Pleural fluid biochemistry – old controversies,new directions

Pleural effusions are a common reason for presentation to medical services. Many effusions have similar fluid appearances, and clinical history and examination may provide definitive treatment plans in only a small percentage of cases. Biochemical analysis of pleural fluid has long been a front-line tool for the respiratory physician, with relatively simple, common tests often able reliably to guide patient management.

The British Thoracic Society (BTS) guideline for the management of pleural disease was first published in 2003. ¹ This document generated substantial debate amongst clinical biochemists. ² Specific concerns included a lack of detail in the advice provided to clinicians regarding how to prepare samples for analysis, and the absence of specialist laboratory advice in the creation of the guidelines. There were also arguments against the use of pH as a routine test, including the fact that as a pleural investigation it is not specific for any particular disease (pH may be low, for example, in malignancy, pleural infection or rheumatoid arthritis), and that samples need to be collected anaerobically, requiring the use of blood gas analysers outside of their licence.

In 2010, the BTS released an updated pleural disease guideline. ² This document was prepared over a three-year period and involved consultation with a wide range of organizations, including the Royal College of Pathologists and The Association for Clinical Biochemistry. Although it addressed many of the points of contention from the 2003 document, some disputed recommendations remain.

Over the last few years there has been a concerted drive to move the management of pleural disease into the outpatient setting, enabled by the rapid expansion of dedicated pleural and ‘admission-avoidance’ clinics. ³ To be successful, these rely on the relevant diagnostic information being immediately available to clinicians using the minimum number of procedures. In our experience, this approach results in almost 95% of new pleural effusion patients avoiding admission for intercostal tube drainage, and the heavy costs this entails. Throughout the 2010 guideline there is an acceptance that biochemical tests must be interpreted in the light of clinical information and this is particularly important in the case of pH measurement due to its relative lack of specificity. However, while we agree that pleural fluid pH need not be measured in all samples taken, especially in those which are clearly purulent (this has the potential to damage machines), appropriate point-of-care analysis of pH remains one of the few tests that can significantly alter a patient’s immediate management course. The BTS guidelines recommend that patients with suspected pleural infection and an effusion pH of <7.2 be managed with immediate intercostal drainage. Thus, point-of-care pH measurement may determine hospital admission or discharge. For this reason, pH has genuine clinical value – a stance recently supported in an independent review. ⁴ However, many hospitals still do not allow ward-based blood gas analysers to be used in this way. Samples taken out of hours may wait many hours before being processed in a laboratory, if at all, and such delays can have a real and significant effect on both the result and clinical outcome. ⁵

The use of blood gas analysers for point-of-care pleural pH measurement is now sanctioned by a number of major device manufacturers, with some analysers now validated for use with pleural fluid samples, providing pleural specific software keys.^6,7 When introducing a pleural fluid sample into a blood gas analyser, in order to stay within warranty guidelines, we would stress the importance in all cases of only measuring free-flowing pleural fluid using a heparinized syringe.

Beyond the well-established diagnostic tests, the management options available to respiratory physicians have expanded rapidly. The rising incidences of both pleural infection and pleural malignancy make choosing, for example, which patients with empyema to refer for surgery, all the more relevant. In our view, the long-term future for pleural fluid biochemistry, and indeed pleural medicine as a whole, is likely to be heavily reliant on the measurement of diagnostic and prognostic biomarkers to augment clinical findings.

In itself, the use of ‘non-standard’ biochemical tests to affect diagnoses is not new. Indeed, the potential roles for the measurement of, for example, amylase, adenosine deaminase and various traditional malignant biomarkers such as carcinoembryonic antigen have been debated before. ⁸ However, there is an ever-increasing variety of alternative molecules coming under scrutiny, recently including galectin-1⁹ and interleukin-17,¹⁰ which typify the focus on traditionally poor-outcome diseases such as mesothelioma. Tests usually reserved for other conditions, such N-terminal pro-B natriuretic peptide in cardiac failure, are now being tested beyond their original remit, and have found niche uses.¹¹ Similarly, a recent study suggested that the addition of pleural fluid C-reactive protein to pH measurement may improve clinical ability to identify complicated effusions in pleural infection which warrant urgent drainage,¹² although this requires further study. Other examples of potentially useful assays include tumour necrosis factor-α, interleukin-1β and myeloperoxidase,¹³ although pleural infection biomarkers remain largely, for the time being, confined to research laboratories.

With the median survival of those with pleural malignancy often measured in months, it is vital that clinicians are able to identify the subgroups of patients who may be more likely to respond to treatment. Although, as yet, the ‘ideal’ biomarker has not been identified, useful candidates have certainly been observed. Perhaps the most thoroughly investigated novel biomarker in malignancy is soluble mesothelin. This test has been shown to have a high negative predictive value, meaning it may find a role as a rule-out test in certain patients, ¹⁴ and in tracking the progression of disease which is either being monitored or treated. ¹⁵ Another marker generating interest is the glycoprotein fibulin-3. Pass et al. ¹⁶ examined its utility in both pleural fluid and blood, positing the encouraging conclusion that fibulin-3 may be used to not only differentiate healthy patients from those with mesothelioma, but also to distinguish different types of malignant pleural effusion.

In the 10 years since the first BTS pleural guideline was published, there has been a remarkable shift in the way pleural medicine is practised. Rapid, ambulatory care is now seen as the gold standard for the majority of pleural effusions and increases in the incidence of many common conditions has made achieving this all the more important. While there have been significant changes in, for example, pleural radiology, biochemical analysis has seen fewer great leaps with the majority of standard pleural tests now many decades old. The old controversies regarding these will undoubtedly be fuelled by the increasing number of large series being published, but it is the newer prognostic and diagnostic biomarkers which are likely to have the most lasting impact upon such patients in the future.