Intrapleural Fibrinolytic Therapy: Past, Present, and Future

Fibrinolysis and complicated parapneumonic effusion/empyema have a longstanding relationship. Many of the first major breakthroughs in the discovery of plasminogen and its activators were made using Streptococcus species isolated from a patient with empyema. Fatefully, the first clinical use of plasminogen activators to treat human disease involved administering the identified streptococcal plasminogen activator, streptokinase, intrapleurally to treat parapneumonic effusion and empyema. Refinement of fibrinolytic therapy has led to the common practice of adjunctive intrapleural fibrinolytic therapy, using a combination of recombinant human tissue plasminogen activator and deoxyribonuclease-1. However, current intrapleural fibrinolytic therapy is inefficient, resulting in an average hospital stay of 14 days. Further, many patients demonstrate residual pleural effusion after therapy, some of whom ultimately require surgery. This leads to billions of dollars of health care expenditure annually in the United States. This review aims to provide a historical overview of intrapleural fibrinolysis, review the current clinical fibrinolytic therapy practices for treatment of complicated parapneumonic effusion/empyema, and highlight knowledge gaps in our understanding of the pathobiology of resistance to intrapleural fibrinolytic therapy. Although nonfibrinolytic modalities such as pleural irrigation and surgery are referenced for context, they are not the focus of this review and are not discussed in depth. Improved knowledge of the mechanisms underlying aberrant fibrinolysis in the pleural space has the potential to improve prognostication, guide precision therapeutics, and enhance the care of patients with complicated parapneumonic effusion/empyema, leading to better individual outcomes and reduced health care expenditure.