diagnostics

Review
Diagnostics in Pleural Disease
Anand Sundaralingam 1, * , Eihab O. Bedawi 1,2 and Najib M. Rahman 1,2,3
1 Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Foundation Trust,
Oxford OX3 7LE, UK; Eihab.Bedawi@ouh.nhs.uk (E.O.B.); najib.rahman@ndm.ox.ac.uk (N.M.R.)
2 Oxford Respiratory Trials Unit, University of Oxford, Oxford OX3 7LE, UK
3 Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, UK
* Correspondence: Anand.Sundaralingam@ouh.nhs.uk




Received: 17 November 2020; Accepted: 1 December 2020; Published: 4 December 2020


Abstract: Pleural disease diagnostics represent a sprawling topic that has enjoyed a renaissance in
recent years from humble beginnings. Whilst pleural patients are heterogeneous as a population
and in the aetiology of the disease with which they present, we provide an overview of the typical
diagnostic approach. Pleural fluid analysis is the cornerstone of the diagnostic pathway; however,
it has many shortcomings. Strong cases have been made for more invasive upfront investigations,
including image-guided biopsies or local anaesthetic thoracoscopy, in selected populations. Imaging
can guide the diagnostic process as well as act as a vehicle to facilitate therapies, and this is never
truer than with the recent advances in thoracic ultrasound.

Keywords: pleural effusion; pleural fluid analysis; image-guided pleural biopsies; thoracoscopy;
thoracic ultrasound; malignant pleural mesothelioma

1. Introduction
Patients with pleural disease represent a heterogenous population and whilst there is not a “one
size fits all” approach to diagnosis or management, we provide an overview of the typical diagnostic
approach and recent developments that have furthered our understanding of diagnostics within pleural
disease. The vast majority of patients with pleural disease will present with a pleural effusion. Therefore,
the main focus of this review will pertain to diagnostics within this context; however, an approach to
investigating pleural thickening will also be explored. Patients with pleural effusion will often present
with symptoms of dyspnoea, chest pain, or cough but with the increasing utilisation of cross-sectional
imaging, effusions and thickening are often identified incidentally, in asymptomatic patients.
Estimates suggest that 0.26 mL of fluid per kg of body weight is contained within each pleural
cavity (approximately 18 mL in a 70 kg adult) [1–3]. Pleural fluid (PF) is produced by the parietal
pleura and reabsorbed via parietal pleural lymphatic channels. This homeostasis is dependent on the
balance of hydrostatic and oncotic pressures between the systemic and pulmonary circulation and
the pleural space itself [4]. Disruptions to this homeostasis often underpin “transudative” effusions,
whilst it is traditionally thought that “exudative” effusions result from an increase in the permeability
of the pleural membranes and microvasculature [5]. In health, the parietal pleural lymphatic channels
are capable of increasing their flow rate and re-absorption by a factor of 20 [4]. It is therefore postulated
that in addition to allowing for frictionless sliding of the pleural membranes during the respiratory
cycle, the pleural space serves as an extrapulmonary reservoir for pulmonary oedema arising from the
pulmonary interstitium, in order to minimise interference with gas exchange [6,7]. Pleural effusion can
therefore be thought of as a state of excessive production that overwhelms the usual mechanisms for
resorption, a disruption to the usual mechanisms of resorption, or a combination of the two [8].
With over 60 documented causes for pleural effusions identified in the literature, with some
examples included in Table 1, no single test is likely to ever provide the entire diagnosis [9].

Diagnostics 2020, 10, 1046; doi:10.3390/diagnostics10121046 www.mdpi.com/journal/diagnostics

Diagnostics 2020, 10, 1046 2 of 20

A combination of history, physical examination, laboratory tests, and radiology is essential in securing
a diagnosis.

Table 1. Causes of pleural effusions [10].

Transudative Effusions Exudative Effusions

Congestive cardiac failure Parapneumonic
Cirrhosis TB pleuritis
Nephrotic syndrome Primary or secondary thoracic malignancy
Glomerulonephritis Pulmonary embolism
Peritoneal dialysis Pancreatitis
Hypoalbuminaemia Post myocardial infarction
Cerebrospinal fluid leak Collagen vascular disorders
Urinothorax Drug-related
Haemothorax
Chylothorax
Benign asbestos-related pleural effusions

2. Pleural Fluid
PF analysis remains the cornerstone in diagnosing pleural effusions of unknown aetiology. It is
however important to note that if the clinician is able to satisfactorily achieve their diagnosis based on
history, examination findings, and radiology and hence, PF analysis would not affect management of
the patient, thoracocentesis as a first line investigation is not required. This is never more applicable
than in the context of congestive cardiac failure. Pleural effusion associated with heart failure has an
estimated annual incidence in the USA of 500,000 cases and remains one of the commonest causes of
pleural effusion worldwide [11]. Whilst traditionally thought to only present with bilateral effusions,
this was the case in only 58% across a large case series covering 3245 consecutive patients, with 27%
appearing on the right only and 14% on the left [12].
The British Thoracic Society (BTS) advocates against pleural aspiration, where there is a strong
pre-test probability for a transudative cause with typical features (e.g., bilateral effusions, responding
to therapies) [13]. However, it is increasingly recognised that a significant proportion of patients
presenting with a pleural effusion will have dual pathology driving their presentation and this bears
consideration. In a prospective study of 126 patients with pleural effusion of unknown aetiology, 30%
(38/126) were found to have more than one cause for their effusion, of which the commonest secondary
cause was congestive cardiac failure [5,14].
Where the diagnosis remains in doubt or when a transudative cause of pleural effusion is
behaving atypically, PF analysis forms the next step in assessment. Table 2 highlights the tests that
all PF specimens should be analysed for, generally considered the minimum standard following
initial thoracocentesis.

Table 2. Minimum standard assays for PF.

Assay
Biochemistry panel: Protein, LDH, Glucose, pH
Microbiology panel: Gram stain + Culture
Pathology panel: Cytology for differential cell count + abnormal cells

3. Pleural Fluid Biochemistry

It is likely the PF biochemistry panel will be the first to return and thereby, initially guide the
diagnostic pathway. Based on the PF biochemistry, the first decision to make is whether the PF
represents a transudate or exudate. Dr Light’s 1972 criteria for differentiating transudative from
exudative effusions, based on the PF biochemistry across 150 effusions he sampled prospectively,
Diagnostics 2020, 10, 1046 3 of 20

retain clinical utility even today. These criteria classified an exudate as meeting one or more criteria
of: a PF protein to serum ratio of greater than 0.5, a PF lactate dehydrogenase (LDH) to serum ratio
of greater than 0.6, or a PF LDH of greater than 200 IU [15]. This latter criterion was later modified
to greater than two-thirds of the upper limit of the normal LDH level [16]. These criteria have been
shown to predict an exudate correctly with a diagnostic accuracy rate of 94.7% in some series [17].
It should be noted, however, that these criteria are skewed towards “overcalling” an exudate—the
so called “pseudo-exudate”. This is such that some 27% of cases of heart failure may be classified as an
exudate, an effect that is exaggerated when prior diuretic therapy has been commenced [18]. In this
situation, the serum to PF albumin difference (>12 g/L) or serum to PF total protein difference (>31 g/L)
can be used to correctly reclassify the effusion as a transudate [19]. One benefit of “overcalling” is
that it is less likely to miss important causes for exudative effusions, such as malignancy. Nonetheless,
case series have demonstrated that between 1 and 10% of malignant pleural effusions (MPE) are
characterised as transudates, despite using Light’s criteria [20,21].
It is worth mentioning the issue of “discordant PF biochemistry”, for example when the protein
criteria suggest an exudate whilst the LDH criteria a transudate and vice versa. In one case series,
up to 29% (229/792) of pleural effusions classified as an exudate were discordant. The discordant
pleural effusions were seen in an older population (75 years vs. 70 years) and where the diagnosis
included global fluid overloaded states (11% vs. <2%) [22]. This once again highlights the role of dual
pathologies contributing to pleural effusion in selected populations and the difficulties this poses in the
classification of pleural effusions by conventional methods [8]. Another area that poses a diagnostic
challenge is in differentiating an inflammatory malignant effusion from pleural infection. By definition,
this is a patient group that does not lend itself easily to study within the setting of a randomised
controlled trial. Procalcitonin has been proposed as a specific marker of bacterial infection and has been
used as a differentiator from other states of systemic inflammation in other infections [23]. However,
procalcitonin showed no statistically significant difference in diagnostic utility when compared to
C-reactive protein (CRP) or white cell count, in a study by Dixon et al. across 425 patients of whom 80
had pleural infection [24]. Whilst this finding was somewhat unexpected, given prior smaller studies,
it may yet have a role in a specific subset of patients hitherto undefined.
PF glucose and pH will often be immediately available, as a point of care test, and may determine
the need for immediate management in some conditions (e.g., pleural infection). This analysis is subject
to error if the sample is exposed to air or local anaesthetic and so care must be taken in processing.
A PF pH < 7.2 and glucose < 3.4 mmol/L have been shown to be reliable in differentiating between a
complicated parapneumonic pleural effusion (CPPE) which requires immediate tube thoracostomy
drainage and an uncomplicated parapneumonic pleural effusion (UPPE) [25–27]. A recent large
(n = 2971), retrospective database study concluded that whilst the relationship between PF pH and
glucose was non-linear, there was concordance between the two in producing clinically meaningful
outcomes. They conclude that either test on its own will provide the necessary information in 90%
of cases, but they recommend exercising caution in patients with a baseline hyperglycaemic state,
which may have resulted in discordance between the two (i.e., low PF pH, normal/high PF glucose) [28].
It should be borne in mind that whilst these criteria are highly sensitive at identifying CPPE, it is not
specific to pleural infection and there are a number of other causes of pleural effusion that may yield
similar results. Of note, it has been shown that PF pH can vary even within the same patient, depending
on which locule is sampled within a multiloculated effusion [29]. As with any test, PF biochemistry
must be interpreted in the appropriate clinical context. Table 3 highlights some typical PF biochemical
features with their corresponding clinical conditions.
Novel PF biomarkers are always on the horizon; however, few have made it into routine clinical
practice. PF adenosine deaminase (ADA), a purine-degrading enzyme found in T-lymphocytes,
has been shown to have a strong negative predictive value in excluding pleural TB in low-incidence
areas (NPV 99% when < 30 IU/L) [30]. However, false positives in empyema, rheumatoid pleuritis,
and malignancy are seen and therefore, reserving its use for only lymphocytic effusions may increase
Diagnostics 2020, 10, 1046 4 of 20
Diagnostics 2020, 10, 1046 4 of 21

positivepredictive
its positive predictive value
value [13].
[13].InIn
higher incidence
higher areas,
incidence an LDH:ADA
areas, ratio may
an LDH:ADA bemay
ratio morebe
specific
moreand
specific
the combination
and the combinationofof ADAADAandandunstimulated interferon-gamma
unstimulated (IFN-γ) in
interferon-gamma PF, which
(IFN-γ) has which
in PF, been shown
has been
to be superior to ADA in all parameters, may be more helpful if accessible [31,32].
shown to be superior to ADA in all parameters, may be more helpful if accessible [31,32].
In the context of pleural infection, PF soluble urokinase Plasminogen Activator Receptor
In the context of pleural infection, PF soluble urokinase Plasminogen Activator Receptor (suPAR)
(suPAR) has been shown to be potentially of use in predicting the need for tube thoracostomy in
has been shown to be potentially of use in predicting the need for tube thoracostomy in parapneumonic
parapneumonic effusions, though prospective validation in a multicentre trial setting is awaited [33].
effusions, though prospective validation in a multicentre trial setting is awaited [33].
Table 3. Typical PF biochemical patterns [8,13,34,35].
Table 3. Typical PF biochemical patterns [8,13,34,35].
Condition Typical PF Biochemical Patterns
Condition Low Protein, Low LDH, N terminal
Typical pro-brain natriuretic
PF Biochemical Patterns peptide (NT-
Cardiac failure
proBNP), but closely mirrors serum NT-proBNP
Low Protein, Low LDH, N terminal pro-brain natriuretic peptide
Cardiacinfection
Pleural failure High Protein, High LDH (>1000), very low Glucose, Low pH
(NT-proBNP), but closely mirrors serum NT-proBNP
Malignant pleural
Pleural infection High Protein, High LDH (>1000), very low Glucose, Low pH
High Protein, High LDH, (Low Glucose)
Malignanteffusion
pleural effusion High Protein, High LDH, (Low Glucose)
Rheumatoid
Rheumatoideffusion
effusion VeryVery
lowlow Glucose
Glucose
TB
TBeffusion
effusion VeryVery
highhigh Protein,
Protein, lowlow glucose
glucose
Dural
Duralleak
leak VeryVery
lowlow Protein
Protein
Urinothorax
Urinothorax VeryVery
lowlow Protein,
Protein, PF/Serum
PF/Serum creatinine
creatinine > 1,>pH
ratio
ratio 1, pH < 7.30
< 7.30
Pancreatitis PF/serum amylase ratio >1, PF amylase > upper limit of normal serum levels
PF/serum amylase ratio >1, PF amylase > upper limit of normal serum
Chylothorax
Pancreatitis Elevated Triglycerides (>1.24 mmol/L), Chylomicrons
Pseudochylothorax levels mmol/L), cholesterol crystals
Elevated cholesterol (>5.18
Chylothorax
Haemothorax Elevated Triglycerides (>1.24
PF haematocrit/Serummmol/L), Chylomicrons
haematocrit > 0.5
Pseudochylothorax Elevated cholesterol (>5.18 mmol/L), cholesterol crystals
Haemothorax PF haematocrit/Serum haematocrit > 0.5
4. Pleural Fluid Microscopy Culture and Sensitivity (MCS)
4. Pleural
Whilst theFluid Microscopy Culture
PF biochemistry and Sensitivity
may be suggestive (MCS)infection, the gold standard for diagnosing
of pleural
the condition
Whilstis with
the PFpositive microbiological
biochemistry growth within
may be suggestive the PF.
of pleural Unfortunately,
infection, the goldyields fromfor
standard PF are
quite diagnosing the condition
poor; a recent systematicis with positive
review acrossmicrobiological growth within
75 studies suggests that PFthe PF. Unfortunately,
culture yields
is only positive in 56%
from
of cases PF are
[36]. This quite
yieldpoor;
may a recent systematic
be improved review
further byacross 75 studies
inoculating thesuggests
PF into that PF culture
enrichment is only [37].
medium
positive in 56% of cases [36]. This yield may be improved further by inoculating
The yield from PF culture for Mycobacterium tuberculosis has traditionally been even worse (quoted the PF into as
enrichment medium [37]. The yield from PF culture for Mycobacterium tuberculosis has traditionally
10–20%) [13,38,39]. However, the use of liquid culture medium (BACTEC, Figure 1) and inoculation
been even worse (quoted as 10–20%) [13,38,39]. However, the use of liquid culture medium
by the bedside has been observed to have greater yields (63% sensitivity) with a reduction in time to
(BACTEC, Figure 1) and inoculation by the bedside has been observed to have greater yields (63%
positive culture with
sensitivity) [40,41].
a reduction in time to positive culture [40,41].

Figure1.1. BACTEC
Figure BACTEC bottles.
bottles.

A number of factors influence microbiological yield from PF, including the prior usage of
antibiotics, polymicrobial infection not accurately represented through standard microscopy and
culture techniques, and infection with fastidious organisms not easily grown in culture medium.
Diagnostics 2020, 10, 1046 5 of 20

With the use of next generation techniques including 16S ribosomal RNA (rRNA) sequencing and
whole genome sequencing (WGS) alongside accelerated diagnostic pathways (see core cutting needle
biopsies), some of these deficits may be overcome.

5. Pleural Fluid Cytology

Cell differentials in PF are a useful adjunct in diagnosing the underlying aetiology, though it
must be noted that it is neither specific nor sensitive. Lymphocyte predominant effusions (>50%)
are most often associated with malignancy, congestive cardiac failure, and tuberculosis, of which the
latter sees particularly high levels [8,13]. Generally, any chronic effusion will eventually produce
a lymphocytic effusion. Neutrophilic effusions are seen in more acute disease processes such as
in a parapneumonic effusion or pulmonary embolism, though 10% of tuberculous effusions can be
neutrophil predominant [42]. Eosinophilic effusions are defined by PF eosinophils of >10% and
are a rarer presentation of pleural effusion. In a large (n = 1868), retrospective series by Krenke et
al., eosinophilic effusions were seen in 7.2% of all patients with pleural effusion from 1995 to 2007.
Malignancy accounted for 34.8% of cases, pleural infection in 19.3%, chest trauma in 8.9%, post-medical
or surgical procedure in 4.4%, pneumothorax in 3.7%, and autoimmune in 1.5% [43]. Whilst drugs
are often implicated in eosinophilic pleural effusions, it is difficult to be certain of the exact incidence
and prevalence as most of the evidence has come exclusively from case reports [44]. Even across
a meta-analysis of eosinophilic pleural effusions by Oba and Abu-Salah with 687 cases, there was
not a single case of drug-induced eosinophilic effusion recorded. The authors concluded that many
studies may have incorrectly classified this important group as “idiopathic eosinophilic effusions” [45].
Diagnosis is fraught with difficulty and relies upon observing the behaviour of the effusion following
cessation of offending agents. Whilst the list of offending agents is not exhaustive, it does continue to
grow and clinicians must be familiar with them [46].
Diagnosing an MPE through PF poses some challenges. Historically, PF cytology yields
were suggested to be 60%; however, more recent data would suggest that this is likely an
overestimation [13,47–49]. It is suggested that 50–75 mL should be sent as a minimum to maximise
yield and a repeat fluid cytology may increase the yield by a further 26%, though this latter claim is
based on a small retrospective series [50,51]. There exists a heterogeneity for yield, varying according
to underlying tumour type. Typically, ovarian and breast cancer have a high diagnostic yield in PF
(94.7% and 70.7%, respectively), lung adenocarcinoma fares the best of the lung cancers (82%), whilst
mesothelioma fares particularly poorly (6.1%) [47].
Diagnosing malignant pleural mesothelioma (MPM) can prove difficult. Many MPMs do not
exfoliate tumour cells into the PF and this is especially true for the sarcomatoid subtype. The presence
of reactive epithelioid mesothelial cells should not necessarily reassure clinicians of a benign aetiology.
Whilst there are some cytological features that may raise the suspicion of MPM—extent of mesothelial
proliferation, presence of papillary structures, scalloped borders of cell clumps, intercellular windows,
variation of cytoplasmic staining and its density, and low nuclear-to-cytoplasmic ratios—these features
may also be found in reactive epithelioid mesothelial cells [52]. When adequate cellular material
has been obtained, certain immunocytochemistry patterns can be useful in diagnosing MPM over
benign disease. The homozygous deletion of BRCA-1 protein (loss of BAP1) shows 100% specificity for
differentiating malignant mesothelial proliferation from benign. In the presence of BAP1, deletions
of p16 are seen in up to 80% of MPM (especially sarcomatoid subtypes) [53,54]. In spite of these
advances, demonstrating tissue invasion histologically (into the chest wall soft tissue or underlying
lung parenchyma) remains the most reliable indicator of malignant pleural disease and therefore,
the authors would always advocate securing a histological diagnosis over relying on a cytological one
where possible. Once malignant pleural disease has been confirmed, a further difficulty encountered is
differentiating MPM from secondary tumours involving the pleural. The current BTS guidance on the
investigation of MPM suggests a combination of at least two positive mesothelial immunohistochemistry
markers (e.g., calretinin, cytokeratin 5/6, Wilms tumour 1, D-240) with at least two negative lung
Diagnostics 2020, 10, 1046 6 of 20

adenocarcinoma immunohistochemistry markers (e.g., TTF1, CEA, Ber-EP4), which is the cancer
subtype MPM is often confused with [55].
Importantly, in this modern age of targeted and personalised therapy, it is important to consider
the definition of “yield” being more than diagnosis alone, but also whether this is sufficient to direct
management. Many patients who were previously not eligible for systemic anti-cancer treatments
are now being offered disease modifying therapies and therefore, the case for diagnostic confirmation
of malignant pleural disease continues to grow. Many novel oncological therapies are predicated on
identifying molecular markers and subsequently, adequacy of samples is also a growing issue. Simply
demonstrating the presence of malignant cells is no longer sufficient; adequate cellular material is
required to perform the necessary molecular diagnostics. It has been demonstrated that a positive PF
cytology result is not enough to affect a change in management and strong cases have been made for
alternative diagnostic pathways for these patients (see thoracoscopic biopsies) [48,49].

6. Pleural Biopsies
In view of the shortcomings of PF cytology, pleural biopsies remain the gold standard for diagnosis
of malignant pleural disease. They have an established role in the diagnosis of pleural TB and recently,
have also found a place in the diagnosis of non-tuberculous pleural infection. Clinicians have a number
of options to choose from in their choice of technique for obtaining pleural biopsies and we outline a
few of these below.

7. Closed Reverse-Bevel Needles (Abrams or Cope)

Blind biopsies using these eponymous needles (Figure 2) date back to the 1950s when they were
first devised. Whilst they have fallen out of practice in many institutions, including our own, they still
enjoy utility in many parts of the world. Their diagnostic accuracy varies according to condition.
In conditions known to cause diffuse pleural disease, typically tuberculosis, they carry a high yield
amongst skilled operators. This has been quoted as high as 90% in the literature [56,57]. Where
the technique falls short however (sens < 60%), is with the diagnosis of malignant pleural disease,
which has a patchier distribution and tends to favour regions not easily accessible percutaneously
Diagnostics 2020, 10, 1046 7 of 21
(posteromedial and diaphragmatic regions).

Figure 2. Abrams needles (left) and Temno needle (right).

Figure 2. Abrams needles (left) and Temno needle (right).
The addition of CT guidance to the Abrams needle technique has been shown to improve sensitivity
8. Core Cutting Needle Biopsy
to 81.8%, increasing to 93% when pleural thickness exceeded 1cm, across all cases of cytology negative
exudatesIninthe above cited RCT,
a randomised the coretrial
controlled cutting needle
(RCT) biopsy was
by Metintas et suggested to be needles
al. [58]. These inferior (sens 67%) than
are larger
compared to an Abrams needle; however, a direct comparison is difficult. The cutting needle biopsy
(Tru-Cut) was used with ultrasound prior to insertion (US assisted) rather than real time visualisation
of the needle (US-guided), whilst the Abrams needle was inserted under CT guidance. Where direct
head-to-head comparisons have been performed, these suggested that US-assisted techniques
favoured the Abrams needle over the Tru-Cut needles in diagnosing pleural TB (sens 81.8% vs.
65.2%). Results from this non-inferiority study are underpowered and open to bias however, as
Diagnostics 2020, 10, 1046 7 of 20

their cutting needle counterparts (Figure 2) and as such, come with significant rates of complications:
pain 15%, iatrogenic pneumothorax 15%, bleeding < 2% [13].

8. Core Cutting Needle Biopsy

In the above cited RCT, the core cutting needle biopsy was suggested to be inferior (sens 67%)
compared to an Abrams needle; however, a direct comparison is difficult. The cutting needle biopsy
(Tru-Cut) was used with ultrasound prior to insertion (US assisted) rather than real time visualisation
of the needle (US-guided), whilst the Abrams needle was inserted under CT guidance. Where direct
head-to-head comparisons have been performed, these suggested that US-assisted techniques favoured
the Abrams needle over the Tru-Cut needles in diagnosing pleural TB (sens 81.8% vs. 65.2%). Results
from this non-inferiority study are underpowered and open to bias however, as recruitment was
terminated early, citing patient safety [59]. Just 89 patients were recruited from a planned 220, following
a pre-planned interim analysis that suggested the yield from the Tru-Cut was lower than the original
estimates investigators had based power calculations on [60].
Studies that have looked at the diagnostic accuracy of core cutting needles using a US-guided
procedure suggest diagnostic accuracy rates closer to 90%, though they are retrospective in nature [61,62].
This would all suggest that diagnostic accuracy hinges more on the use of image guidance rather
than the choice of needle. Therefore, by extension, it would not be unreasonable to suggest larger
reverse-bevel needles would have a greater yield in blind biopsies for diffuse pleural disease compared
to their cutting needle counterparts, but once image guidance is employed, this effect is attenuated [63].
A role for image-guided cutting needle biopsies in pleural infection has recently been brought
to light through the recent AUDIO study. This was a feasibility pilot study where patients with a
confirmed diagnosis of pleural infection following a diagnostic aspirate went on to have a US-guided
Temno (Figure 2) cutting needle biopsy in the same sitting as an intercostal drain. The pleural biopsies
produced a higher diagnostic yield than either PF or blood cultures (45% vs. 20% vs. 10%), with an
exaggerated difference in patients already receiving antibiotics (40% vs. 13% vs. 7%) [64]. A multicentre
trial is now planned in order to test this hypothesis.

9. Ultrasound vs. CT-Guided

The literature comparing ultrasound-guided to CT-guided biopsies is sparse. A recent meta-analysis
across seven studies and 165 patients with US-guided pleural biopsies across both cutting needles and
reverse-bevel needles suggested a pooled sensitivity of 83% (95% CI 75–89%) with rates of pneumothorax
at 3.6%, wound infection 3%, and empyema < 1% [65]. This is similar to the sensitivity suggested by
Metintas et al. for their CT-guided Abrams needle technique.
A large retrospective series across 273 patients suggested there was little difference in diagnostic
accuracy between the two techniques (technical success of 97.1% in the US-guided group vs. 96.5%
in the CT-guided group). The series included both pleural-based lesions as well as peripheral lung
lesions, highlighting additional utility of the US approach. Importantly, this study also concluded that
US-guided procedures were quicker, cheaper, and had a lower risk of iatrogenic pneumothorax (14.7%
vs. 5.8%) [66]. In practice, the availability of skilled operators in either technique is likely to be the
rate limiting step in choice of test. Traditionally, CT-guided procedures have been within the remit of
radiologists, whilst US-guided procedures are increasingly being delivered by respiratory physicians.
Both techniques have their advantages and disadvantages. Thoracic US uses non-ionising radiation,
is quicker to use, and allows for the operator to react to respiratory motion in real-time without reliance
on breath-holding techniques, which some patients may be unable to perform. In contrast, CT can be
used to target lesions that would not be identifiable on US (shielded beneath bony structures or at
depth) (Figures 3 and 4).
At this point, it is worth mentioning the role of PET-CT. The TARGET study set out to specifically
assess the role of PET-CT-guided biopsies in patients with ongoing suspicion of pleural malignancy
despite a negative CT-guided biopsy. This was built on the premise that malignant pleural mesothelioma
 A large retrospective series across 273 patients suggested there was little difference in diagnostic
accuracy between the two techniques (technical success of 97.1% in the US-guided group vs. 96.5%
in the CT-guided group). The series included both pleural-based lesions as well as peripheral lung
lesions, highlighting additional utility of the US approach. Importantly, this study also concluded
that US-guided procedures were quicker, cheaper, and had a lower risk of iatrogenic pneumothorax
(14.72020,
Diagnostics % vs.10,5.8%)
1046 [66]. In practice, the availability of skilled operators in either technique is likely to8 of 20
be the rate limiting step in choice of test. Traditionally, CT-guided procedures have been within the
remit of radiologists, whilst US-guided procedures are increasingly being delivered by respiratory
(MPM) in particular
physicians. proves diagnostically
Both techniques challenging
have their advantages andgiven its radiological
disadvantages. appearance
Thoracic and the degree
US uses non-ionising
of overlap withisbenign
radiation, quickerpleural
to use, thickening [67].
and allows for theSurprising
operator totoreact
mosttopleural physicians
respiratory motion and radiologists,
in real-time
without reliance on breath-holding techniques, which some patients nd
may be unable
their primary outcome of pleural malignancy correctly identified on 2 biopsy was not met (presented to perform. In
contrast, CT can be used to target lesions that would not be identifiable on US (shielded beneath
at BTS Winter 2019); however, the trial is still pending full publication and there is certainly more to bony
learnstructures
from this.or at depth) (Figures 3 and 4)

Diagnostics 2020, 10, 1046 9 of 21

Figure 3. Image
Figure of a US-guided
3. Image needleneedle
of a US-guided biopsy; whitewhite
biopsy; arrowhead = needle,
arrowhead white white
= needle, = pleural
arrow arrow thickening.
= pleural
thickening.

Figure 4. Image of a CT-guided needle biopsy; white arrow = needle.

Figure 4. Image of a CT-guided needle biopsy; white arrow = needle.
10. Thoracoscopic Biopsies
At this point, it is worth mentioning the role of PET-CT. The TARGET study set out to
Pleural biopsies
specifically assessperformed via an endoscopic
the role of PET-CT-guided approach
biopsies (thoracoscopy)
in patients under
with ongoing directofvisualisation
suspicion pleural
are considered
malignancy thedespite
gold standard
a negativeforCT-guided
diagnosingbiopsy.
an unexplained pleural
This was built on effusion and that
the premise particularly
malignantuseful
pleural mesothelioma (MPM) in particular proves diagnostically challenging given its radiological
appearance and the degree of overlap with benign pleural thickening [67]. Surprising to most pleural
physicians and radiologists, their primary outcome of pleural malignancy correctly identified on 2nd
biopsy was not met (presented at BTS Winter 2019); however, the trial is still pending full publication
and there is certainly more to learn from this.
Diagnostics 2020, 10, 1046 9 of 20

in diagnosing malignant pleural disease. Thoracoscopic biopsies can be performed through the Local
Anaesthetic Thoracoscopy (LAT) approach, also entitled Medical Thoracoscopy (MT), often through a
single port or the more invasive Video-Assisted Thoracoscopic Surgical (VATS) approach, using up to
three ports. LATs are usually performed by physicians in an awake patient, spontaneously breathing
under sedation whereas VATS are usually performed by thoracic surgeons in an anaesthetised patient
with single-lung ventilation. Whilst both techniques allow for visual inspection of the pleural cavity,
performing both a diagnostic and therapeutic procedure in the same sitting (to achieve long-term
effusion control through pleurodesis), LAT does have some limitations. In order to safely insert
the thoracoscopic port and other instruments, adequate access within the pleural space is required.
In the presence of moderate-large pleural effusions, this is straightforward; however, where this is
not the case, it may be necessary to induce an artificial pneumothorax through the use of a Boutin
needle. This technique is both safe and highly effective in the hands of skilled operators in enabling
LAT in patients with inadequate PF. In a series of 77 consecutive patients in whom this was attempted,
in 67 (87%), the operators were able to proceed with LAT with no adverse events reported [68]. The
ability for the lung to collapse down on Boutin needle induction is heavily dependent on the presence
or absence of adhesions between the visceral and parietal pleura, a feature common to malignant
pleural disease. Pre-procedural thoracic US has been shown to be quite effective at detecting a lung
that is unlikely to collapse on Boutin needle induction, by way of detecting “lung sliding” [63,69]. In
these situations, opting for a VATS approach that the surgeon may convert to an open thoracotomy or
an image-guided approach are alternative options, depending on patient suitability.
Both approaches are suggested to have a diagnostic sensitivity exceeding 90% in detecting
malignant pleural disease. The 2010 BTS guidelines pooled results across 22 case series to demonstrate
a diagnostic sensitivity of 92.6% in diagnosing malignant pleural disease via LAT [70]. A similar
diagnostic sensitivity rate was also observed in an RCT comparing LAT to CT-guided Abrams needle
biopsy (94.1% vs. 87.5%) [71]. For VATS approaches, diagnostic sensitivities of 89–95% have been
quoted in the literature for diagnosing malignant pleural disease [72,73].
LAT is generally considered a safe procedure; across 47 studies and 4756 patients, major
complications were reported in 1.8% of cases, minor complications in 7.8%, and mortality in 0.34% [70].
Major complications consisted of empyema, haemorrhage, port-site tumour growth, bronchopleural
fistula, persistent air leak, and pneumonia. Minor complications consisted of subcutaneous emphysema,
minor haemorrhage, operative skin site infection, hypotension peri-procedure, fever, and atrial
fibrillation. Across these studies, no deaths were observed in diagnostic thoracoscopies alone (0/2421)
and were all seen in the therapeutic thoracoscopy arm (16/2315). Nine out of sixteen were seen in
a single randomised control trial, attributed to the use of non-graded talc leading to unintended
absorption and toxicity, with resultant acute respiratory distress syndrome and respiratory failure [74].
As a result, best practice is now for the use of graded talc to avoid such complications and this approach
has been validated in a large prospective multicentre cohort study [75].
VATS is considered more invasive and patients by definition need to be fit enough to survive a
general anaesthetic and therefore, in comparing complication rates between LAT and VATS, it must be
understood that the patient groups are different. Reported complication rates in VATS vary; in one
series across 185 patients, 15% were reported to have had a major complication whilst in another across
86 patients, the major complication rate was just 1.2% [73,76]. A recent retrospective review of patients
undergoing LAT (described as “awake thoracoscopy” through a single port) and VATS were compared
in a single centre and the rates of major complications were similar (LAT 2.6% vs. VATS 4%) but cost
was significantly lower in the LAT group. However, as suggested above, there were significant baseline
differences in the patient characteristics between groups [77]. True head-to-head comparator trials that
hold clinical meaning for LAT against a VATS approach in diagnosing malignant pleural disease are
unlikely to occur (due to patient selection bias and therefore, applicability).
There remains some debate over the use of rigid (RT) vs. semi-rigid thoracoscopes (SRT) and more
recently, the rigid mini-thoracoscope (RMT) has joined the fray. RTs allow for larger biopsies, given
Diagnostics 2020, 10, 1046 10 of 20

their larger working channels, and this may facilitate deeper pleural biopsies, which contain fat and
skeletal muscle. This allows it to overcome some of the difficulties presented by a densely thickened
or fibrotic pleura, which can result in false negative biopsies [78]. This becomes more relevant when
the leading diagnosis is MPM and the degree of invasion provides both diagnostic and prognostic
information. Head-to-head trials comparing all three are lacking. Similar diagnostic yields between
RT vs. SRT have been reported in a retrospective case series (96.3% vs. 92.3%) [79]. These yields are
reproduced in both a systematic review and meta-analysis of SRT [80,81]. In the MINT study, a single
centre RCT comparing RMT to SRT, the authors did find a greater diagnostic yield in the SRT group
(81.1% vs. 69.4%) [82]. However, the results lacked statistical significance and this is likely due to the
small sample size. Operator expertise with this novel technology compared to the more familiar SRT
may have also affected their measured outcomes [78].
The take-home message from all of these studies is perhaps, the thoracoscopic approach has
extremely high
Diagnostics diagnostic
2020, 10, 1046 yield, irrespective of device or operator, physician or surgeon. It is11preferable
of 21
to start with an awake thoracoscopic procedure where possible and reserve a procedure under general
preferable to start with an awake thoracoscopic procedure where possible and reserve a procedure
anaesthesia with single lung ventilation for those in whom the alternative is not technically feasible.
under general anaesthesia with single lung ventilation for those in whom the alternative is not
technically feasible.
11. Imaging
11. Imaging
Whilst the use of imaging in specifically targeting biopsies has been explored, there are some
wider points around
Whilst theofrole
the use of imaging
imaging as a diagnostic
in specifically targeting tool to discuss.
biopsies has been explored, there are some
wider points around the role of imaging as a diagnostic tool to discuss.
12. Chest Radiograph
12. Chest
This Radiograph
modality has largely withstood the test of time and still remains the most easily accessible
form of chest
This and pleural
modality has imaging, worldwide.
largely withstood It of
the test will often
time andbestillthe initialthe
remains imaging performed
most easily for any
accessible
form of chest and pleural imaging, worldwide. It will often be the initial imaging
patient with suspected pleural disease. Whilst higher quality images are obtained by performing performed for any
patient within
the radiograph suspected pleural disease.
a posteroanterior (PA)Whilst higheroften
projection, quality
inimages are obtained
emergencies, bynot
this is performing
possible.theChest
radiograph in a posteroanterior (PA) projection, often in emergencies, this is
radiographs (CXR) performed in the supine anteroposterior position are less sensitive in detectingnot possible. Chest
radiographs (CXR) performed in the supine anteroposterior position are less sensitive in detecting
pleural air or fluid. It has been estimated that a pleural effusion of approximately 200 mL in volume
pleural air or fluid. It has been estimated that a pleural effusion of approximately 200 mL in volume
would be visible on an PA CXR (Figure 5), whilst a smaller volume of 50 ml would be detectable on a
would be visible on an PA CXR (Figure 5), whilst a smaller volume of 50 ml would be detectable on
lateral CXR [83].
a lateral CXR [83].

Figure
Figure 5. Chest
5. Chest radiograph (CXR)
radiograph (CXR) demonstrating
demonstrating a pleural effusion.
a pleural effusion.

13. Ultrasound
Thoracic ultrasound (TUS) has revolutionised the diagnosis and delivery of care in pleural
disease. TUS is far more sensitive at detecting pleural effusions than CXR, being able to detect even
just 3–5 ml of pleural effusion and >100 mL of effusion with a sensitivity of 100% [84,85]. Furthermore,
TUS allows for better characterisation of an effusion, for example the degree of echogenicity or
septations (Figure 6). In fact, TUS has much greater sensitivity for identifying septations within an
Diagnostics 2020, 10, 1046 11 of 20

13. Ultrasound
Thoracic ultrasound (TUS) has revolutionised the diagnosis and delivery of care in pleural disease.
TUS is far more sensitive at detecting pleural effusions than CXR, being able to detect even just 3–5 ml
of pleural effusion and >100 mL of effusion with a sensitivity of 100% [84,85]. Furthermore, TUS allows
for better characterisation of an effusion, for example the degree of echogenicity or septations (Figure 6).
In fact, TUS has much greater sensitivity for identifying septations within an effusion compared to
computed tomography (CT) [86]. However, interpretation of these findings is not always clear cut.
Whilst convention would suggest a hyperechoic, septated effusion must be an exudate and indeed,
there is some evidence to support this, these rules are not absolute. Across 320 patients with both
transudates and exudates, this prospective observational series by Yang, now 28 years old, suggested
Diagnostics 2020, 10, 1046 12 of 21
transudates were always anechoic in appearance whereas exudates had a variety of appearances
across a spectrum
transudates must of beechogenicity,
anechoic hasincluding anechoic
been refuted with[87]. Thisevidence
recent assertiontothat
theallcontrary.
transudates mustand
Asciak be
anechoic has been refuted with recent evidence to the contrary. Asciak and colleagues
colleagues demonstrated in their own prospective series that the specificity of “echogenicity” in demonstrated in
their own prospective series that the specificity of “echogenicity” in identifying an
identifying an exudative effusion over a transudate was only 57.1% [88]. In their series across 140exudative effusion
over a they
cases, transudate
identifiedwassix
only 57.1%
(7%) [88]. In
patients their
with series across
echogenic 140 cases,
effusions they identified
that were ultimatelysix (7%) patients
diagnosed as a
with echogenic effusions that were ultimately diagnosed as a transudate. Their finding
transudate. Their finding is supported by other retrospective work and questions some assumptions is supported by
other retrospective work
we have made about TUS [89,90]. and questions some assumptions we have made about TUS [89,90].

Figure 6. Thoracic
Thoracic ultrasound
ultrasound (TUS) image of a septated effusion.

The role
roleofofTUS
TUSgoes beyond
goes beyondrecognition and and
recognition classification of effusions.
classification In a study
of effusions. In amirroring some of
study mirroring
the CTof
some characteristics of malignant
the CT characteristics pleural disease
of malignant by Leung
pleural diseaseet by
al., Leung
Qureshietand
al., colleagues
Qureshi anddemonstrated
colleagues
the presence ofthe
demonstrated diaphragmatic
presence of and parietal pleural
diaphragmatic and nodularity,
parietal pleuralparietal pleural thickening
nodularity, > 1 cm,
parietal pleural
and hepatic>metastases
thickening 1 cm, and in diagnosing
hepatic malignant
metastases pleural disease
in diagnosing has a pleural
malignant sensitivity of 73%
disease hasand specificity
a sensitivity
of 73%
100%and
[91,92].
specificity of 100% [91,92].
There has been increasing enthusiasm recently in the role of TUS in diagnosing diagnosing pneumothorax,
pneumothorax,
perhaps more so by the emergency and critical care world. Detecting Detecting thethe absence
absence of of “lung
“lung sliding”
sliding”
on B-mode and loss of the “sea-shore” sign sign on M-mode
M-mode is is aa more
more sensitive
sensitive tool
tool than
than aa supine
supine CXR.
CXR.
However, care must be taken in differentiating a pneumothorax
pneumothorax from bullous emphysema or prior
pleurodesis. As of yet, there is no role for TUS in quantifying the size of a pneumothorax or for
procedural guidance in this condition [90]. The authors’ view is that the use of TUS in detecting
pneumothorax lies solely in the urgent/trauma setting and where there is any doubt on CXR, a CT
scan is the next investigation of choice.
The ability of TUS to identify lung sliding has also highlighted a role for its use in predicting
Diagnostics 2020, 10, 1046 12 of 20

pleurodesis. As of yet, there is no role for TUS in quantifying the size of a pneumothorax or for
procedural guidance in this condition [90]. The authors’ view is that the use of TUS in detecting
pneumothorax lies solely in the urgent/trauma setting and where there is any doubt on CXR, a CT scan
is the next investigation of choice.
The ability of TUS to identify lung sliding has also highlighted a role for its use in predicting
pleurodesis success. Corcoran and colleagues used a “pleural adhesion” score (based on the presence
or absence of lung sliding) to estimate pleurodesis success after talc slurry instillation. They found
that a lower score correlated with failure [93]. A multicentre randomised controlled trial is now “in
submission” (SIMPLE, ISRCTN 16441661) to validate these findings and to determine if a TUS-directed
approach to pleurodesis in MPE results in a shortened length of stay when compared to daily CXR [94].
Diagnostics 2020,
Finally, TUS10, 1046 13 of 21
can be used to predict non-expansile lung prior to pleural intervention. Salomonsen
and colleagues demonstrated that in cases of entrapped lung, both the motion and strain related to the
the transmission of the cardiac impulse through an atelectatic segment of lower lobe measured during
transmission of the cardiac impulse through an atelectatic segment of lower lobe measured during both
both M-mode and speckle-tracking imaging fared better at predicting entrapped lung compared to
M-mode and speckle-tracking imaging fared better at predicting entrapped lung compared to pleural
pleural elastance measurement [95]. At present, this technique is likely to be available only to
elastance measurement [95]. At present, this technique is likely to be available only to advanced US
advanced US operators and is still awaiting multisite validation.
operators and is still awaiting multisite validation.

14. CT
14. CT
Whilst TUS
Whilst TUS has
has its
its many
many uses,
uses, there
there isis no
no replacement
replacement forfor cross-sectional
cross-sectional imaging
imaging which
which can
can
provide a three-dimensional reconstruction of the chest and pleural cavity in a
provide a three-dimensional reconstruction of the chest and pleural cavity in a way TUS might struggle way TUS might
struggle
to, exceptto,
in except
the handin the hand
of the of skilled
most the most skilled operators.
operators. In health, In health,
it is it istodifficult
difficult visualisetothe
visualise
pleura the
on
pleura
CT scanonand
CTthe
scan and the “intercostal
“intercostal stripe” is stripe”
often a issurrogate;
often a surrogate;
it consists it of
consists
visceralof visceral and parietal
and parietal pleura,
pleura, extrapleural
extrapleural fat, endothoracic
fat, endothoracic fascia,
fascia, and the and the innermost
innermost intercostal
intercostal muscles muscles
(Figure 7)(Figure
[96]. 7) [96].

Figure 7. CT
Figure 7. CT appearances
appearances of
of the
the “pleural
“pleural stripe”;
stripe”; (white
(white arrow
arrow head)
head)

To optimise CT imaging of the pleura, iodinated intravenous contrast is recommended and ideally,
To optimise CT imaging of the pleura, iodinated intravenous contrast is recommended and
a venous phase or “Pleural phase” scan 60–90 s post infusion should be taken. Failure to achieve a
ideally, a venous phase or “Pleural phase” scan 60–90 s post infusion should be taken. Failure to
“Pleural phase” scan has been shown to result in poorer diagnostic yields [97,98]. PF drainage prior
achieve a “Pleural phase” scan has been shown to result in poorer diagnostic yields [97,98]. PF
to imaging is not a prerequisite and in a series across 32 patients with pre and post drainage CTs,
drainage prior to imaging is not a prerequisite and in a series across 32 patients with pre and post
the second scan did not provide any new information to influence clinical management [99].
drainage CTs, the second scan did not provide any new information to influence clinical management
Whilst it can be argued that all patients with complex pleural pathology, whether that be
[99].
tethered pneumothoraces, unexplained effusions, diffuse pleural thickening, broncho-pleural fistulae,
Whilst it can be argued that all patients with complex pleural pathology, whether that be
or any other relevant thoracic pathology (e.g., lung abscess, oesophageal leak, etc.) should have
tethered pneumothoraces, unexplained effusions, diffuse pleural thickening, broncho-pleural
fistulae, or any other relevant thoracic pathology (e.g., lung abscess, oesophageal leak, etc.) should
have cross-sectional imaging, where CT really proves essential is in the diagnosis and management
of late-stage empyema and malignant pleural disease.
Whilst TUS can identify septations within an effusion better than CT, in cases of advanced
empyema with a non-draining collection, CT can be used to check drain position and plan for thoracic
surgical intervention. The “split pleura” sign (Figure 8) and the presence of > 30 mm distance between
Diagnostics 2020, 10, 1046 13 of 20

cross-sectional imaging, where CT really proves essential is in the diagnosis and management of
late-stage empyema and malignant pleural disease.
Whilst TUS can identify septations within an effusion better than CT, in cases of advanced empyema
with a non-draining collection, CT can be used to check drain position and plan for thoracic surgical
intervention. The “split pleura” sign (Figure 8) and the presence of >30 mm distance between the
parietal and visceral pleura were shown to correctly identify a complex parapneumonic pleural effusion
(CPPE) from a simple PPE with a sensitivity of 79.4% and specificity of 80.9% [100,101]. A number of
other features are also seen in empyema, though they are not specific to the condition and can represent
a PPE too: contrast enhancement of the pleura, thickened parietal pleura, increased attenuation and/or
thickness of extra
Diagnostics 2020, pleural subcostal fat, gas bubbles suspended within PF, or loculation of PF [96].
10, 1046 14 of 21

Figure
Figure 8. CTs showing
8. CTs showing the
the “Split
“Split Pleura”
Pleura” sign.
sign.

The
The CTCT features
features of of malignant
malignant pleural
pleural disease
disease have
have been
been derived
derived through
through a a number
number of of small
small
retrospective
retrospective studies;
studies;though
thoughnotnotthethelargest,
largest,the series
the seriesbyby
Leung
Leung et al. was
et al. thethe
was earliest
earliestandandremains
remainsthe
most recognised and cited. These studies largely agree that the following features
the most recognised and cited. These studies largely agree that the following features on CT are more on CT are more
suggestive
suggestive of ofmalignant
malignantdisease
diseasethan
than benign
benign(Figure 9): 9):
(Figure nodular
nodularpleural thickening
pleural thickening(sens(sens
38–53%, spec
38–53%,
87–100%), pleural
spec 87–100%), thickening
pleural alongalong
thickening mediastinal surfaces
mediastinal (sens 14–74%,
surfaces spec 83–97%),
(sens 14–74%, thickening
spec 83–97%), of the
thickening
parietal pleura >1 cm (sens 36–57%, spec 64–94%), and circumferential pleural
of the parietal pleura >1 cm (sens 36–57%, spec 64–94%), and circumferential pleural thickening thickening encasing the
lung (sensthe
encasing 8–54%,
lung spec
(sens63–100%)
8–54%, spec[92,96,98,102–105]. However, CT isHowever,
63–100%) [92,96,98,102–105]. not the be-all
CT isand notend-all when
the be-all andit
comes to securing a diagnosis of pleural malignancy. Both Tsim et al. and Hallifax
end-all when it comes to securing a diagnosis of pleural malignancy. Both Tsim et al. and Hallifax et et al. demonstrated
that the negative predictive
al. demonstrated value ofpredictive
that the negative CT in detecting
valuemalignant pleural disease
of CT in detecting sits somewhere
malignant pleural diseasebetweensits
54 and 65% and that therefore, there are a significant number of patients with
somewhere between 54 and 65% and that therefore, there are a significant number of patients with malignant disease who
have a “benign”
malignant diseaseCT who(1 in every
have 2–3 cases)
a “benign” CT[97,106]. Therefore,
(1 in every 2–3 cases)where the pre-test
[97,106]. probability
Therefore, where the is high
pre-
enough, more definitive investigations should be undertaken (the current gold
test probability is high enough, more definitive investigations should be undertaken (the current gold standard for which
is thoracoscopy).
standard for whichThe utility of CT might
is thoracoscopy). be increased
The utility of CT might further by also imaging
be increased further by the abdomen
also imagingand the
pelvis. Whilst this is standard of care for all patients who enter a cancer pathway,
abdomen and pelvis. Whilst this is standard of care for all patients who enter a cancer pathway, it is not necessarily
it is
the
not first choice of
necessarily theinvestigation
first choice of forinvestigation
an unexplained for aneffusion. Syer et
unexplained al. has Syer
effusion. recently published
et al. has recentlythe
results from an observational series of 249 patients presenting with a unilateral
published the results from an observational series of 249 patients presenting with a unilateral effusion, in whom
clinically
effusion, insignificant findingssignificant
whom clinically were identified beneath
findings werethe diaphragm
identified beneathin 59the
patients (24%).inThey
diaphragm define
59 patients
clinically
(24%). They significant as a finding
define clinically that either
significant as identified
a finding the
thatprimary diagnosis (identified
either identified the primary thediagnosis
primary
tumour in 6.8%), upstaged any malignant disease (12.9%), or highlighted
(identified the primary tumour in 6.8%), upstaged any malignant disease (12.9%), or highlighted a favourable site for furthera
investigation (alternative biopsy site in 2%) [107].
favourable site for further investigation (alternative biopsy site in 2%)[107].
not necessarily the first choice of investigation for an unexplained effusion. Syer et al. has recently
published the results from an observational series of 249 patients presenting with a unilateral
effusion, in whom clinically significant findings were identified beneath the diaphragm in 59 patients
(24%). They define clinically significant as a finding that either identified the primary diagnosis
(identified the primary tumour in 6.8%), upstaged any malignant disease (12.9%), or highlighted a
Diagnostics 2020, 10, 1046 14 of 20
favourable site for further investigation (alternative biopsy site in 2%)[107].

Figure 9.
Figure CTimages
9. CT imagesshowing
showingsome
somefeatures
features of
ofmalignant
malignant pleural
pleural disease:
disease: (A)
(A)Circumferential
Circumferential pleural
pleural
thickening; (B)
thickening; (B) Nodular
Nodular pleural
pleural thickening
thickening involving mediastinal surfaces and fissures.

15. Other Diagnostic Tests

Pleural manometry (PM) describes the measurement of intrapleural pressures using a water or
digital manometer. Studies measuring the change in intrapleural pressure during thoracocentesis, to
derive a measure of pleural elastance and therefore, predict non-expansile lung, have produced mixed
results. Chopra et al. demonstrated that although patients with elevated pleural elastance were less
likely to achieve lung expansion (OR 6.3 of achieving lung re-expansion on CXR if normal pleural
elastance), there was a degree of discordance in this relationship as some 28% of patients with lung
re-expansion also had elevated pleural elastance [108].
The Pre-EDIT trial was a feasibility study randomising patients into pleural elastance-driven
therapy (indwelling pleural catheter vs. talc slurry pleurodesis via chest drain) against standard care
of chest drain with a view to talc slurry pleurodesis if lung expansion was achieved. As a feasibility
study, the authors demonstrated the suitability for a phase 3 study [109]. Though not powered to
demonstrate any difference, across small patient numbers, a high pleural elastance (seven patients)
showed a sensitivity of 100% and specificity of 67% for non-expansile lung.
Lentz and colleagues explored the use of PM as an aid to preventing pleural pressure-related
complications in large-volume thoracocentesis against a symptom-guided approach in a multisite
randomised controlled trial. They found no difference in their primary outcome (chest discomfort) [110].
PM also has utility in pneumothorax assessment. The mechanisms underpinning PM
measurements in pleural effusion and pneumothorax do vary and lessons learnt from one cannot be
applied in the other. Heidecker et al. were able to use PM to differentiate between pneumothorax
ex vacuo (“stable”) from iatrogenic pneumothorax (“unstable”) during a pleural procedure. “Stable”
or “pressure-dependent” pneumothoraces (seen in non-expansile lung) bear the hallmark of a stable
pleural pressure when the chest drain is clamped as opposed to the rising pleural pressure during
clamping that is seen in an “unstable pneumothorax” (traumatic or spontaneous pneumothoraces) [111].
Whilst there is physiological plausibility in using pleural manometry as a diagnostic tool and to
guide treatments, as of yet there is no compelling evidence for its routine use in the management of
pleural disease. With the advent of further studies, this may change [112].

16. Conclusions
Whilst the topic of “Diagnostics” in pleural disease is an expansive field and one that is ever
growing, basic principles hold true and no single test will ever provide the complete answer. It is
through a thorough history, clinical assessment, evaluation of pre-test probabilities, and careful
selection of diagnostic tests, of which there are many, can the physician be confident in their diagnosis.
Diagnostics 2020, 10, 1046 15 of 20

Whilst conventional wisdom would suggest starting with the least invasive diagnostic tools, mounting
evidence points to accelerated diagnostic pathways with greater clinical efficacy as the future direction
of travel in pleural disease.

Author Contributions: A.S., E.O.B., N.M.R. conceived and designed the review article. A.S. wrote the first draft
of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This work received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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