lymphocytes in peripheral blood identifies adults at risk of incident tuberculosis among HIV-infected adults initiating antiretroviral therapy. J Infect Dis. 2014;209:500–509. doi: 10.1093/infdis/jit494.
    1. Rogers PM. A study of the blood monocytes in children with tuberculosis. N Engl J Med. 1928;198:740–749. doi: 10.1056/NEJM192805241981410.
    1. Madhi SA, Nachman S, Violari A, Kim S, Cotton MF, Bobat R, Jean-Philippe P, McSherry G, Mitchell C. Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med. 2011;365:21–31. doi: 10.1056/NEJMoa1011214.
    1. The South African National Tuberculosis Control Programme: Practical guidelines: The South African National Tuberculosis Control Programme: Practical guidelines. 2004. Pretoria, South Africa.
    1. Royston P, Sauerbrei W. A new approach to modelling interactions between treatment and continuous covariates in clinical trials by using fractional polynomials. Stat Med. 2004;23:2509–2525. doi: 10.1002/sim.1815.
    1. Royston P, Ambler G, Sauerbrei W. The use of fractional polynomials to model continuous risk variables in epidemiology. Int J Epidemiol. 1999;28:964–974. doi: 10.1093/ije/28.5.964.
    1. Naranbhai V, Hill AV, Abdool Karim SS, Naidoo K, Abdool Karim Q, Warimwe GM, McShane H, Fletcher H. Blood monocyte – lymphocyte ratios identify adults at risk of incident tuberculosis amongst patients initiating antiretroviral therapy. J Infect Dis. 2014;209:500–509. doi: 10.1093/infdis/jit494.
    1. Warimwe GM, Murungi LM, Kamuyu G, Nyangweso GM, Wambua J, Naranbhai V, Fletcher HA, Hill AV, Bejon P, Osier FH, Marsh K. The ratio of monocytes to lymphocytes in peripheral blood correlates with increased susceptibility to clinical malaria in Kenyan children. PLoS One. 2013;8:e57320. doi: 10.1371/journal.pone.0057320.
    1. Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, Schrier SL, Weissman IL. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A. 2011;108:20012–20017. doi: 10.1073/pnas.1116110108.
    1. Muller-Sieburg CE, Sieburg HB, Bernitz JM, Cattarossi G. Stem cell heterogeneity: implications for aging and regenerative medicine. Blood. 2012;119:3900–3907. doi: 10.1182/blood-2011-12-376749.
    1. Coleman CM, Wu L. HIV interactions with monocytes and dendritic cells: viral latency and reservoirs. Retrovirology. 2009;6:51. doi: 10.1186/1742-4690-6-51.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren