Translational Research in Pleural Infection and Beyond

Abstract

The incidence of pleural infection has been rising in recent years. Intrapleural therapy with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) has significantly reduced the need for surgery, and its impact on clinical care is rising worldwide. Efforts are underway to optimize the delivery regimen and establish the short and longer term effects of this therapy. The complex interactions of bacterial infection within the pleura with inflammatory responses and clinical interventions (antibiotics and tPA/DNase or other fibrinolysins) require further studies to improve future treatment options. Intrapleural instillation of tPA potently induces pleural fluid formation, principally via a monocyte chemotactic protein (MCP)-1 dependent mechanism. Activation of transcriptional programs in pleural resident cells and infiltrating cells during pleural infection and malignancy results in the local secretion of a cocktail of proinflammatory signaling molecules (including MCP-1) within the pleural confines that contributes to effusion formation. Understanding the biology of these molecules and their interaction may provide novel targets for pleural fluid control.

Recent developments in the management of pleural infection: A comprehensive review

“…As well as finding the optimal dosing and administration strategy, an attractive idea in this era of personalized medicine is the question of whether the dose of IPFT can be individualized to different patients. Samples of pleural fluid from the MIST‐2 study were found to have highly variable fibrinolytic potential prior to treatment, and it has been stipulated, though not yet clinically tested, that patients with reduced plasminogen activator activity theoretically require higher doses of fibrinolytics . The knowledge that PAI‐1 levels are elevated in locules, and therefore likely to contribute to the formation of pleural septations, has led to attempts at therapy targeting this specific pathway.…”

“…Samples of pleural fluid from the MIST-2 study were found to have highly variable fibrinolytic potential prior to treatment, and it has been stipulated, though not yet clinically tested, that patients with reduced plasminogen activator activity theoretically require higher doses of fibrinolytics. 86 The knowledge that PAI-1 levels are elevated in locules, and therefore likely to contribute to the formation of pleural septations, 87 has led to attempts at therapy targeting this specific pathway. PAI-1 targeting monoclonal antibodies could be used as adjunctive therapy to allow reduction in the dose of IPFT and lessen bleeding risk.…”

Precision-guided, Personalized Intrapleural Fibrinolytic Therapy for Empyema and Complicated Parapneumonic Pleural Effusions: The Case for The Fibrinolytic Potential

“…Unfortunately, dosing of intrapleural fibrinolytic therapy (IPFT) has since its inception remained empiric and off-label, which may underlie the variable responses to its application in adults. While a variety of approaches including the use of fibrinolysins alone or in combination with DNase have been advocated, the search for optimal IPFT and how best to deliver that in adults remains a high priority 12 . Along these lines, a personalized approach to the application of IPFT in adults remains unavailable.…”

Pathogenesis of pleural infection: A complex warfare

“…Bacterial invasion of the pleural cavity is a serious illness associated with high morbidity and mortality . Gram‐positive bacteria (GPB) are the leading cause of empyema.…”

“…‘ The supreme art of war is to subdue the enemy without fighting ’ (The Art of War). In the complex warfare of pleural infection pathology, enemies and allies are far from clear‐cut and their roles often interchange . Fibrin deposition and resultant adhesion/loculation formation are often regarded as the ‘enemy’ in pleural infection as they impair fluid evacuation.…”