The diagnostic value and validation of Th17-related cytokines in tuberculosis pleural effusion

doi:10.21203/rs.3.rs-3336087/v1

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The diagnostic value and validation of Th17-related cytokines in tuberculosis pleural effusion

https://doi.org/10.21203/rs.3.rs-3336087/v1

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Background

There has been a great deal of evidence indicating that cytokines participate in tuberculosis immune defense. This study aimed to evaluated the levels of Th17-related cytokines in pleural effusion to discriminate tuberculosis pleurisy with malignant pleurisy.

Methods

82 patients with pleural effusion were included in training cohort and 76 patients with pleural effusion were included in validation cohort. Individuals were divided into tuberculosis and malignant pleurisy group. The concentrations of Th17-related cytokines in pleural effusion were detected using multiplex cytokine assay. The threshold value was calculated according the ROC analysis to help diagnose tuberculosis pleurisy. Furthermore, the combination diagnosis was validated in validation cohort.

Results

The pleural effusion levels of Th17-related cytokines among the patients with tuberculosis infection were all higher than malignant pleurisy group (all P < 0.05). The AUC was ≥ 0.920 for the IL-22, sCD40L, IFN-γ, TNF-α and IL-31 found significantly increased in TPE in training cohort. A threshold value of 95.80 pg/mL in IFN-γ, 41.80 pg/mL in IL-31 and 18.87 pg/mL in IL-22 could be used to obtain sensitivity and specificity ≥ 90% to discriminate between tuberculosis pleurisy and malignant pleurisy in training cohort. IL-22 associated with sCD40L had the best sensitivity and specificity (94.0% and 96.9%) in diagnosis of tuberculosis pleurisy and was validated in validation cohort.

Conclusion

We demonstrated that the level of Th17-related cytokines in pleural effusion had significant difference between tuberculosis pleurisy and malignant pleurisy. IL-22 ≥ 18.87 pg/mL and sCD40L ≥ 53.08 pg/mL can be clinically utilized as an efficient diagnosis strategy for tuberculosis pleurisy.

tuberculosis pleural pleurisy

Th17-related cytokines

IL-22

sCD40L

Tuberculosis (TB) is a communicable disease that is a major cause of ill health and one of the leading causes of death worldwide. TB is caused by the bacillus Mycobacterium tuberculosis (M.tb), which typically affects the lung but can affect other sites. About a quarter of the world’s population has been infected with M.tb [1]. Tuberculosis pleurisy is one of most common sites of extrapulmonary TB, the incidence of tuberculosis pleurisy could approach 30% in TB endemic areas[2]. Definitive diagnosis of tuberculosis pleurisy requires invasive procedures to demonstrate histological evidence of caseating granulomas or microbiological evidence of the organism on smear or culture[3], which exits traumatic and time-consuming. The analysis of biomarkers such as adenosine deaminase (ADA) in pleural effusions can improve the diagnostic efficiency of tuberculous pleurisy and achieves high accuracy[4]. However, ADA activity can be elevated in various conditions such as pulmonary empyema and rheumatoid arthritis[5]. Therefore, the search for novel biomarkers will help to improve the diagnosis of tuberculous pleurisy.

Th1 and Th17 cells are the main effector CD4⁺ T cells during M.tb infection. Th1 cells have been shown to contribute to TB protection by secreting interferon-γ (IFN-γ) to activate macrophages and stimulate phagocytosis, phagosome maturation, production of reactive nitrogen intermediates, and antigen presentation[6, 7]. Th17 cells secreting interleukin-17 (IL-17) and inducing the expression of proinflammatory genes such as granulocyte colony-stimulating factor (G-CSF), CXC chemokines, IL-6, which induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology[6, 8, 9]. Published studies suggest that Th17-related cytokine pathways may be manipulated by M.tb microorganisms for their survival benefits in primary tuberculosis (TB)[10]. Then in M.tb infection, the various levels of cytokines contribute to determining outcomes of infection[11]. Studies found that cytokines of IL-1β, IL-6, IL-17, IL-31, IL-33, tumor necrosis factor-α (TNF-α) and IFN-γ, may contribute to more efficient diagnosis strategies in the management of tuberculous pleurisy[12–16]. But there was no synchronous comparison of the diagnostic value of each cytokine in tuberculous pleurisy.

In the current study, we have evaluated the levels of different Th-17 related cytokines in pleural effusion obtained from pleurisy patients to discriminate tuberculosis pleurisy, or if the combination of different biomarkers could be useful as biosignature of tuberculosis pleural effusion.

2.1. Characteristics of enrolled patients.

There were 50 patients with tuberculosis pleural effusion (TPE) and 32 patients with malignant pleural effusion (MPE) in learning cohort, 51 patients with TPE and 25 patients with MPE in validation cohort. The clinical characteristic of the learning cohort and validation cohort were presented in Table 1. In the learning cohort, there was no significant difference of sex (TPE vs MPE, 74.0% vs 68.8%, P = 0.606) and age (TPE vs MPE, 47.6 years vs 64.7 years, P = 0.108) between tuberculosis pleurisy and malignant pleurisy group. The age in validation cohort had statistical difference between tuberculosis pleurisy and malignant pleurisy group (TPE vs MPE, 44.2 years vs 66.5 years, P = 0.001) but had no significant difference of sex (TPE vs MPE, 66.7% vs 48%, P = 0.139). 11 (22.0%) patients had positive result of sputum smear or culture for M.tb in learning cohort and 14 (27.5%) patients in validation cohort.

Table 1

The clinical characteristic of learning cohort and validation cohort.
	Tuberculous pleurisy (n = 50)	Malignant pleurisy (n = 32)	P value*
Learning cohort
Male/Female	37/13	22/10	0.623
Age, median (range)	47.6 (12.0–84.0)	64.7 (39.0–89.0)	0.108
Sputum smear or culture positive, n (%)	11 (22.0)	--	--
Validation cohort
Male/Female	34/17	12/13	0.139
Age, median (range)	44.2 (14.0–87.0)	66.5 (44.0–84.0)	0.001
Sputum AFB smear or culture positive, n (%)	14 (27.5)	--	--

2.2. Pleural effusion levels and ROC curve of Th17-related cytokines in learning cohort.

The levels of Th17-related cytokines of all patients in learning cohort were showed in heatmap (Fig. 1). The level of IL-6 had highest concentration but IL-25 had lowest concentration in pleural effusion. We found that the levels of all Th17-related cytokines in tuberculosis pleurisy group were significantly higher than malignant pleurisy group (IL-1β, 6.12 vs 0.99 pg/mL, IL-4, 28.25 vs 3.17 pg/mL, lL-6, 99547.00 vs 33268.00 pg/mL, IL-10, 314.00 vs 94.28 pg/mL, IL-17A, 9.09 vs 3.92 pg/mL, IL-17F, 141.40 vs 29.71 pg/mL, IL-21, 135.60 vs 13.52 pg/mL, IL-22, 132.20 vs 4.51 pg/mL, IL-25, 3.38 vs 1.54 pg/mL, IL-31, 529.40 vs 9.20 pg/mL, IL-33, 24.91 vs 0.00 pg/mL, IFN-γ, 1989.00 vs 6.34 pg/mL, sCD40L, 84.74 vs 27.34 pg/mL, and TNF-α, 157.40 vs 12.54 pg/mL, all P < 0.001). We used ROC curve analysis to determine for the optimal cut-off value of each marker that discriminated TBE versus MPE (Fig. 2). The AUC, P value, 95% CI, optimal cut-off value, sensitivity and specificity of each cytokine was showed in Table 2. The AUC of all Th17-related cytokines were > 0.7, IL-22, sCD40L, IFN-γ, TNF-α, IL-17F and IL-31 of all were > 0.9. The sensitivity and specificity of IFN-γ, IL-31 and IL-22 were ≥ 90%.

Table 2

Pleural effusion levels and ROC of Th17-related cytokines in learning cohort.
Cytokines	Median (pg/mL)	AUC	P value	95% CI	Cut-off value (pg/mL)	Sensitivity (%)	Specificity (%)
IL-6	83681.00	0.793	< 0.001	0.689–0.898	76752.00	72.3	77.4
IFN-γ	258.00	0.979	< 0.001	0.956-1.000	95.80	90.0	96.9
IL-10	165.40	0.830	< 0.001	0.735–0.924	141.10	82.0	80.7
IL-17F	115.50	0.902	< 0.001	0.832–0.97	63.02	91.8	75.0
IL-31	84.32	0.979	< 0.001	0.957-1.000	41.80	90.0	93.8
IL-21	64.71	0.864	< 0.001	0.784–0.945	41.69	82.0	84.4
IL-22	27.72	0.959	< 0.001	0.919-1.000	18.87	90.0	100.0
TNF-α	56.66	0.938	< 0.001	0.875-1.000	25.96	96.0	87.5
sCD40L	47.71	0.921	< 0.001	0.861–0.980	53.08	78.0	96.9
IL-4	22.30	0.834	< 0.001	0.742–0.927	13.49	87.8	71.9
IL-33	5.60	0.843	< 0.001	0.758–0.929	5.07	72.0	80.7
IL-17A	7.15	0.745	< 0.001	0.628–0.862	6.56	70.0	68.8
IL-1β	3.73	0.843	< 0.001	0.751–0.936	2.99	82.0	78.1
IL-25	2.63	0.829	< 0.001	0.742–0.916	2.55	72.0	80.7

2.3. Combination diagnosis of IL-22 with sCD40L, TNF-α, IL-31 and IFN-γ in learning cohort.

The AUC was ≥ 0.920 for the IL-22, sCD40L, TNF-α, IL-31 and IFN-γ and found significantly increased in TPE. These markers have proven to be very effective in distinguishing TPE from MPE. Since IL-22 had the highest specificity, diagnosis threshold ≥ 18.87 pg/mL was used in combination diagnosis with other cytokines (sCD40L ≥ 53.08 pg/mL, TNF-α ≥ 25.96 pg/mL, IL-31 ≥ 41.80 pg/mL and IFN-γ ≥ 95.80 pg/mL) (Fig. 3). As summarized in Table 3, compared with other cytokines, IL-22 associated with sCD40L had the best sensitivity and specificity (94.0% and 96.9%). The sensitivity of IL-22 combined with IFN-γ, TNF-α and IL-31 were 92.0%, 98.0% and 94.0%, respectively, and the specificity were 96.9%, 87.5% and 93.8%, respectively.

Table 3

The sensitivity and specificity of IL-22 combined with sCD40L, TNF-α, IL-31 and IFN-γ in learning cohort.
	TPE	MPE	Sensitivity	Specificity	PPV	NPV
IL-22 combined with sCD40L	47/50	1/32	94.0%	96.9%	97.9%	91.2%
IL-22 combined with TNF-α	49/50	4/32	98.0%	87.5%	92.5%	96.6%
IL-22 combined with IL-31	47/50	2/32	94.0%	93.8%	95.9%	90.9%
IL-22 combined with IFN-γ	46/50	1/32	92.0%	96.9%	97.9%	88.6%

2.4. Diagnostic performance of IL-22 combined with sCD40L in validation cohort.

We had found that combination diagnosis of IL-22 with sCD40L had best sensitivity and specificity, then we used 76 independent samples to confirm the accuracy of this test. As shown in Table 4, the AUC of IL-22 and sCD40L were > 0.860 in validation cohort. In validation cohort, the median value of IL-22 was higher than learning cohort (68.31 vs 27.72 pg/ml), the median value of sCD40L was lower than learning cohort (38.36 vs 47.71 pg/ml), but the cut-off value of IL-22 and sCD40L were lower than learning cohort (3.44 vs 18.87, and 31.27 vs 53.08 pg/ml). We next applied the previously determined threshold levels in learning cohort by the ROC curves approach (IL-22 was 18.87 pg/mL and sCD40L was 53.08 pg/mL). As shown in Fig. 4, the combination diagnosis of IL-22 with sCD40L can efficiently discriminate TPE versus MPE in validation cohort, the sensitivity was 90.2% and specificity was 88.0%.

Table 4

Diagnostic performance of IL-22 combined with sCD40L in validation cohort
Cytokines	Median (pg/mL)	AUC	P value	95% CI	Cut-off value (pg/mL)	Sensitivity (%)	Specificity (%)
IL-22	68.31	0.956	< 0.001	0.910-1.000	3.44	96.0	92.2
sCD40L	38.36	0.869	< 0.001	0.761–0.977	31.27	88.0	82.4
IL-22 combined with sCD40L	--	--	--	--	--	90.2	88.0

In the present study, we had investigated the potential role of Th17-related cytokines in pleural effusion, as biomarkers of disease by comparing patients with tuberculosis pleurisy and malignant pleurisy. We had shown that multiple biomarkers detected in pleural effusion can contribution to a diagnostic signature to discriminate TPE and MPE. The diagnostic accuracies of the different cytokines ware evaluated by ROC curve analysis in order to discriminate the different study populations. Similar to previous results, we found that several cytokines were able to discriminate, with a good performance, TPE from MPE. From this analysis, 6 cytokines IL-17F, IL-22, IL-31, sCD40L, IFN-γ and TNF-α showed a good performance with the AUC > 0.9, with 3 markers IL-22, IFN-γ and IL-31 able to reach the best sensitivity and specificity of ≥ 90%. Further combination diagnosis was conducted, and it was found that IL-22 combined with sCD40L had higher sensitivity and specificity, and was verified in the validation cohort.

Published studies had suggested that Th17-related cytokine pathways played a crucial roles in tuberculosis infection[10]. Th17 cells produced a cytokine Th17, IL-17A and IL-17F share a similar structure and have similar roles in the immune response against M.tb infection[17]. In patients with chronic TB, IL-17A production appears to be decreased. Studies found that IL-17 levels in patients with tuberculosis pleural effusion were higher than that in peripheral blood[18, 19]. In this study, we had found that the level of IL-17A and IL-17F in TPE were higher than MPE, but the sensitivity and specificity were not superior to other cytokines. The current research suggests that IFN-γ have extremely higher diagnostic accuracy for TPE[20–22]. In this study, the sensitivity and specificity of IFN-γ in diagnosis of TPE were 90.0% and 96.9%, consistent with those studies. Therefore, IFN-γ can be used as a reference to evaluate the diagnostic accuracy of other cytokines.

IL-22 is a recently described IL-10 family cytokine that is produced by Th 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells. A role for IL-22 has also been described in host defense within barrier

tissues such as the intestine, oral mucosa, skin and lung[23]. Studies found that IL-22 has various roles in tuberculosis immune responses [24]. Previous study indicating higher concentrations of IL-22 in the bronchoalveolar lavage fluid (BALF) of ATB patients than in the BALF of healthy controls[25]. Liu et.al found that significantly higher IL-22 levels in the pleural fluid of TPE patients than in the blood of TPE patients[26]. CD40L and sCD40L belong to the tumor necrosis factor superfamily, and they are molecules with a dual prothrombotic and proinflammatory role. They are expressed in a variety of tissues such as the immune system (in both B and T cells), the vascular wall, and activated platelets.[27]. CD40L binding with CD40 is considered a critical step in priming and expansion of antigen-specific CD4 T cells, their upregulation of CD25 expression and cytokine production[28, 29]. Study found that CD40-deficient DCs were unable to induce antigen-specific IL-17 responses after M.tb infection and CD40-CD40L pathway represents a novel strategy to improve adaptive immunity to TB[30, 31]. Studies had found that IL-22 may be useful for diagnosing TPE, and combining it with ADA may further enhance diagnostic accuracy[32]. In this study, we combined IL-22 with sCD40L, TNF-α, IL-31 and IFN-γ, found IL-22 combined with sCD40L had the best sensitivity and specificity, comparing with other cytokines. And it was validated in the validation cohort, the sensitivity was 90.2% and specificity was 88.0%. then, we speculated that combination diagnosis of IL-22 with sCD40L provided new insights into the diagnosis of TPE.

This study has several limitations. First, only malignant pleural effusion was included as control, and the diagnosis of parapneumonic pleural effusion and tuberculous pleural effusion was also difficult in clinical. It is hoped that this part of data can be implemented in the subsequent cohort. Second, we verified the combination diagnosis of IL-22 with sCD40L in the validation cohort, but IL-22 with other cytokines were not yet implement.

In conclusion, this study compared the AUC, sensitivity and specificity of pleural effusion Th17-related cytokines for diagnosis of tuberculosis pleurisy, found that IL-22, IFN-γ and IL-31 had the higher sensitivity and specificity, and the combination of IL-22 and sCD40L can be clinically utilized as an efficient diagnosis strategy for tuberculosis pleurisy.

5.1. Patients

From January 2011 to October 2013, totally 82 patients with pleural effusion in Wuxi Fifth People’s Hospital and Huashan Hospital of Fudan University were consecutively enrolled as learning cohort to establish threshold value. From April 2018 to July 2021, totally 76 patients with pleural effusion in Wuxi Fifth People’s Hospital, 905th Hospital of PLA Navy and Huashan Hospital of Fudan University were consecutively enrolled as validation cohort to confirm these thresholds value.in this study, subjects with human immunodeficiency virus (HIV), fungi or bacterial infection or in-take immunosuppressive agents and glucocorticoids were excluded. Patients were divided into tuberculosis pleurisy group and malignant pleurisy group. The tuberculosis pleurisy was including confirmed tuberculosis and clinical diagnosis of tuberculosis. The confirmed tuberculous pleurisy was diagnosed with M. tuberculosis culture-positive in pleural effusion and/or confirmed tuberculosis infection by pleural biopsy. The clinical diagnosis of tuberculous pleurisy was diagnosed with one of the following criteria: M. tuberculosis acid-fast bacilli (AFB) smear of culture positive in sputum, M. tuberculosis culture positive in other biologic specimens, positive response to antituberculosis medication without other possible causes of pleural effusion. The malignant pleurisy were patients with malignant tumor and the pleural effusion were found tumor cells.

5.2. Measurement of Th17-related Cytokines in pleural effusion

2 mL pleural effusion of enrolled patient was collected in sterile tubes and centrifuged at 1500 rpm for 10 min. the supernatants were stored at -80°C until analysis. Pleural effusion samples (25 µl) were diluted 1:1 with the kit serum matrix. The levels of Th17-related cytokines in pleural effusion, including IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L) and TNF-α, which were measured simultaneously using the Bio-Plex Multiplex Immunoassay of Th17 cytokines (Bio-Rad Laboratories, Inc..USA), according to the instructions of the kit manufacturers. The data were analyzed with Bio-Plex 200 system (Bio-Rad Laboratories, Inc.,USA), and all the results were expressed in pg/mL.

5.3. Statistical analysis

The statistical analysis was performed with GraphPad Prism software (version 9.2.0; GraphPad Software, Inc.). The data were compared by using the non-parametric Mann-Whitney test and Chi-square test or Fisher’s exact test. Significance was inferred for P < 0.05. Receiver operating characteristic (ROC) curve analysis was performed to determine the discriminative ability of selected cytokines to distinguish tuberculosis pleurisy and malignant pleurisy with the overall accuracy assessed by area under curve (AUC) values. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) were calculated. Ninety-five percent confidence intervals (95% CI) were calculated using the Wilson method for proportions.

TB tuberculosis

M.tb Mycobacterium tuberculosis

ADA adenosine deaminase

IFN-γ interferon-γ

IL interleukin

G-CSF granulocyte colony-stimulating factor

TNF-α tumor necrosis factor-α

AFB acid-fast bacilli

HIV human immunodeficiency virus

sCD40L soluble CD40 ligand

ROC receiver operating characteristic

AUC area under curve

PPV positive predictive values

NPV negative predictive values

CI confidence intervals

TPE tuberculosis pleural effusion

MPE malignant pleural effusion

Ethics approval and consent to participate

Our study was approved by the Ethics Committee of Huashan Hospital affiliated with Fudan University Ethics Committee (KY2021-978). All the experiments were performed in accordance with the Helsinki Declaration.Written informed consent was obtained from all of the patients prior to participation in our study.

Consent for publication

Not Applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 82171743 and 82101852), Shanghai Science and Technology Committee (grant numbers 20dz2210401 and 21NL2600100), Shanghai Municipal Science and Technology Major Project (HS2021SHZX001), and Shanghai Sailing Program (grant numbers 22YF1404900).

Authors' contributions

Yuzhen Xu, Jing Wu and Qiuju Yao contributed to the manuscript drafting and statistical analysis, Qianqian Liu, Chen Huaxin and Bingyan Zhang contributed to the methodology and enrollment of patients, Yuanyuan Liu, Sen Wangand Lingyun Shao contributed to the curation of data and supervision, Wenhong Zhang, Qinfang Ouand Yan Gao contributed to the study design and critical revision of the manuscript.

Acknowledgements

The authors would like to thank all the study participants for their participation and contribution to the study.

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No competing interests reported.

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The diagnostic value and validation of Th17-related cytokines in tuberculosis pleural effusion

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Abstract

Background

Methods

Results

Conclusion

Figures

1. Background

2. Results

2.1. Characteristics of enrolled patients.

2.2. Pleural effusion levels and ROC curve of Th17-related cytokines in learning cohort.

2.3. Combination diagnosis of IL-22 with sCD40L, TNF-α, IL-31 and IFN-γ in learning cohort.

2.4. Diagnostic performance of IL-22 combined with sCD40L in validation cohort.

3. Discussion

4. Conclusions

5. Material and methods

5.1. Patients

5.2. Measurement of Th17-related Cytokines in pleural effusion

5.3. Statistical analysis

Abbreviations

Declarations

References

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