There are more than 60 reported causes of pleural effusions (1). Existing diagnostic algorithms are based on the premise that pleural effusions almost always have a single etiology. This assumption has been long suspected to be oversimplistic. The study in this month’s issue of AnnalsATS by Bintcliffe and colleagues (pp. 1050–1056) provides important proof-of-concept data from 126 patients presenting with an undiagnosed unilateral pleural effusion to a tertiary pleural disease center (2). They found that 30% of referred patients had more than one etiology, with congestive heart failure (CHF) being an additional cause in half of the cases.

This reported figure is likely an underestimate of the true incidence of concurrent or multiple etiologies for pleural effusions. The work by Bintcliffe and colleagues illustrates the many hurdles in the journey toward characterization of all contributing causes underlying accumulation of a pleural effusion. Arguably the most important of these is a lack of a definitive test for many recognized causes. Bintcliffe and colleagues (2) determined the additional diagnoses through chart reviews by two experts and assessment of information gathered at the time of 12-month return visits. This clinical approach almost certainly under-recognizes concurrent etiologies.

Disease-specific tests are critical to uncovering concurrent etiologies of pleural effusion. The use of N-terminal probrain natriuretic peptide (NTproBNP) for the diagnosis of CHF effusion is an excellent example. Light’s criteria, used since the 1970s (3), cannot determine the presence of more than one cause for a pleural effusion and are known to overdiagnose transudates as exudates, especially in patients using diuretics. The finding of an elevated NTproBNP blood level can support the diagnosis of CHF, even in the presence of other apparent causes of transudative or exudative effusions (4). Establishing the contribution of CHF may enhance fluid control via diuretic therapy.

No specific biomarkers are available yet for most other causes of transudative effusions, such as liver cirrhosis or nephrotic syndrome (5). Likewise, a large number of recognized causes of pleural effusions, such benign asbestos pleural effusion, lymphatic dysfunction, drug-induced pleuritis, and hypothyroidism, can only be established by exclusion of other causes in an appropriate clinical setting. This makes their inclusion as concurrent causes almost impossible unless a specific diagnostic test becomes available.

Concurrent causes may also be “silent” and overlooked unless specifically searched for. Bintcliffe and colleagues included chest computed tomographic (CT) imaging in their diagnostic evaluation protocol: however, they did not test routinely for pulmonary embolism. High incidences of pleural effusions (approaching 50%) were found in several observational series of patients with pulmonary emboli proven on CT pulmonary angiography (6, 7). Pulmonary emboli are known to be common in subjects with certain conditions known to cause pleural effusions, such as cancer (8). The associated breathlessness may be mild and easily overlooked or attributed to the pleural effusion, rather than an underlying pulmonary embolism.

It is also unknown whether the discovery of concurrent etiologies for pleural effusions will increase if more invasive tests such as pleural tissue biopsy are obtained. Some malignant effusions will escape cytological diagnosis and require histological confirmation. Secure diagnoses of pleural amyloidosis (which can present as a transudate [9]), rheumatoid pleuritis, or pleural effusion caused by IgG₄ disease (10), among others, often necessitate pleural tissue examination. Likewise, it is unknown to what extent routine testing of pleural fluid for established markers for uncommon diseases will increase the diagnostic yield for concurrent etiologies. Examples include chylomicrons for chylothorax, cholesterol for pseudochylothorax, amylase for esophageal rupture or pancreatitis, and β₂-transferrin for duro-pleural fistula.

The ultimate goal to determine all the contributing causes for the formation of a pleural effusion will require an application of a panel of high-performance biomarkers. Current biomarker discovery strategies are generally based on a multistep pipeline that requires screening for huge numbers of candidate markers using various high-throughput “-omic” platforms; for example, genomics, proteomics, immunomics, or metabolomics, to identify marker profiles that differentiate between a set of cases and controls (11). However, even for any one type of pleural effusion, heterogeneity in composition of the fluid and variations in patient characteristics exist. Hence, a large set of clinical samples are needed, which can be challenging for the less common pleural diseases. Biobanking of samples obtained in the assembly of large, multicenter patient registries may be the way forward.

Over the years, many candidate biomarkers for pleural diagnoses suggested by small single-center studies were not verified when tested on independent sets of samples collected by other centers (12). Validation of novel protein markers may require the development of a new assay platform and the screening of hundreds of samples from multiple centers in a blinded and/or clinically meaningful way before the marker assay and its intended use can be approved by a health agency, such as the U.S. Food and Drug Administration. To date, relatively few biomarkers for clinical conditions have emerged from such pipelines, and multiple reasons for this lack of success have been suggested, including problems and biases related to experimental design, data analysis, samples collection, processing, and storage, as well as lack of assay reproducibility. Clinical uptake of biomarkers also entails additional challenges such as availability of technology and demonstration of cost-effectiveness (11).

Clearly discovery of novel biomarkers is challenging, often costly, and time-consuming without guarantee of success. To apply the approach outlined here to a clinical situation with such a wide differential diagnosis base as seen with pleural effusion etiology is practically an impossible dream. However, with rapidly advancing technology that can process huge samples in a fast and affordable fashion, this goal may still be achievable in the not-too-distant future. Active research effort and resources are going into biomarker discovery in many of the individual diseases that cause pleural effusions. Direct adaptation of the fruits of these works to pleural fluid diagnoses is an interim option.

Once discovered, the precise role of a biomarker will need to be defined, as does the clinical context for which it should be applied; for example, to improve diagnostic efficiency, predict patient outcome or treatment response, and so on. Bintcliffe and colleagues found that an elevated pleural fluid NTproBNP has an interesting role, in that it supports recognition of an additional etiology for a pleural effusion that may otherwise be overlooked.

These issues highlight the long and challenging journey ahead to reveal the full extent of underlying causes for all pleural effusions. The types and frequencies of multiple concurrent etiologies for pleural effusions uncovered by Bintcliffe and colleagues are likely to represent the tip of an iceberg. Nonetheless, the study serves as an important first step toward the ultimate aim of understanding the full causes of pleural effusions. This information may provide guidance for better clinical care and permit discovery of novel therapeutic targets to stop the effusion formation.

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