Longitudinal Measurement of Pleural Fluid Biochemistry and Cytokines in Malignant Pleural Effusions

Our plain-English summary of Longitudinal Measurement of Pleural Fluid Biochemistry and Cytokines in Malignant Pleural Effusions, by R. Thomas, H.M. Cheah, J. Creaney, et al (Chest, 2016).

The study

• Authors: R. Thomas, H.M. Cheah, J. Creaney, B.A. Turlach, Y.C. Lee
• Journal: Chest
• Published: 2016;149(6):1494-500
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural effusion (MPE) is common. Existing literature on pleural fluid compositions is restricted to cross-sectional sampling with little information on longitudinal changes of fluid biochemistry and cytokines with disease progression. Indwelling pleural catheters provide the unique opportunity for repeated sampling and longitudinal evaluation of MPE, which may provide insight into tumor pathobiology.

Methods: We collected 638 MPE samples from 103 patients managed with indwelling pleural catheters over 95 days (median, range 0-735 days) and analyzed them for protein, pH, lactate dehydrogenase, and glucose levels. Peripheral blood was quantified for hematocrit, platelets, leukocytes, protein, and albumin. Cytokine levels (monocyte chemotactic protein [MCP]-1; vascular endothelial growth factor; interleukin-6, -8, and -10; tumor necrosis factor-α; and interferon-gamma) were determined in 298 samples from 35 patients with mesothelioma. Longitudinal changes of all parameters were analyzed using a linear mixed model.

Results: Significant decreases were observed over time in pleural fluid protein by 8 g/L per 100 days (SE, 1.32; P < .0001) and pH (0.04/100 days; SE, 0.02; P = .0203), accompanied by a nonsignificant rise in lactate dehydrogenase. The ratio of pleural fluid to serum protein decreased by 0.06/100 days (SE, 0.02; P = .04). MPEs from mesothelioma (n = 63) had lower pleural fluid glucose (P = .0104) at baseline and a faster rate of decline in glucose (P = .0423) when compared with non-mesothelioma effusions (n = 38). A progressive rise in mesothelioma pleural fluid concentration of [log] MCP-1 ([log] 0.37 pg/mL per 100 days; SE, 0.13; P = .0046), but not of other cytokines, was observed.

Conclusions: MPE fluids become less exudative and more acidic over the disease course. The rise in MCP-1 levels suggests a pathobiological role in MPE.

Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

In plain English

This study, from a hospital pleural service in Perth, Australia, looked back at fluid repeatedly drained from the chest through indwelling pleural catheters. The patients had malignant pleural effusion, which is fluid around the lung caused by cancer, and were treated between July 2009 and February 2013. Pleural fluid was analyzed in 103 patients, most of whom had mesothelioma, and 638 fluid samples were tested for protein. Using a statistical model of change over time, the authors found that fluid protein fell by 8 g/L per 100 days and fluid pH fell by 0.04 per 100 days. A rise in LDH was not statistically significant. Blood albumin fell, but blood protein did not change significantly. Patients with mesothelioma started with lower fluid glucose than other patients. In 35 mesothelioma patients, the substance MCP-1 rose significantly over time, while VEGF, IL-6 and IL-8 did not. The authors concluded that the fluids became less exudative and more acidic over the disease course, and that the MCP-1 rise may suggest a role in these effusions. They noted the study was retrospective. Asbestos exposure was not examined.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective longitudinal analysis of repeated pleural fluid and blood samples from a hospital patient cohort, analyzed with linear mixed models
• Who was studied: 107 patients with malignant pleural effusion had indwelling pleural catheters inserted at a pleural service in Perth, Western Australia, between 1 July 2009 and 28 February 2013. Pleural fluid analysis was done in 103 of them. The text reports 82% male and 62% with mesothelioma; Table 1 gives 82 (80%) male, 63 (61%) mesothelioma, 16 lung cancer, 6 breast cancer and 18 other cancers. Cytokines were measured in a subset of 35 mesothelioma patients.
• Exposure: No asbestos exposure, fiber type or occupation was studied or reported. The factor analyzed was time since the first pleural fluid collection. Outcomes were pleural fluid biochemistry (protein, pH, LDH, glucose), cytokines, and blood tests.
• Main results:
  • Whole cohort: pleural fluid protein (starting value 40.97 g/L; 638 samples) decreased by 8 g/L per 100 days (SE 1.32; p less than 0.0001).
  • Whole cohort: pleural fluid pH (starting value 7.34; 570 samples) decreased by 0.04 per 100 days (SE 0.02; p=0.0203).
  • Whole cohort: log pleural fluid LDH (624 samples) increased by 0.08 log U/L per 100 days (SE 0.05; p=0.0787), a non-significant rise.
  • Whole cohort: pleural fluid glucose (627 samples) showed a non-significant decrease of 0.07 mmol/L per 100 days (SE 0.12; p=0.4855).
  • Subgroup of 364 samples from 88 cases with paired fluid and blood protein results: the pleural fluid to serum protein ratio (starting value 0.56) decreased by 0.06 per 100 days (SE 0.02; p=0.04).
  • Blood: serum protein decreased by 0.75 g/L per 100 days (SE 0.47; p=0.1068), which was not significant. Serum albumin decreased by 3 g/L per 100 days (SE 0.51; p less than 0.0001).
  • Effusions from mesothelioma patients (n=63) had significantly lower starting pleural fluid glucose than effusions from non-mesothelioma patients (n=38), p=0.0104.
  • The rate of glucose change differed between the mesothelioma and non-mesothelioma groups (p=0.0423). The results section says this suggested a greater glucose reduction in the non-mesothelioma group, but the article's own abstract says mesothelioma effusions declined faster. The authors said the significance of this finding is not clear.
  • 35 mesothelioma patients: log pleural fluid MCP-1 (298 samples) increased by 0.37 log pg/ml per 100 days (SE 0.13; p=0.0046).
  • 35 mesothelioma patients: none of the other cytokines increased significantly over time. VEGF changed with p=0.14, IL-6 with p=0.64 and IL-8 with p=0.42. IL-10, interferon-gamma and TNF-alpha were tested in only 39 samples from 5 patients because they were below the assay's detection limit.
  • Blood counts: hemoglobin decreased by 13 g/L per 100 days (SE 2.11; p less than 0.0001) in 480 samples. Lymphocyte counts decreased and platelet counts increased significantly.
  • At the final measurement, the pleural fluid to serum protein ratio was above 0.5 in 53% of cases, and pleural fluid LDH was above two-thirds of the upper limit of normal in 93% of cases.
• The authors' conclusion: The authors concluded that malignant pleural effusion fluids become less exudative (lower in protein) and more acidic over the disease course, and that the rise in MCP-1 levels may suggest a role for MCP-1 in the biology of these effusions. They also reported that blood protein did not fall significantly even with regular drainage.
• Limitations the authors state:
  • The analysis was retrospective.
  • The cohort had a relatively high proportion of mesothelioma because mesothelioma is common in Western Australia.
  • Mesothelioma patients contributed more samples because they were more likely to survive and keep the catheter longer than patients with metastatic carcinomas.
  • Blood results drawn up to 14 days from the fluid sample were accepted. The authors noted that 49% of pairs were taken the same day and 70% within 3 days.
  • The choice to log-transform some measurements can change how the results are interpreted.
  • The statistical model assumed independent, identically distributed residual errors.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cytokine, Pleural Effusion, Disease Progression, Indwelling Pleural Catheter, Lactate Dehydrogenase (LDH), Necrosis, Mesothelioma.

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• NK cells from malignant pleural effusions are not anergic but produce cytokines and display strong antitumor activity on short-term IL-2 activation — P. Vacca, S. Martini, et al. (2013)
• Malignant pleural fluid from mesothelioma has potent biological activities — H.M. Cheah, S.M. Lansley, et al. (2017)
• Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid — A. Scherpereel, B.D. Grigoriu, et al. (2013)
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