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. 2026 Feb 25;26:695. doi: 10.1186/s12879-026-12803-y

Utility of CBC-derived ratios in the diagnosis and prediction of active tuberculosis in people with rheumatic diseases

Fengying Wu 1, Xiaochun Shi 1,2, Yuanchun Li 1, Lantian Xie 1, Yuchen Liu 1, Ye Liu 1, Lifan Zhang 1,2,3, Xiaoqing Liu 1,2,3,4,✉
PMCID: PMC13041332  PMID: 41742046

Abstract

Objective

Active tuberculosis (ATB) largely relied on clinical diagnosis because of the limited sensitivity of microbiologic testing. We assessed whether complete blood cell count (CBC)-derived ratios could assist in ATB diagnosis and risk assessment.

Methods

This study enrolled 305 people with ATB and 171 healthy controls (HC) to evaluate the diagnostic efficiency of CBC-derived ratios for ATB by receiver operating characteristic curves and validated in a multi-center rheumatic disease (RD) cohort, in which a nested case-control study was designed to reveal the relationship between CBC-derived ratios and risk of developing ATB.

Results

Platelet, monocyte, and neutrophil count increased, but lymphocyte count decreased, thereby, platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR) were elevated significantly in people with ATB compared to HC, the similar tendency was shown between people with post- and pre-the onset ATB. These indices were restored after anti-tuberculosis treatment. Moreover, PLR, MLR, NLR, especially combining monocyte count, PLR, and NLR (area under the curve (AUC) = 0.916, P < 0.001) exhibited good diagnostic efficiency for ATB. Additionally, people with RD concomitant ATB demonstrated a similar tendency of CBC-derived ratios but their diagnostic efficiency for ATB was limited in the RD population. Interestingly, the risk of developing ATB of people with PLR ≥ 130.27 was higher by 23.761-fold than those with PLR < 130.27 in this population within one year.

Conclusion

CBC-derived ratios have limited standalone diagnostic value in RD populations (AUC = 0.637) but may aid risk stratification. CBC-derived ratios should be considered complementary tools, not replacements, for microbiological tests, particularly in resource-limited settings or to prompt further definitive testing.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-026-12803-y.

Keywords: Platelet-to-lymphocyte ratio, Monocyte-to-lymphocyte ratio, Neutrophil-to-lymphocyte ratio, Active tuberculosis, Rheumatic disease

Introduction

Active tuberculosis (ATB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Globally, ATB ranks as the 13th cause of global death and is the second deadliest infectious disease after coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) estimated that there were 10.6 million new ATB cases and 1.6 million people died from ATB in 2021, with over 80% of cases and deaths in developing countries [1], these countries are financially constrained and cannot afford the expenses associated with ATB diagnosis, such as the high sensitive but costly molecular biology reagents and related equipment. Therefore, it is urgent to need simple and reliable immediate indicators to assist in diagnosing ATB and assessing the risk of developing ATB, especially in high-risk populations.

Leukocytes and platelets contribute crucially to Mtb infection and ATB development, wherein platelets modulate innate immunity and tissue responsest [2–5], while monocytes, neutrophils, T cells, and B cells collectively participate in granuloma formation, bacterial control, and inflammatory lung damage [6–9], together offering potential evaluative markers of disease status [10, 11]. In particular, the ratios derived from leukocytes and platelets, including the platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR). A meta-analysis systematically proved that MLR can be considered as a key biomarker to identify tuberculosis and monitor the effectiveness of anti-tuberculosis therapy [12]. Moreover, patients with ATB exhibit elevated platelet counts and reduced lymphocyte counts in peripheral blood, leading to a high PLR [13]. Elevated PLR (≥ 200) is associated with pulmonary cavity formation in culture-positive pulmonary tuberculosis patients [11]. PLR > 216.82 serves as an effective indicator to differentiate whether chronic obstructive pulmonary disease patients are infected with Mtb [14] and PLR holds promise for the early detection of genitourinary tuberculosis [15]. A high NLR could distinguish people with ATB from non-ATB [16], and the NLR obtained at the initial diagnostic stage is a useful laboratory marker to discriminate people with pulmonary tuberculosis from people with bacterial community-acquired pneumonia [17]. NLR levels also could be a valuable laboratory diagnostic for distinguishing people with spinal tuberculosis from those who have pyogenic spinal infection [18]. In addition, NLR are promising, easy-to-obtain diagnostic biomarkers to differentiate children with tuberculosis from other lower respiratory tract infections [19], and may be used as markers of inflammation to help clinically manage people with tuberculosis and to determine disease severity [20]. Although no association was found between CBC-derived ratios (including PLR, MLR and NLR) and the interferon-γ (IFN-γ) release assay (IGRA) conversion rate of adolescent tuberculosis patients (ages: 13–15) [21], these studies generally proved CBC-derived ratios could potentially assist with the ATB diagnosis and evaluate the effectiveness of anti-tuberculosis treatment.

However, these studies are limited by small sample sizes, single observation time point, and different study populations, thus there are discrepancies in these results. Currently, the variations in complete blood cell count (CBC)-derived ratios at different clinical stages of ATB, including before and after anti-tuberculosis treatment and the onset of ATB are unknown. On the other hand, people with rheumatic disease (RD) are a high-risk population for developing ATB, with a nearly 2-fold higher prevalence rate than the general population [22], and the risk of developing ATB ranges from 3- to 10-fold in the future [23]. Management of high-risk population of tuberculosis is an important way to control tuberculosis. However, there is no study to evaluate the value of CBC-derived ratios in assisting with ATB diagnosis and risk assessment of RD populations.

Therefore, in this study, we collected CBC data from people with ATB at three time points which included before the onset of ATB, at the initially diagnosed ATB, and after anti-tuberculosis treatment. The changes in leukocyte count, platelet count, and their derived ratios at different clinical stages were analyzed, and the diagnostic efficiency of CBC-derived ratios for ATB was explored. Meanwhile, we validated the results in a large multi-center RD cohort study. This study aimed to evaluate the potential of CBC-derived ratios not as standalone diagnostic tests, but as ancillary tools to assist in risk stratification and to prompt more intensive application of gold-standard microbiological investigations.

Methods

Cross-sectional analysis population

This study retrospectively enrolled people with ATB (n = 305) in Peking Union Medical College Hospital between 2012 and 2023. CBC data at three time points: at the initial ATB diagnosis (n = 305), after anti-tuberculosis treatment of two months (n = 88, 88 of 305 people with ATB have data at this time point), and before the onset of ATB (n = 20, 20 of 305 people with ATB have data at this time point, which originated from the regular health screen data at least 1 year before the diagnosis of ATB) were collected. The inclusion criteria for people with ATB were as follows: (1) age over 18 years; (2) microbiologically or pathologically confirmed ATB, including positive acid-fast staining, mycobacterial culture, and Mtb molecular biology test, or histological evidence of caseous necrosis and epithelioid granulomas; (3) Presumptively diagnosed ATB based on clinical manifestations, laboratory findings compatible with ATB, and effective response to anti-tuberculosis treatment, meanwhile, other analogous diseases were excluded [24]. The exclusion criteria were as follows: (1) pregnant or lactating women; (2) using immunosuppressive drugs such as glucocorticoids within the past 2 months; (3) whole blood or platelet product transfusion within the past 2 weeks; (4) concurrent diseases except for diabetes, hypertension, and coronary heart disease, which might affect immune cell counts, such as blood and hematopoietic system disease, liver cirrhosis, uremia, human immunodeficiency virus (HIV) infection, malignant tumors, and autoimmune diseases. Meanwhile, CBC data of the healthy controls (HC) (n = 171) were also collected between 2019 and 2023 as the control group. The inclusion criteria for the HC group were as follows: (1) no symptoms such as fever, poor appetite, fatigue, cough, chest pain, or hemoptysis; (2) no suspicious abnormalities on chest imaging (X-ray or Computed Tomography). The exclusion criteria were as follows: (1) Malignant tumors or severe organ damage; (2) using long-term glucocorticoids, immunosuppressive drugs, or biological agents; (3) acute illness within the past 3 months. The baseline characteristics of the enrolled subjects were shown in Table 1. This study was approved by the Ethics Review Committee of Peking Union Medical College Hospital (Project number: K4070), and subjects were exempted from written consent.

Table 1.

Demographical and clinical characteristics of people with ATB and HC

Characteristics ATB (n = 305) HC (n = 171) P value
Male, n (%) 190 (62.3) 117 (68.42) 0.180a
Age (years), ±SD 49.47 ± 18.68 53.37 ± 16.11 0.017b
Hemoglobin (g/L), ±SD 119.57 ± 21.00 146.67 ± 16.42 <0.001b
hsCRP (mg/L), ±SD 46.84 ± 47.06 1.84 ± 4.40 <0.001b
TB Site, n (%)
 Lung 194 (63.61) / /
 Lymph node 13 (4.26) / /
 Bone 19 (6.23) / /
 Kidney 14 (4.59) / /
 Spleen 2 (0.66) / /
 Abdominal cavity 19 (6.23) / /
 Gut 10 (3.28) / /
 Liver 5 (1.63) / /
 Brain 16 (5.25) / /
 Pancreas 9 (2.95) / /
 Conjunctiva 1 (0.33) / /
 Skin 3 (0.98) / /
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(a) Chi-square test; (b) Mann–Whitney U test

ATB=Active tuberculosis. HC=healthy control, n=Number. SD=Standard deviation. hsCRP=high-sensitivity C-reactive protein. TB=tuberculosis

Matching people with ATB and without ATB in an RD follow-up cohort

Our team previously screened ATB in RD outpatients and inpatients in 13 large tertiary comprehensive hospitals (including: Peking Union Medical College Hospital, Beijing; The First Affiliated Hospital of Zhengzhou University, Zhengzhou; Xiangya Hospital, Central South University, Changsha; The First Affiliated Hospital of Harbin Medical University, Harbin; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou; Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; The Affiliated Hospital of Inner Mongolia Medical University, Hohhot; Xijing Hospital, Air Force Medical University, Xi‘an; People’s Hospital of Xinjiang Uygur Autonomous Region, Ürümqi; Tianjin First Central Hospital, Tianjin; West China Hospital, Sichuan University, Chengdu; The First Affiliated Hospital of Nanjing Medical University, Nanjing; Qilu Hospital of Shandong University, Jinan) in China and established a multi-center RD follow-up cohort (ETHERTB study) (n = 13,550) between September 16, 2014, and March 15, 201622. The inclusion criteria for the ETHERTB study were as follows: (1) age over 15 years; (2) meeting the diagnosis criteria for RD, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), sjögren’s syndrome (SS), systemic sclerosis (SSc), mixed connective tissue disease, dermatomyositis, giant cell arteritis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, behçet’s disease (BD), ankylosing spondylitis, and psoriatic arthritis. The exclusion criteria were as follows: (1) pregnant or lactating women; (2) concurrent HIV infection. Unfortunately, monocyte count data were not routinely available in the ETHERTB study. This study was approved by the Ethics Review Committee of Peking Union Medical College Hospital and the Ethics Review Committees of the other 12 participating hospitals (Project number: S-715).

This study included people with ATB in the RD population at baseline (n = 105) of the ETHERTB study, excluding people with RD involving the blood and hematopoietic system, those with malignant tumors, liver cirrhosis, and aged under 18 years (n = 20). A total of 85 people with ATB were enrolled. Simultaneously, we matched 170 people without ATB from the RD population (n = 13,445) using a 1:2 individual matching ratio and based on the following criteria: (1) same RD disease type; (2) excluding RD involving the blood and hematopoietic system, malignant tumors, and liver cirrhosis; (3) similar maximum daily glucocorticoids dose at baseline and within the past 2 years (± 10 mg/d); (4) same usage of immunosuppressive agents and biological agents at baseline and within the past 2 years. The screening and matching process for people with ATB was shown in Supplement Fig. 1.

Nested case-control study design based on the ETHERTB study

Totally 15 new cases of ATB were identified through a one-year follow-up of the ETHERTB study cohort. A nested case-control study was conducted within the cohort. Each of the 15 identified ATB cases (the case group) was matched with four controls from the cohort members who had not developed ATB at the time of the case’s diagnosis (risk-set sampling). The matching was performed at a 1:4 individual matching ratio based on the following criteria: age, type of RD, hematological system involvement, use of immunosuppressive agents (including cyclophosphamide, methotrexate, azathioprine, and leflunomide) within past two years, with evidence of previous TB and duration of glucocorticoids within past two years [22]. The average age of participants in the case and control groups was 48.9 ± 15.5 and 49.8 ± 14.5 years, respectively. RDs encompassed SLE, RA, SS, SSc, takayasu’s arteritis, and BD. “Duration of glucocorticoids within past two years” denote the weeks of glucocorticoid use at a dose of ≥ 30 mg/day within that period. Detailed characteristics of the enrolled subjects are elaborated in Supplement Table 1. RD patients enrolled in the ETHERTB study were required to undergo a CBC examination within two weeks of recruitment. Subsequently, we extracted baseline CBC data of the control and case groups for conditional logistic regression analysis. The nested case-control study design was shown in Supplement Fig. 2.

Statistical analysis

Data analysis was performed by GraphPad Prism 8 and SPSS 26.0 software. The Kolmogorov-Smirnov test was used to assess the normality of continuous data. Normally distributed continuous variables were expressed as mean and standard deviation, and independent samples or paired t-tests were used for comparisons between groups. Non-normally distributed continuous data were expressed as median and 95% confidence interval, and the Mann-Whitney U test or Wilcoxon test was used for independent or paired comparisons, respectively. Categorical data were presented as n (%) and compared using the corresponding chi-square test, continuity correction, or Fisher’s exact test based on the total and expected frequencies. The diagnostic efficiency of CBC-derived ratios for ATB was evaluated using receiver operating characteristic (ROC) curve analysis. Conditional logistic regression models were used to analyze the risk factors affecting the development of ATB in the RD population. To address potential bias due to the small number of events, a sensitivity analysis was performed using Firth’s penalized maximum likelihood method, which reduces small-sample bias in logistic regression coefficients. All statistical results were based on two-sided tests, and P < 0.05 was considered statistically significant.

Results

Dynamic changes of CBC-derived ratios in different clinical stages of ATB

Compared to HC, people with ATB showed that platelet count (290.0 vs. 212.0 × 109/L, P < 0.0001), monocyte count (0.465 vs. 0.290 × 109/L, P < 0.0001), and neutrophil count (4.695 vs. 3.310 × 109/L, P < 0.0001) increased markedly, while lymphocyte count was decreased significantly (1.155 vs. 1.660 × 109/L, P < 0.0001). Consequently, people with ATB showed CBC-derived ratios, namely PLR i.e., increased platelets divided by decreased lymphocytes (243.0 vs. 127.6, P < 0.0001), MLR i.e., increased monocytes divided by decreased lymphocytes (0.415 vs. 0.180, P < 0.0001), and NLR i.e., increased neutrophils divided by decreased lymphocytes (4.155 vs. 2.020, P < 0.0001) were elevated prominently by comparison with HC (Fig. 1A-G).

Fig. 1.

Fig. 1

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Comparisons of CBC-derived ratios among different ATB stages in general population. (A-G) Comparisons of CBC-derived parameters including lymphocyte count (A), platelet count (B), monocyte count (C), neutrophil count (D), PLR (E), MLR (F), and NLR (G) between people with ATB and HC; (H-N) Variations of CBC-derived parameters including lymphocyte count (H), platelet count (I), monocyte count (G), neutrophil count (K), PLR (L), MLR (M) and NLR (N) of people with ATB after anti-tuberculosis treatment; (O-U) Changes of CBC-derived parameters including lymphocyte count (O), platelet count (P), monocyte count (Q), neutrophil count (R), PLR (S), MLR (T) and NLR (U) before and after the onset of ATB. * means P < 0.05, ** means P < 0.01, *** means P < 0.001, **** means P < 0.0001, ns means not significant

Next, we analyzed that CBC-derived ratios of people with ATB after anti-tuberculosis treatment (n = 88) and found that platelet count (209.5 vs. 291.5 × 109/L, P < 0.0001), monocyte count (0.340 vs. 0.440 × 109/L, P < 0.0001), and neutrophil count (3.175 vs. 4.680 × 109/L, P < 0.0001) reduced significantly, while lymphocyte count increased significantly (1.430 vs. 1.195 × 109/L, P < 0.0001), additionally, PLR (140.0 vs. 246.0, P < 0.0001), MLR (0.245 vs. 0.375, P < 0.0001), and NLR (2.115 vs. 4.120, P < 0.0001) also reduced significantly (Fig. 1H-N) after two months of treatment.

Furthermore, CBC-derived ratios before the onset of ATB and at initial ATB diagnosis (n = 20) were compared and found that lymphocyte count (1.040 vs. 1.800 × 109/L, P < 0.001) decreased, accompanied by significantly elevated PLR (195.7 vs. 113.0, P < 0.01), MLR (0.355 vs. 0.175, P < 0.0001), and NLR (4.555 vs. 2.270, P < 0.05) at initial ATB diagnosis. However, there were no significant differences in platelet count, monocyte count, and neutrophil count (Fig. 1O-U).

The diagnostic efficiency of CBC-derived ratios in distinguishing people with ATB from HC

The diagnostic efficiency of CBC-derived ratios in distinguishing people with ATB from HC was analyzed by plotting ROC curves. Lymphocyte count (area under the curve (AUC) = 0.760, P < 0.001), platelet count (AUC = 0.725, P < 0.001), monocyte count (AUC = 0.767, P < 0.001), neutrophil count (AUC = 0.742, P < 0.001), PLR (AUC = 0.846, P < 0.001), MLR (AUC = 0.873, P < 0.001), and NLR (AUC = 0.847, P < 0.001) all can assist diagnosis. Next, binary logistic regression analysis was performed to evaluate the diagnostic efficiency of combining multiple indicators, with whether the subject was an ATB patient as the dependent variable, incorporating the above seven indicators into the model. The model finally generated a predicted probability based on the three variables with predictive significance for ATB: monocyte count, PLR, and NLR. Combining monocyte count, PLR, and NLR demonstrated the optimal diagnostic efficiency in distinguishing people with ATB from HC (AUC = 0.916, P < 0.001) (Table 2; Fig. 2A).

Table 2.

Diagnostic efficiency of CBC-derived ratios for discriminating people with ATB from HC

Parameters AUC P value 95% Confidence Interval
Lower Bound Upper Bound
Lymphocytes 0.760 <0.001 0.718 0.802
Platelets 0.725 <0.001 0.681 0.770
Monocytes 0.767 <0.001 0.725 0.809
Neutrophils 0.742 <0.001 0.698 0.786
PLR 0.846 <0.001 0.812 0.881
MLR 0.873 <0.001 0.842 0.904
NLR 0.847 <0.001 0.812 0.881
Monocytes + PLR+NLR 0.916 <0.001 0.891 0.941
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AUC=Area under the curve. PLR=Platelet-lymphocyte ratio. MLR=Monocyte-lymphocyte ratio. NLR=Neutrophil-lymphocyte ratio

Fig. 2.

Fig. 2

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ROC analysis. (A) ROC of CBC-derived ratios for discriminating people with ATB from HC; (B) ROC of CBC-derived ratios for diagnosing people with ATB in the RD population

The diagnostic efficiency of CBC-derived ratios for people with ATB among the RD population

We further explored the diagnostic efficiency of CBC-derived ratios for people with ATB in the RD population according to the ETHERTB study cohort. Lymphocyte count (1.370 vs. 1.585 × 109/L, P < 0.05) decreased, platelet count increased (231.0 vs. 220.5 × 109/L, P < 0.05), and no significant difference in neutrophil count (Supplement Fig. 3A-C), while the PLR (173.4 vs. 140.6, P < 0.001) and NLR (3.185 vs. 2.455, P < 0.01) were elevated significantly (Supplement Fig. 3D-E) in people with ATB when compared with those without ATB in RD population. Subsequently, the diagnostic efficiency of CBC-derived ratios for people with ATB in the RD population was analyzed by drawing ROC curves. Neutrophil count (AUC = 0.541, P = 0.293) had no diagnostic value, while lymphocyte count (AUC = 0.595, P = 0.015), platelet count (AUC = 0.576, P = 0.049), PLR (AUC = 0.629, P < 0.001), and NLR (AUC = 0.624, P < 0.001) had diagnostic efficiency. Next, combining PLR and NLR was identified as the highest diagnostic efficiency in differentiating people with ATB and without ATB in the RD population (AUC = 0.637, P < 0.001) (Table 3; Fig. 2B). It should be noted that, monocyte count and MLR could not be evaluated in RD population due to missing monocyte data.

Table 3.

Diagnostic efficiency of CBC-derived ratios for people with ATB in the RD population

Parameters AUC P value 95% Confidence Interval
Lower Bound Upper Bound
Lymphocytes 0.595 0.015 0.521 0.668
Platelets 0.576 0.049 0.502 0.651
Neutrophils 0.541 0.293 0.463 0.618
PLR 0.629 <0.001 0.557 0.699
NLR 0.624 <0.001 0.551 0.697
PLR + NLR 0.637 <0.001 0.566 0.708
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AUC=Area under the curve. PLR=Platelet-lymphocyte ratio. NLR=Neutrophil-lymphocyte ratio

The relationship between CBC-derived ratios and the risk of developing ATB in the RD population

Totally 15 people with RD who were newly diagnosed with ATB within a one-year follow-up of the ETHERTB study cohort were included as the case group and matched with people with RD who did not develop ATB in a 1:4 ratio as the control group. The matching criteria eliminated confounding factors which were confirmed to influence the onset of ATB. The cutoff values of PLR and NLR from the ROC curves drawn in this cohort were used to categorize the enrolled subjects into two groups (PLR ≥ 130.27 or PLR < 130.27, and NLR ≥ 2.99 or NLR < 2.99) to visually assess the association between PLR and NLR and the risk of developing ATB in RD population. The reclassified PLR and NLR, as well as lymphocyte count, platelet count, and neutrophil count, were included in a conditional logistic regression model. There was no correlation between lymphocyte count, platelet count, neutrophil count, and NLR and the risk of developing ATB in the RD population. Interestingly, the logistic regression analysis revealed that a high PLR was significantly associated with ATB (OR = 23.761, 95% CI: 1.145-493.178). Given the small number of cases, a sensitivity analysis using Firth’s penalized regression was performed, which confirmed the association (OR = 9.539, 95% CI: 1.735–52.448) when the baseline PLR of people with RD was ≥ 130.27, the risk of developing ATB within one year was 23.761-fold higher than those with PLR < 130.27 (Table 4).

Table 4.

Risk factors of developing ATB in the RD population

Parameters Odds ratio for TB activity (95% CI) Odds ratio for TB activity (95% CI)
Platelets 0.997 (0.990–1.004) graphic file with name 12879_2026_12803_Figa_HTML.gif
Neutrophils 0.957 (0.750–1.222)
PLR ≥ 130.27 23.761 (1.145-493.178)
PLR < 130.27 1.000 (Reference)
NLR ≥ 2.99 0.569 (0.056–5.761)
NLR < 2.99 1.000 (Reference)
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PLR=Platelet-lymphocyte ratio. NLR=Neutrophil-lymphocyte ratio

Discussion

The WHO reported ATB cases globally remain significantly lower in 2021 than in 2019 (pre-COVID-19 pandemic), with approximately 3 million missed cases, predominantly in developing countries [1]. Bacteriological evidence is the gold standard for diagnosing ATB, and acid-fast staining and mycobacterial culture are the most widely used laboratory techniques. However, positivity rates of pulmonary tuberculosis ranged from 42% to 64% for microscopy smears [25, 26], and from 44.8% to 75% for sputum culture [27, 28]. The new generation of rapid diagnostic techniques for early ATB diagnosis has emerged with the rapid development of molecular biology technologies, such as GeneXpert MTB/RIF [29]. These techniques complement traditional bacteriological methods and have been recommended by the WHO for initial ATB screening. However, only 38% of people with ATB applied the WHO-recommended rapid molecular tests as their initial diagnostic tests in 2021, indicating rapid molecular diagnostics remains limited. Furthermore, the limitation of bacteriological diagnostic techniques has led to a slight increase in the bacteriological positive rate of global pulmonary tuberculosis cases (63%) in 2021 compared to 2020 (59%) [1]. Additionally, the Chinese Center for Disease Control and Prevention has conducted a nationwide cross-sectional study and reported the bacteriological positive rate of people with extrapulmonary tuberculosis was only 3.5% in China in 2021 [30]. These findings suggested that a considerable proportion of ATB cases rely on clinical diagnosis. Therefore, discovering simple and affordable diagnostic indicators which assist in the clinical diagnosis of ATB holds potentially clinical significance.

Our study found significant alterations in leukocyte count, platelet count, and their derived ratios of people with ATB compared to healthy individuals. Except for decreased lymphocyte count, all other indicators, particularly CBC-derived ratios (including PLR, MLR, and NLR), were increased markedly, which was consistent with previous research [31]. Furthermore, we collected baseline CBC data from people with ATB before the onset of ATB, the results further confirmed these ratios were elevated significantly after the onset of ATB. The pre-ATB analysis was limited to the 20 patients who had pre-diagnosis CBC data available from routine health screens. Therefore, the potential for selection bias due to differential health-seeking behaviors between these patients and the broader cohort must be considered. These findings implied that CBC-derived ratios could help distinguish people with ATB from healthy individuals. Therefore, a ROC curve analysis was conducted and found that these indicators displayed good diagnostic efficiency for ATB (AUC > 0.7). PLR, MLR, and NLR showed better diagnostic efficiency compared to platelet count and leukocyte count alone, indicating that CBC-derived ratios could serve as laboratory-based simple indicators for auxiliary diagnosis of ATB. These findings were consistent with previous studies, which found that PLR could effectively distinguish chronic obstructive pulmonary disease complicated with or without ATB [14], MLR could assist in diagnosing ATB in children with HIV [32], and NLR helped differentiate ATB from latent tuberculosis infection [16], ATB from bacterial community-acquired pneumonia [17], adult spinal tuberculosis from pyogenic spinal infection [18], and pediatric ATB from other lower respiratory tract infections [19]. However, these studies did not evaluate the diagnostic efficiency of combining multiple CBC-derived ratios for ATB. Therefore, in this study, we identified monocyte count, PLR, and NLR as risk factors for developing ATB, generating a predictive probability for ATB occurrence based on the combination of three indicators. The combination of monocyte count, PLR, and NLR improved significantly the diagnostic efficiency of ATB in the general population (AUC = 0.916, P < 0.001), and could serve as a great potential indicator of auxiliary diagnosis of ATB.

It is critical to note that the diagnostic approach for tuberculosis employs tools with distinct clinical roles. Xpert MTB/RIF, as a WHO-endorsed rapid molecular test, serves as a highly accurate confirmatory diagnostic. In contrast, the combined model of monocytes, PLR, and NLR (AUC = 0.916) identified in our study is positioned differently. It is derived from a routine, low-cost, and rapidly available complete blood count, which inherently positions it as a potential pre-screening or triaging tool, rather than a confirmatory test. Our study did not conduct a direct comparison between these CBC-derived indices and confirmatory standards like GeneXpert MTB/RIF or culture. Consequently, while the high AUC suggests utility for initial patient stratification, the exact added value of this model within a diagnostic cascade that culminates in molecular or microbiological confirmation cannot be quantified from our data. Future studies designed to directly benchmark this hematological model against gold-standard diagnostics are necessary to precisely define its operational role as an efficient screening component in a comprehensive diagnostic algorithm. In addition, despite excluding patients with conditions that affect CBC parameters (like immunosuppressive drug use, chronic inflammatory diseases), confounding is still possible. This is shown by the baseline differences in Table 1: the ATB group had significantly lower hemoglobin and higher hsCRP than HC group (both P < 0.001). These represent the key confounders of anemia and systemic inflammation. Therefore, our model’s good performance (AUC = 0.916) might reflect not just TB, but also these general disease effects, which could limit its specificity in other settings. Future studies that adjust for these variables are needed.

Furthermore, the platelet count, monocyte count, and neutrophil count were reduced, while lymphocyte count was increased, correspondingly, PLR, MLR, and NLR decreased significantly after anti-tuberculosis treatment. These results indicated that CBC-derived ratios were useful for monitoring anti-tuberculosis treatment and could assist in medication management for people with ATB. All the above results collectively demonstrated that CBC-derived ratios served as potential laboratory-based simple indicators for assisting in diagnosing ATB in the general population and monitoring the efficacy of anti-tuberculosis treatment.

Previous studies have found that PLR could discriminate people with RA from RA-associated interstitial lung disease [33]. However, the diagnostic efficiency of CBC-derived ratios for ATB among the RD population is unknown. Based on a multi-center RD follow-up cohort with 13 large tertiary comprehensive hospitals enrollment (n = 13,550). which is the first study conducted using a stratified multistage cluster sampling design to estimate the prevalence of ATB and follow up morbidity of ATB and to identify risk factors in people with RD in China. We found that people with RD complicated with ATB exhibited elevated platelet count and decreased lymphocyte count, resulting in significantly increased PLR and NLR. These elevated PLR and NLR might distinguish people with or without ATB in the RD population (AUC = 0.629, P < 0.001, AUC = 0.624, P<0.001, respectively). However, their diagnostic efficiency was suboptimal. The combination of PLR and NLR limitedly improved the diagnostic efficiency (AUC = 0.637, P < 0.001). These results suggested the limited value of CBC-derived ratios in directly identifying people with ATB in the RD population. We have already proved that anti-tuberculosis treatment will increase the lymphocyte count, and reduce the platelet count, neutrophil count, PLR and NLR of people with ATB, while people with RD complicated with ATB who were receiving anti-tuberculosis treatment still displayed a decreased lymphocyte count and an elevated platelet count, PLR and NLR. Therefore, receiving anti-tuberculosis treatment may be a reason for the limited diagnostic efficiency of CBC-derived ratios and these ratios may demonstrate a better value in diagnosing new ATB in the RD population. In addition, this might be attributed to immune dysfunction, decreased immune defense capabilities, and using immunosuppressive medication among people with RD [34], which could suppress the activation of the immune system and further weaken the immune response against Mtb. Furthermore, RD especially those with SLE have accompanied immune system dysregulation, which was caused by long-term glucocorticoids or immunosuppressive therapy, as well as the disease itself. Consequently, the positive rate of IFN-γ release assays for Mtb infection was lower significantly in the SLE population than in the general population [35]. A combination of simple CBC-derived ratios and IGRA might increase the detection rate of Mtb infection in the RD population and deserves further investigation.

Our findings regarding the elevated PLR, MLR, and NLR in people with ATB should be interpreted within the context of the WHO-recommended diagnostic algorithms, which prioritize microbiological confirmation [1]. While these-derived ratios lack the specificity to replace definitive diagnostic tests, they hold potential as accessible and inexpensive screening tools. In clinical practice, particularly in resource-limited settings or high-risk populations such as people with RD undergoing immunosuppressive therapy, an abnormal ratio could serve as a ‘red flag’. This would prompt clinicians to maintain a higher index of suspicion and expedite the application of WHO-recommended tests (e.g., Xpert MTB/RIF assay or culture), potentially reducing diagnostic delays. Future studies should explore the integration of these hematological parameters into a stepwise diagnostic algorithm that aligns with WHO standards, where they could function as an initial risk-stratification tool prior to more specific but costly investigations.

CBC-derived ratios also potentially predicted the risks of developing ATB and assessed prognosis in ATB besides tumors [36], dermatomyositis [37], and psychiatric disorders [38]. Elevated MLR in infants aged from 3 months to 4 months was closely associated with an increased risk of developing ATB within two years [39]. High MLR has been identified as a risk factor for primary ATB in children aged from 6 months to 15 years [40]. And study reported that MLR below 0.09 or above 0.25 could predict ATB in adults [31]. A prospective cohort study enrolled adult people with HIV and found that the risk of developing ATB increased significantly in people with MLR below the 5th percentile or above the 95th percentile, implying that MLR could stratify the risk of developing ATB in people with HIV. Another study involved women with HIV and suggested that the risk of developing ATB within 18 months postpartum could increase in women with perinatal elevated MLR [41]. Furthermore, NLR could potentially predict acute respiratory distress syndrome and mortality of people with ATB [42]. However, the risk assessment potential of CBC-derived ratios for ATB development in the RD population has not been explored. Our study has utilized the nested case-control study, which is a new research method formed by combining the traditional case-control study and cohort study, that is, based on a predetermined cohort for follow-up observation, the design idea of case-control study is applied for research and analysis. This new research method has revealed that baseline PLR ≥ 130.27 of the RD population could be a risk factor for developing ATB (odds ratio (OR) = 23.761). Previous studies have found that PLR could serve as an inflammatory marker in RD [43], which assisted in diagnosing RA and assessing disease activity [44–47]. Besides, PLR could predict treatment response in people with RA after 12 weeks of anti-tumor necrosis factor-α therapy [48]. However, no research explored the risk assessment potential of PLR, as a simple, economical, and real-time indicator for developing ATB in the RD population. Our study provided new evidence for this issue. It should be noted, our study determined the optimal PLR cutoff of 130.27 for identifying ATB in RD population—a value lower than the 216.82 threshold established for TB discrimination in COPD population [14]. This divergence likely reflects the distinct immunopathological context of RD, where chronic immune dysregulation and frequent immunosuppressive therapy may depress lymphocyte counts and alter platelet profiles. Consequently, the baseline PLR in this population is likely shifted, requiring a lower threshold to detect superimposed ATB.

In summary, our study demonstrated that CBC-derived ratios contributed to early ATB screening and risk assessment for developing ATB, especially in developing countries and high-risk populations for ATB. However, there were several limitations. Firstly, the sample size of people with pre- and post-the onset of ATB was relatively small (n = 20), which might have underestimated the changes in immune cell profiles before and after the onset of ATB. Secondly, the ETHERTB study lacked data on monocyte count, preventing the analysis of monocyte count and MLR in the RD population. Thirdly, despite the sample size of the RD population in the ETHERTB study being as high as 13,550, only 15 RD patients developed ATB after one year of follow-up, the relatively small ATB cases could potentially influence the study results, but the incidence was significantly higher than that of the general population (55/100000) reported by WHO [1]. Thus, we have designed a nested case-control study with the assistance of a statistician. Rigorous matching criteria eliminated confounding factors that were confirmed to influence the onset of ATB, such as age, previous history of tuberculosis, RD disease type, involvement of the blood and hematopoietic system, using immunosuppressive agents (including cyclophosphamide, methotrexate, azathioprine, and leflunomide) within the past 2 years, and dosage and duration of glucocorticoids within past two years, and a 1:4 matching ratio in the control group, these largely reduced the selection bias and restored the true contribution of CBC-derived ratios at baseline to the risk of developing ATB in RD population one year later. However, the relatively small number of ATB events in the RD cohort, means that the effect estimates (e.g., the OR for PLR) are unstable, as indicated by their wide confidence intervals, and should be interpreted with caution. Additionally, due to the exploratory nature of our analysis, we did not adjust for multiple comparisons, which increases the risk of false-positive findings. Therefore, our results, especially for factors with modest significance levels, should be considered hypothesis-generating rather than definitive. Certainly, further follow-up with more cases is also needed to assess the predictive value of CBC-derived ratios for ATB and their long-term prognostic value to anti-tuberculosis treatment in the RD population. Fourthly, the interpretation of CBC-derived ratios in our study must be considered in light of limitations. These ratios are non-specific and can be influenced by factors other than active tuberculosis. These include the inflammatory state of the underlying rheumatic disease [49], the use of certain medications like corticosteroids [50] which can alter leukocyte counts, and the presence of other concurrent infections. While we attempted to match patients by rheumatic disease type, we could not fully account for all these potential confounders. This reinforces the concept that these ratios should be used as a prompt for further investigation rather than as a definitive diagnostic tool. Future research should explore combination approaches and evaluate their real-world application. Fifthly. Although hemoglobin and hsCRP levels showed significant differences between the ATB and HC groups, we did not include them in the final regression model. This omission was due to the lack of consistently available laboratory data for these parameters in the RD cohort. Therefore, the potential independent or combined diagnostic value of these routine biomarkers within our predictive model remains unevaluated and represents an important avenue for future prospective studies. Lastly. the generalizability of our findings is limited by the study’s confinement to Chinese tertiary hospitals and a middle-aged adult cohort. Consequently, the applicability of the CBC ratio to other populations—such as children, older adults, or community settings with different TB epidemiology—requires external validation.

Conclusion

CBC-derived ratios have limited standalone diagnostic value in RD populations (AUC = 0.637) but may aid risk stratification. Moreover, a high PLR was identified as a risk factor for incident ATB within one year among RD populations. These readily available CBC-derived ratios could therefore serve as practical and low-cost adjuncts to facilitate risk assessment and prioritize further definitive testing, particularly in resource-constrained settings.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1 (491.7KB, docx)

Acknowledgements

The authors acknowledge Assistant Researcher Nan Zhao who is proficient in epidemiology and medical statistics from the Medical Science Research Center of Peking Union Medical College Hospital for her professional guidance in the statistical methodology.

Abbreviations

ATB

Active tuberculosis

CBC

Complete blood cell count

PLR

Platelet-to-lymphocyte ratio

MLR

Monocyte-to-lymphocyte ratio

NLR

Neutrophil-to-lymphocyte ratio

RD

Rheumatic disease

HC

Healthy controls

AUC

Area under the curve

Mtb

Mycobacterium tuberculosis

COVID-19

Coronavirus disease 2019

WHO

World Health Organization

IFN-γ

Interferon-γ

IGRA

Interferon-γ release assay

HIV

Human Immunodeficiency Virus

SLE

Systemic lupus erythematosus

RA

Rheumatoid arthritis

SS

Sjögren's syndrome

SSc

Systemic sclerosis

BD

Behçet's disease

ROC

Receiver operating characteristic

OR

Odds ratio

Author contributions

Xiaoqing Liu and Xiaochun Shi conceived, designed, and supervised this research. Fengying Wu, Yuanchun Li, and Lantian Xie collected data. Fengying Wu analyzed and performed interpretation of data, and wrote the first draft of the manuscript. Yuchen Liu and Ye Liu assisted with revisions. Lifan Zhang, Xiaochun Shi, and Xiaoqing Liu provided comments and modifications to the final version. All authors approved the final manuscript to be published.

Funding

This work was supported by the National High-Level Hospital Clinical Research Funding (2022-PUMCH-C-013) and the Zhiqian Chen Health Decision Making Fund Project of Peking Union Medical Foundation.

Data availability

Data is provided within the manuscript or supplementary information files.

Declarations

Ethics approval and consent to participate

The patient’s written consent for the ETHERTB study was obtained, and other subjects were exempt from written consent which was in accord with ethical principles. The design of the work has been approved by the Ethics Committee of Peking Union Medical College Hospital (Project number: K4070 and S-715).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Supplementary Material 1 (491.7KB, docx)

Data Availability Statement

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