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Abstract

Selecting appropriate laboratory tests based on available evidence is central to improve clinical effectiveness and impacting on patient outcome. Although long studied, there is no mutual agreement upon pleural fluid (PF) management in the laboratory context. Given the experienced confusion about the real contribution of laboratory investigations to guide clinical interpretation, in this update, we tried to identify useful tests for the PF analysis, aiming to unravel critical points and to define a common line in requesting modalities and practical management. We performed a careful literature review and a deepened study on available guidelines to finalize an evidence-based test selection, intended for clinicians’ use to streamline PF management. The following tests depicted the basic PF profile routinely needed: (1) abbreviated Light’s criteria (PF/serum total protein ratio and PF/serum lactate dehydrogenase ratio) and (2) cell count with differential analysis of haematological cells. This profile fulfils the primary goal to determine the PF nature and discriminate between exudative and transudative effusions. In specific circumstances, clinicians may consider additional tests as follows: the albumin serum to PF gradient, which reduces exudate misclassification rate by Light’s criteria in patients with cardiac failure assuming diuretics; PF triglycerides, in differentiating chylothorax from pseudochylothorax; PF glucose, for identification of parapneumonic effusions and other causes of effusion, such as rheumatoid arthritis and malignancy; PF pH, in suspected infectious pleuritis and to give indications for pleural drainage; and PF adenosine deaminase, for a rapid detection of tuberculous effusion.

Keywords

Pleural effusion test appropriateness biochemistry test cell count

Background

Pleural fluid (PF) is a plasma ultrafiltrate, in a steady balance between filtration and reabsorption, providing lubrification between the pleural membranes. In medical laboratories, it represents a precious sample taken by an invasive procedure (i.e. thoracentesis), and therefore, caution should be pursued when handling and exploring this biological material with the aim to define its nature and achieving a final diagnosis for proper patient management.¹ Historically, pleural effusions have been classified as of exudative or transudative nature. Pleural fluid examination gained interest through time, starting 50 years ago with the proposal of so-called Light’s criteria² until the more recent release of guidelines and recommendations.^3–8 Nevertheless, confusion still exists about the real utility of different tests for investigating the nature of PF, usually proposed as a simple list of examinations with a summary of pros and cons supporting (or not) the use, but without any definitive clarification about which exams clinicians should request to achieve correct diagnoses, with the aim of pursuing both appropriateness and effective clinical management. Given this unclear situation, which did not permit to the laboratories to standardize their service and to assure cost-effectiveness, we decided to define, based on existing scientific evidence, the best practice for PF laboratory investigation, including the optimal cut-offs to be applied for the recommended tests.

Pre-analytical phase: A frequently neglected aspect

Contrary to the normal practice, it is nowadays more and more evident that it is essential to pay special attention to the aspects related to sample collection and consider possible potential interferents in the PF examinations. Avoiding pre-analytical errors is particularly important given the usual unrepeatability of this fluid collection.

Selection of tubes for PF collection and sample handling

As per all laboratory analyses, special care should be taken when selecting the container for PF collection. Cell count and differential cell analysis should be directly performed on samples collected with EDTAK₂ or K₃ anticoagulants. No anticoagulants or additives are necessary for most biochemistry tests, although heparinized tubes may be used, except for glucose, for which PF sample must be collected in tubes containing a glycolysis inhibitor to avoid in vitro glucose consumption, especially in heavily cellular samples.⁹ Before biochemical analyses, centrifugation is required to eliminate cell debris and correctly carry out investigations, including PF inspection (see below). For pH measurement, the PF sample must be collected in air-tight non-ventilated syringes and transported to the laboratory or point-of-care blood-gas station rapidly and, ideally, ice packed. Sterile tubes for adenosine deaminase (ADA) analysis are recommended. Finally, it should be remembered that lactate dehydrogenase (LDH) activity is very sensitive to cold and is lost if the PF (and serum) samples are stored frozen. Therefore, if not immediately assayed, PF specimens should be stored at room temperature, at which no loss of LDH activity occurs for at least 3 days.¹⁰

Macroscopic PF inspection

Gross PF examination should be carried out both by clinicians performing thoracentesis, as it can give preliminary diagnostic indications, and by laboratorians to detect potential pre-analytical problems, such as the presence of clots in samples for cell count or haemolysis. Similarly to serum, PF is generally transparent and straw-yellow coloured. A haemorrhagic aspect can be related to a true haemorrhagic effusion (i.e. haemothorax) or to a vasal rupture during sample withdrawal.¹¹ If the sample remains red in colour after centrifugation, in vitro haemolysis may be suspected. Pleural fluid turbidity is often related to inflammation, infection, or elevated lipid concentrations. Also in this case, distinction about the turbidity origin can be made by centrifugation: if the sample becomes transparent, previous turbidity is most likely caused by an increased cellular count; on the opposite, if the sample remains turbid, elevated lipid concentrations can be suspected.¹¹ A list of common and uncommon PF macroscopic characteristics, and their corresponding underlying conditions, are reported in Table 1.^11,12

Table 1.

Macroscopic appearance/odour of pleural fluids and possible underlying conditions.

Appearance	Underlying conditions
Clear, pale-yellow, odourless	Transudate, most exudates
Purulent	Infection, empyema
Haemorrhagic (red)	Haemothorax, cancer, pulmonary embolism, trauma, contamination during pleural fluid withdrawal
Milky	Infection, chylothorax or pseudochylothorax, presence of cells or debris
Anchovy paste or chocolate sauce	Amoebiasis with hepatopleural fistula
Brown	Parapneumonic effusion
Viscous	Mesothelioma
Putrid odour	Anaerobic infection
Urine odour	Urinothorax

Interferences

As for blood samples, sample quality and integrity should be considered in PF analysis. Lactate dehydrogenase activity is present at high levels in cytoplasm of many cells. This implies that, if cellular damage is present, for example, after a traumatic PF withdrawal, LDH activity may significantly increase. Consequently, LDH results can be misinterpreted, causing a diagnostic misclassification when Light’s criteria are employed (see below). A strategy, such as automatic photometric determination of interference indices, to evaluate sample quality before analysis would therefore be desirable even for the PF samples. A major limitation of this approach is however a lack of interference thresholds for this fluid.¹³ Therefore, until specific investigations are conducted to define these thresholds, visual inspection by laboratory professionals is at minimum recommended to identify possible interference problems.

Analytical interferences can also be an issue. Almost all studies measuring albumin gradient (see below) used non-specific albumin assays based on the bromocresol green principle.⁶ As recently demonstrated, the use of non-specific methods for the measurements of serum albumin may however have a high negative clinical impact.¹⁴ It is unclear if this lack of method selectivity may significantly influence albumin gradient results and their interpretation.⁷

Test selection

Light’s criteria and albumin gradient

Studies from which current guidelines are drawn focus on PF testing and concentrate on the management of this peculiar sample.^3–5 First in line is the distinction between transudates and exudates and their different pathophysiology. Transudates origin from a gap between hydrostatic and osmotic pressure, frequent causes of which are cardiac failure and cirrhosis. Exudates derive from an increased capillary permeability of the pleural membranes, generally related to inflammation, infection, or malignancy. Light’s criteria were conceived for PF discrimination in exudate or transudate, originally requiring measurement of LDH and total proteins, both in PF and serum, and calculation of PF to serum ratios as well as the interpretation of LDH absolute value in PF.² In their initial study, Light and co-workers² found both elevated sensitivity [99.0%, 95% confidence interval (CI): 94.7%–99.9%] and specificity (97.9%, CI: 88.7%–99.9%) for these criteria. However, all following authors failed to obtain the same optimal results for several reasons, including the fact that Light’s proposed cut-offs cannot be easily extrapolated in other settings or populations and that the use of an absolute LDH cut-off is controversial,^11,15,16 since enzyme results are strictly dependent from the employed laboratory method (while ratios are method independent).¹⁰ Considering Light’s criteria, one important concept should be emphasized: a panel testing is useful only when each included test helps identifying a different subset of the evaluated population; if tests of the panel provide overlapping information, it should be recommended to perform only the more accurate one. Heffner et al.¹⁷ had the merit to show that the LDH absolute value in PF can be removed from Light’s criteria because, as expected, it is highly correlated with LDH ratio (r = 0.84) and does not add anything of significance to the discriminative power of the criteria. They proposed the introduction of ‘abbreviated Light’s criteria’, which include only PF/serum total protein and PF/serum LDH ratios, as the best biochemical approach to diagnose exudates, avoiding duplication of data relative to reporting LDH absolute value in PF, as the diagnostic accuracy of these abbreviated criteria when both ratios exceed the related cut-offs remains unchanged when compared to the classical Light’s criteria.

The main limit of Light’s criteria, both classic and abbreviated, is the misclassification of transudates as exudates, because they lack in specificity.^11,18,19 This is true mainly for patients with cardiac failure treated with diuretics, causing a great loss of fluids with no effect on serum proteins, which in turn increase inside the pleural cavity mimicking the exudate range.¹⁸ To try to solve this issue, and generally bypass the dichotomic classification of transudates and exudates, Heffner et al. proposed to apply a Bayesian approach in which they suggest calculating continuous likelihood ratios to deduce the post-test probability of an effusion being of a certain aetiology, starting from a clinically established pre-test probability.²⁰ Although interesting, this approach is however of difficult application in clinical practice.¹⁹ To overcome the problem of PF misclassification in cardiac failure patients, the calculation of serum to effusion albumin gradient (SEAG) was therefore proposed. In the original study, using a SEAG >12 g/L to indicate a transudate gave a specificity of 100%.²¹ As often happens for a newly proposed test, the SEAG specificity decreased to 92% in a further validation study, which however confirmed that the use of SEAG was able to reduce the misclassification rate in patients receiving diuretics.²² In a further study, the improvement was not statistically significant.²³ Nevertheless, Light²⁴ himself more recently supported the use of SEAG.

In conclusion, even if some authors advanced criticisms based upon the uselessness of LDH ratio calculation because of the presumed independency of PF and serum enzyme values,^25,26 Light’s criteria remain the first-level approach as biochemical investigation of PF.^3–5 As the ‘abbreviated Light’s criteria’ (PF/serum total protein ratio >0.5 and PF/serum LDH ratio >0.6, respectively) maintain the same diagnostic accuracy, they should be preferred. SEAG calculation should be limited to evaluate pleural effusions in patients with cardiac failure assuming diuretics.

Automated cell count

Modern haematological analysers allow to automate PF cell counting, reporting absolute numbers of nucleated cells and leucocytes, and percentages of polymorphonucleated cells, lymphocytes, and eosinophils, by using specific dedicated channels. This is undoubtedly a step forward compared to previous practice when PF cellular analysis was performed manually by optical microscopy. Validation of body fluid parameters that, in most analysers, are still considered only for research, such as absolute and percentage count of neutrophils, lymphocytes, and eosinophils, is therefore important for their possible role in establishing the origin of the pleural effusion. Table 2 depicts the most important PF cellular parameters together with their decision thresholds for specific clinical conditions.^27,28

Table 2.

Differential cell count parameters in the pleural fluid and corresponding decision thresholds for specific clinical conditions.

Cellular parameter	Decision threshold
Total nucleated cells	In ∼80% of transudative effusions: <1 × 10⁹/L In ∼100% of transudative effusions: <2 × 10⁹/L In parapneumonic effusions/acute inflammation: >10 × 10⁹/L
Polymorphonucleocytes	In acute inflammation: >50% of PF leucocytes
Lymphocytes	In transudative, tuberculotic, metastatic carcinoma, lymphoproliferative disorder, and chylothorax: >50% of PF leucocytes
Eosinophils	In effusions from pneumothorax, pulmonary embolism, traumatic haemothorax, parasitic or fungal disease: >10% of PF leucocytes

Presence of red blood cells in PF is mainly related to traumatic withdrawal. A strategy has been proposed to differentiate between this condition and the presence of a true haemorrhagic effusion utilizing a haematocrit measurement on the PF sample and on a paired blood sample. A PF haematocrit 50% higher than the corresponding value on blood would suggest a haemorrhagic effusion.¹¹

Additional tests useful in specific situations

PF Triglycerides

Both total cholesterol and triglyceride measurements have been proposed to differentiate chylothorax, an effusion caused by leakage of lymphatic fluid from thoracic duct into the pleural space, from pseudochylothorax, a long-standing effusion related to chronic inflammation.²⁸ Nevertheless, performing both tests does not add information in comparison to only one. Therefore, to avoid redundancy, it is recommended to perform only one of the two tests because of their equivalent significance for the above-mentioned purpose. Triglyceride measurement alone can adequately detect chylothorax, having a 99% positive predictive value for values >110 mg/dL (1.25 mmol/L) and a 95% negative predictive value for values <50 mg/dL (0.50 mmol/L).^3,11,16,29 In the 50–110 interval, clinical information becomes central for discerning if a chylothorax is present, together with the observation of a floating chylomicron layer on allowing the specimen to stand for 24 h in a refrigerator Table 3.⁷

Table 3.

Interpretative criteria for selected biochemical tests on pleural fluid.

Test	Decision threshold
Serum–effusion albumin gradient (SEAG)	>12 g/L for transudate effusion
PF triglycerides	>110 mg/dL (1.25 mmol/L) in chylothorax
PF pH	<7.30 in infective effusions <7.20 may indicate PF drainage
PF glucose	<60 mg/dL (3.4 mmol/L) in parapneumonic effusions, rheumatoid arthritis, malignancy
PF adenosine deaminase	>40 U/L in tuberculous pleurisy

PF pH and glucose

The biochemical tests with a better performance for detecting an infective aetiology of a pleural effusion are glucose and pH measured in PF.^3,30 In these conditions, both test values decrease because of the inflammatory cell and infectious agent metabolisms. A PF acidosis, that is, a pH value <7.30, shows a good accuracy. Furthermore, when the pH value goes below 7.20, it may indicate the need for draining a parapneumonic effusion.³⁰ A PF glucose concentration <60 mg/dL (3.4 mmol/L) may indicate various clinical scenarios, including parapneumonic effusions, but even malignancy or rheumatoid arthritis.²⁸ This test is therefore not very specific but helpful if considered together with clinical data.^8,11 Some authors have restricted its use only to the investigation of suspected rheumatoid effusion, as the only condition with undetectable glucose concentrations in PF was rheumatoid empyema.^16,31 In addition to preservation of PF samples for assay by using tubes containing a glycolysis inhibitor, glucose measurements on PF should be performed after at least 8 h of fasting to permit the PF/plasma equilibration.

PF ADA

A marked increase in PF ADA levels has long been proposed as a diagnostic marker of extrapulmonary tuberculosis.³² Nevertheless, only recently the scientific evidence has supported its introduction in the related guidelines.^33,34 In a meta-analysis, which included 174 studies, the determination of ADA in PF showed sensitivity and specificity of 0.92 (CI: 0.90–0.93) and 0.90 (CI: 0.88–0.91), respectively, for tuberculous pleurisy, with positive and negative likelihood ratios of 8.92 and 0.09 at an ADA decision level of 40 U/L.³⁵

Evidence gaps

The role of amylase measurement in PF remains greatly controversial. Basically, there is no evidence of the utility of this test, since amylase (or better pancreatic lipase)¹⁰ can be easily measured on serum samples to identify the presence of a pancreatic injury, avoiding thoracentesis and its possible complications, while pancreatic fistulas are better detected by other clinical and instrumental means.³⁶ Accordingly, CLSI guideline and other authoritative works do not recommend routinely performing amylase in PF.^3,6 Epithelial tumours of the lung and ovary may produce considerable amylase activity (usually salivary-type) and give rise to hyperamylasemia.¹⁰ PF may also contain the enzyme as a result of the presence of the tumour. It remains however unclear which added value the measurement of amylase in PF may provide in these conditions.³⁷

The NT-proBNP determination in PF has been proposed as an alternative to SEAG for detecting transudates related to cardiac failure, which are potentially misclassified as exudates by using Light’s criteria.³⁸ However, if a cardiac origin of pleural effusion is suspected and drainage is not necessary, the cardiac impairment can be detected through B-type natriuretic peptide measurement in blood, avoiding thoracentesis, also considering that blood and PF concentrations of this analyte are strictly related.⁷

Areas for further research

Although a plenty of publications have referred to diagnostic accuracy of Light’s criteria and/or SEAG for distinguishing exudates from transudates, few studies have investigated other combined ratios or grandients.^26,39 For instance, the albumin PF/serum ratio could be considered in further research for the main diagnostic purpose, either singly or in combination with LDH ratio as a replacement of total protein ratio. Study protocols should be performed aiming to evaluate the accuracy in distinguishing between exudates and transudates of estimates containing the measurement of albumin instead of the measurement of total proteins both as simple PF/serum albumin ratio and ‘modified’ Light’s criteria, that is, PF/serum albumin and PF/serum LDH ratios. These studies should be carefully designed to establish optimal diagnostic thresholds, without forgetting the impact of the assay selectivity in measuring albumin on serum and PF and the need to use accurate methods.^7,40 Another area of investigation can be the definition of the interference thresholds by haemolysis on the LDH assay on PF at which the misclassification between exudates and transudates by using Light’s criteria becomes clinically relevant; this should be obtained by a systematic evaluation of the haemolysis index detected automatically by chemistry platforms.^13,41 More in general, studies about PF must explicitly report pre-analytical and analytical details.⁷ Finally, external quality assessment exercises should be routinely organized by scheme providers to assure the adequate quality of PF and other body fluid measurements. As Chubb and Williams anticipated few years ago,⁷ in an era of new regulatory frameworks, the lack of measuring systems specifically validated and marketed for use with body fluids other than serum and urine may become an issue difficult to solve.⁴²

Conclusions

Management and measurements of PF samples should be conducted rigorously through a clear definition of clinically useful tests to avoid inappropriateness, redundancy, and result misinterpretation. Our daily experience however attests that PF analysis often remains a challenge in the laboratory scenario. Clinicians continue to order multiple exams without a clinical rationale and scientific literature reports conflicting information too. In this report, we suggest a harmonized approach to be adopted by medical laboratories, which is summarized in Table 4 and in the diagnostic flowchart reported in Figure 1. First, the analysis should always start with macroscopic evaluation as this gives an initial indication about possible differential diagnoses (Table 1), and in turn guiding subsequent testing. First-line tests should include differential cell count and PF/serum total protein ratio plus PF/serum LDH ratio (abbreviated Light’s criteria), with the main purpose of distinguishing between exudative and transudative nature of the effusion. If exudate is excluded, PF analysis can stop at this level. On the other hand, if exudate diagnosis is suspected, additional analyses can be additionally performed as described in the Appendix below.

Table 4.

Recommended steps for pleural fluid analysis.

1) Macroscopic evaluation of samples

2) Analysis of lactate dehydrogenase and total protein on PF and serum (with application of abbreviated Light’s criteria) and cell count on PF looking to cellular characteristics of the effusion

3) In patients with heart failure treated with diuretics, analysis of serum-PF albumin gradient to avoid misclassification as exudate

4) If exudate confirmed, additional analyses should be performed for determining causes of effusion

PF-Triglycerides for suspected chylothorax

PF-pH for suspected infective aetiology

PF-Glucose for suspected infective aetiology, malignancy, or rheumatoid arthritis

PF-Adenosine deaminase for suspected extrapulmonary tuberculosis

Figure 1.

Flowchart describing pleural fluid (PF) management. LDH, lactate dehydrogenase; SEAG, serum–effusion albumin gradient; ADA, adenosine deaminase.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Not applicable.

Guarantor

MP.

Contributorship

CA and LR researched literature. CA and MP conceived the study. CA and EA cured data analysis. CA wrote the first draft of the manuscript. EA, AD, and MP supervised the study and reviewed and edited the manuscript. All authors approved the final version of the manuscript.

ORCID iD

Claudia Arrigo

Appendix

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The laboratory investigation of pleural fluids: An update based on the available evidence

Abstract

Keywords

Background

Pre-analytical phase: A frequently neglected aspect

Selection of tubes for PF collection and sample handling

Macroscopic PF inspection

Interferences

Test selection

Light’s criteria and albumin gradient

Automated cell count

Additional tests useful in specific situations

PF Triglycerides

PF pH and glucose

PF ADA

Evidence gaps

Areas for further research

Conclusions

Footnotes

Declaration of conflicting interests

Funding

Ethical approval

Guarantor

Contributorship

ORCID iD

Appendix

References