The potential of CBC-derived ratios (monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte) to predict or diagnose incident TB infection in Tanzanian adolescents

Christiaan A Rees, Dwan B Pineros, Maryam Amour, Patricia Munseri, Jamila Said, Albert Magohe, Mecky Matee, Kisali Pallangyo, C Fordham von Reyn, Christiaan A Rees, Dwan B Pineros, Maryam Amour, Patricia Munseri, Jamila Said, Albert Magohe, Mecky Matee, Kisali Pallangyo, C Fordham von Reyn

Abstract

Background: Ratios of different immune cell populations (i.e., monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte ratios) have been studied as a means of predicting future tuberculosis (TB) disease risk or to assist in the diagnosis of incident TB disease. No studies to-date, however, have evaluated the potential of these ratios to predict or assist in the diagnosis of incident TB infection - the first step in the natural history of TB disease.

Methods: In this prospective study, we evaluated the complete blood count (CBC)-derived metrics of monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) as predictors of future TB infection risk or aids in the diagnosis of TB infection among 145 Tanzanian adolescents enrolled in the DAR-901 vaccine trial, using paired CBCs and interferon-gamma release assays (IGRAs) obtained at 0, 60 and 720 days after study enrollment.

Results: At baseline, there were no significant differences between study participants who remained persistently IGRA negative throughout the study period and those who subsequently converted to IGRA positive with respect to MLR (0.18 vs 0.17, p = 0.10), NLR (0.88 vs 1.02, p = 0.08), or PLR (115 vs 120, p = 0.28). Similarly, no significant differences were noted with respect to MLR, NLR, and PLR between IGRA converters and time-matched negative controls at the time of IGRA conversion. With respect to other blood cell measures, however, there were modest but significant differences between IGRA negatives and IGRA converters with respect to red blood cell count (4.8 vs 4.6 × 106 cells/mcL, p = 0.008), hemoglobin (12.6 vs 12.3 g/dL, p = 0.01), and hematocrit (38.8 vs 37.8%, p = 0.005).

Conclusions: In contrast to prior studies that have suggested that the ratios of different immune cell populations are associated with development of TB disease, our present findings do not demonstrate an association between these ratios and the development of TB infection. However, decreased red blood cell measures were associated with the subsequent development of TB infection, suggesting either that dysregulation of iron metabolism may play a role in TB pathogenesis or that following TB infection, iron dysregulation may precede IGRA positivity.

Trial registration: Clinicaltrials.gov NCT02712424 . Date of registration: March 14, 2016.

Keywords: Complete blood count; Mycobacterium tuberculosis; Red blood cells; TB vaccine; Tuberculosis infection; White blood cells.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
ROC curves for baseline MLR (green), NLR (blue), and PLR (orange) in the comparison of IGRA converters and IGRA-negative participants. AUROC: area under the receiver operating characteristic curve; 95% CI: 95% confidence interval for AUROC; Sens: sensitivity; Spec: specificity

References

    1. Global tuberculosis report 2019. Geneva: World Health Organization; 2019:297. Available from: . Accessed 25 Apr 2020.
    1. Pai M, Denkinger CM, Kik SV, Rangaka MX, Zwerling A, Oxlade O, et al. Gamma interferon release assays for detection of mycobacterium tuberculosis infection. Clin Microbiol Rev. 2014;27(1):3–20.
    1. Sweeney TE, Braviak L, Tato CM, Khatri P. Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis. Lancet Respir Med. 2016;4(3):213–224.
    1. Warsinske HC, Rao AM, Moreira FMF, Santos PCP, Liu AB, Scott M, et al. Assessment of validity of a blood-based 3-gene signature score for progression and diagnosis of tuberculosis, disease severity, and treatment response. JAMA Netw Open. 2018;1(6):e183779.
    1. Naranbhai V, Kim S, Fletcher H, Cotton MF, Violari A, Mitchell C, et al. The association between the ratio of monocytes:lymphocytes at age 3 months and risk of tuberculosis (TB) in the first two years of life. BMC Med. 2014;12:120.
    1. Naranbhai V, Moodley D, Chipato T, Stranix-Chibanda L, Nakabaiito C, Kamateeka M, et al. The association between the ratio of monocytes: lymphocytes and risk of tuberculosis among HIV-infected postpartum women. J Acquir Immune Defic Syndr 1999. 2014;67(5):573–575.
    1. Naranbhai V, Hill AVS, Abdool Karim SS, Naidoo K, Abdool Karim Q, Warimwe GM, et al. 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(4):500–509.
    1. Choudhary RK, Wall KM, Njuguna I, Pavlinac PB, LaCourse SM, Otieno V, et al. Monocyte-to-Lymphocyte Ratio Is Associated With Tuberculosis Disease and Declines With Anti-TB Treatment in HIV-Infected Children. J Acquir Immune Defic Syndr 1999. 2019;80(2):174–181.
    1. La Manna MP, Orlando V, Dieli F, Di Carlo P, Cascio A, Cuzzi G, et al. Quantitative and qualitative profiles of circulating monocytes may help identifying tuberculosis infection and disease stages. PLoS One. 2017;12(2):e0171358.
    1. Wang J, Yin Y, Wang X, Pei H, Kuai S, Gu L, et al. Ratio of monocytes to lymphocytes in peripheral blood in patients diagnosed with active tuberculosis. Braz J Infect Dis Off Publ Braz Soc Infect Dis. 2015;19(2):125–131.
    1. Amalia R, Turbawaty DK, Sugianli AK, Aminah S. Monocyte to lymphocyte ratio in peripheral blood of Tuberculous meningitis with HIV patients in tertiary Hospital in West Java. Int J Integr Health Sci. 2018;6(1):42–47.
    1. Agarwal A, Bhat MS, Kumar A, Shaharyar A, Mishra M, Yadav R. Lymphocyte/monocyte ratio in osteoarticular tuberculosis in children: a haematological biomarker revisited. Trop Dr. 2016;46(2):73–77.
    1. von Reyn CF, Lahey T, Arbeit RD, Landry B, Kailani L, Adams LV, et al. Safety and immunogenicity of an inactivated whole cell tuberculosis vaccine booster in adults primed with BCG: a randomized, controlled trial of DAR-901. PLoS One. 2017;12(5):e0175215.
    1. von Reyn CF, Mtei L, Arbeit RD, Waddell R, Cole B, Mackenzie T, et al. Prevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine. AIDS Lond Engl. 2010;24(5):675–685.
    1. Miyahara R, Piyaworawong S, Naranbhai V, Prachamat P, Kriengwatanapong P, Tsuchiya N, et al. Predicting the risk of pulmonary tuberculosis based on the neutrophil-to-lymphocyte ratio at TB screening in HIV-infected individuals. BMC Infect Dis. 2019;19(1):667.
    1. Yin Y, Kuai S, Liu J, Zhang Y, Shan Z, Gu L, et al. Pretreatment neutrophil-to-lymphocyte ratio in peripheral blood was associated with pulmonary tuberculosis retreatment. Arch Med Sci AMS. 2017;13(2):404–411.
    1. Han Y, Kim SJ, Lee SH, Sim YS, Ryu YJ, Chang JH, et al. High blood neutrophil-lymphocyte ratio associated with poor outcomes in miliary tuberculosis. J Thorac Dis. 2018;10(1):339–346.
    1. Yoon N-B, Son C, Um S-J. Role of the neutrophil-lymphocyte count ratio in the differential diagnosis between pulmonary tuberculosis and bacterial community-acquired pneumonia. Ann Lab Med. 2013;33(2):105–110.
    1. Berhane M, Melku M, Amsalu A, Enawgaw B, Getaneh Z, Asrie F. The role of neutrophil to lymphocyte count ratio in the differential diagnosis of pulmonary tuberculosis and bacterial community-acquired pneumonia: a cross-sectional study at Ayder and Mekelle hospitals, Ethiopia. Clin Lab. 2019;65(4). 10.7754/Clin.Lab.2018.180833.
    1. Iliaz S, Iliaz R, Ortakoylu G, Bahadir A, Bagci BA, Caglar E. Value of neutrophil/lymphocyte ratio in the differential diagnosis of sarcoidosis and tuberculosis. Ann Thorac Med. 2014;9(4):232–235.
    1. Abakay O, Abakay A, Sen HS, Tanrikulu AC. The relationship between inflammatory marker levels and pulmonary tuberculosis severity. Inflammation. 2015;38(2):691–696.
    1. Chen G, Wu C, Luo Z, Teng Y, Mao S. Platelet–lymphocyte ratios: a potential marker for pulmonary tuberculosis diagnosis in COPD patients. Int J Chron Obstruct Pulmon Dis. 2016;11:2737–2740.
    1. Ozdemir C, Sökücü SN, Önür ST. Can neutrophil/lymphocyte ratio and platelet/lymphocyte ratio be used in differential diagnosis of stage I sarcoidosis from tuberculosis lymphadenopathy? Eurasian J Pulmonol. 2018;20(1):22.
    1. Jeon YL, Lee W-I, Kang SY, Kim MH. Neutrophil-to-monocyte-plus-lymphocyte ratio as a potential marker for discriminating pulmonary tuberculosis from nontuberculosis infectious lung diseases. Lab Med. 2019;50(3):286–291.
    1. He Q, Tang W, Deng Y, He Y, Xie L, Qin X, et al. The diagnostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in tuberculous spondylitis. 2016.
    1. Bilen MA, Martini DJ, Liu Y, Lewis C, Collins HH, Shabto JM, et al. The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy. Cancer. 2019;125(1):127–134.
    1. Xiang J, Zhou L, Li X, Bao W, Chen T, Xi X, et al. Preoperative monocyte-to-lymphocyte ratio in peripheral blood predicts stages, metastasis, and histological grades in patients with ovarian Cancer. Transl Oncol. 2017;10(1):33–39.
    1. Song X, Chen D, Yuan M, Wang H, Wang Z. Total lymphocyte count, neutrophil–lymphocyte ratio, and platelet–lymphocyte ratio as prognostic factors in advanced non–small cell lung cancer with chemoradiotherapy. Cancer Manag Res. 2018;10:6677–6683.
    1. Shi L, Qin X, Wang H, Xia Y, Li Y, Chen X, et al. Elevated neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio and decreased platelet-to-lymphocyte ratio are associated with poor prognosis in multiple myeloma. Oncotarget. 2016;8(12):18792–18801.
    1. Kang MH, Go S-I, Song H-N, Lee A, Kim S-H, Kang J-H, et al. The prognostic impact of the neutrophil-to-lymphocyte ratio in patients with small-cell lung cancer. Br J Cancer. 2014;111(3):452–460.
    1. Naess A, Nilssen SS, Mo R, Eide GE, Sjursen H. Role of neutrophil to lymphocyte and monocyte to lymphocyte ratios in the diagnosis of bacterial infection in patients with fever. Infection. 2017;45(3):299–307.
    1. Yue S, Zhang J, Wu J, Teng W, Liu L, Chen L. Use of the monocyte-to-lymphocyte ratio to predict diabetic retinopathy. Int J Environ Res Public Health. 2015;12(8):10009–10019.
    1. Djordjevic D, Rondovic G, Surbatovic M, Stanojevic I, Udovicic I, Andjelic T, et al. Neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and mean platelet volume-to-platelet count ratio as biomarkers in critically ill and injured patients: which ratio to choose to predict outcome and nature of bacteremia? Mediat Inflamm. 2018;2018:3758068.
    1. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32–35.
    1. Panteleev AV, Nikitina IY, Burmistrova IA, Kosmiadi GA, Radaeva TV, Amansahedov RB, et al. Severe Tuberculosis in Humans Correlates Best with Neutrophil Abundance and Lymphocyte Deficiency and Does Not Correlate with Antigen-Specific CD4 T-Cell Response. Front Immunol. 2017;8 Available from: . Cited 2020 Feb 27.
    1. Koethe JR, von Reyn CF. Protein-calorie malnutrition, macronutrient supplements, and tuberculosis. Int Union Tuberc Lung Dis. 2016; Available from: . Cited 2020 Apr 9.
    1. Minchella PA, Donkor S, Owolabi O, Sutherland JS, McDermid JM. Complex Anemia in tuberculosis: the need to consider causes and timing when designing interventions. Clin Infect Dis. 2015;60(5):764–772.
    1. McDermid JM, Hennig BJ, van der Sande M, Hill AVS, Whittle HC, Jaye A, et al. Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11-year retrospective cohort study. BMC Infect Dis. 2013;13:48.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel