thesis topics on pleural effusion

• Research article
• Open access
• Published: 19 March 2021

A retrospective study on the combined biomarkers and ratios in serum and pleural fluid to distinguish the multiple types of pleural effusion

• Liyan Lin 1 , 3 ,
• Shuguang Li   ORCID: orcid.org/0000-0003-0613-0386 1 , 2 ,
• Qiao Xiong 4 &
• Hui Wang 1 , 2  

BMC Pulmonary Medicine volume  21 , Article number:  95 ( 2021 ) Cite this article

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Pleural effusion (PE) is a common clinical manifestation, and millions of people suffer from pleural disease. Herein, this retrospective study was performed to evaluate the biomarkers and ratios in serum and pleural fluid (PF) for the differential diagnosis of the multiple types of PE and search for a new diagnostic strategy for PE.

In-patients, who developed tuberculous PE (TPE), malignant PE (MPE), complicated parapneumonic effusion (CPPE), uncomplicated PPE (UPPE), or PE caused by connective tissue diseases (CTDs) and underwent thoracentesis at Peking University People’s Hospital from November 2016 to April 2019, were included in this study. Eleven biomarkers and their ratios in serum and PF were investigated and compared between pairs of the different PE groups, and a decision-tree was developed.

Totally 112 PE cases, including 25 MPE, 33 TPE, 19 CPPE, 27 UPPE, and 8 PE caused by CTDs, were reviewed. Biomarkers and ratios showed good diagnostic performance with high area under the curve values, sensitivities, and specificities for the differential diagnosis of the multiple types of PE. According to the decision-tree analysis, the combination of adenosine deaminase (ADA), serum albumin, serum lactate dehydrogenase, total protein, PF-LDH/ADA, and PF-LDH/TP provided the best predictive capacity with an overall accuracy of 84.8%; the sensitivity and specificity for TPE diagnosis were 100% and 98.7%, respectively.

The biomarkers and ratios showed good diagnostic performance, and a decision-tree with an overall accuracy of 84.8% was developed to differentiate the five types of PE in clinical settings.

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Introduction

Pleural effusion (PE) is a common clinical manifestation, and about 3000 per million people in the world suffer from pleural disease [ 1 ]. The main types of PE include tuberculous PE (TPE), malignant PE (MPE), and parapneumonic effusion (PPE) [ 2 ]; besides, it is well established that connective tissue diseases (CTDs) can also cause PE [ 3 , 4 ]. About one-third of tuberculosis patients showed extra-pulmonary tuberculosis (EPTB), while a quarter of them developed TPE [ 5 ]. Globally, MPE incidence is 660 per million people, resulting in more than 1 million people being affected [ 6 ]. About 57% PPE is caused due to community-acquired pneumonia (CAP) [ 7 , 8 ], and approximately 1 million patients in the United States develop PPE annually [ 9 ].

Traditional microbiology and molecular biology methods (such as Xpert MTB/RIF) show poor performance when pleural fluid (PF) specimens are detected for TPE diagnosis, especially in acute setting [ 10 , 11 ]. Further invasive surgery (such as pleural biopsy) can be used to detect caseating granuloma. Due to the poor preservation of tumor cells and the small sample size, the low cytological examination rate (about 60%) in the detection of MPE has become a long-term clinical problem. Thoracoscopic biopsy is a high-performance diagnostic method for both TPE and MPE, but its invasiveness limits clinical application [ 12 ]. Therefore, serum biomarkers, including adenosine deaminase (ADA), lactate dehydrogenase (LDH), C-reaction protein (CRP) and many inflammatory cytokines are used as a means of auxiliary noninvasive detection to assist clinical diagnosis. The Light’s criteria is an early standard established for the classification of exudates or transudates effusion, which involves the ratio of serum LDH (S-LDH) and PF-LDH [ 13 ]. ADA is investigated more commonly for TPE diagnosis [ 10 , 14 ]. However, equivalent or higher ADA levels may occur in other types of PPE [ 15 ], thus limiting the diagnostic performance of ADA. PF-LDH and S-LDH may also be used to identify TPE and PPE [ 16 ], but their use is limited due to low sensitivity [ 17 ]. Recent studies showed that the PF-LDH/ADA and CRP/ADA ratios, interleukin (IL)-1β, IL-γ induced protein (IP)-10, interferon (IFN)-γ, IL-13, and basic fibroblast growth factor can also be used to identify TPE and PPE [ 16 , 18 , 19 ], while PF presepsin, CRP, and procalcitonin (PCT) levels can be used as additional tools for the assessment of the differential diagnosis of PE [ 18 ]. A combination of serum calprotectin and neutrophil gelatinase-associated lipocalin serological markers and chest X-ray constitutes a high performance assay used for differentiating CPPE from empyema [ 20 ]. To our knowledge, research has mainly focused on only a few types of PE and/or indicators, which have been extensively studied [ 10 , 15 , 17 ], and relatively little attention has been given to the combined application of these biomarkers and ratios for the differential diagnosis of the multiple types of PE. Although plenty of serum and PF biomarkers have been previously mentioned as potential diagnostic indicators, performance of their diagnostic value is still doubtful, especially in a clinical setting in general hospitals in China that patients with common and rare PE are included. To further understand and rationally use the potential application value of biomarkers in the diagnosis of common clinical PE, we investigated the biomarkers and their ratios in the serum and PF for the differential diagnosis of TPE, MPE, complicated PPE (CPPE), uncomplicated PPE (UPPE), and PE caused by CTDs, and developed a diagnostic strategy for PE for reference and guidance.

Study design

This is a retrospective survey and analysis of the biomarkers and ratios in the serum and PF for the differential diagnosis of the multiple types of PE. Inpatients, who underwent thoracentesis at Peking University People’s Hospital (PKUPH, a non-TB specialist, comprehensive teaching hospital in Beijing, China) from November 2016 to April 2019 with exudative PE according to Light’s criteria, were enrolled in this study. Exudative PE was further classified as TPE, MPE, CPPE, UPPE, or PE caused by CTDs.

We classified exudative PE etiology into five categories. (1) TPE diagnosis was based on the presence of a caseous granuloma in the pleural biopsy and/or a positive culture for Mycobacterium tuberculosis (MTB) in the PF or pleural tissue with exudative PE, presenting with both clinical and radiological responses to anti-TB treatment [ 18 ]. (2) MPE was diagnosed when PF cytology or pleural biopsy was positive for malignant cells [ 19 ]. (3) PPE was defined as exudative effusion associated with bacterial pneumonia, lung abscess, or bronchiectasis, with no MTB in the PF obtained by continuous thoracentesis procedures and no evidence of MTB in the pathological manifestations of inflammatory pleuritis, pleural fibrosis and plaques, or chronic empyema [ 16 ]. PPE was further divided into UPPE, when patients responded to antibiotic treatment alone, and CPPE, when non-purulent-appearing effusions required medical interventions such as drainage [ 2 , 16 ]. (4) PE caused by CTDs was defined by positive histopathology or serology with a final diagnosis of CTDs and excluding other causes of PE [ 4 , 21 , 22 , 23 , 24 ].

Biomarker assays

Eleven biomarkers in the serum and PF were investigated in this study. The white blood cell (WBC) count in the serum was tested using Coulter DxH800 (Beckman Coulter Inc., Miami, FL, USA); serum CRP (CRP), PF total protein (TP), PF glucose (Glu), PF ADA (ADA), PF albumin (PF-Alb), and PF-LDH levels were investigated using the routine analyzer LABOSPECT 008 (Hitachi High-Technologies, Tokyo, Japan); serum albumin (S-Alb) and S-LDH were tested using the AU5800 analyzer (Beckman Coulter Inc., Miami, FL, USA); PF total cell count was manually tested using the Neubauer counting chamber (Qijing Biochemical Instrument Co., Ltd., Shanghai, China); and PF pH was manually measured using pH paper (Sanaisi glass instrument, shanghai, China). As CRP results of some patients could not be obtained, they were excluded from CRP analysis.

Data analysis

The Shapiro–Wilk test was used to evaluate the distribution, while the Kruskal–Wallis test was used to determine the differences in variables among the groups for non-normal distribution. A comparison between two groups was analyzed by the Mann–Whitney U test. Only parameters that yielded statistically significant P values < 0.01 between the two groups were entered for the construction of the receiver operating characteristic (ROC) curve. The ROC curve was analyzed, and the diagnostic accuracy was assessed from the area under the curve (AUC). Statistical analyses were performed using the SPSS software version 22.0 (SPSS Inc., Chicago, IL, USA) and MedCalc (MedCalc Software, Ostend, Belgium). Then the three parameters with the highest AUC values were enrolled in the decision-tree construction (if the number of parameters was less than 3, or the number of parallels was more than 3, all were selected). Salford Predictive Modeler 8.0 (Salford Systems, San Diego, CA, USA), a data mining platform for creating predictive models from databases and identifying the most predictive cut-off for each independent variable [ 25 ], was used to differentially diagnose these five types of PE, and cross-validation was repeated 10 times to evaluate the accuracy of the model.

Patient characteristics

Totally 112 patients with a definitive PE diagnosis, including 25 MPE, 33 TPE, 46 PPE (19 CPPE and 27 UPPE) patients, and 8 PE caused by CTDs, were reviewed (Table 1 ). All information of the 11 biomarkers of 92 patients, among the 112 patients, was collected, while CRP results of 20 patients (5 TPE, 4 MPE, 3 CPPE, 7 UPPE, and 1 PE caused by CTDs) could not be obtained. The mean age of the patients was 58.4 ± 17.2 years, and 72 cases were male (64.3%).

Differentiating TPE from other causes of PE

(1) TPE versus (vs) MPE To distinguish TPE from MPE (Table 1 , Fig.  1 , Additional file 1 : Table S1, and Additional file 1 : Fig. S1), ADA, WBC/ADA, and WBC levels were investigated, and significant differences ( P  < 0.01) were observed. According to the ROC curve, the AUC values were 0.993 for both ADA (> 19.5 U/L) and WBC/ADA (≤ 271.8). The sensitivity of both ADA and WBC/ADA was 100% (95% confidence interval [CI] was 89.4–100%), and the specificity of both was 92.0% (95% CI 74.0–99.0%). With both positive likelihood ratios (LR+) greater than 10 and negative likelihood ratios (LR-) less than 0.1 [ 26 ], both ADA (> 19.5 U/L) and WBC/ADA (≤ 271.8) can provide highly credible positive and negative results.

Comparison of the five different types of pleural effusion. The grid shows the biomarkers and ratios that show significant differences ( P  < 0.01) and the calculated cutoff values. These parameters are arranged in descending order of their corresponding area under the curve (AUC) values. TPE, tuberculous pleural effusion; MPE, malignant pleural effusion; CPPE, complicated parapneumonic effusion; UPPE, uncomplicated parapneumonic effusion; CTDs, connective tissue diseases. Blood parameters: CRP, C-reactive protein; S-Alb, serum albumin; S-LDH, serum lactate dehydrogenase; WBC, white blood cells. Pleural fluid parameters: ADA, adenosine deaminase; Glu, glucose; PF-Alb, pleural fluid albumin; PF-LDH, pleural fluid lactate dehydrogenase; TP, total protein

(2) TPE vs CPPE To differentiate TPE from CPPE (Table 1 , Fig.  1 , Additional file 1 : Table S2, and Additional file 1 : Fig. S2), WBC/PF-Alb (≤ 287.9) was shown to have the highest AUC value (0.968, 95% CI 0.878–0.997), with 93.9% (95% CI 79.8–99.3%) sensitivity and 89.5% (95% CI 66.9–98.7%) specificity. PF-LDH/PF-Alb (≤ 33.67) and WBC (≤ 7700.0 cells/μL) also showed high AUC values (> 0.94), with high sensitivities (> 90%) and specificities (> 94%).

(3) TPE vs UPPE To differentiate TPE from UPPE (Table 1 , Fig.  1 , Additional file 1 : Table S3, and Additional file 1 : Fig. S3), ADA (> 19.5 U/L) and WBC/ADA (≤ 271.8) were shown to have the largest AUC value (1), with 100% (95% CI 89.4–100%) sensitivity and 100% (95% CI 87.2–100%) specificity. TP/ADA(≤ 1.9) and ADA/Glu (> 3.6) also showed high AUC values (> 0.96), with high sensitivities (> 93%) and specificities (> 92%).

(4) TPE vs PE caused by CTDs To differentiate TPE from PE caused by CTDs (Table 1 , Fig.  1 , Additional file 1 : Table S4, and Additional file 1 : Fig. S4), ADA (> 22.4 U/L) and ADA/Glu (> 3.8) were shown to have the highest AUC value (0.989), with high sensitivities (> 90%) and 100% specificities. PF-Alb/ADA (≤ 1.2) and PF-LDH (> 206.0 U/L) also showed high AUC values (> 0.95), with 93.9% sensitivity and 87.5% specificity.

Differential diagnosis of MPE, CPPE, UPPE, and PE caused by CTDs

(5) MPE vs CPPE When the MPE and CPPE groups were compared (Table 1 , Fig.  1 , Additional file 1 : Table S5, and Additional file 1 : Fig. S5), ADA (≤ 19.5 U/L) showed the best diagnostic performance (AUC = 0.955), with 92.0% (95% CI 74.0–99.0%) sensitivity and 89.5% (95% CI 66.9–98.7%) specificity. CRP/Glu (≤ 15.2), PF-LDH (≤ 614.0 U/L), ADA/Glu (≤ 3.7), PF-LDH/Glu (≤ 127.1), and WBC/PF-LDH (> 10.3) also showed high AUC values (> 0.91).

(6) MPE vs UPPE To differentiate MPE from UPPE (Table 1 , Fig.  1 , Additional file 1 : Table S6, and Additional file 1 : Fig. S6), TP (> 40.0 g/dL) was shown to have the largest AUC value (0.788), with 88.0% (95% CI 68.8–97.5%) sensitivity and 70.4% (95% CI 49.8–86.2%) specificity. PF-Alb (> 20.6 g/dL) (AUC = 0.750) showed 84.0% (95% CI 63.9–95.5%) sensitivity and 59.3% (95% CI 38.8–77.6%) specificity.

(7) MPE vs PE caused by CTDs Statistically significant difference in only the PF-LDH levels between the PE caused by CTDs and MPE groups was observed (AUC = 0.895) ( P  < 0.01) (Table 1 , Fig.  1 , Additional file 1 : Table S7, and Additional file 1 : Fig. S7). At a cutoff value of > 206.0 U/L, PF-LDH showed 76.0% (95% CI 54.9–90.6%) sensitivity and 87.5% (95% CI 47.3–99.7%) specificity.

(8) CPPE vs UPPE On comparing the CPPE and UPPE groups (Table 1 , Fig.  1 , Additional file 1 : Table S8, and Additional file 1 : Fig. S8), ADA (> 19.5 U/L), PF-LDH (> 586.0 U/L), PF-LDH/Glu (> 157.6), and ADA/Glu (> 3.6) were all found to show high AUC values (> 0.94), with high sensitivities (> 84%) and specificities (> 88%).

(9) CPPE vs PE caused by CTDs To distinguish CPPE from PE caused by CTDs (Table 1 , Fig.  1 , Additional file 1 : Table S9, and Additional file 1 : Fig. S9), CRP (> 19.3 mg/L), PF-LDH (> 354.0 U/L), WBC/PF-LDH (≤ 13.1), CRP/Glu (> 3.4), and PF-LDH/Glu (> 59.4) were all shown to have the best diagnostic performances (AUC = 1), with 100% sensitivity and 100% specificity.

(10) UPPE vs PE caused by CTDs Significant difference in only the CRP levels between the PE caused by CTDs and UPPE groups was observed (AUC = 0.871) ( P  < 0.01) (Table 1 , Fig.  1 , Additional file 1 : Table S10, and Additional file 1 : Fig. S10). At a cutoff value of > 9.74 mg/L, CRP showed 85.0% (95% CI 62.1–96.8%) sensitivity and 85.7% (95% CI 42.1–99.6%) specificity.

Differential diagnosis of the five types of PE by the decision-tree analysis

The biomarkers and ratios were subjected to the decision-tree analysis, and the combination of ADA, S-Alb, S-LDH, TP, PF-LDH/ADA, and PF-LDH/TP were found to provide the best predictive capacity (Fig.  2 ). At cutoff values of ADA > 19.65 U/L, PF-LDH/ADA ≤ 29.61, and S-Alb > 23.95 g/dL, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for TPE diagnosis were 100% (95% CI 89.6–100%), 98.7% (95% CI 93.2–100%), 97.1% (95% CI 85.1–99.6%), and 100.% (95% CI 95.3–100%), respectively (Table 2 ). Similarly, the sensitivity, specificity, PPV, and NPV for MPE diagnosis were 80.0%, 87.4%, 64.5%, and 93.8%, respectively; for CPPE diagnosis were 89.5%, 98.9%, 94.4%, and 97.9%, respectively; for UPPE diagnosis were 66.7%, 96.5%, 85.7%, and 90.1%, respectively; and for the diagnosis of PE caused by CTDs were 87.5%, 99.0%, 87.5%, and 99.0%, respectively. The overall accuracy of the decision-tree analysis was 84.8% (95/112, 95% CI 77.0–90.3%).

Differential diagnosis of the five types of pleural effusion by decision-tree analysis. The combination of ADA, S-Alb, S-LDH, TP, PF-LDH/ADA, and PF-LDH/TP provided the best predictive capacity, with an overall accuracy of 84.8% (95/112). TPE, tuberculous pleural effusion; MPE, malignant pleural effusion; CPPE, complicated parapneumonic effusion; UPPE, uncomplicated parapneumonic effusion; CTDs, connective tissue diseases. ADA, pleural fluid adenosine deaminase; PF-LDH, pleural fluid lactate dehydrogenase; S-Alb, serum albumin; S-LDH, serum lactate dehydrogenase; TP, pleural fluid total protein

ADA showed good diagnostic performance (AUC > 0.98) in differentiating TPE from MPE, UPPE, and PE caused by CTDs, and this finding supported evidences from previous studies [ 10 , 16 , 19 , 27 ]. It is now well established that the observed increase in ADA, attributed to the rise in the levels of different types of ADA: increased ADA levels in tuberculosis, is primarily due to an increase in the activity of ADA isoenzyme (ADA-2), which is only found in monocytes-macrophages. However, high levels of ADA-1 are usually associated with CPPE or empyema [ 16 , 28 , 29 ]. Beside its application in tuberculosis diagnosis, ADA also showed great diagnostic value in distinguishing MPE and CPPE, CPPE and UPPE, and CPPE and PE caused by CTDs (AUC > 0.93), as mentioned previously [ 16 , 30 ]. The diagnostic values of ADA were further examined by using likelihood ratios (LR). Agreed with those evaluated by ROC curves, ADA showed both high LR+ (> 10) and low LR− (< 0.1) in distinguish TPE from MPE, UPPE, and PE caused by CTDs (Table S1, S3 and S4). However, it is still difficult to distinguish TPE from CPPE based on ADA alone.

A significant association of high PF-LDH level with high degree of necrosis in pleural cavity has been observed previously [ 31 ]. In our study, PF-LDH played an important role in differentiating CPPE and TPE from the other three types of PE, thus expanding previous research [ 10 , 30 , 32 ]. Significant difference in only the PF-LDH levels between the PE caused by CTDs and MPE groups ( P  < 0.001) was observed, and this might be due to the LDH released from cells that were invaded and destroyed by the tumor; meanwhile, tumor cells preferentially use glycolysis, rather than oxidative phosphorylation (a switch, which is mediated by LDH, in the ATP generation pathway), to obtain energy [ 31 , 33 , 34 , 35 , 36 ]. In future studies, we must investigate more immunological and oncological indicators for MPE diagnosis by taking clinical diagnosis into account. Previous study believed that the use of biomarkers in MPE diagnosis is still limited due to inadequate validation [ 37 ]. However, this study revealed promising biomarkers in the diagnosis of MPE, including PF-LDH, ADA, TP, and so on, thereby strengthening the use of biomarkers in MPE diagnosis and promoted a further understanding of the clinical application of biomarkers.

As a widely used diagnostic indicator for differentiating infectious and non-infectious diseases, (serum) CRP showed high clinical diagnostic value (AUC > 0.87) in differentiating infectious PE (TPE, CPPE, and UPPE) from PE caused by CTDs. This result extended the findings of previous investigations, which reported the value of PF-CRP in diagnosing infectious effusions (AUC = 0.82) [ 18 ], and a high AUC (0.899) also observed in (serum) CRP for differentiating MPE and CPPE [ 38 ]. Significant difference in only CRP levels (AUC = 0.871) between the PE caused by CTDs and UPPE groups was observed; thus, the clinical diagnostic, traditional microbiology culture method and immunological biomarkers remain essential. Interestingly, CRP, CRP/PF-Alb, CRP/Glu, CRP/ADA, and WBC/CRP showed great value in distinguishing CPPE from TPE, MPE, and PE caused by CTDs, which seems to imply CRP-based CPPE identification strategies could be developed. However, the CRP value is affected by many factors, for instance, inflammation caused by injury, infection, and autoimmune diseases can lead to increased (serum) CRP levels [ 39 , 40 , 41 , 42 ]; other factors, including smoking and obesity, can also lead to high levels of CRP [ 43 , 44 ]. Therefore, the universality of using serum CRP for PE identification is limited, and its clinical application should be cautious.

According to the diagnostic classification tree, the combination of ADA, S-Alb, S-LDH, TP, PF-LDH/ADA, and PF-LDH/TP provided the best predictive capacity, with an overall accuracy of 84.8%, thus showing great potential in the clinical differential diagnosis of the five types of PE, especially TPE (100% sensitivity and 98.7% specificity).

Considering the poor performance of the traditional tuberculosis culture (time-consuming) and molecular techniques (including Xpert MTB/RIF, showed low sensitivity) in detecting TPE, the method of integrated biomarkers and ratios provided a strategy for rapid and accurate TPE diagnosis, and could be clinically practiced. Little was known about the biomarkers of PE caused by CTDs previously, and this study suggested that the combination of a few biomarkers and ratios could provide a diagnostic strategy for PE caused by CTDs with 87.5% sensitivity and 99.0% specificity. Moreover, UPPE (29.6%, 8/27), CPPE (10.5%, 2/19), and PE caused by CTDs (12.5%, 1/8) could be misdiagnosed as MPE, while MPE could be misdiagnosed as UPPE (12.0%, 3/25), TPE (4.0%, 1/25), or CPPE (4.0%, 1/25), implying that there were more concerns in the clinical differential diagnosis of MPE. The sensitivity for UPPE diagnosis was only 66.6%; thus, microbial culture was still found to be necessary to detect UPPE. The total accuracy was only slightly lower in this study than in previous studies (94.6%-96.6%), which only reported the differentiation of TPE from MPE by investigating QuantiFERON-TB Gold In-Tube (QFT-GIT), pleural ADA, PF-LDH, and a few demographic factors (age, fever) [ 45 , 46 ]. However, for patients with unknown PE in clinical settings, the decision-tree analysis developed in this study could help in diagnosing more types of PE and provide doctors with a more detailed diagnostic guidance.

Since there are few studies that use biomarkers (and their ratios) and decision-tree to assist in the diagnosis of multiple types of PE in China, this research could help clinicians better perform early diagnosis and treatment (especially for TPE, due to the limitation of traditional methods, and for CPPE, as the patients requiring surgery), reduce invasive medical operations, and provide a reference for the research of using biomarkers to assist in the diagnosis of PE in general hospitals in China. It also provides a foundation for future multi-center, large-scale and in-depth research.

Study limitations

This study has some limitations. First, it was a retrospective study performed in a single center. Second, the study included a relatively small number of patients with PE caused by CTDs (n = 8), thus limited the relevant scope of our findings. For instance, PF-LDH showed a high diagnostic performance in differentiating MPE and PE caused by CTDs; however, whether it is suitable to be used as a clinical diagnostic index for other CTD patients must be verified. Third, the absence of CRP results of a few patients (n = 20) produced uncertain results based on the CRP level and corresponding ratio. However, since the sensitivity and specificity of the cutoff values and corresponding 95% CI between pairs of the different types of PE groups were obtained, future prospective studies that cover a larger sample size and more comprehensive parameters can be designed.

Conclusions

In this study, we investigated the significant differences in the biomarkers and ratios, such as ADA, CRP, PF-Alb, PF-LDH, WBC, WBC/PF-LDH, and PF-LDH/ADA, between pairs of the different types of PE groups and developed a decision-tree with an overall accuracy of 84.8% to help differentially diagnose the five types of PE in clinical settings. Notably, the strategy with cutoff values of ADA > 19.65 U/L, PF-LDH/ADA ≤ 29.61, and S-Alb > 23.95 g/dL provided 100% sensitivity and 98.7% specificity for the differential diagnosis of TPE. Decision-tree analysis is a comprehensive and rapid method that based on serum/PF biomarkers/ratios routinely assessed in clinical practice, which could provide more help in early target treatment and appropriate patient care, contributing to better prevention of disease progression.

Availability of data and materials

The full data and materials can be obtained from Dr. Li (Shuguang Li) upon sufficient and reasonable request.

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Acknowledgements

We would like to thank Editage ( www.editage.cn ) for English language editing. We also thank the editor and reviewers for relevant and helpful comments on the manuscript.

The study was partially supported by National Natural Science Foundation of China (Grant No. 81625014). The funding had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Department of Clinical Laboratory, Peking University People’s Hospital, Xizhimen South Avenue No. 11, Beijing, 100044, China

Liyan Lin, Shuguang Li & Hui Wang

Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China

Shuguang Li & Hui Wang

Department of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, 2006, Australia

School of Public Health, The University of Sydney, Sydney, 2006, Australia

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LL, SL and HW designed the work. LL, SL, and QX contributed to data collection and analyses. LL, SL and HW wrote the manuscript. All authors read and approved the final manuscript.

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Lin, L., Li, S., Xiong, Q. et al. A retrospective study on the combined biomarkers and ratios in serum and pleural fluid to distinguish the multiple types of pleural effusion. BMC Pulm Med 21 , 95 (2021). https://doi.org/10.1186/s12890-021-01459-w

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• Pleural effusion
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Advancement in pleura effusion diagnosis: a systematic review and meta-analysis of point-of-care ultrasound versus radiographic thoracic imaging

• Hany A. Zaki   ORCID: orcid.org/0000-0002-3994-7088 1 ,
• Bilal Albaroudi   ORCID: orcid.org/0000-0002-7728-8394 1 ,
• Eman E. Shaban 2 ,
• Ahmed Shaban 3 ,
• Mohamed Elgassim 1 ,
• Nood Dhafi Almarri 1 ,
• Kaleem Basharat 1 &
• Aftab Mohammad Azad 1 , 4  

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Pleural effusion is a fluid buildup in the pleural space that mostly result from congestive heart failure, bacterial pneumonia, malignancy, and pulmonary embolism. The diagnosis of this condition can be challenging as it presents symptoms that may overlap with other conditions; therefore, imaging diagnostic tools such as chest x-ray/radiograph (CXR), point-of-care ultrasound (POCUS), and computed tomography (CT) have been employed to make an accurate diagnosis. Although POCUS has high diagnostic accuracy, it is yet to be considered a first-line diagnostic tool as most physicians use radiography. Therefore, the current meta-analysis was designed to compare POCUS to chest radiography.

n extended search for studies related to our topic was done on five electronic databases, including PubMed, Medline, Embase, Scopus, and Google Scholar. A quality assessment using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) was performed on all eligible articles obtained from the databases. Moreover, the diagnostic accuracy of POCUS and CXR was performed using STATA 16 software.

Our search yielded 1642 articles, of which only 18 were eligible for inclusion and analysis. The pooled analysis showed that POCUS had a higher diagnostic accuracy compared to CXR (94.54% (95% CI 91.74–97.34) vs. 67.68% (95% CI 58.29–77.08) and 97.88% (95% CI 95.77–99.99) vs. 85.30% (95% CI 80.06–90.54) sensitivity and specificity, respectively). A subgroup analysis based on the position of patients during examinations showed that POCUS carried out in supine and upright positions had higher specificity than other POCUS positions (99%). In comparison, lateral decubitus CXR had higher sensitivity (96%) and specificity (99%) than the other CXR positions. Further subgroup analyses demonstrated that CXR had higher specificity in studies that included more than 100 patients (92.74% (95% CI 85.41–100). Moreover, CXR tends to have a higher diagnostic accuracy when other CXR positions are used as reference tests (93.38% (95% CI 86.30–100) and 98.51% (95% CI 94.65–100) sensitivity and specificity, respectively).

POCUS as an imaging modality has higher diagnostic accuracy than CXR in detecting pleural effusion. Moreover, the accuracy is still high even when performed by physicians with less POCUS training. Therefore, we suggest it is considered a first-line imaging tool for diagnosing pleural effusion at the patients’ bedside.

Introduction

Pleural effusion is a fluid buildup in the pleural space that affects approximately 320 persons out of every 100,000 in developed nations and at least 1.5 million people in the United States annually [ 1 , 2 ]. The majority of these cases are caused by congestive heart failure, bacterial pneumonia, malignancy, or pulmonary embolism. Research suggests that over two-thirds of malignant pleural effusions occur in women, notably those with breast and gynecologic malignancies [ 3 , 4 ]. Similarly, pleural effusions caused by systemic lupus erythematosus are more frequent in women than in males [ 4 ]. However, in the United States alone, pleural effusions resulting from malignant mesothelioma are more likely to manifest in males owing to increased occupational asbestos exposure [ 4 ]. Furthermore, pleural effusion mostly occurs in adult patients. However, it is becoming increasingly prevalent in children as a result of underlying pneumonia [ 5 ]. Pleural effusion in fetuses has also been documented, and in certain scenarios, it may be managed before birth [ 6 ].

The diagnosis of pleural effusion can be very challenging as it presents symptoms that may overlap with conditions such as pneumonia, pulmonary embolism, acute coronary syndrome, pneumothorax, chromonic obstructive pulmonary disease, heart failure, and pulmonary edema. Therefore, diagnostic tools are vital as they aid healthcare professionals make accurate diagnosis. Various imaging tests, including chest x-ray/radiograph (CXR), ultrasound, and computerized tomography (CT), have been adopted in detecting pleural effusion. Traditionally, CXR was considered a first-line imaging tool for pleural effusions. However, evidence reveals that upright CXR may miss a considerable percentage of pleural effusions. Brixey and colleagues found that upright CXR missed as much as 10% of parapneumonic effusions that were substantial enough to suggest the need for drainage [ 7 ]. Moreover, other researchers have reported that supine anterior–posterior CXR might miss a large number of pleural effusions compared to chest CT, ultrasound, and lateral decubitus radiographs [ 8 , 9 , 10 ].

On the other hand, point-of-care ultrasound (POCUS) has gained popularity in diagnosing pleural effusions because it aids healthcare professionals to gather and analyze images at the bedside and make quick decisions. Moreover, data pooled from previous studies have shown that it has a very high sensitivity and specificity [ 11 ]. However, it is yet to be considered a first-line diagnostic tool for pleural effusion as most physicians use radiography. Therefore, the current meta-analysis was designed to compare POCUS to chest radiography and make a clear recommendation for healthcare professionals.

Protocol and registration

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guiding principles and protocol registered on PROSPERO article (CRD42023420515) .

Eligibility criteria

Two independent reviewers derived a set of conditions to include and exclude articles in the present study. In case of discrepancies during this process, the reviewers engaged in constructive debates. The criteria used to select studies for inclusion were as follows:

Randomized trials or observational studies written and published in English. This criterion assisted us in evading the literal translation of scientific terminologies, which would have hampered our scientific goal.

Studies that directly compared POCUS to chest x-ray or individually assessed the role of these imaging tests in the diagnosis of pleural effusions.

Studies reporting at least one of the following outcomes: sensitivity, specificity, or true positives, true negatives, false negatives, and false positives.

Conversely, studies were regarded ineligible for inclusion due to the following reasons.

Studies that were designed as either systematic reviews, meta-analyses, abstracts without full articles, case reports and series, letters to the editor, guidelines, or recommendations.

Studies that evaluated the accuracy of either POCUS or CXR in diagnosing underlying diseases associated with pleural effusion or other conditions.

Studies that integrated POCUS or CXR with other diagnostic tools when evaluating pleural effusion.

Literature search

Two reviewers independently explored five electronic databases (PubMed, Medline, Embase, Scopus, and Google Scholar) for papers related to the topic at hand. To ease the search on these databases, the reviewers employed the Boolean operators “AND” and “OR” to integrate keywords and produce well-defined mesh phrases. These mesh phrases were as follows: (“Point of care ultrasound” OR “POCUS” OR “bedside ultrasound” OR “sonography”) AND (“Chest x-rays” OR “Chest Radiography” OR “Radiology”) AND (“pleural effusion” OR “parapneumonic effusion” OR “effusion” OR “Pleural free fluid”). The reviewers also screened reference lists of articles from these databases for additional studies and excluded all close or exact duplicates and grey literature to improve the scientific purpose of our study.

Quality appraisal

Our research was structured as a diagnostic review; therefore, two experienced reviewers were asked to independently evaluate methodological quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool provided in the Review Manager software (RevMan 5.4.1). Using this framework, the reviewers derived various signaling questions to judge the risk of bias, applicability, and concerns. Any discrepancies during this process were resolved by consulting a third reviewer.

Data extraction

The two reviewers assigned for data extraction independently gathered and assembled relevant data in a tabular manner (Table 1 ). The data extracted included; Author ID (surname of the first author and year the study was published), study design, location of the study (Country), characteristics of the study population (sample size, gender distribution, and mean/median age), reference tests, ultrasound and x-ray machines used, operators, and main outcomes. The main outcomes were specificity, sensitivity, false negatives, and false positives. In case of disagreements, the two reviewers resolved their issues through constructive dialogues or by sorting the opinion of a third reviewer. Moreover, web-based programs were used to calculate either sensitivity or specificity in studies where data were not presented.

Data synthesis

STATA 16 statistical software was used to calculate the overall diagnostic accuracy of CXR and POCUS in detecting pleural effusion. To analyze the diagnostic accuracy, the sensitivity and specificity values with their 95% confidence intervals were pooled using the Der Simonian-Laird random effect model. Heterogeneity was also calculated using the I 2 statistics, of which values between 0 and 49%, 50–70%, and 71–100% were regarded as low, moderate, and high, respectively. Moreover, we carried out subgroup analyses based on the position of the patients during the examinations, sample size, the country in which the study was carried out, reference test, POCUS level of training, POCUS machine, and CXR operator,

Study selection

After applying the mesh terms mentioned earlier on the electronic databases, 1642 articles were attained. A duplicate analysis of these articles revealed that 308 were either close or exact duplicates and were excluded. Titles and abstracts of the remaining articles were then screened, and 948 articles that did not meet the screening criteria were excluded. Out of the 386 remaining articles, 301 were not retrieved because they were either recommendation studies abstract without full articles, diagnostic algorithm studies, case reports, or systematic reviews. Finally, we included 18 articles [ 7 , 8 , 9 , 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] (Table 1 ) as the other 67 articles were deemed ineligible due to the following reasons; 16 were published in other languages, 33 evaluated the accuracy of either POCUS or chest x-rays in the diagnosis of underlying diseases associated with the pleural effusion or other conditions and 18 articles integrated POCUS or CXR with other diagnostic tools when evaluating pleural effusion. The full selection criteria is summarized in PRISMA flow diagram below (Fig.  1 ).

PRISMA flow diagram for study selection

Quality assessment results

The risk of bias assessment is summarized in Fig.  2 below. The overall assessment using the QUADAS-2 tool has shown that all the studies included in our analysis have good methodological quality as they satisfied at least 4 of the 7 assessment criteria. In regard with patient selection, our evaluation revealed that most of the studies had an unclear risk bias because they did not specify the sampling method or used a convenience sampling. However, one of the studies showed a high risk of bias because it used a case control study design. Similarly, one study showed a high risk of bias based on the index test. This risk of bias was associated with the fact the radiologist who interpreted the reference test results (CT scan) also interpreted results of the index test (CXR); therefore, blinding of this interpreter to the index results was not possible. Moreover, our assessment revealed that the reference tests of three articles introduced a high a risk of bias to our analysis. The bias in these studies was because they used reference tests that were unlikely to classify pleural effusion correctly.

QUADAS-2 risk of bias summary

Diagnostic performance of POCUS

12 studies with 653 patients suspected of pleural effusion used POCUS as the imaging diagnostic tool. Data pooled from these studies resulted in an overall sensitivity and specificity of 94.54% (95% CI 91.74–97.34) and 97.88% (95% CI 95.77–99.99), respectively (Figs. 3 , 4 ). Moreover, we carried out a subgroup analysis based on the patient’s position during examinations and found that the test for subgroup analysis on the sensitivity of POCUS was statistically insignificant ( p  = 0.26), suggesting that the position of ultrasound examinations did not influence the sensitivity of POCUS. However, the test for subgroup analysis on the specificity of POCUS was statistically significant ( p  < 0.001), meaning that position during examinations influenced the specificity of POCUS. In these analyses, the specificity was lowest for POCUS exams in the lateral decubitus position (70%) and highest for exams in both supine and upright positions (99%).

Forest plot showing the sensitivity of POCUS in detecting pleural effusion according to the patients’ position during examination

Forest plot showing the specificity of POCUS in detecting pleural effusion according to the patients’ position during examination

Diagnostic performance of CXR

15 studies with 955 patients suspected to have pleural effusion used CXR as the imaging diagnostic tool. Data pooled from these studies resulted in 67.68% (95% CI 58.29–77.08) sensitivity and 85.30% (95% CI 80.06–90.54) specificity in detecting pleural effusion (Figs.  5 , 6 ). Our subgroup analysis also showed that the test for differences was significant for both CXR sensitivity ( p  < 0.001) and specificity ( p  < 0.001), meaning that the position of examinations highly influenced the diagnostic accuracy of CXR. From the analyses, we noted that CXR carried out in lateral decubitus position had higher sensitivity and specificity for detecting pleural effusion than supine and upright CXR.

Forest plot showing the sensitivity of CXR in detecting pleural effusion according to the patients’ position during examination

Subgroup analyses

Further subgroup analyses have shown that the sensitivity of POCUS was higher for procedures carried out in Africa, Europe, and the United States and lower for procedures carried out in Asia. However, none of the other factors, including sample size, machine type, level of training, and reference test, influenced the diagnostic accuracy of this imaging modality. On the other hand, our results have shown that the sample size and reference test influenced the diagnostic accuracy of CXR. The pooled data suggest that the specificity of CXR is higher in studies including 100 patients or more. Additionally, our results suggest that the diagnostic accuracy becomes higher when CXR carried out in other positions is used as the reference test (Table  2 ).

The current meta-analysis has shown that POCUS has a higher sensitivity and specificity in the diagnosis of pleural effusion than CXR (94.54 vs. 67.68% and 97.88 vs. 85.30%, respectively). When the results were limited to the position of examinations, we noted that the specificity of POCUS can be improved by carrying out the procedure in both upright and supine positions. On the other hand, we noted that CXR performed in the lateral decubitus position has higher diagnostic accuracy than when performed in the supine or upright position.

Our findings are consistent with two previous reviews comparing ultrasonography and CXR in detecting pleural effusion. Yousefifard and colleagues pooled data from 12 studies and found that ultrasonography was 94% sensitive and 98% specific, while CXR was 51% sensitive and 91% specific in diagnosing pleural effusion [ 26 ]. Similarly, Grimberg et al. [ 11 ] found the sensitivity of ultrasound to be higher than that of CXR in detecting pleural effusion (93 vs. 24%). However, the specificity of CXR was similar to that of ultrasound (100 vs. 96%). The variation in this study can be attributed to the fact the authors included fewer studies in their analyses. Based on these findings, it is safe to say that POCUS is a superior diagnostic tool for detecting pleural effusion than CXR.

Although our findings support the superiority of POCUS, it is evident that CXR carried out in lateral decubitus position has a high sensitivity and specificity. This high diagnostic accuracy can be explained by the fact that lateral decubitus CXR and chest ultrasound are considered more efficient diagnostic tools for detecting small amounts of free pleural fluids [ 27 , 28 ]. Reports have also shown lateral decubitus CXR is highly sensitive in detecting as little as 50 ml of fluid accumulating in the lungs [ 29 ]. Furthermore, the studies used to analyze the diagnostic accuracy of lateral decubitus CXR employed other radiographic findings as their reference test, which affected their results. This is evident from our subgroup analysis which has shown that reference test has a significant impact on the diagnostic accuracy of CXR. Research has also shown that the false negatives and positives in CXR are high, meaning that using it as a reference test is not recommended as some of the diagnoses can be missed and influence the management of pleural effusion.

Our findings also suggest that pocket-size ultrasound devices have lower specificity compared to other ultrasound devices. Additionally, POCUS carried out on Asian patients seems to have a lower sensitivity compared to when it is carried out on patients from other regions. Although there is no definitive reason for these outcomes, we can attribute them to the different study population. For example, Graven et al. [ 13 ] included cardiac patients, Danish et al. [ 23 ] included patients with acute lung injury score of ≥ 1 and Mumtaz et al. [ 24 ] evaluated road traffic patients. Nevertheless, the sample sizes of the studies used in these subgroup analyses was small (< 100). Therefore, further investigation is required to establish the diagnostic accuracy of pocket-size ultrasound devices and determine whether the geographic region of POCUS application might affect its diagnostic accuracy for pleural effusion diagnosis.

Apart from diagnosing pleural effusion, research has also shown that ultrasound examinations can identify the nature of pleural effusion. According to pathogenesis, pleural effusions are categorized as either exudative or transudative. Exudative pleural effusion (EPE) results from inflammatory processes of the pleura and/or decreased lymphatic drainage and is mainly caused by diseases such as pleural tuberculosis and cancer [ 30 , 31 ], while transudative (TPE) results from the oncotic and hydrostatic pressure imbalances and is mainly caused by systematic factors such as congestive heart failure and cirrhosis. Yang and colleagues investigated the role of high-frequency (3.5, 5.0, and 7.5 MHz) real-time ultrasound in identifying the nature of pleural effusions in 320 patients and found that all 96 patients with TPE exhibited anechoic appearance on the ultrasound exams [ 32 ]. On the other hand, of the 224 EPE categorized into non-malignant and malignant, 78 were anechoic, 50 were complex non-septate, 76 were complex septate, and 22 were homogenous. Similarly, Qureshi et al. [ 33 ] evaluated the diagnostic accuracy of chest ultrasound in identifying malignant diseases among patients with pleural effusions and noted that it could distinguish between malignant and benign effusions (79% sensitive and 100% specific). In this study, malignancy was associated with a mural or visceral pleura thickness, the presence of visceral pleural nodules, and abnormalities of the diaphragm. It was also reported that ultrasound was capable of revealing the existence of liver metastases. Although these findings show that ultrasound findings can identify EPE and TPE, further studies are required to investigate whether this differentiation is mainly due to sonographic findings alone or combined with other clinical data.

Additionally, POCUS is essential in assessing the volume of pleural effusion, which is important in deciding whether to drain the effusion. Research has revealed that various ultrasound methods have been proposed to estimate pleural fluid accumulation. Roch and colleagues carried out a study to investigate the accuracy of lung ultrasound in predicting pleural effusions of greater than 500 ml in 44 patients on mechanical ventilation [ 34 ]. They found a correlation between the interpleural distance measured by ultrasound at the base of the lung or fifth rib space and volume drainage. Additionally, Usta and colleagues measured the maximum distance between the diaphragm mid-height and seated visceral pleura ( D ) and found a strong correlation between D and the expired volume ( V ). Therefore, they derived the equation for estimating the volume of pleural volume as V (ml) = 16* D (mm) [ 35 ]. Balik et al. [ 36 ] also found that there was a strong correlation between pleural volume and the maximum maximal interpleural distance (Sep); therefore, they proposed that the pleural volume can be estimated using the following equation; V (ml) = 20*Sep(mm). Despite these proposed estimations, a reliable estimation is still challenging due to various reasons. First, Ultrasound findings are usually affected by the chest cavity size. In taller patients with large chest cavities, the volume of the fluid is normally distributed over a larger area compared to those with smaller chest cavities. Therefore, the amount of fluid in the pleural cavity can be underestimated or overestimated. Secondly, the position of patients during ultrasound exams can influence the distribution of pleural fluid and consequently affect the measurement of the fluid. Third, very large volumes of pleural fluids can influence the measurements due to lung collapse, which causes fluid displacement. Furthermore, visualization of an entire portion of a very large pleural effusion is impossible. Fourth, the shape of fluid accumulation can be affected by the existence of pulmonary solidities. Lastly, research suggests that transverse ultrasound scans tend to overestimate the volume of pleural fluid; thus, a stern standardized ultrasound protocol is required to avoid errors [ 37 ].

Unlike CXR, POCUS can also be used to guide the management of pleural effusion. Research has shown that ultrasound-guided thoracentesis is considered the standard care for many patients with pleural effusion in the United States [ 38 ]. Moreover, the British Thoracic Society has recommended that all thoracentesis be carried out under ultrasound guidance [ 39 ]. Similarly, the American College of Graduate Medical Education requires that pulmonary and critical care professionals are proficient in using ultrasound for thoracentesis [ 40 ]. These recommendations have risen from the fact that ultrasound-guided drainage of pleural effusion is increasingly becoming more successful and has low complication rates. For example, a study evaluating site selection using physical exams, CXR, and ultrasound showed that CXR and physical exams resulted in inaccurate site selection in about 15% of patients, while ultrasound prevented accidental organ puncture during thoracentesis in 10% of the cases [ 41 ]. Furthermore, it has been reported that the success rate of thoracentesis improves from 66 to 90% when guided by ultrasound [ 39 ]. This ultrasound-guided thoracentesis is normally performed using two methods: “site marking” or “direct needle guidance” [ 42 ]. In the “site marking” method, the physicians use ultrasound to identify the optimal site and mark it on the skin, after which the thoracentesis is performed without ultrasound. However, when the position of patients is changed, the distribution of fluid changes; therefore, puncture should be performed immediately after site marking. On the other hand, the direct needle guidance method involves observing the correct needle position during puncture in real time and constantly monitoring it. Mayo and colleagues evaluated the safety of ultrasound-guided thoracentesis without real-time visualization and found a very low pneumothorax incidence (1.3%) [ 43 ]. Out of the 3 cases of pneumothorax, one resulted from stopcock malposition, while the others resulted either from lung puncture, entrapment, or entrainment of air through the catheter needle assembly. Based on evidence from this study, real-time visualization seems irrelevant during puncture. However, evidence in other studies suggests ultrasound is carried out before and after puncture to assess normal gliding of the lung and to rule out pneumothorax [ 44 ]. Furthermore, POCUS can be used to ease and provide safer pleural drainage by guiding the pigtail-type of drainage [ 45 ]. Additionally, ultrasound guidance has been found important in managing other conditions. For instance, our previous meta-analysis reported that ultrasound-guided regional anesthesia was superior to parenteral opioids in patients undergoing hip fracture management [ 46 ].

Limitations

The current meta-analysis was also subject to various limitations. First, the study only included studies published in English, meaning that data from studies published in other languages were excluded from our analysis, thus limiting our meta-analysis outcome. Second, our meta-analyses have shown high heterogeneity values. However, this heterogeneity was addressed by carrying out further subgroup analyses, and the fact that most of the studies were of good methodological quality meant that the heterogeneity did not influence the findings of our meta-analyses. Thirdly, most of the studies in this review included small populations (< 100), meaning they had a small sample size bias which may have been transferred to our analyses. Finally, it is difficult to derive the incidences of false negatives and positives between CXR and POCUS from our study because very few studies reported these values to carry out an analysis. Moreover, we did not carry out a subgroup analysis based on the sizes of pleural effusions; therefore, the results presented in this study are general and not for only small or large pleural effusions.

In summary, our study has found that POCUS has a higher diagnostic value in detecting pleural effusion than CXR. Therefore, considering that POCUS is non-invasive, quick, and can repeatedly be performed at the patients’ bedside, we encourage that it is considered the first-line diagnostic tool for patients presenting signs of pleural effusion. This recommendation is further reinforced by the fact that our results have shown the diagnostic accuracy for POCUS is still very high even with physicians having less training. Moreover, the specificity of this diagnostic tool can be improved by carrying out the examinations in both upright and supine positions.

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Hany A. Zaki, Bilal Albaroudi, Mohamed Elgassim, Nood Dhafi Almarri, Kaleem Basharat & Aftab Mohammad Azad

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Eman E. Shaban

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Ahmed Shaban

Hamad Medical Corporation, Collège of Medicine QU and Weil Cornell Medical College, Doha, Qatar

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The authors confirm contribution to the paper as follows: study conception and design: HAZ, BA, EES, AS, ME, NDA, KB, AMA; literature search: HAZ, EES; Data collection: ME, NDA; analysis and interpretation of results: HAZ, BA, EES, AS, ME, NDA, KB; draft manuscript preparation: HAZ, BA; Supervision: AMA.

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Zaki, H.A., Albaroudi, B., Shaban, E.E. et al. Advancement in pleura effusion diagnosis: a systematic review and meta-analysis of point-of-care ultrasound versus radiographic thoracic imaging. Ultrasound J 16 , 3 (2024). https://doi.org/10.1186/s13089-023-00356-z

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• Pleural effusion
• Diagnostic imaging
• Emergency medicine
• Meta-analysis
• Point-of-care systems
• Chest X-ray
• Sensitivity
• Specificity
• Systematic review

• Open access
• Published: 21 June 2022

New biomarkers for the diagnosis of pleural effusion

• Raafat T. El-Sokkary 1 ,
• Nermen M. Abuelkassem   ORCID: orcid.org/0000-0002-4102-7483 1 ,
• Mohamed Ismail Seddik 2 &
• Ahmed Metwally 1  

The Egyptian Journal of Bronchology volume  16 , Article number:  38 ( 2022 ) Cite this article

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Metrics details

Persistent undiagnosed effusion is present in approximately 15% of all causes of exudative effusion. Pleural effusion caused by immunoglobulin G4 (IgG4) is a new type of pleural effusion. Tumor markers such as Carcinoembryonic antigen (CEA) may play a role in the diagnosis of malignant pleural effusion. This study aimed to evaluate the use of serum Immunoglobulin G4 and carcinoembryonic antigen in diagnosing pleural effusion.

This observational descriptive cross-sectional study comprised 89 individuals with exudative pleural effusion who visited the Assiut university hospital's chest department. All patients were examined and asked about their medical history. Also, chest X-ray, MSCT chest, transthoracic ultrasonography, pleural fluid analysis and cytology, serum level of carcinoembryonic antigen, and immunoglobulin G4 were performed. In addition, pleural biopsy, bronchoscopy, and thoracoscopy were performed when required.

In comparison to another diagnosis, the level of serum IgG 4 was observed to be substantially greater in individuals with IgG4-associated effusion (725± 225.45). Patients with malignant mesothelioma (70± 16.24) and metastatic adenocarcinoma (93.52± 19.34) had lower levels of IgG4. In contrast, the serum level of CEA was significantly higher in individuals with malignant mesothelioma (79.50± 29.47) and metastatic adenocarcinoma (68.71± 28.98). Patients with para-pneumonic effusion had a minor serum level of CEA (0.36 ± 0.26). At cutoff point > 152 mg/dl serum IgG-4 had 100% sensitivity and 94% specificity in the diagnosis of IgG4 related pleural effusion with an overall accuracy of 95.3% and area under the curve of 0.97. At the cutoff point > 5 ng/ml serum CEA had 77% sensitivity and 100% specificity in diagnosing malignant pleural effusion with an overall accuracy of 91.1% and area under the curve of 0.88.

Serum IgG4 higher than 152 mg/dl has good diagnostic accuracy in cases of undiagnosed pleural effusion. Carcinoembryonic antigen aids in diagnosing malignant pleural effusion with a cutoff point higher than 5 ng/ml in serum.

Trial registration

ClinicalTrials.gov registration ID NCT03260088

Pleural effusion is the most prevalent pleural disease, with various etiologies as cardiac disorders, tuberculous effusion, and malignant diseases, all of which necessitate immediate examination and treatment [ 1 ].

Pleural fluid cytology, pleural biopsy, thoracoscopy, and computed tomography have all been employed to diagnose PE etiology (CT). These methods, however, have their own set of limitations, pleural biopsy has a limited diagnostic utility, and thoracoscopy, as an interventional surgery, is not available in many hospitals [ 2 ].

Diagnosis of malignant pleural effusion needs different modalities. Approximately one-fourth of all pleural effusion and 30–70% of exudative effusion in hospital settings are secondary to cancer [ 3 ]. Thoracoscopy could establish the diagnosis in approximately 92.6% of cases [ 4 ].

Tumor markers play a role in the diagnosis of malignant effusion [ 5 ]. Despite this, in some cases of exudative effusions, the etiology of the pleural effusion remains unknown despite of full history taking, physical examination, and pleural fluid biochemical and cytological investigations. After multiple investigations, up to 15% of patients were found to have no diagnosis. As a result, a novel strategy to detect the cause(s) of idiopathic pleural effusions is required [ 6 ].

IgG4-related disease (IgG4-RD), formerly known as IgG4-related systemic illness, is an inflammatory syndrome marked by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, varying degrees of fibrosis (scarring), and a typically rapid response to oral steroids. During the acute phase of this condition, blood IgG4 values are high in 51–70% of patients [ 7 ].

It is critical to recognize IgG4-related disease early to avoid organ damage and failure [ 8 ].

Glucocorticoids cause a rapid and often significant improvement in clinical aspects, as well as the remission of symptoms [ 9 ].

IgG4-related pleural effusion affects 1.6% of IgG4-RD patients and 4.6% of IgG4-RD patients with intrathoracic lesions [ 9 ].

In roughly 40% of IgG4-RD patients, thoracic involvement can be observed. Pleural mass, pleuritis with fibrosis (nodular or widespread pleural thickening), and pleural effusion are all pleural symptoms of IgG4-RD. Although thoracic involvement in IgG4-RD is usually seen in conjunction with other organ disorders such as pancreatitis and sialadenitis, pleural effusions in IgG4-RD without other organ involvements are more prevalent [ 10 ].

Pleural effusions in IgG4-RD are exudative, with lymphocytes and plasma cells as major cellular elements. Fibrinous pleuritis with lymphoplasmacytic inflammation, including many IgG4-positive plasma cells and active fibrosis, is revealed by histopathological analysis of the biopsied pleura [ 11 ].

The following diagnostic criteria for IgG4-related respiratory illness have been proposed:

An abnormal chest CT shadow

A serum IgG4 level > 135 mg/dL

Histopathologic characteristics that meet the full diagnostic criteria

Extrathoracic lesions (IgG4-related diseases can cause interstitial pneumonia, inflammatory nodules, and airway inflammation)

Pleural effusion caused by IgG4-related disease is predicted to be exudative pleural effusion due to inflammation, with unilateral or bilateral pleural effusion patterns. Pleural effusion in IgG4-related pleuritis has been described as a lymphocyte-dominated exudative pleural effusion with high level of ADA [ 12 ].

This study aimed to evaluate the accuracy of serum level of Ig G4 and CEA in the diagnosis of IgG4-related pleural effusion and malignant pleural effusion, respectively.

Patients and methods

Study design: an observational descriptive cross-sectional study.

Study settings: The Chest Diseases and Tuberculosis Department, Assiut University Hospital, Egypt.

Study period: From October 2017 to 0ctober 2020.

Ethical considerations: First, the study was approved by the Scientific Ethics Committee of the Faculty of Medicine of Assiut University and was registered at www.clinicaltrials.gov under ID: NCT03260088. Second, informed consent was obtained to deal with patient data.

Inclusion criteria

Adult patients with exudative pleural effusion.

Exclusion criteria

All patients with transudative effusion

All patients were subjected to full history taking and clinical examination, laboratory investigations, including complete blood count and coagulation profile, and imaging, including chest X-ray, MSCT chest, and chest ultrasonography; besides, pleural fluid aspiration analysis and cytology with the assessment of both serum CEA and IgG4. In addition, pleural biopsy, bronchoscopy, and thoracoscopy were performed when required.

Carcinoembryonic antigen (CEA)

CEA was measured in serum using Siemens Healthcare Diagnostic Inc., the ADVIA Centaur system according to the manufacturer’s instructions.

Immunoglobulin G4 (Lot No. of Kits SG-10225)

Immunoglobulin G4 was measured in serum using (SinoGeneClon Biotech Co., Ltd., Hangzhou, China) according to the manufacturer’s instructions.

The final diagnosis was established according to the histopathological examination results of the pleural biopsy obtained either by ultrasound-guided closed pleural biopsy or medical thoracoscopy. Sections from paraffin blocks were cut at (3 to 5 μm thickness) and mounted over ordinary slides for hematoxylin and eosin staining. All slides were examined by pathologists who were blinded to the results of biochemical analysis. According to histopathological examination, the diagnosis was metastatic adenocarcinoma or malignant mesothelioma, caseating tuberculous granuloma, or lymphoplasmacytic infiltration.

Statistical analysis

The data was collected and analyzed by using SPSS (Statistical Package for the Social Science, version 20, IBM, and Armonk, New York). The Shapiro test was used to determine compliance of the data to normal distribution. All quantitative data were expressed as a mean ± standard deviation (SD). In case of normally distributed data, it was compared by Student’s t test (two different means) or ANOVA (more than two means), while in case of not normally distributed data, it was compared by Mann-Whitney U test (two means) or Kruskall-Wallis test (more than two means).

Nominal data are given as number ( n ) and percentage (%). Chi 2 test was implemented on such data. Diagnostic accuracy of both IgG4 and CEA in serum was determined by receiver operator characteristics (ROC) curve in which the cutoff point was determined based in histopathological diagnosis.

In all statistical tests, p -value <0.05 was considered statistically significant.

Baseline data of enrolled patients ( n = 89)

The mean age of enrolled patients was 53.23 ± 14.98 years. Out of enrolled patients, 52 (58.4%) patients were males, and 37 (41.6%) patients were females. The majority (53.9%) of the patients came from urban areas, and also, the majority (85.4%) were married. Only two patients were opioid addicts.

A total of 17 (19.1%) patients were none smokers, and 20 (22.5%) patients were passive smokers. Thirty (33.7%) patients were smokers, and 22 (47.7%) patients were ex-smokers (Table 1 ).

Baseline clinical and laboratory data in enrolled patients ( n = 89)

The most frequent presentations were chest pain (97.8%), cough (85.4%), and dyspnea (79.8%). Fever, expectoration, anorexia, and hemoptysis were found in 56 (62.9%), 52 (58.4%), 47 (52.8%), and 28 (31.5%) patients, respectively.

The mean serum level of immunoglobulin G4 (IgG4) was 417.68 ± 128.93 (mg/dl). Other presentations and laboratory data are summarized in Table 2 .

The final diagnosis of enrolled patients ( n = 89)

Based on clinical, radiological, laboratory, and histopathological evaluation, the most frequent diagnoses were metastatic adenocarcinoma (25.80%), para-pneumonic effusion (24.73%), and IgG4-related effusion (19.10%). Caseating tuberculous granuloma was found in 15 (16.90%) patients. Nine (10.10%) and 3 (3.37%) patients had malignant mesothelioma and pulmonary embolism, respectively (Table 3 ).

Characteristics of patients with IgG4-related effusion ( n = 17)

The mean age of those patients was 52.88 ± 16.24 years. Out of those patients, 10 (58.8%) patients were males. Three patients were smokers, and another three patients were ex-smokers. All patients had chest pain. The most frequent presentations were dyspnea (94.1%), cough (88.2%), and expectoration (58.8%). The mean serum level of IgG4 level among those patients was 725 ± 225.45 mg/dl (Table 4 ).

Radiological data and pleural fluid analysis of patients with IgG4 related effusion ( n = 17)

The majority (58.8%) of IgG4 had right effusion. Also, all of them had complex effusion, either septated (11.8%) or non-septated (88.2%). The majority (47.1%) of those patients had predominant lymphocyte effusion. Six (35.3%) patients had consolidation, and 7 (41.2%) patients had mediastinal lymphadenopathy.

Only three patients had positive adenosine deaminase. The appearance of pleural fluid was serosanguinous in 13 (76.5%) patients, while each serous and hemorrhagic fluid were present in two patients (Table 5 ).

Serum level of IgG-4 and CEA based on final diagnosis ( n = 89)

It was found that serum level of IgG4 was significantly higher among patients with IgG4-related effusion (725 ± 225.45) in comparison to other diagnoses. The low level of serum IgG4 was observed in patients with malignant mesothelioma (70 ± 16.24) and metastatic adenocarcinoma (93.52 ± 19.34).

In contrast, the serum level of CEA was significantly higher among patients with malignant mesothelioma (79.50 ± 29.47) and metastatic adenocarcinoma (68.71 ± 28.98) in comparison to other diagnoses. Patients with para-pneumonic effusion had the least serum level of CEA (0.36 ± 0.26) (Table 6 ).

Different procedures and serum levels of IgG-4 and CEA in IgG4-related effusion and malignant effusion

The serum level of immunoglobulin G-4 was significantly higher in patients with IgG4-related effusion (725 ± 225.45 vs. 86.90 ± 22.45 (mg/dl); p < 0.001), while the serum level CEA was significantly higher in patients with malignant pleural effusion (71.94 ± 15.87 vs. 1.21 ± 0.67 (ng/ml); p < 0.001) (Table 7 ).

Different procedures and serum levels of IgG-4 and CEA in IgG4-related effusion infiltration and TB effusion

The serum level of immunoglobulin G-4 was significantly higher in patients with IgG4 related effusion (725 ± 225.45 vs. 109.40 ± 22.67 (mg/dl); p < 0.001), while serum level CEA showed no significant differences between both groups (0.43 ± 0.22 vs. 1.21 ± 0.67 (ng/ml); p = 0.50) (Table 8 , Figs. 1 and 2 ).

Accuracy of serum level of IgG4 in diagnosis of pleural effusion secondary to lymphoplasmacytic infiltration. At cutoff point > 152 mg/dl; IgG-4 had 100% sensitivity, and 94% specificity in diagnosis of pleural effusion secondary to IgG 4-related effusion with overall accuracy was 95.3% and area under the curve

The accuracy of serum level of CEA in diagnosis of malignant pleural effusion. At cutoff point > 5 ng/ml in serum; CEA had 77% sensitivity and 100% specificity in diagnosis of malignant pleural effusion with overall accuracy was 91.1% and area under curve was 0.88

Pleural effusion is still one of the most critical issues in chest medicine despite the significant advances in diagnostic and therapeutic tools.

The study was performed in the Chest Department of Assiut University and included 89 pleural effusion patients. Of them, 17 were diagnosed with IgG4-related pleural effusion. On the other hand, 22 had para-pneumonic effusion, three had pulmonary embolisms, 23 were metastatic adenocarcinoma, nine had malignant mesotheliomas, and 15 had TB.

Pleural effusion is a common symptom of IgG4-RD and can occur in various conditions, including congestive heart failure and viral and malignant disorders. Even after a thorough examination, including a thoracoscopic biopsy, patients may have idiopathic exudative effusions [ 6 ].

Almost 19% of pleural effusion patients included in this study were diagnosed with IgG4-related disease. Due to the novelty of the diseases, to our knowledge, no consensus has been published to estimate its prevalence. However, a large study in Japan found that 34% of patients with idiopathic pleural effusion were associated with IgG4. The study screened 830 patients. Only 35 were undiagnosed [ 6 ].

In the current study, there was slight male predominance in patients with IgG4-related diseases (58,8%), which agreed with previous reports that IgG4-RD pleural disease occurred more frequently in men (78%) [ 13 ].

In the current study, the mean age of patients with IgG4-related pleural effusion was 52.88 years. Zen et al. (2009) reported that 63.5 years was the mean age of their included patients. Generally, IgG4 RD is a disease of middle-aged to elderly patients, with an average age of 69 years [ 10 ].

There was no relation between smoking condition and IgG4-related disease in the current study. However, according to a large recent randomized controlled experiment, current smoking was linked to a higher risk of IgG4-RD, especially among women and those with normal IgG4 levels. The first known modifiable risk factor for IgG4-RD was current smoking. This disagreement might be because only the included patients were with manifested pleural effusion, not all cases of IgG4-related disease [ 14 ].

Our study revealed that 35% of patients with IgG4-related pleural effusion reported fever, and 47% reported anorexia and weight loss. Yamamoto et al. (2014) found that patients with IgG4-RD demonstrated symptoms, such as fever, malaise, night sweats, or weight loss [ 15 ].

In our study, the following findings were reported in combination with the effusion; consolidation in (35.3%) and mediastinal lymphadenopathy (41.2%). The pleural effusion was predominantly the right side and complex non-septated with diffuse pleural thickening. According to Miyake et al. (2008), common radiological findings of IgG4-related lung disease included hilar and mediastinal lymphadenopathy, thickening of the perilymphatic interstitium with or without subpleural or peribronchovascular consolidation, and lymphoplasmacytic infiltration with fibrosis are correlated well with the radiological manifestations [ 16 ].

Laboratory diagnosis of IgG4 related diseases depends on serum IgG4 concentration greater than 135 mg/dl [ 17 ]. Our study reported that the mean level of IgG4 in patients with IgG4-related pleural effusion was 725± 225.45 mg/dl. The optimum cutoff point for diagnosing IgG4 RD in our study was 152 mg/dl, with 100% sensitivity and 94% specificity in the diagnosis of pleural effusion and overall accuracy of 95.3% and area under the curve 0.97. Inoue et al. (2009) reported that IgG4 serum concentration greater than 135 mg/dl was found to have a 97% sensitivity and 79.6% specificity in the diagnosis of IgG4-RD. The higher level in our study might be explained by the inclusion of patients with only manifested pleural effusion, not all cases of IgG4 RD. [ 18 ]

Carruthers et al. (2015) showed that elevated serum IgG4 concentrations had a 60% specificity and a 34% positive predictive value, respectively [ 19 ].

In our study, all patients with IgG4-related disease had elevated IgG4 in serum. Lang et al. (2015) reported that elevated IgG4 levels were found in only 51% of patients. Another potential pitfall in detecting IgG4 levels was the so-called “Prozone effect,” which occurred when too much antigen was in the test system, inhibiting agglutination and resulting in artificially low serum IgG4 levels. It could be avoided by diluting the material properly [ 20 ].

Another laboratory biomarker that might have a significant role in the diagnosis of IgG4-related diseases was the adenosine deaminase (ADA) level in pleural fluid. ADA is a lymphocyte-produced enzyme that participates in purine degradation in the pathway from adenosine to inosine [ 21 ].

The presence of adenosine deaminase (ADA) in pleural fluid was linked to lymphocyte activation and was commonly employed in the supplementary diagnosis of tuberculous pleuritic effusion [ 12 ].

The most generally used pleural fluid ADA cutoff value for diagnosing tuberculous pleurisy is 40 U/L, with a sensitivity and specificity of 92% and 90%, respectively. As a result, a high pleural fluid ADA level can help diagnose tuberculous pleurisy [ 22 ].

Although ADA levels were usually normal in IgG4-RD pleural effusions, some IgG4-RD patients showed increased ADA levels (>40 IU/l) in their pleural fluids [ 23 ].

Our study found positive ADA positive in 60% of tuberculous patients and 17% of IgG4-related effusion. Kasashima et al. (2019) found that pleural fluid ADA levels were modestly raised, with a median of 32.2 U/L (range 26.6–50.1), which was substantially higher than in non-IgG4-related cases without tuberculous pleurisy ( P =.05) [ 24 ]. This result is consistent with Shimoda et al. (2021), who compared ADA level in IgG4 related effusion and tuberculous pleural effusion of 18 patients with IgG4-related pleural effusion, and 14 (77.8%) showed a high pleural fluid ADA of more than 40 U/L [ 17 ].

Considering the data above, we cannot depend on laboratory investigations alone to confirm the diagnosis of IgG4-related diseases. Cytological and histopathological examination is a cornerstone in the diagnosis. Two or more of the following features are required for the histopathologic diagnosis of IgG4-RD: (i) a dense lymphoplasmacytic infiltrate, (ii) fibrosis with a typical storiform pattern, (iii) obliterative phlebitis, (iv) an increased number of IgG4+ plasma cells/HPF, and (v) an IgG4+/IgG+ plasma cell ratio >40% [ 25 , 26 ].

However, IgG4-related respiratory disease has distinct histology than IgG4-related solid organ diseases, such as the pancreas or kidney, and storiform fibrosis may not be a significant characteristic in thoracic IgG4-RD [ 27 ]. In the current study, the prominent pathological mark was the dense lymphoplasmacytic infiltrate with minimal fibrosis.

In our study, CEA was significantly higher among patients with malignant mesothelioma (79.50 ± 29.47) and metastatic adenocarcinoma (68.71 ± 28.98) in comparison to other diagnoses. By evaluating the accuracy of carcinogenic embryonic antigen in the diagnosis of malignant pleural effusion, we were able to detect a specificity of 77% and a sensitivity of 100% for a serum CEA level of 5ng/ml, which was the best eligible cutoff value according to ROC curve with an overall accuracy of 91.1% and area under the curve of 0.88. CEA showed high specificity for malignancy in serum (97 %), with a serum sensitivity of 33% for CEA.

Another study estimated the optimum cutoff point to be 5.5 ng/ml. The isolated diagnostic performance (sensitivity, specificity, PPV, and NPV) of CEA in serum (cutoff 5.5 ng/ml) was as follows: 0.54, 0.89, 0.83, and 0.67 [ 28 ]. According to Hernández et al. The CEA serum level of 5 ng/ml showed 97% specificity and 33% sensitivity with area under the curve equal 0.66 in the diagnosis of malignant pleural effusion [ 29 ]. On the other hand, a lower cut off point was previously estimated (3.27 ng/ml) with lower sensitivity and specificity [ 30 ].

Availability of data and materials

The datasets used or analyzed during the current study are available from the corresponding author when required.

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Chest Department, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt

Raafat T. El-Sokkary, Nermen M. Abuelkassem & Ahmed Metwally

Clinical Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt

Mohamed Ismail Seddik

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Raafat T. El-Sokkary and Nermen M. Abuelkassem: conception and design. Nermen M. Abuelkassem and Mohamed Ismail Seddik: data collection. Ahmed Metwally: statistical analysis. Nermen M. Abuelkassem: medical writing. The authors revised and approved the final manuscript.

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El-Sokkary, R.T., Abuelkassem, N.M., Seddik, M.I. et al. New biomarkers for the diagnosis of pleural effusion. Egypt J Bronchol 16 , 38 (2022). https://doi.org/10.1186/s43168-022-00137-7

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• Pleural effusion
• Malignant pleural effusion
• Immunoglobulin G4 related effusion
• Carcinoembryonic antigen

Diagnosis and Treatment of Pleural Effusion. Recommendations of the Spanish Society of Pulmonology and Thoracic Surgery. Update 2022

Affiliations.

• 1 Unidad de Técnicas Broncopleurales, Servicio de Neumología, Hospital Álvaro Cunqueiro (Vigo), Instituto de Investigación Sanitaria Galicia Sur, Spain. Electronic address: [email protected].
• 2 Servicio de Neumología, Hospital General Universitario Santa Lucía, Cartagena, Murcia, Spain.
• 3 Servicio de Neumología, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
• 4 Servicio de Neumología, Hospital Universitario Central de Asturias. Oviedo, Spain.
• 5 Unidad de Medicina Pleural, Servicio de Medicina Interna, Hospital Universitario Arnau de Vilanova, IRB Lleida, Universidad de Lleida, Lleida, Spain.
• 6 Departamento de Cirugía Torácica, Clínica Universidad de Navarra. Madrid, Spain.
• 7 Unidad de Endoscopia Respiratoria, Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Hospital Virgen del Rocío, Sevilla, Spain.
• 8 Servicio de Neumología, Complejo Hospitalario Universitario de Santiago, Instituto de Investigación Sanitaria de Santiago de Compostela, Departamento de Medicina, Universidad de Santiago de Compostela, Spain.
• 9 Servicio de Neumología, Hospital Universitario 12 de Octubre, Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Spain.
• 10 Servicio de Neumología, Hospital Universitario de Salamanca, Spain.
• PMID: 36273933
• DOI: 10.1016/j.arbres.2022.09.017

Pleural effusion (PE) is a common yet complex disease that requires specialized, multidisciplinary management. Recent advances, novel diagnostic techniques, and innovative patient-centered therapeutic proposals have prompted an update of the current guidelines. This document provides recommendations and protocols based on a critical review of the literature on the epidemiology, etiology, diagnosis, prognosis, and new therapeutic options in PE, and addresses some cost-effectiveness issues related to the main types of PE.

Keywords: Cost-effectiveness; Diagnosis; Pleural effusion; Prognosis; Treatment.

Copyright © 2022 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.

Publication types

• Practice Guideline
• Exudates and Transudates
• Pleural Effusion* / diagnosis
• Pleural Effusion* / etiology
• Pleural Effusion* / therapy
• Pulmonary Medicine*
• Thoracentesis / adverse effects
• Thoracentesis / methods
• Thoracic Surgery*

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• v.58(2); Mar-Apr 2017

Etiology, clinical characteristics, and management of pleural effusion in Ilorin, Nigeria

Peter oladapo adeoye.

Department of Surgery, University of Ilorin Teaching Hospital, Ilorin, Nigeria

Wahab Rotimi Johnson

1 Department of Child Health, University of Ilorin Teaching Hospital, Ilorin, Nigeria

Olufemi Olumuyiwa Desalu

2 Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Nigeria

Chima Pascal Ofoegbu

Ademola emmanuel fawibe, alakija kazeem salami, abayomi fadeyi.

3 Department of Medical Microbiology, University of Ilorin Teaching Hospital, Ilorin, Nigeria

Akingbade Adebayo Akin-Dosumu

Ibraheem m. rasheedat, background:.

Pleural effusion (PE) is a primary manifestation or secondary complication of many disorders. This study reviews the pattern and management of PE in a Nigerian hospital.

Materials and Methods:

The medical records of 213 patients with clinical diagnosis of PE over a period of 3 years were reviewed.

PE accounted for 0.5% of the total hospital admissions. The most common cause of PE was tuberculosis (TB) (32.9%), followed by malignancy (29.1%) and pneumonia (15.0%). The male to female ratio was 1.3:1. TB was the leading cause of effusion in males, while it was malignancy in females. Pneumonia accounted for 61.9% of PE in preschool age and 66.7% in school age. Breathlessness (50.0%), cough (39.4%), and chest pain (24.9%) were the common presentations. Most (90.1%) of them were exudative effusion and with half in the right lung. Chest radiography (91.6%), pleural fluid for Ziehl–Neelsen stain (74.7%), cytology (59.2%), and tissue biopsy (57.8%) were the common diagnostic investigations. The majority (92.0%) had closed thoracostomy tube drainage, while 9.9% had chemical pleurodesis. The intra-hospital mortality was 10 (4.7%).

Conclusion:

TB, malignancy, and pneumonia are the leading causes of PE. A multidisciplinary approach is needed for optimal management.

INTRODUCTION

Pleural effusion (PE) is defined as the excessive accumulation of fluid in the pleural space, resulting from an imbalance between pleural fluid formation and removal. 1 It is a common clinical problem which can be a primary manifestation or a secondary complication of many disorders. 2 The PE can be due to either exudative or transudative process. 3 Common causes of transudative effusion are heart failure, liver cirrhosis, and hypoalbuminemia; common causes of an exudative effusion are malignancy, emphysema, parapneumonic effusion, and tuberculosis (TB). 1 , 2 , 3 However, the etiology of PE remains unclear in nearly 20% of cases. 1 , 2 The estimated prevalence of PE is 320 cases per 100,000 people in industrialized countries, with a distribution of etiologies related to the prevalence of underlying diseases. 4 The incidence in the United States is estimated to be at least 1.5 million cases annually 5 and >0.3% of the population each year in the UK. 1 In Southwest Nigeria, pleural diseases accounted for 7.7% of respiratory morbidity with the majority between the ages of 15 and 44 years. 6 Ogunleye et al . reported 372 cases of the pleural fluid collection over a 55-month period with male to female ratio of 1:1 and most of them between the ages of 20 and 49 years. 7 Patients with PE most commonly present with dyspnea, initially on exertion, predominantly dry cough, and pleuritic chest pain. To treat PE appropriately, it is important to determine its etiology and distinguish pleural fluid transudate from exudates. 8 , 9 There is a paucity of information on the burden of PE and most of the earlier works were on TB-related effusion. 10 , 11 , 12 There is a need to document our local experiences in order to contribute the body of knowledge in Nigeria. The aims of this study were to determine the pattern and management of PE in a Nigerian hospital.

MATERIALS AND METHODS

This was a retrospective study carried out at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. The study center is a tertiary hospital that serves as a referral center to four neighboring states. The hospital also runs an internship and postgraduate training programs in all the branches of medicine. We retrieved and reviewed all the medical case records of all patients who had a clinical diagnosis of PE in the hospital between November 2010 and October 2013 to obtain necessary data. Cases that had complete information and met the clinical criteria for diagnosis and classification of PE subtypes were studied. Sociodemographic information, clinical features, etiology, risk factors, comorbid conditions, duration of hospital stay, clinical characteristics, diagnostic approach, and modalities of managements were extracted from their case records. In addition, physical examination findings at admission, hematological, biochemical, cytological, histopathological, and microbiological results were obtained.

Diagnosis of pleural effusion

The diagnosis of PEs in the study participants was based on (1) clinical manifestations and (2) radiologic investigation – chest radiography and computed tomography (CT).

Ethical approval was obtained from the Institution Ethical Research Committee for the study.

Data analysis

The data were extracted by a postgraduate resident undergoing a clerkship rotation to remove bias; the clinical information was coded and entered into the computer Excel spreadsheet. Medical records with important missing information were excluded from the analysis. The data were analyzed using the Statistical Package for the Social Sciences, version 16 (SPSS Inc., Chicago, IL, USA). Descriptive and frequency statistics were obtained for the variables of interest. Etiology of PEs in patients was stratified by gender. Chi-square test was used to test for statistical significance between categorical variables. A P < 0.05 was considered statistically significant.

A total of 40,301 patients were admitted during the period of review; this included 30,680 adults and 9621 children and adolescents. Out of the 40,301 admissions, 213 were clinically diagnosed as PE and this figure accounted for 0.5% of the total hospital admissions. The age of the patients ranged from 2 months to 90 years, with a median age of 38 (interquartile range [IQR] 22–55) years. One hundred and twenty three patients (57.7%) were males and the male to female ratio was 1.3:1. Twenty-six (12.2%) of the patients were below the age of 18 years and this accounted for approximately 0.3% of the hospital admissions within this age range; in addition, they also have equal sex distribution. The median hospital stay was 14 (IQR 9–22) days. The other characteristics of the patients are shown in Table 1 .

General characteristics' of the patients

The most common cause of PE was TB (32.9%), followed by malignancy (29.1%) and pneumonia (15.0%). In the males, TB was the leading cause of PE, while it was malignancy among females [ Table 2 ]. Pneumonia was the leading cause of PE in the preschool (61.9%) and school age (66.7%), while it was chest trauma in adolescent (45.0%). There were two cases of malignant PE in childhood (one due to nephroblastoma and one occult malignancy). TB was the most common cause of PE in adults <50 years (45.0%) and malignancy (58.2%) in 50 years and above [ Figure 1 ]. Lung cancer (49.2%) and advanced breast cancer (25.4%) were the leading causes of malignant PE [ Figure 2 ]. Furthermore, 89.1% of the cases had exudative PE. In this study, half of the cases have their effusion located in the right hemithorax and also presented with difficulty in breathing, while 39.4% reported a cough [ Table 3 ]. Chest radiography (91.6%) and pleural fluid acid-alcohol-fast bacilli (74.7%) were leading methods of investigations. Nearly two-third of the patients were evaluated by pleural fluid cytology (59.2%) and tissue (either pleura or lung) biopsy (57.8%) and with less than half screened for HIV infection [ Table 4 ]. In the treatment of PE, 196 (92.0%) cases had closed thoracostomy tube drainage (CTTD). Twenty-one cases (9.9%) had CTTD and chemical pleurodesis (2 g of tetracycline or 2 g of doxycycline in 60 ml slurry of 0.5% lidocaine). Seventeen out of 21 (81%) cases who had CTTD and chemical pleurodesis reported pleural drainage of ≤3 days postpleurodesis. Chemical pleurodesis was performed only in patients with malignant etiology. There was no significant difference ( P = 0.573) in duration of drainage postpleurodesis between tetracycline (mean = 2.9 days) and doxycycline (mean = 2.5 days). The majority (67.1%) of the patients were treated with antimicrobials which consisted of antibiotics and anti-TB medication [ Table 5 ]. A total ten patients with PE died within the period of admission in the hospital giving an intra-hospital mortality of 4.7% and 3 (1.4%) discharge themselves against medical advice.

Etiology of pleural effusions in patients by gender

Etiology of pleural effusions in patients by age group

Etiology of malignant pleural effusion

Clinical presentations of patients with pleural effusion

Diagnostic approach to pleural effusion

Treatment modalities in pleural effusion

Our study was conceived to determine the pattern and management of PE. Overall, PE accounted for 0.5% of the total hospital admissions meaning 5 out of every 1000 hospital admissions. The occurrence of PE varies across the Francophone West Africa countries from 1%–7% to 23%. 13 , 14 , 15 , 16 In Ibadan, Nigeria, Onadeko et al noted that 56% of PE was caused by TB. 17 However, there is a lack of uniformity in the methods or criteria used in reporting the burden of this condition making it difficult to compare results of study across different study populations. The demography in this study showed that the median age of the cases with PE was 38 years and this figure is similar to 37.8 years which was reported in Lagos, Nigeria, 7 and 34.7 years reported from our center earlier, 8 but it was less what was report from another part of the world. 18 , 19 , 20 , 21 , 22 These variations may be attributed to the variation in the study population and the etiology and frequency of predisposing factors for PE in the different parts of the world. We also found a predilection for males in our study and this is in agreement with many other studies. 7 , 8 , 18 , 19 , 21 , 22 , 23 The reason for this was due to more males high prevalence of smoking of tobacco and consumption of alcohol compared to female in our setting. 24 , 25

TB accounted for one-third of effusion (32.9%) and is the leading cause of PE, followed by malignancy (18.7%). Lung cancer was responsible for half of the malignant PE. This is observation is in agreement with other previous studies; 18 , 19 , 21 , 22 , 23 , 26 , 27 , 28 however, it is in contrast to the study by Ogunleye et al ., 7 which reported breast cancer as the leading cause of cancer-related effusion. TB was the leading cause of PE in males while it was malignancy among females. The preponderance of TB as a leading cause of PE in this study was also reported previously from our center and other developing countries. 8 , 18 , 19 , 20 , 21 , 22 , 26 , 27 , 28 On the other hand, this result is different from what is reported in Lagos, Nigeria, the Islamic Republic of Iran, and other developed countries. 7 , 23 , 29 , 30 The second leading cause of PE was a malignancy and this result is similar to other observation 18 , 20 , 21 , 22 and is in contrast to other studies that reported pneumonia. 19 , 20 These etiological differences in PE causes could be explained by the fact that TB, HIV endemicity, and low socioeconomic status which are the risk factors for TB development are very common in this settings compared to the developed countries. In those studies that reported a contrasting result, this can be explained by the epidemiologic transition from communicable diseases to noncommunicable diseases such as cancer. Other factors might also be due to the type of patient's referral and clinic, the level of collaboration between the general and cardiothoracic surgeons, and the availability of video-assisted thoracoscopic surgery (VATS). Before this study, only 8.9% of cases of PE were reported to be of malignant etiology in our institution when VATS and percutaneous transthoracic biopsy were not available. 8 In the center where VATS is not available, the diagnosis of malignant effusion is reportedly low 6 and often patients with unexplained PE are made to undergo a therapeutic trial of anti-TB medication. In childhood, the leading cause of PE in the first decade of life is pneumonia, TB was the most common cause in adults <50 years, and malignancy in 50 years and above. This result is comparable to other studies in developed and developing countries. 10 , 18 , 19 , 21 , 22 The risk of developing malignant effusion increases with age. 2 , 3 Parapneumonic effusion is common in childhood because of the high incidence of acute respiratory infection in this age group. There is 8%–40% prevalence of parapneumonic effusions among the children with pneumonia in several other studies. 31 , 32 , 33 , 34

The combination of clinical information, microbiological, and histological examination was the useful diagnostic tests for PE in this study. We did not determine the diagnostic yield of each diagnostic test because of the nature of the study, the role of predictive value in evidenced-based medicine may implicate the need for a future prospective study on PE. In the evaluation of the cases, it was an irony that 21% had HIV screening considering the fact that TB was the leading cause of PE. Early identification of comorbidity and concurrent management of immune depressive illness can improve the outcome of cancer cases. There was a right-sided dominance of PEs in this study which is similar to the findings of other previous studies. 7 , 13 , 19 , 20 , 21 , 22 , 26 , 27 , 28 , 35 This result can be partly ascribed to the anatomy of the right bronchus, because the right bronchus is wider and shorter and runs more vertically than the left bronchus, aspirated microbes and biochemical particles are more likely to enter and lodge in it or one of its branches. There is also the hypothesis that greater blood volume is circulated through the right lung than the left.

The majority (67.1%) was treated with antibiotics and anti-TB medication, 92.0% had CTTD, and 9.9% had chemical pleurodesis. Malignant PE commonly complicates advanced cancer, especially in those with lung cancer, metastatic breast carcinoma, and lymphoma. This complication usually leads patients to suffer from troublesome dyspnea, which may impair their mobility and reduce their quality of life. 36 A total ten patients with PE died during the period of admission in the hospital giving an intra-hospital mortality of 4.7%. This was lower than 16.6% reported in Eastern Nigeria, 6.4% in Ethiopia, and 13% in the Benin Republic. 26 , 27 , 28 In view of the fact that the common causes of PE in this study are similar to the etiologies in these three latter studies, the lower mortality recorded may be due to the level care as a result of the collaboration of the physicians, surgeon, pathologies, and other healthcare workers in the PE study group. Other contributory factors are associated comorbidity and early presentation and diagnosis.

Limitations of the study

The study is retrospective in conduct and it is confronted with the problems of inability to carry out some studies such as CT scan, magnetic resonance imaging, tumor markers, which would have been useful in some cases due to out-of-pocket cost to the patients. Despite these limitations, we have been able to report the pattern of PE in our setting.

PE is a common clinical problem confronting physicians in Nigeria. TB, malignancy, and pneumonia are the leading causes of PE. A combination of clinicolaboratory and endoscopic approach is required for diagnosis. HIV screening is recommended as part of workup in patients with PE in our setting. Therefore, a multidisciplinary approach is needed for proper management.

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INTRODUCTION

The initial approach to pleural fluid analysis will be presented here. An initial approach to pleural effusions of uncertain etiology, pleural imaging, and the technique of thoracentesis are discussed separately. (See "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion" and "Imaging of pleural effusions in adults" and "Ultrasound-guided thoracentesis" .)

The diagnostic approach in specific patient populations is also discussed separately:

● (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults" .)

● (See "Tuberculous pleural effusion" .)

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Clive, Amelia Olga. "Management of malignant pleural effusion." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683557.

Mishra, Eleanor Kate. "Assessment and treatment of malignant pleural effusions : visual analogue scale, ultrasound and drainage." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:d1121dbf-5568-47a6-bfed-8526a481c6ca.

Taberner, Bonastre Mª Teresa. "Perfil proteómico (micromatrices proteínicas) del líquido pleural en pacientes con derrame pleural maligno y tuberculoso." Doctoral thesis, Universitat de Lleida, 2015. http://hdl.handle.net/10803/378654.

Araujo, Pedro Henrique Xavier Nabuco de. "Relação entre a elastância pleural e efetividade da pleurodese no derrame pleural maligno recidivante." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5156/tde-04082015-143102/.

Puka, Juliana. "Perfil biomolecular do derrame pleural maligno experimentalmente induzido: frequência de mutações e impacto de terapias-alvo." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5150/tde-06022017-154634/.

Rosolem, Debora Cristina Batista. "Avaliação citogenética molecular de células do líquido pleural de pacientes com derrame pleural maligno." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5150/tde-09122014-115852/.

Alves, Sergio Henrique Saraiva. "Impacto na ventilação e aeração pulmonar após remoção de derrame pleural neoplásico: um estudo com tomografia de impedância elétrica." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5150/tde-20052013-104626/.

Ukale, Valiant. "Pleurodesis in chronic effusions : studies on inflammatory mediators, respiratory function, predictability of treatment outcome, drug efficiency and survival after treatment /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-031-1/.

Srour, Nadim. "Comparison of Indwelling Pleural Catheters and Chemical Pleurodesis Through Tube Thoracostomy for the Management of Malignant Pleural Effusions." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20441.

Luplow, Silke. "Talkum-Pleurodese." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2006. http://dx.doi.org/10.18452/15402.

Wu, Da-Wei, and 吳大緯. "Detection of pleural effusion vascular endothelial growth factor level to assist distinction of benign or primary and secondary malignant pleural effusion." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/14670886328102455678.

Cheng, Yi-Jing, and 鄭意靜. "Plasma-activated Medium as Adjuvant Therapy on Lung Cancer Malignant Pleural Effusion." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/ks5tca.

Chiou, Ien Chiuam, and 邱彥筌. "Discovering drug resistance-associated biomarkers from malignant pleural effusion of lung adenocarcinoma." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/e7p43f.

Hsu, I.-Lin, and 許以霖. "Potential Angiogenetic Biomarkers in Non-small Cell Lung Cancer with Malignant Pleural Effusion." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/60736405196379857763.

Hsiao, Shu-Wen, and 蕭述文. "Proteomic and genetic expression profiles in the malignant pleural effusion associated lung adenocarcinoma." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/21741212311315150580.

Liao, Nai Ding, and 廖乃鼎. "The investigation of CAIX and GLUT-1 protein expressions in pleural effusion to improve the detection of malignant effusion." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/62261941863103416856.

Chi-Li, Chung. "Effect of Repeated Thoracenteses on Fluid Characteristics, Cytokines, and Fibrinolytic Activity in Malignant Pleural Effusion." 2003. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0007-1704200714513288.

Chung, Chi-Li, and 鍾啟禮. "Effect of Repeated Thoracenteses on Fluid Characteristics, Cytokines, and Fibrinolytic Activity in Malignant Pleural Effusion." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/37867156478213945695.

Hung, Tsui Lien, and 洪翠蓮. "The underlying mechanisms of high invasiveness in tumor cells from lung cancer patients with malignant pleural effusion." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/52852434576744912387.

Kuo-Li, Chen, and 陳國麗. "Characterization of novel transforming growth factor-beta type I receptors found in malignant pleural effusion tumor cells." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/14663457420122116557.

Yu-TszLi and 李育慈. "The identification of lung cancer stem cells in malignant pleural effusion and studying their responses to interferon-γ." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/38786784171059481340.

Ηλιοπούλου, Μαριάνθη. "Λειτουργική μελέτη της διαγονιδιακής μεταφοράς στην υπεζωκοτική κοιλότητα." Thesis, 2013. http://hdl.handle.net/10889/7954.

Chien-ChungLin and 林建中. "Malignant pleural effusion cells show aberrant glucose metabolism gene expression and the level of cellular Stat1 phosphorylation reflects the chemoresistance." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/48749653687430192782.

Yeh, Hsuan-Heng, and 葉宣亨. "Roles of Stat3 activation in the malignant pleural effusion associated lung adenocarcinoma and the effects of oncogenic Ha-Ras on Stat3 expression." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/90836582283604094961.

Tsai, Tzu-Hsiu, and 蔡子修. "RNA-based Genetic Testing for Targeted Therapy in Non-small Cell Lung Cancer: Application to Cytological Specimens of Malignant Pleural Effusion and Bronchoscopic Brushing." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/ujjb78.

Lee, Yen-chien, and 李妍蒨. "The clinical relationship between IL-6, immune microenvironment and malignant pleura effusion lung adenocarcinoma." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/62635533996146239573.

Hsu, Pei-Chi, and 許珮綺. "Role of Osteopontin, Vascular Endotheliol Growth Factor, Urokinase-type Plasminogen Activator and Plasminogen Activator Inhibitor in Malignant Pleural Effusions." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/49011992045888819153.

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• Volume 05 Issue 06 June 2017
• Clinical and Etiological Profile of Patients with Pleural Effusion in A Tertiary Care Centre
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Title:  Clinical and Etiological Profile of Patients with Pleural Effusion in A Tertiary Care Centre

Authors: Suresh Raghavan, Jayachandran.R, Sandra Mosses

Corresponding Author

Background: Pleural Effusion is defined as the accumulation of fluid in the pleural space. A pleural effusion is always abnormal and its presence indicates an underlying disease. Pleural effusion is one of the commonest respiratory problems with which patients are admitted. Diseases of the pleura, lung, heart, liver, kidney, or other multisystem illness can lead to pleural effusion. Hence, a detailed clinical evaluation including history taking, physical examination and relevant diagnostic tests are essential to identify the cause of pleural effusion, which is essential for arriving at the treatment decision.

Materials and Methods: This study included 100 cases of pleural effusion admitted in the Department of Medicine, Government TD Medical College, Alappuzha over a period of 1 year. A detailed history and physical examination was carried out along with chest radiograph and diagnostic thoracocentesis. The effusions were then appropriately classified as transudative and exudative and further evaluated.

Results: Of the 100 cases, the commonest cause of pleural effusion was tuberculosis, followed by malignancy. The commonest presenting symptom was dyspnoea. Most of the pleural effusions were right sided and were mild. Pleural fluid ADA was sensitive for the diagnosis of tuberculous effusion. Adenocarcinoma of the lung was the commonest malignancy causing pleural effusion.

Conclusions: Pleural effusion is more commonly seen in males than in females. The commonest causes were Pulmonary tuberculosis followed by malignancy. Least common cause was collagen vascular disease. Parapneumonic effusions were typically mild in severity.

Keyword: Pleural effusion.

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Jayachandran.R

Assistant Professor, Dept of General Medicine,

Govt.T.D Medical College, Alappuzha, Kerala

India 688005

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