Multi-agent pleurodesis: a new horizon in management

Although the global incidence of spontaneous pneumothoraces is relatively low, the downstream sequelae that can occur from a persistent air leak, including pneumonia, empyema, prolonged hospital stays, and readmissions, can be clinically significant. While patients with primary spontaneous pneumothoraces are often young and without comorbidities, patients presenting with secondary spontaneous pneumothoraces often carry underlying diagnoses such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), tuberculosis, or cystic fibrosis. As a result, they may be unable to tolerate the incremental increases in morbidity or mortality risk that may come from complications during the management of the pneumothorax. While the initial management should involve placement of a small-bore chest tube (1), which is successful in approximately 70% of the time (2), a persistent air leak or recurrence is not uncommon. In those patients that do not resolve with conservative measures, options for management include both surgery and pleurodesis, individually or combined, to treat the underlying pathology and prevent recurrence. In patients unfit for surgery, there remains significant institutional variability in both approach and agent selection for pleurodesis. Although single-agent approaches have been well characterized in terms of efficacy, the literature on multi-agent pleurodesis remains sparse, largely limited to isolated case reports and small case series.

Koh and Sekine (3) highlight a case at their institution in which a combined sclerosing regimen of minocycline and autologous blood was successful in treating a secondary spontaneous pneumothorax in a patient with a history of pulmonary tuberculosis for which surgery was contraindicated. While informative, this case more importantly highlights the limited understanding the medical community has of the clinical interplay underlying combination regimens. More importantly, their work suggests that a combined approach may hold a therapeutic potential benefit in the management of refractory pneumothoraces and effusions for select patients.

The American College of Chest Physicians and European Respiratory Society/European Association for Cardio-Thoracic Surgery/European Society of Thoracic Surgeons (ERS/EACTS/ESTS) consensus guidelines for secondary spontaneous pneumothoraces emphasize the importance of initial placement of a tube thoracostomy (4,5). Additionally, the guidelines recommend escalating care after 3–5 days if the lung has not expanded, the air leak persists, or both. However, unified recommendations regarding the specific approach and regimen in how to do so in these cases, especially when an air leak persists and the lung is not fully expanded, are lacking (4,5). While both documents demonstrate a preference for thoracoscopic approach with surgical pleurodesis, this is largely attributable to the lower recurrence rates in comparison to medical approaches. However, some patients are unfit for surgery for various reasons including comorbidities or inability to tolerate single lung ventilation, such as the case presented by Koh and Sekine. This patient’s history of a pulmonary tuberculosis destroyed lung on the contralateral side to the pneumothorax posed a barrier to surgical approaches due to an inability to tolerate single lung ventilation. While the ERS/EACTS/ESTS guideline does recommend autologous blood patch in similar patients, it was a conditional recommendation due to very low quality of evidence. Furthermore, neither guideline established a shared consensus on a preferred sclerosing agent in the management of secondary spontaneous pneumothoraces. Cases such as this reveal the boundaries of guideline-driven care and highlight the need for rigorous evaluation of the efficacy of commonly used agents and combination regimens.

A systematic review by Hallifax and colleagues highlight the efficacy of various commonly used sclerosing agents for spontaneous pneumothoraces (6). This serves as a valuable reference for clinicians seeking a more in-depth overview of such agents. Due to the heterogeneity of study design and studied outcomes, the authors were unable to perform a robust meta-analysis. However, when selectively looking at the recurrence rates referenced across studies, talc emerged as the most efficacious and extensively studied sclerosing agent. The first reported use of an autologous blood patch in humans for the treatment of prolonged air leak was in 1992 (7). Since then, it has gained traction as a viable treatment option in patients with prolonged air leaks, especially when pleural-pleural apposition cannot be obtained with just a chest tube. The published success rate for autologous blood patches is 71–96.8% (8-13), while the reported recurrence rate is 12.9–36.4% (9,11).

Despite an established body of work on single-sclerosing agent strategies, there is very little in the published literature on multi-agent pleurodesis regimens. In fact, a search of PubMed evaluating for the combination regimen of minocycline and autologous blood reveals two additional publications by the same authors, Koh and Sekine (14,15). One reports the successful treatment of bilateral secondary spontaneous pneumothoraces using the same combination regimen (14). Then in a subsequent case series of 22 patients with persistent air leaks despite initial chest tube management, the authors, again, describe experience with the same combination regimen of autologous blood and minocycline (15). Median time to air-leak cessation was 5 days, with successful cessation in all 22 patients (15). Importantly, this regimen reported no post-intervention empyemas, transient fevers, nor early recurrence. Therefore, with their experience, it is not unexpected that in the patient described in this case report, that Koh and Sekine attempted pleurodesis using the combination of autologous blood and minocycline in a patient with secondary spontaneous pneumothorax that was unable to undergo surgery due to an inability to tolerate single lung ventilation.

As the success rate for autologous blood patch for prolonged air leak ranges from 71% to 96.8% (8-13), combining it with another known sclerosing agent is intriguing. From a mechanistic perspective, a multi-agent pleurodesis may offer additional benefits that single agent therapy simply cannot, possibly resulting in improved success rates and lower rates of recurrence. If mesothelial cells are presumptively mediating the chemical pleurodesis response, efficacious sclerosing agents would be directed to stimulate these cells’ secondary mediators. These mediators include growth factors such as vascular endothelial growth factor and transforming growth factor beta alongside chemokines such as interleukin-8. In addition, these cells recruit pleural cells, fibroblasts, and extracellular matrix components and stimulate the coagulation cascade. Of these processes, fibrin-mediated coagulation offers the most rapid response in the spectrum of pleurodesis responses. The quick-acting coagulation mediated by autologous blood combined with the chemical pleurodesis from the minocycline offers the potential for a rapid acting and durable pleurodesis response.

This single institution experience with two case reports and a small case series which now totals 24 patients, may serve as a signal to the clinical and scientific community to explore multi-agent pleurodesis for the treatment of prolonged air leaks, when indicated. Work should expand beyond anecdotal reports and begin to systematically evaluate multi-agent regimens in a prospective and comparative manner, including compared to surgical intervention. A translational approach, that leverages our understanding of the complex immunologic pathways underlying pleurodesis, will ultimately be successful in tailoring pleurodesis approaches in high-risk patient populations.

Acknowledgments

The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Case Reports. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0072/coif). The authors have no conflicts of interest to declare.

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