The Role of CD4 + Cells,Monocyte-Lymphocyte Ratio,and Fibrinogen Elevation in the Progression of Focal Lesions in Brucellosis

Abstract

Background:

The focal lesions were the significant clinical challenge for brucellosis, a widespread infectious disease. The aim of this study was to investigate the risk factors for focal lesions in brucellosis, thereby providing support for clinical diagnosis and treatment.

Methods:

A total of 339 brucellosis patients were recruited, including 147 patients with focal complications and 192 patients without focal complications. The patient’s medical records were reviewed, and laboratory findings were recorded. All the data were analyzed using SPSS 27.0.

Results:

Spondylitis (65.99%) was the main focal complication in the 147 brucellosis patients. The percent of CD3+ cells and CD3+ CD4+ cells, the levels of neutrophil, monocyte, platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), IL-6, IL-10, IL-12p70, and FIB (fibrinogen) showed a statistically upward trend, while the absolute counts of CD+ 19 cells, CD16+ CD56+ cells and the percent of CD16+ CD56+ cells were significantly decreased in patients with focal complication (p < 0.05). Percent of CD3+ CD4+ cells (odds ratio [OR]: 1.033, 95% confidence interval [CI]: 1.003–1.063, p = 0.030), MLR (OR: 38.115, 95% CI: 2.396–606.305, p = 0.010), and FIB (OR: 1.363, 95% CI: 1.089–1.705, p = 0.007) were the independent risk factors for focal complications in brucellosis patients in the multivariate logistic regression analysis and the areas under curve (AUC) of receiver operating characteristic for the three factors were 0.576, 0.640, and 0.641, respectively. The AUC for the model including these three indicators was 0.716, and the risk of focal lesions increased almost three times in patients with value above the cutoff value.

Conclusion:

CD3+ CD4+ cell percent, MLR and FIB were the independent risk factors for focal lesions in human brucellosis.

Keywords

brucellosis fibrinogen focal lesion monocyte-lymphocyte ratio risk factor

Introduction

Brucellosis, caused by brucella infection, was a widespread infectious disease that severely affects human and animal health. It primarily spreads through contacting with infected cattle, sheep or their secretions, consuming raw beef, mutton, or dairy products. Clinically, brucellosis often presents with prolonged fever, excessive sweating, fatigue, joint pain, liver and spleen enlargement, and lymph node swelling (Deng et al., 2019; Zheng et al., 2018). What more, the high propensity of focal complications or relapse was a hallmark and clinically significant challenge of brucellosis (Zhang et al., 2025). These insidious focal lesions most frequently involve the osteoarticular system, genitourinary tract, cardiovascular structures and neurological tissues and frequently leading to chronic debilitating pain, functional impairment, increased treatment costs, and heightened risk of relapse (Jia et al., 2017; Arslan et al., 2024; Varikkodan et al., 2024). Consequently, focal complications significantly amplify the disease’s overall morbidity, mortality, and socioeconomic impact, underscoring the critical need for enhanced diagnostic and therapeutic strategies.

Dysregulated immune responses appear to be the critical biological risk factors of focal complications, with studies suggesting that impaired neutrophil function, altered macrophage polarization may facilitate persistent intracellular infection and localized inflammation, contributing to lesion formation (Demirdal and Sen, 2020; Kuruoglu et al., 2023). Concomitantly, elevated levels of proinflammatory cytokines have been associated with more severe disease, including focal complications (Karaoglan et al., 2009). Emerging evidence also points toward a potential role of coagulation cascade activation in brucellosis focal lesions (Zhang et al., 2022). It is still lacking that comprehensive analyses directly linking immune cell subsets, cytokine signatures, and coagulation markers indices to the development of focal lesions in brucellosis.

The aim of this study was to conduct a comprehensive analysis including lymphocyte subpopulations, cytokines, blood routine tests, coagulation factors, etc., to explore the risk factors for focal lesions in brucellosis and provide evidence for clinical diagnosis and treatment.

Patients and Methods

Patients

A total of 435 brucellosis patients were recruited from January 2022 to December 2024 in Tianjin Second People’s Hospital. Of these, 96 patients were excluded due to having immune system disorders, concurrent infections with other pathogens, or no available laboratory data, and 339 patients were included in the final analysis for the retrospective study. All patients had a diagnosis of brucellosis confirmed by positive results of blood culture based on the national guideline of “Updated Guidelines for the Diagnosis of Human Brucellosis—China, 2019.” The 339 patients including 99 chronic patients and 240 acute patients were divided into two groups based on the presence or absence of focal lesions. All subjects gave their consent, and the ethical approval for this study was obtained from the ethics committee of Tianjin Second People’s Hospital (2021 No.43).

Data collection

The epidemiological information included age, gender, the clinical features (arthritis, spondylitis, encephalitis, orchitis, and endocarditis, etc.), and the laboratory findings (neutrophil, lymphocyte, monocyte, platelet, lymphocyte subpopulations, interleukin[IL]-2, IL-4, IL-6, IL-10, IL-12P70, IL-17, tumor necrosis factor[TNF]-α, interferon[IFN]-r, prothrombin time [PT], international normalized ratio, PT-%, activated partial thromboplastin time [APTT], fibrinogen [FIB], thrombin time [TT]) of all the 339 enrolled brucellosis patients were collected from the electronic medical system. Some patients were excluded from the analysis due to missed data.

Statistical analysis

Normally distributed quantitative data were presented as mean ± standard deviation (SD), and abnormally distributed quantitative data were presented as median ± interquartile range. The chi-square test was used to examine the different distribution of enumeration data. The comparison analysis of quantitative data between groups was performed using t test, ANOVA LSD test, Kruskal–Wallis test, and Mann–Whitney test according to the observed variable distribution. Logistical regression analysis was employed to analyze the correlation between risk factors and focal complications of brucellosis, with results being expressed as odds ratios (ORs), 95% confidence intervals (95% CIs), and corresponding p values. Receiver operating characteristic (ROC) curves were constructed to determine the optimal cutoff values. All analyses were performed using the SPSS 27.0 software. A p value less than 0.05 was considered to indicate a significant difference.

Results

The characteristics of enrolled brucellosis patients in the study

The 339 enrolled brucellosis patients were divided into two groups, cohort 1 was defined as patients with focal complications (n = 147), and cohort 2 was defined as patients without focal complications (n = 192). The age distribution for the two groups was 53 ± 18.00 and 58 ± 14.75, and the gender ratio was 2.41:1 and 2.37:1, respectively (Fig. 1). As for the 147 patients with focal complications, 97 patients (65.99%) had spondylitis, 25 patients (17.01%) had arthritis, 12 patients (8.16%) had encephalitis, 8 patients (5.44%) had orchitis, 4 patients (2.72%) had enthesisitis, and 1 patient (0.68%) had endocarditis.

FIG. 1.

Study flowchart. M, male; F, female.

Comparison analysis between brucellosis patients with or without focal complications

The lymphocyte subpopulations analysis showed that the percent of CD3+ cells and CD3+ CD4+ cells were increased while the absolute counts of CD 19+ cells, CD16+ CD56+ cells and the percent of CD16+ CD56+ cells were decreased in patients with focal complication compared to patients without focal complications (p < 0.05, all) (Table 1). A total of 146 patients in cohort 1 and 190 patients in cohort 2 were included to analyze the blood cell detection data, including neutrophil, lymphocyte, monocyte, and platelet. Platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), and monocyte-lymphocyte ratio (MLR) were calculated as platelet to lymphocyte ratio, neutrophil-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio. As showed in Table 1, patients with focal complications showed higher neutrophil, monocyte, PLR, NLR, and MLR (p < 0.05, all). As to the cytokines analysis including 135 patients in cohort 1 and 178 patients in cohort 2, the levels of IL-6, IL-10, and IL-12p70 significantly increased in patients with focal complication (p < 0.05, all) (Table 1). Finally, for the coagulation-related indicators including130 patients in cohort 1 and 159 patients in cohort 2, the level of FIB showed a statistically upward trend in cohort 1 (p < 0.05) (Table 1).

Table 1.

Comparison Analysis of Clinical Test Data in Brucellosis Patients

Variable	Patients with focal complications	Patients without focal complications	p
Neutrophil (10⁹/L)	3.00 ± 1.89	2.65 ± 1.46	0.003
Lymphocyte (10⁹/L)	1.73 ± 0.79	1.81 ± 0.84	0.085
Monocyte (10⁹/L)	0.52 ± 0.26	0.47 ± 0.24	0.003
Platelet (10⁹/L)	251.00 ± 119.25	229.50 ± 100.25	0.056
PLR	149.07 ± 85.96	123.39 ± 66.35	0.006
NLR	1.78 ± 1.17	1.41 ± 0.84	<0.01
MLR	0.31 ± 0.17	0.24 ± 0.15	<0.01
CD3+ cells (%)	81.04 ± 8.61	79.74 ± 9.77	0.034
CD3+ cells (cells/μL)	1505.60 ± 791.82	1547.10 ± 772.29	0.456
CD3+ CD4+ cells (cells/μL)	707.84 ± 415.54	727.78 ± 386.22	0.884
CD3+ CD4+ cells (%)	40.40 ± 8.23	38.21 ± 9.37	0.023
CD3+ CD8+ cells (cells/μL)	605.55 ± 398.53	593.40 ± 388.09	0.680
CD3+ CD8+ cells (%)	32.40 ± 8.02	31.97 ± 12.79	0.375
CD19+ cells (cells/μL)	124.58 ± 144.39	148.03 ± 132.15	0.028
CD19+ cells (%)	7.08 ± 5.94	7.78 ± 5.77	0.122
CD3-CD16+ CD56+ cells (cells/μL)	166.61 ± 169.63	202.17 ± 191.03	0.015
CD3-CD16+ CD56+ cells (%)	9.08 ± 6.44	10.66 ± 6.61	0.040
PT (s)	11.40 ± 1.13	11.30 ± 1.10	0.359
INR	1.00 ± 0.10	1.00 ± 0.10	0.178
PT-%	92.70 ± 21.28	96.60 ± 18.70	0.295
APTT (s)	29.70 ± 6.27	30.10 ± 6.30	0.670
FIB (g/L)	3.91 ± 1.69	3.29 ± 1.68	<0.01
TT (s)	18.10 ± 2.02	18.30 ± 2.10	0.141
IL-2 (pg/mL)	0.00 ± 1.71	0.00 ± 1.67	0.979
IL-4 (pg/mL)	1.67 ± 1.81	1.38 ± 1.91	0.070
IL-6 (pg/mL)	12.43 ± 14.57	7.43 ± 12.27	<0.001
IL-10 (pg/mL)	3.26 ± 1.97	2.76 ± 2.30	0.039
IL-12p70 (pg/mL)	1.46 ± 1.89	0.71 ± 1.65	0.011
IL-17 (pg/mL)	0.99 ± 1.95	1.10 ± 1.48	0.987
TNF-α (pg/mL)	1.43 ± 1.55	1.12 ± 1.51	0.140
IFN-γ (pg/mL)	3.34 ± 3.55	3.37 ± 4.20	0.818

PLR, platelet-lymphocyte ratio; NLR, neutrophil-lymphocyte ratio; MLR, monocyte-lymphocyte ratio; PT, prothrombin time; INR, international normalized ratio; APTT, activated partial thromboplastin time; FIB, fibrinogen; TT, thrombin time; IL: interleukin; TNF: tumor necrosis factor; IFN：inerferon.

Comparison analysis between acute and chronic brucellosis patients

Then, the laboratory data were compared between acute and chronic brucellosis patients, and the results were showed in Figure 2. The percent of CD3+ CD4+ cells was increased while the percent and absolutely count of CD4+ CD8+ cells was decreased, thus leading to the higher CD4+/CD8+ in chronic brucellosis patients (p < 0.05). Moreover, acute patients showed higher levels of APTT and IFN-γ (p < 0.05). There were no significant differences between the two groups about other indicators.

FIG. 2.

Comparison analysis of percent of CD4+ cell (A), absolutely count of CD8+ cell (B), percent of CD8+ cell (C), CD4+/CD8+ ratio (D), APTT (E) and IFN-γ (F) between acute and chronic brucellosis patients. APTT, activated partial thromboplastin time.

Logistical regression analysis for risk factors of focal complications in brucellosis patients

Logistic regression analysis was used to analyze the risk factors for focal lesions of brucellosis. Age, CD3+ cell percent, CD3+ CD4+ cell percent, level of neutrophil, monocyte, PLR, NLR, MLR, and FIB were found to be associated with focal lesions in brucellosis in the univariate analysis (Table 2). Through multivariate logistic regression analysis, age (OR: 0.962, 95% CI: 0.943–0.982, p < 0.001), percent of CD3+ CD4+ cell (OR: 1.033, 95% CI: 1.003–1.063, p = 0.030), MLR (OR: 38.115, 95% CI: 2.396–606.305, p = 0.010), and FIB (OR: 1.363, 95% CI: 1.089–1.705, p = 0.007) were found to be the independent risk factors for focal complications in brucellosis patients (Table 2). CD3+ cells, neutrophils, and monocytes were not included in the multivariate logistic regression analysis because these data were presented in CD3+ CD4+ cells, NLR, and MLR. Moreover, we performed the ROC curves to determine the cutoff values of percent of CD3+ CD4+ cells, MLR, and FIB to maximize the sensitivity and specificity as the predictor of focal complications of brucellosis. The area under curve (AUC) of CD3+ CD4+ cells percent, MLR, and FIB were 0.576, 0.640, 0.641, and the cutoff values were 36.245%, 0.319, and 3.574 g/L, respectively (Fig. 3A). The risk of focal complications increased 1.939 times in patients with a higher percent of CD3+ CD4+ cells (95% CI: 1.218–3.086, p = 0.005). The higher level of MLR more than 0.319 was associated with higher risk of focal complications (OR: 2.289, 95% CI: 1.420–3.691, p = 0.004). The OR of FIB ≥ 3.574 g/L vs. <3.574g/L was 2.793 (95% CI: 1.709–4.565, p < 0.001). (Table 3). All the OR was adjusted on gender and age. The AUC of the ROC curve for the model including the three indicators was 0.716 (Fig. 3B), and patients with value above the cutoff still have about three times the risk of focal lesions after adjusting on age and gender (Table 3).

Table 2.

Logistic Analysis About Risk Factors of Focal Lesions in Brucellosis Patients

Variable	Univariate logistic analysis		Multivariate logistic analysis
Variable	OR (95% CI)	p	OR (95% CI)	p
Gender	0.979 (0.611–1.569)	0.931
Age	0.963 (0.945–0.980）	<0.001	0.962 (0.943–0.982)	<0.001
CD3+ cells (%)	1.034 (1.003–1.065)	0.030
CD3+ CD4+ cells (%)	1.028 (1.003–1.054)	0.026	1.033 (1.003–1.063)	0.030
CD19+ cells (cells/μL)	0.999 (0.997–1.000)	0.133
CD3-CD16+ CD56+ cells (cells/μL)	0.999 (0.997–1.000)	0.061
CD3-CD16+ CD56+ cells (%)	0.965 (0.927–1.004)	0.079
Neutrophil (10⁹/L)	1.258 (1.084–1.460)	0.003
Monocyte (10⁹/L)	6.003 (1.879–19.179)	0.002
PLR	1.004 (1.001–1.008)	0.011
NLR	1.331 (1.080–1.640)	0.007
MLR	35.010 (5.871–208.781)	<0.001	38.115 (2.396–606.305)	0.010
FIB (g/L)	1.431 (1.176–1.740)	<0.001	1.363 (1.089–1.705)	0.007
IL-6 (pg/mL)	1.000 (0.996–1.004)	0.830
IL-10 (pg/mL)	1.043 (0.963–1.129)	0.304
IL-12p70 (pg/mL)	1.083 (0.989–1.186)	0.085

PLR, platelet-lymphocyte ratio; NLR, neutrophil-lymphocyte ratio; MLR, monocyte-lymphocyte ratio; FIB, fibrinogen.

FIG. 3.

Receiving operating curves for percent of CD4+ cells, MLR and FIB (A) and the model including theses three indicators (B) in predicting focal lesions in brucellosis patients.

Table 3.

Logistic Analysis About Risk of Focal Lesions in Brucellosis Patients Stratified by the Cut-off of ROC

Variable	Level compared to cut-off value	Crude OR (95% CI)	Crude p	Adjusted OR (95% CI)*	Adjusted p*
CD3+ CD4+ cells (%)	Lower	1^ref		1^ref
CD3+ CD4+ cells (%)	Higher	1.981 (1.259–3.116)	0.003	1.939 (1.218–3.086)	0.005
MLR	Lower	1^ref		1^ref
MLR	Higher	2.585 (1.642–4.069)	<0.001	2.289 (1.420–3.691)	0.004
FIB (g/L)	Lower	1^ref		1^ref
FIB (g/L)	Higher	3.060 (1.895–4.941)	<0.001	2.793 (1.709–4.565)	<0.001
Combination mode	Lower	1^ref		1^ref
Combination mode	Higher	2.907 (1.756–4.814)	<0.001	2.775 (1.661–4.635)	<0.001

*Adjusted on age and gender.

MLR, monocyte-lymphocyte ratio; FIB, fibrinogen.

Discussion

Our study identified elevated peripheral CD3+ CD4+ cells percent, monocyte-to-lymphocyte ratio (MLR), and increased plasma FIB level as significant independent risk factors for the development of focal complications in patients with brucellosis. This finding underscores the critical interplay between dysregulated immune responses and hypercoagulability in the pathogenesis of localized brucellar lesions.

Brucellosis is often categorized into acute and chronic forms based on the course of the disease, with differences in immune system responses. The data from this study also indicated differences in CD4+/CD8+ and APTT levels between acute and chronic patients, which were consistent with previous studies (Zheng et al., 2019; Lin et al., 2020; Sun et al., 2021). Our previous results have also shown that immune cell indicators and coagulation-related markers were risk factors for the chronicization of brucellosis (Yang et al., 2023). However, the classification of acute and chronic brucellosis is usually based on subjective judgment of the disease course. So, this study categorizes brucellosis patients into two groups based on the symptoms and complications. In the present study, osteoarticular disease is one of the main complication of brucellosis, which aligns with previous research (Esmaeilnejad-Ganji SM et al., 2019).

Brucella is an intracellular facultative parasite, and CD4+ T cells are the crucial defenders in anti-Brucella immunity. During Brucella infection, the immune system tends to differentiate into a Th1-type immune response, which may help the body to clear the infected pathogen by the activation of macrophages and the release of proinflammatory cytokines such as IFN-γ (Zangger et al., 2021; Liang et al., 2023). When the body cannot completely eliminate the pathogen due to various immune escape mechanisms of Brucella (Yang et al., 2024), the continuously activated of CD4+ cells may secrete inflammatory factors at high levels persistently at the infection site. This persistent inflammation at specific sites may facilitate abscess development or osteoarticular destruction, which are the hallmarks of focal brucellosis. Thus, the persistent activation of CD4+ cells may also lead to the functional exhaustion, thereby causing the continuous occurrence of infections (Gao et al., 2022). Our data suggested that an exaggerated or dysregulated CD4+ response may contribute to tissue damage and focal complication development, which may be illustrated by the previous studies mentioned above. Therefore, the effect of CD4+ cells on brucella focal lesions may include factors such as immune disorders caused by imbalance of Th1/Th2 cells and T cell exhaustion. Surely, the specific mechanisms of the impact of immune cells on focal lesions in brucellosis still need further research, including not only the quantity of immune cells but also their functions.

Monocytes, as key mediator of inflammation, may contribute to tissue damage through excessive proinflammatory cytokine release and impaired bacterial clearance, while lymphopenia reflects immunosuppression, potentially facilitates persistent infection and localized complications. Prior studies have linked high MLR to severe infections, suggesting its broader utility as a biomarker of unbalanced immune responses (Li et al., 2025; Cursi et al., 2023). For brucellosis, focal lesions often arise from chronic granulomatous inflammation, and an elevated MLR also was identified to be a significant risk factor for focal lesions in brucellosis in the present study. The founding suggested that an imbalance in monocyte-driven inflammation relative to lymphocyte-mediated immune regulation may facilitate tissue invasion and persistent focal infection.

FIB, a key acute-phase reactant, plays a crucial role in inflammation and thrombosis. Previous studies have demonstrated that hyperfibrinogenemia was associated with persistent inflammatory responses and tissue damage, which could predispose patients to the development of localized complications (Yakovlev et al., 2022; Raghu and Flick, 2011). Excessive fibrin deposition also can impair microcirculation, promote a prothrombotic state, and facilitate bacterial persistence in affected tissues (Luyendyk et al., 2019). The association between high FIB level and focal lesions suggested that sustained inflammatory processes may contribute to tissue invasion. The finding that elevated FIB levels was a risk factor for focal lesions in brucellosis provides important insights into the pathogenesis and clinical management of this disease.

Age was observed to be associated with risk of focal lesions in both univariate and multivariate regression analyses in the study, which are often related to factors such as case collection methods, medical-seeking habits, exposure risks, differences in disease manifestations, and immunosenescence (Goyani et al., 2024). Therefore, this study cannot conclude that age is a protective or risk factor for focal lesions. Further research with larger sample cohorts with different age distributions is needed to investigate the effect of age on focal lesions in brucellosis.

Localized lesions cause physical discomfort and increased treatment costs for brucellosis patients, which point to the importance of detection and prevention of localized lesions early. The risk factors found in the present study have significant clinical implications. Although the AUCs were relatively lower of the three focal lesions risk indicators found in the study, the AUC of the model combined these three factors reaches 0.716. Moreover, these indicators are routine testing metrics for brucellosis patients, and the combination detection was expected to provide an affordable reference for assessing focal lesions risk in clinical settings. Monitoring these factors in brucellosis patients could serve as a potential predictive biomarker for identifying patients at higher risk of developing focal complications, thus potentially provide evidences for more aggressive therapeutic strategies to prevent irreversible tissue damage. The study has some limitations. First, the sample size was small, and it was a single-center study. Second, this was a retrospective study, and no further follow-up was conducted on the included patients. Thirdly, this study did not delve into the mechanisms of focal lesions in brucellosis. More large-scale, multicenter, prospective studies are necessary to further investigate the mechanisms by which the aforementioned risk factors contribute to localized lesions in brucellosis.

Conclusions

In this study, FIB was found to be the independent risk factor of local lesions in brucellosis patients firstly. What more, the model combined FIB with MLR and CD4+ cells performed about three times of local lesions risk in brucellosis patients. Therefore, monitoring the above indicators during the diagnosis and treatment of brucellosis can effectively prevent the occurrence of focal lesions.

Authors’ Contributions

K.Q. wrote the main article text and prepared figures and tables. Y.C. and W.L. collected the clinical data. N.L. conducted the clinical tests on patient samples. S.Z. conducted the data analysis and reviewed the patient’s medical records. Y.L. and Y.Y. diagnosed the patients and gave the fund support. R.S. guided the study. All authors reviewed the article.

Footnotes

Acknowledgments

The authors are responsible for the interpretation of the data. They wish to thank the study participants for their contribution to the research.

Availability of Data and Materials

The authors do not have permission to share data.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by Tianjin Municipal Education Commission Research Project (2024KJ236), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-059B) and Tianjin Key Medical Discipline Construction Project (TJYXZDXK-3-019B).

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