Ratio of monocytes to lymphocytes in peripheral blood identifies adults at risk of incident tuberculosis among HIV-infected adults initiating antiretroviral therapy
Vivek Naranbhai, Adrian V S Hill, Salim S Abdool Karim, Kogieleum Naidoo, Quarraisha Abdool Karim, George M Warimwe, Helen McShane, Helen Fletcher, Vivek Naranbhai, Adrian V S Hill, Salim S Abdool Karim, Kogieleum Naidoo, Quarraisha Abdool Karim, George M Warimwe, Helen McShane, Helen Fletcher
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
References
- Cohen T, Murray M, Wallengren K, Alvarez GG, Samuel EY, Wilson D. The prevalence and drug sensitivity of tuberculosis among patients dying in hospital in KwaZulu-Natal, South Africa: a postmortem study. PLoS Med. 2010;7:e1000296.
- Cox JA, Lukande RL, Lucas S, Nelson AM, Van Marck E, Colebunders R. Autopsy causes of death in HIV-positive individuals in sub-Saharan Africa and correlation with clinical diagnoses. AIDS Rev. 2010;12:183–94.
- Rana FS, Hawken MP, Mwachari C, et al. Autopsy study of HIV-1-positive and HIV-1-negative adult medical patients in Nairobi, Kenya. J Acquir Immune Defic Syndr. 2000;24:23–9.
- Walzl G, Ronacher K, Hanekom W, Scriba TJ, Zumla A. Immunological biomarkers of tuberculosis. Nat Rev Immunol. 2011;11:343–54.
- Lawn SD, Zumla AI. Tuberculosis. Lancet. 2011;378:57–72.
- Rangaka MX, Wilkinson KA, Glynn JR, et al. Predictive value of interferon-gamma release assays for incident active tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12:45–55.
- Samandari T, Agizew TB, Nyirenda S, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377:1588–98.
- Lawn SD, Wood R, De Cock KM, Kranzer K, Lewis JJ, Churchyard GJ. Antiretrovirals and isoniazid preventive therapy in the prevention of HIV-associated tuberculosis in settings with limited health-care resources. Lancet Infect Dis. 2010;10:489–98.
- Madhi SA, Nachman S, Violari A, et al. Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med. 2011;365:21–31.
- Berry MP, Graham CM, McNab FW, et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature. 2010;466:973–7.
- Maertzdorf J, Repsilber D, Parida SK, et al. Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes Immun. 2011;12:15–22.
- Cunningham RS, Sabin FR, Sugiyama S, Kindwall JA. The role of the monocyte in tuberculosis. Bull Johns Hopkins Hosp. 1925;XXXVII:231–80.
- Sabin FR, Doan CA, Cunningham RS. Studies of the blood in experimental tuberculosis: the monocyte-lymphocyte ratio; the anemia-leucopenia phase. Trans 22nd Annu Meeting Natl Tuberc Assoc; 1926. pp. 252–6.
- Rogers PM. A study of the blood monocytes in children with tuberculosis. N Engl J Med. 1928;198:740–49.
- Doan CA, Sabin FR. The relation of the tubercle and the monocyte:lymphocte ratio to resistance and susceptibility in tuberculosis. J Exp Med. 1930;52:113–52.
- Naranbhai V, Abdool Karim Q, Naidoo K, Yende Zuma N, Abdool Karim SS. Task-shifting for antiretroviral treatment is not only effective but also sustainable and improves over time. Lancet. 2012;380:1907–8.
- Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329:1168–74.
- Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010;362:697–706.
- van Loggerenberg F, Mlisana K, Williamson C, et al. Establishing a cohort at high risk of HIV infection in South Africa: challenges and experiences of the CAPRISA 002 acute infection study. PLoS One. 2008;3:e1954.
- Republic of South Africa Department of Health of South Africa, Pretoria, South Africa. South African National Antiretroviral Treatment Guidelines. 2004.
- Republic of South Africa Department of Health of South Africa, Pretoria, South Africa. South African National Tuberculosis Management Guidelines. 2009.
- Republic of South Africa Department of Health of South Africa, Pretoria, South Africa. South African National Antiretroviral Treatment Guidelines. 2010.
- Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365:1492–501.
- Lawn SD, Badri M, Wood R. Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort. AIDS. 2005;19:2109–16.
- Dembele M, Saleri N, Carvalho AC, et al. Incidence of tuberculosis after HAART initiation in a cohort of HIV-positive patients in Burkina Faso. Int J Tuberc Lung Dis. 2010;14:318–23.
- Seyler C, Toure S, Messou E, Bonard D, Gabillard D, Anglaret X. Risk factors for active tuberculosis after antiretroviral treatment initiation in Abidjan. Am J Respir Crit Care Med. 2005;172:123–7.
- Carpenter E, Fray L, Gormley E. Cellular responses and Mycobacterium bovis BCG growth inhibition by bovine lymphocytes. Immunol Cell Biol. 1997;75:554–60.
- 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.
- Tobin DM, Roca FJ, Oh SF, et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell. 2012;148:434–46.
- Casadevall A, Pirofski LA. The damage-response framework of microbial pathogenesis. Nat Rev Microbiol. 2003;1:17–24.
- Merekoulias G, Alexopoulos EC, Belezos T, Panagiotopoulou E, Jelastopulu DM. Lymphocyte to monocyte ratio as a screening tool for influenza. PLoS Curr. 2010;2:RRN1154.
- Muller-Sieburg CE, Cho RH, Thoman M, Adkins B, Sieburg HB. Deterministic regulation of hematopoietic stem cell self-renewal and differentiation. Blood. 2002;100:1302–9.
- Pang WW, Price EA, Sahoo D, et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A. 2011;108:20012–7.
- Schroeder T. Hematopoietic stem cell heterogeneity: subtypes, not unpredictable behavior. Cell Stem Cell. 2010;6:203–7.
- Muller-Sieburg CE, Sieburg HB, Bernitz JM, Cattarossi G. Stem cell heterogeneity: implications for aging and regenerative medicine. Blood. 2012;119:3900–7.
- Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature. 2010;465:793–7.
- Das B, Kashino SS, Pulu I, et al. CD271+ bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl Med. 2013;5 170ra13-ra13.
- Gideon HP, Flynn JL. Latent tuberculosis: what the host “sees”? Immunol Res. 2011;50:202–12.
- Kato K. Effect of tuberculin test on monocyte-lymphocyte ratio in children. J Pediatr. 1935;7:238–44.
- Warimwe GM, Murungi LM, Kamuyu G, et al. The ratio of monocytes to lymphocytes in peripheral blood correlates with increased susceptibility to clinical malaria in Kenyan children. PLoS One. 2013;8:e57320.
Source: PubMed