The incidence of non-malignant pleural effusions far outweighs that of malignant pleural effusions and is estimated to be at least 3-fold higher. These so-called benign effusions do not follow a “benign course” in many cases, with mortality rates matching and sometimes exceeding those of malignant pleural effusions. In addition to the impact on patients, healthcare systems are also significantly affected, with recent US epidemiological data demonstrating that 75% of resource allocation for pleural effusion management is spent on non-malignant pleural effusions (excluding empyema). Despite this significant burden of disease, and by existing at the junction of multiple medical specialties, reflecting a heterogenous constellation of medical conditions, non-malignant pleural effusions are rarely the focus of research or the subject of management guidelines. With this European Respiratory Society Task Force, we assembled a multispecialty collaborative across 11 countries and three continents to provide a statement based on systematic searches of the medical literature to highlight evidence in the management of the following clinical areas: a diagnostic approach to transudative effusions, heart failure, hepatic hydrothorax, end-stage renal failure, benign asbestos-related pleural effusion, post-surgical effusion and nonspecific pleuritis.

Rationale: Sonographic septations are assumed to be important clinical predictors of outcome in pleural infection, but the evidence for this is sparse. The inflammatory and fibrinolysis-associated intrapleural pathway(s) leading to septation formation have not been studied in a large cohort of pleural fluid (PF) samples with confirmed pleural infection matched with ultrasound and clinical outcome data. Objectives: To assess the presence and severity of septations against baseline PF PAI-1 (Plasminogen-Activator Inhibitor-1) and other inflammatory and fibrinolysis-associated proteins as well as to correlate these with clinically important outcomes. Methods: We analyzed 214 pleural fluid samples from PILOT (Pleural Infection Longitudinal Outcome Study), a prospective observational pleural infection study, for inflammatory and fibrinolysis-associated proteins using the Luminex platform. Multivariate regression analyses were used to assess the association of pleural biological markers with septation presence and severity (on ultrasound) and clinical outcomes. Measurements and Main Results: PF PAI-1 was the only protein independently associated with septation presence (P < 0.001) and septation severity (P = 0.003). PF PAI-1 concentrations were associated with increased length of stay (P = 0.048) and increased 12-month mortality (P = 0.003). Sonographic septations alone had no relation to clinical outcomes. Conclusions: In a large and well-characterized cohort, this is the first study to associate pleural biological parameters with a validated sonographic septation outcome in pleural infection. PF PAI-1 is the first biomarker to demonstrate an independent association with mortality. Although PF PAI-1 plays an integral role in driving septation formation, septations themselves are not associated with clinically important outcomes. These novel findings now require prospective validation.

Pleural infection is a millennia-spanning condition that has proved challenging to treat over many years. Fourteen percent of cases of pneumonia are reported to present with a pleural effusion on chest X-ray (CXR), which rises to 44% on ultrasound but many will resolve with prompt antibiotic therapy. To guide treatment, parapneumonic effusions have been separated into distinct categories according to their biochemical, microbiological and radiological characteristics. There is wide variation in causative organisms according to geographical location and healthcare setting. Positive cultures are only obtained in 56% of cases; therefore, empirical antibiotics should provide Gram-positive, Gram-negative and anaerobic cover whilst providing adequate pleural penetrance. With the advent of next-generation sequencing techniques, yields are expected to improve. Complicated parapneumonic effusions and empyema necessitate prompt tube thoracostomy. It is reported that 16–27% treated in this way will fail on this therapy and require some form of escalation. The now seminal Multi-centre Intrapleural Sepsis Trials (MIST) demonstrated the use of combination fibrinolysin and DNase as more effective in the treatment of empyema compared to either agent alone or placebo, and success rates of 90% are reported with this technique. The focus is now on dose adjustments according to the patient’s specific ‘fibrinolytic potential’, in order to deliver personalised therapy. Surgery has remained a cornerstone in the management of pleural infection and is certainly required in late-stage manifestations of the disease. However, its role in early-stage disease and optimal patient selection is being re-explored. A number of adjunct and exploratory therapies are also discussed in this review, including the use of local anaesthetic thoracoscopy, indwelling pleural catheters, intrapleural antibiotics, pleural irrigation and steroid therapy.

Pleural effusions are a common respiratory condition with many etiologies. Nonmalignant etiologies explain most pleural effusions and despite being nonmalignant, they can be associated with poor survival; thus, it is important to understand their pathophysiology. Furthermore, diagnosing a benign pleural pathology always harbors the uncertainty of a false-negative diagnosis for physicians and pathologists, especially for the group of non-specific pleuritis. This review aims to present the role of the inflammation in the development of benign pleural effusions, with a special interest in their pathophysiology and their association with malignancy.