Predictors of septation in malignant pleural effusions: a retrospective cohort study

Predictors of septation in malignant pleural effusions: a retrospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Predictors of septation in malignant pleural effusions: a retrospective cohort study Viktor Sekowski, Ashley-Mae Gillson, Sahar Nazari, Pen Li, Daniel Stollery, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4731865/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Malignant pleural effusions (MPEs) are often managed with indwelling pleural catheter (IPC) insertion, however drainage can be limited by internal septations. Predictors of septated MPE remain uncertain. We aimed to determine the predictors of septated MPE. Methods Demographic and clinical characteristics were collected for 437 adult patients and 515 IPCs inserted at a Canadian pleural effusion clinic from 2012 to 2018. We utilized logistic regression analysis to identify independent predictors for development of septated pleural effusion. Results Systemic therapy (OR 1.78, p = 0.011) and moderate to large effusion size (OR 2.44, p = 0.004) were predictors of septated MPE among our studied cohort. The most common IPC-related complications were superficial skin/soft tissue infection (4%) followed by pleural infection (3%). No IPC-related deaths were observed in our study. Conclusions Systemic therapy and moderate to large pleural effusions may be independent risk factors for the development of septated MPE. predictors pleural septations malignant pleural effusions indwelling pleural catheters Background Indwelling pleural catheters (IPCs) are considered a first-line intervention in the management symptomatic, recurrent malignant pleural effusions (MPE). 1 However, septated pleural effusions are a recognized sequela of IPCs, affecting between 5–14% of patients with MPE managed with IPC. 2 , 3 Typically occurring 2 months after insertion, IPC-related septations can result in impaired drainage and worsening dyspnea if left untreated. 2 , 4 , 5 Patients with septated non-draining MPE have reduced survival compared to unselected patients with MPE, with median time to death 58 days vs. 187 days in one cohort 6 , with similar findings in patients with pleural adhesions. 7 Non-draining IPCs due to pleural septations may require repeat tube thoracostomy, instillation of fibrinolytics and mucolytics, and/or surgical intervention. 4 , 8 The predictors of septated MPE are not fully understood. Previous studies found that repeated thoracentesis 9 – 11 as well as higher pleural fluid lactate dehydrogenase and serum C-reactive protein levels were associated with non-draining pleural effusions. 6 In two retrospective studies of patients with MPE who underwent thoracoscopy, adhesions (which may share some similarities in pathogenesis with pleural septations) 6 , 12 , were associated with lower pleural fluid pH, higher pleural tumour burden 7 , and higher duration of effusion. 13 Apart from this, however, studies assessing clinical risk factors for development of pleural fluid septations in MPE are lacking. Given that the incidence of MPE in the United States is estimated to be over 150 000 per year 3 , septated MPE represent a major cause of morbidity and a significant therapeutic challenge encountered by respirologists, oncologists, and thoracic surgeons. The purpose of this study is to elucidate the predictors associated with the development of pleural fluid septation in individuals with MPE. Knowledge of risk factors for pleural septation could have substantial impact on management of patients with MPE by identifying high-risk patients who may warrant closer surveillance or alternative therapy. Methods We conducted a retrospective cohort study of patients who underwent IPC (PleurX™) insertion for MPE at our center between November 2012 and October 2018. Our study included individuals with malignant or paramalignant effusions and underwent the insertion of an IPC by either an interventional pulmonologist or a thoracic surgeon affiliated with our pleural effusion clinic. IPCs are typically drained three times a week by home care nursing staff however frequency of drainage is adapted according to the clinical needs and preferences of each patient. Patients with suspected pleural infection were excluded from our study. The primary objective of this study was to identify predictors of symptomatic pleural fluid septation in patients with MPE, defined by ultrasound evidence of pleural effusion septation with impairment of IPC drainage. Age, cancer diagnosis, smoking history, pleural fluid ultrasound appearance, effusion size on pre-procedural chest X-ray, chest radiation, systemic therapy (i.e. chemotherapy, immunotherapy, targeted therapy, hormone therapy), positive cytology or pleural biopsy, history of thoracoscopy, time from diagnosis to IPC insertion, time IPC in situ, and prior procedures were evaluated as potential predictors. Clinical data was obtained from retrospective paper and electronic medical record chart review. Follow up was complete to October 31, 2019. Institutional review board approval was obtained at study outset (University of Alberta Health Research Ethics Board Pro00108928). SPSS was used to analyze the data. Collinearity among variables was determined by using Spearman rank correlation coefficients, the χ2 method, Mann-Whitney U test, and Kruskal-Wallis test. Backward stepwise logistic regression was used to determine independent predictors for development of septated pleural effusion. Statistical significance was defined as p < 0.05 for all analyses. Results A total of 437 patients underwent IPC insertion and 515 IPCs were inserted during the study period. Patient and IPC characteristics in this cohort have been previously reported. 14 The most common cause of MPE was non-small cell lung cancer, followed by breast cancer. The majority of pleural effusions on initial chest X-ray were either moderate or large in size, with 18% of patients developing septation post-IPC insertion. Pleural effusions were classified by their size based on pre-procedural chest X-ray imaging. Effusions occupying less than 25% of the hemithorax were labeled as small, those spanning 25 to 50% were considered moderate, and those exceeding 50% were categorized as large. The most common complications were superficial skin/soft tissue infection in 4%, followed by pleural infection in 3%. We did not observe IPC-related deaths during the study period. 37% of patients eventually had their IPC removed, however most patients died with IPC in situ. The list of variables and the results from the logistic regression analysis are presented in Table 1 . Due to collinearity of tested variables, we had to limit the included variables in the model to total number of procedures, chest radiation, systemic therapy, and effusion size. Systemic therapy (OR 1.78, 95% CI 1.13 to 2.81; p = 0.011) and moderate to large effusions on initial chest X-ray (OR 2.44, 95% CI 1.21 to 4.92, p = 0.004) were identified as statistically significant predictors of septations. Table 1 Regression for potential predictors of septated malignant pleural effusion (n = 515) Potential Predictors Odds Ratio 95% Confidence Interval p-value Total number of procedures 1.04 0.95–1.14 0.409 Chest radiation 1.16 0.55–2.42 0.706 Systemic therapy 1.78 1.13–2.81 0.011 Moderate to large pleural effusions 2.44 1.21–4.92 0.004 Discussion To the best of our knowledge, our study is the first to provide evidence that systemic therapy and larger pleural effusion size may serve as predictive factors for the development of septated pleural effusions. Historically, anti-neoplastic systemic therapy primarily consisted of chemotherapy. The advent of immunotherapy and targeted therapy has led to an increased number of patients undergoing systemic treatments beyond traditional chemotherapy, particularly in the field of lung cancer treatment. Although these novel therapies have improved the prognosis for many patients with advanced cancer, they have been associated with unique toxicities including numerous immune-related adverse events such as pneumonitis, hepatitis and neurotoxic effects. 15 It is possible that these newer agents lead to an amplified inflammatory response, potentially increasing the likelihood of septated pleural effusions. This phenomenon has been previously reported in a case study where a patient developed worsening pleural effusion shortly after receiving erlotinib for non-small cell lung cancer. 16 In addition, improved life expectancy from recently developed anti-neoplastic therapy may also provide more opportunity to develop pleural septations unrelated to treatment. Larger pleural effusions have been previously associated with higher rates of complicated parapneumonic effusions and unfavorable clinical outcomes. 17 This may relate to increased pro-inflammatory and angiogenic cytokines found within complex effusions. A similar process may occur in malignant effusions as well. Patients exhibiting these characteristics might benefit from more vigilant monitoring to facilitate the early detection of symptomatic septations, or consideration of alternative treatment options such as a pleurodesis procedure. There are several limitations to our study, primarily its retrospective nature and small sample size. Significant collinearity of variables resulted in a limit to the number of explored variables; we selected which factors were clinically felt to impact formation of septations. Additionally, the category of systemic therapy is heterogeneous and included patients undergoing chemotherapy, immunotherapy, targeted therapy, and hormonal therapy. The number of patients in each specific systemic therapy subgroup was insufficient to conduct separate analyses. Future studies could assess which systemic therapy is associated with a higher likelihood of septated MPE. Conclusions In summary, systemic therapy and moderate to large pleural effusions may serve as potential indicators for the presence of septated MPE. Patients exhibiting these characteristics might benefit from more vigilant monitoring to facilitate the early detection and treatment of septated MPE. Further prospective studies may be helpful in further elucidating predictors of symptomatic septated MPEs. Abbreviations IPC = intrapleural catheters MPE = malignant pleural effusions Declarations Ethics approval and consent to participate This study protocol was reviewed and approved by University of Alberta Health Research Ethics Board, approval number Pro00108928. Written informed consent was not required for the study given that the original database was constructed for quality improvement and the data extracted was retrospective. Personal and health information was handled in a confidential manner. It was not feasible to contact all eligible patients to obtain consent due to volume and remoteness of potential patients. In addition, a large proportion of the patients have died prior to the study and would not have been able to provide consent. Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analysed during the current study are not publicly available due privacy restriction but are available from the corresponding author [C.C.] on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was not supported by any sponsor or funder. Authors’ Contributions V.S. helped formulate the study, collected data, assisted with analysis, wrote the first and final draft of the manuscript, and approved the final version. S.N. performed the analysis for the study, contributed to, and approved the final manuscript version. C.C., A.G., P.L. and D.S. helped formulate the study, collected data, assisted with analysis, contributed to, and approved the final manuscript version. Acknowledgements Not applicable. References Mark E Roberts, Najib M Rahman, Nick A Maskell, Anna C Bibby, Kevin G Blyth, John P Corcoran, et al. British Thoracic Society Guideline for pleural disease. Thorax. 2023 Jul 1;78(Suppl 3):s1. Thomas R, Piccolo F, Miller D, MacEachern PR, Chee AC, Huseini T, et al. Intrapleural Fibrinolysis for the Treatment of Indwelling Pleural Catheter-Related Symptomatic Loculations: A Multicenter Observational Study. CHEST. 2015 Sep 1;148(3):746–51. Management of Malignant Pleural Effusions. Am J Respir Crit Care Med. 2000 Nov;162(5):1987–2001. Feller-Kopman D, Light R. Pleural Disease. N Engl J Med. 2018 Feb 22;378(8):740–51. Lui MMS, Thomas R, Lee YCG. Complications of indwelling pleural catheter use and their management. BMJ Open Respir Res. 2016 Feb 5;3(1):e000123. Banka R, Terrington D, Mishra EK. Management of Septated Malignant Pleural Effusions. Curr Pulmonol Rep. 2018;7(1):1–5. Bielsa S, Martín-Juan J, Porcel JM, Rodríguez-Panadero F. Diagnostic and Prognostic Implications of Pleural Adhesions in Malignant Effusions. Journal of Thoracic Oncology. 2008 Nov 1;3(11):1251–6. Davies HE, Davies RJO, Davies CWH. Management of pleural infection in adults: British Thoracic Society pleural disease guideline 2010. Thorax. 2010 Aug 1;65(Suppl 2):ii41–53. Chung CL, Chen YC, Chang SC. Effect of Repeated Thoracenteses on Fluid Characteristics, Cytokines, and Fibrinolytic Activity in Malignant Pleural Effusion. Chest. 2003 Apr 1;123(4):1188–95. Sahn SA. Malignancy Metastatic to the Pleura. Clinics in Chest Medicine. 1998 Jun 1;19(2):351–61. Viallat JR, Rey F, Astoul P, Boutin C. Thoracoscopic Talc Poudrage Pleurodesis for Malignant Effusions: A Review of 360 Cases. Chest. 1996 Dec 1;110(6):1387–93. Chung CL, Chen CH, Sheu JR, Chen YC, Chang SC. Proinflammatory Cytokines, Transforming Growth Factor-β1, and Fibrinolytic Enzymes in Loculated and Free-Flowing Pleural Exudates. Chest. 2005 Aug 1;128(2):690–7. Wolff A, Anderson E, Read C. Predictors of Pleural Adhesion Formation and Success of Pleurodesis in Patients With Pleural Effusion. Journal of Bronchology & Interventional Pulmonology. 2004 Jan 1;11:6–11. Chan C, Sekowski V, Zheng B, Li P, Stollery D, Veenstra J, et al. Combination Tissue Plasminogen Activator and DNase for Loculated Malignant Pleural Effusions: A Single-center Retrospective Review. Journal of Bronchology & Interventional Pulmonology. :10.1097/LBR.0000000000000871. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019 Sep;16(9):563–80. Toh CK, Lee P, Chowbay B, Goh JWK, Mancer K, Tan PH. An inflammatory response with worsening of pleural effusion on treatment with erlotinib in non-small cell lung cancer. Acta Oncologica. 2007 Jan 1;46(2):256–8. Chung CL, Hsiao SH, Hsiao G, Sheu JR, Chen WL, Chang SC. Clinical Importance of Angiogenic Cytokines, Fibrinolytic Activity and Effusion Size in Parapneumonic Effusions. PLoS One. 2013 Jan 7;8(1):e53169. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4731865","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":330927088,"identity":"b38ee94d-3a2c-479d-a70f-6958f93b50e1","order_by":0,"name":"Viktor Sekowski","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Viktor","middleName":"","lastName":"Sekowski","suffix":""},{"id":330927095,"identity":"5c364315-12f3-4d63-a41b-c2af45987e1d","order_by":1,"name":"Ashley-Mae Gillson","email":"","orcid":"","institution":"University of 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17:23:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4731865/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4731865/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67320520,"identity":"78411c71-697d-48ed-b3d7-1bea7c8b3ccd","added_by":"auto","created_at":"2024-10-23 15:31:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":284175,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4731865/v1/3d3a7897-bb83-4ed0-8b51-2ebfd107a7db.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Predictors of septation in malignant pleural effusions: a retrospective cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003eIndwelling pleural catheters (IPCs) are considered a first-line intervention in the management symptomatic, recurrent malignant pleural effusions (MPE).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e However, septated pleural effusions are a recognized sequela of IPCs, affecting between 5\u0026ndash;14% of patients with MPE managed with IPC.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Typically occurring 2 months after insertion, IPC-related septations can result in impaired drainage and worsening dyspnea if left untreated.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Patients with septated non-draining MPE have reduced survival compared to unselected patients with MPE, with median time to death 58 days vs. 187 days in one cohort\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, with similar findings in patients with pleural adhesions.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Non-draining IPCs due to pleural septations may require repeat tube thoracostomy, instillation of fibrinolytics and mucolytics, and/or surgical intervention.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe predictors of septated MPE are not fully understood. Previous studies found that repeated thoracentesis\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e as well as higher pleural fluid lactate dehydrogenase and serum C-reactive protein levels were associated with non-draining pleural effusions.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e In two retrospective studies of patients with MPE who underwent thoracoscopy, adhesions (which may share some similarities in pathogenesis with pleural septations)\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, were associated with lower pleural fluid pH, higher pleural tumour burden\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, and higher duration of effusion.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Apart from this, however, studies assessing clinical risk factors for development of pleural fluid septations in MPE are lacking. Given that the incidence of MPE in the United States is estimated to be over 150 000 per year\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, septated MPE represent a major cause of morbidity and a significant therapeutic challenge encountered by respirologists, oncologists, and thoracic surgeons.\u003c/p\u003e \u003cp\u003eThe purpose of this study is to elucidate the predictors associated with the development of pleural fluid septation in individuals with MPE. Knowledge of risk factors for pleural septation could have substantial impact on management of patients with MPE by identifying high-risk patients who may warrant closer surveillance or alternative therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe conducted a retrospective cohort study of patients who underwent IPC (PleurX\u0026trade;) insertion for MPE at our center between November 2012 and October 2018. Our study included individuals with malignant or paramalignant effusions and underwent the insertion of an IPC by either an interventional pulmonologist or a thoracic surgeon affiliated with our pleural effusion clinic. IPCs are typically drained three times a week by home care nursing staff however frequency of drainage is adapted according to the clinical needs and preferences of each patient. Patients with suspected pleural infection were excluded from our study.\u003c/p\u003e \u003cp\u003eThe primary objective of this study was to identify predictors of symptomatic pleural fluid septation in patients with MPE, defined by ultrasound evidence of pleural effusion septation with impairment of IPC drainage. Age, cancer diagnosis, smoking history, pleural fluid ultrasound appearance, effusion size on pre-procedural chest X-ray, chest radiation, systemic therapy (i.e. chemotherapy, immunotherapy, targeted therapy, hormone therapy), positive cytology or pleural biopsy, history of thoracoscopy, time from diagnosis to IPC insertion, time IPC in situ, and prior procedures were evaluated as potential predictors.\u003c/p\u003e \u003cp\u003eClinical data was obtained from retrospective paper and electronic medical record chart review. Follow up was complete to October 31, 2019. Institutional review board approval was obtained at study outset (University of Alberta Health Research Ethics Board Pro00108928).\u003c/p\u003e \u003cp\u003eSPSS was used to analyze the data. Collinearity among variables was determined by using Spearman rank correlation coefficients, the χ2 method, Mann-Whitney U test, and Kruskal-Wallis test. Backward stepwise logistic regression was used to determine independent predictors for development of septated pleural effusion. Statistical significance was defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for all analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 437 patients underwent IPC insertion and 515 IPCs were inserted during the study period. Patient and IPC characteristics in this cohort have been previously reported.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e The most common cause of MPE was non-small cell lung cancer, followed by breast cancer. The majority of pleural effusions on initial chest X-ray were either moderate or large in size, with 18% of patients developing septation post-IPC insertion. Pleural effusions were classified by their size based on pre-procedural chest X-ray imaging. Effusions occupying less than 25% of the hemithorax were labeled as small, those spanning 25 to 50% were considered moderate, and those exceeding 50% were categorized as large. The most common complications were superficial skin/soft tissue infection in 4%, followed by pleural infection in 3%. We did not observe IPC-related deaths during the study period. 37% of patients eventually had their IPC removed, however most patients died with IPC in situ.\u003c/p\u003e \u003cp\u003eThe list of variables and the results from the logistic regression analysis are presented in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Due to collinearity of tested variables, we had to limit the included variables in the model to total number of procedures, chest radiation, systemic therapy, and effusion size. Systemic therapy (OR 1.78, 95% CI 1.13 to 2.81; p\u0026thinsp;=\u0026thinsp;0.011) and moderate to large effusions on initial chest X-ray (OR 2.44, 95% CI 1.21 to 4.92, p\u0026thinsp;=\u0026thinsp;0.004) were identified as statistically significant predictors of septations.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRegression for potential predictors of septated malignant pleural effusion (n\u0026thinsp;=\u0026thinsp;515)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e Potential Predictors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOdds Ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% Confidence Interval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal number of procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.95\u0026ndash;1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.409\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChest radiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.55\u0026ndash;2.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.706\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.13\u0026ndash;2.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate to large pleural effusions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.21\u0026ndash;4.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, our study is the first to provide evidence that systemic therapy and larger pleural effusion size may serve as predictive factors for the development of septated pleural effusions. Historically, anti-neoplastic systemic therapy primarily consisted of chemotherapy. The advent of immunotherapy and targeted therapy has led to an increased number of patients undergoing systemic treatments beyond traditional chemotherapy, particularly in the field of lung cancer treatment. Although these novel therapies have improved the prognosis for many patients with advanced cancer, they have been associated with unique toxicities including numerous immune-related adverse events such as pneumonitis, hepatitis and neurotoxic effects.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e It is possible that these newer agents lead to an amplified inflammatory response, potentially increasing the likelihood of septated pleural effusions. This phenomenon has been previously reported in a case study where a patient developed worsening pleural effusion shortly after receiving erlotinib for non-small cell lung cancer.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e In addition, improved life expectancy from recently developed anti-neoplastic therapy may also provide more opportunity to develop pleural septations unrelated to treatment.\u003c/p\u003e \u003cp\u003eLarger pleural effusions have been previously associated with higher rates of complicated parapneumonic effusions and unfavorable clinical outcomes.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e This may relate to increased pro-inflammatory and angiogenic cytokines found within complex effusions. A similar process may occur in malignant effusions as well. Patients exhibiting these characteristics might benefit from more vigilant monitoring to facilitate the early detection of symptomatic septations, or consideration of alternative treatment options such as a pleurodesis procedure.\u003c/p\u003e \u003cp\u003eThere are several limitations to our study, primarily its retrospective nature and small sample size. Significant collinearity of variables resulted in a limit to the number of explored variables; we selected which factors were clinically felt to impact formation of septations. Additionally, the category of systemic therapy is heterogeneous and included patients undergoing chemotherapy, immunotherapy, targeted therapy, and hormonal therapy. The number of patients in each specific systemic therapy subgroup was insufficient to conduct separate analyses. Future studies could assess which systemic therapy is associated with a higher likelihood of septated MPE.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, systemic therapy and moderate to large pleural effusions may serve as potential indicators for the presence of septated MPE. Patients exhibiting these characteristics might benefit from more vigilant monitoring to facilitate the early detection and treatment of septated MPE. Further prospective studies may be helpful in further elucidating predictors of symptomatic septated MPEs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIPC = intrapleural catheters\u003c/p\u003e\n\u003cp\u003eMPE = malignant pleural effusions\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003e\u003cu\u003eEthics approval and consent to participate\u003c/u\u003e\u003c/h3\u003e\n\u003cp\u003eThis study protocol was reviewed and approved by University of Alberta Health Research Ethics Board, approval number Pro00108928.\u003c/p\u003e\n\u003cp\u003eWritten informed consent was not required for the study given that the original database was constructed for quality improvement and the data extracted was retrospective.\u0026nbsp;Personal and health information was handled in a confidential manner. \u0026nbsp;It was not feasible to contact all eligible patients to obtain consent due to volume and remoteness of potential patients. In addition, a large proportion of the patients have died prior to the study and would not have been able to provide consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eConsent for publication\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAvailability of data and materials\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due privacy restriction but are available from the corresponding author [C.C.] on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis study was not supported by any sponsor or funder.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eV.S. helped formulate the study, collected data, assisted with analysis, wrote the first and final draft of the manuscript, and approved the final version. S.N. performed the analysis for the study, contributed to, and approved the final manuscript version. C.C., A.G., P.L. and D.S. helped formulate the study, collected data, assisted with analysis, contributed to, and approved the final manuscript version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAcknowledgements\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMark E Roberts, Najib M Rahman, Nick A Maskell, Anna C Bibby, Kevin G Blyth, John P Corcoran, et al. British Thoracic Society Guideline for pleural disease. Thorax. 2023 Jul 1;78(Suppl 3):s1. \u003c/li\u003e\n\u003cli\u003eThomas R, Piccolo F, Miller D, MacEachern PR, Chee AC, Huseini T, et al. Intrapleural Fibrinolysis for the Treatment of Indwelling Pleural Catheter-Related Symptomatic Loculations: A Multicenter Observational Study. CHEST. 2015 Sep 1;148(3):746\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eManagement of Malignant Pleural Effusions. Am J Respir Crit Care Med. 2000 Nov;162(5):1987\u0026ndash;2001. \u003c/li\u003e\n\u003cli\u003eFeller-Kopman D, Light R. Pleural Disease. N Engl J Med. 2018 Feb 22;378(8):740\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eLui MMS, Thomas R, Lee YCG. Complications of indwelling pleural catheter use and their management. BMJ Open Respir Res. 2016 Feb 5;3(1):e000123. \u003c/li\u003e\n\u003cli\u003eBanka R, Terrington D, Mishra EK. Management of Septated Malignant Pleural Effusions. Curr Pulmonol Rep. 2018;7(1):1\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eBielsa S, Mart\u0026iacute;n-Juan J, Porcel JM, Rodr\u0026iacute;guez-Panadero F. Diagnostic and Prognostic Implications of Pleural Adhesions in Malignant Effusions. Journal of Thoracic Oncology. 2008 Nov 1;3(11):1251\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eDavies HE, Davies RJO, Davies CWH. Management of pleural infection in adults: British Thoracic Society pleural disease guideline 2010. Thorax. 2010 Aug 1;65(Suppl 2):ii41\u0026ndash;53. \u003c/li\u003e\n\u003cli\u003eChung CL, Chen YC, Chang SC. Effect of Repeated Thoracenteses on Fluid Characteristics, Cytokines, and Fibrinolytic Activity in Malignant Pleural Effusion. Chest. 2003 Apr 1;123(4):1188\u0026ndash;95. \u003c/li\u003e\n\u003cli\u003eSahn SA. Malignancy Metastatic to the Pleura. Clinics in Chest Medicine. 1998 Jun 1;19(2):351\u0026ndash;61. \u003c/li\u003e\n\u003cli\u003eViallat JR, Rey F, Astoul P, Boutin C. Thoracoscopic Talc Poudrage Pleurodesis for Malignant Effusions: A Review of 360 Cases. Chest. 1996 Dec 1;110(6):1387\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003eChung CL, Chen CH, Sheu JR, Chen YC, Chang SC. Proinflammatory Cytokines, Transforming Growth Factor-\u0026beta;1, and Fibrinolytic Enzymes in Loculated and Free-Flowing Pleural Exudates. Chest. 2005 Aug 1;128(2):690\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eWolff A, Anderson E, Read C. Predictors of Pleural Adhesion Formation and Success of Pleurodesis in Patients With Pleural Effusion. Journal of Bronchology \u0026amp; Interventional Pulmonology. 2004 Jan 1;11:6\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eChan C, Sekowski V, Zheng B, Li P, Stollery D, Veenstra J, et al. Combination Tissue Plasminogen Activator and DNase for Loculated Malignant Pleural Effusions: A Single-center Retrospective Review. Journal of Bronchology \u0026amp; Interventional Pulmonology. :10.1097/LBR.0000000000000871. \u003c/li\u003e\n\u003cli\u003eMartins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019 Sep;16(9):563\u0026ndash;80. \u003c/li\u003e\n\u003cli\u003eToh CK, Lee P, Chowbay B, Goh JWK, Mancer K, Tan PH. An inflammatory response with worsening of pleural effusion on treatment with erlotinib in non-small cell lung cancer. Acta Oncologica. 2007 Jan 1;46(2):256\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eChung CL, Hsiao SH, Hsiao G, Sheu JR, Chen WL, Chang SC. Clinical Importance of Angiogenic Cytokines, Fibrinolytic Activity and Effusion Size in Parapneumonic Effusions. PLoS One. 2013 Jan 7;8(1):e53169. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"predictors, pleural septations, malignant pleural effusions, indwelling pleural catheters","lastPublishedDoi":"10.21203/rs.3.rs-4731865/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4731865/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMalignant pleural effusions (MPEs) are often managed with indwelling pleural catheter (IPC) insertion, however drainage can be limited by internal septations. Predictors of septated MPE remain uncertain. We aimed to determine the predictors of septated MPE.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eDemographic and clinical characteristics were collected for 437 adult patients and 515 IPCs inserted at a Canadian pleural effusion clinic from 2012 to 2018. We utilized logistic regression analysis to identify independent predictors for development of septated pleural effusion.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSystemic therapy (OR 1.78, p\u0026thinsp;=\u0026thinsp;0.011) and moderate to large effusion size (OR 2.44, p\u0026thinsp;=\u0026thinsp;0.004) were predictors of septated MPE among our studied cohort. The most common IPC-related complications were superficial skin/soft tissue infection (4%) followed by pleural infection (3%). No IPC-related deaths were observed in our study.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSystemic therapy and moderate to large pleural effusions may be independent risk factors for the development of septated MPE.\u003c/p\u003e","manuscriptTitle":"Predictors of septation in malignant pleural effusions: a retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-07 10:58:27","doi":"10.21203/rs.3.rs-4731865/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2048de52-2b04-4aaf-8dc3-d467c3c9ebc3","owner":[],"postedDate":"August 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-23T06:38:27+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-07 10:58:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4731865","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4731865","identity":"rs-4731865","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}