Unusual Causes of Pleural Effusion: A Comprehensive Review of Diagnostic Challenges and Management Strategies

Pleural effusions are common in critical care and pulmonary medicine, often attributed to congestive heart failure, pneumonia, or malignancy. However, a significant proportion of effusions remain undiagnosed or are caused by less common etiologies, posing diagnostic dilemmas and delaying appropriate treatment. This review aims to consolidate knowledge on these rare causes to improve diagnostic acumen among PCCM specialists.

This was a narrative review synthesizing evidence from case reports, case series, and observational studies published between 2000 and 2022. A systematic search of PubMed, Embase, and Web of Science was conducted using keywords such as 'unusual pleural effusion', 'rare pleural fluid', 'atypical pleurisy', and specific rare etiologies. Data on clinical presentation, diagnostic modalities, and management strategies were extracted and critically appraised.

The review identified over 50 unusual causes of pleural effusion, categorizing them into infectious (e.g., fungal, parasitic, Nocardia), inflammatory/autoimmune (e.g., drug-induced lupus, sarcoidosis, IgG4-related disease), metabolic (e.g., uremic, chylothorax, pseudochylothorax), iatrogenic (e.g., drug-induced, esophageal rupture, central line complications), and miscellaneous (e.g., yellow nail syndrome, ovarian hyperstimulation syndrome). Diagnostic approaches often required advanced imaging (e.g., PET-CT, pleural elastography), specialized pleural fluid analysis (e.g., adenosine deaminase, cytology with specific stains, flow cytometry), and sometimes invasive procedures like thoracoscopy. Early recognition of specific clinical clues (e.g., drug history, systemic symptoms, specific imaging findings) was crucial for guiding targeted investigations.

PCCM fellows should maintain a high index of suspicion for unusual causes of pleural effusion when common etiologies are ruled out or atypical features are present. A systematic diagnostic approach integrating detailed history, advanced imaging, and specialized pleural fluid analysis is essential for timely and accurate diagnosis, leading to appropriate management.

As a narrative review, it is subject to selection bias and does not provide quantitative data on prevalence or diagnostic accuracy of specific tests for rare conditions. The heterogeneity of reported cases and lack of randomized controlled trials for rare etiologies limit definitive recommendations. The diagnostic algorithms presented are largely expert opinion-based.