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Oliver J Bintcliffe
Point-of-care ultrasound guidance should be used for all pleural
procedures involving fluid
If the pleural fluid protein concentration is 25e35 g/litre, Light’s
criteria can be used to differentiate exudates from transudates
Only 60% of malignant effusions can be diagnosed by cytology
Image-guided pleural biopsy has a higher diagnostic yield than
blind pleural biopsy for malignancy
Indwelling pleural catheters are increasingly being used to
manage symptomatic malignant pleural effusions, reducing
hospitalization and enabling management in the community
Pleural fluid specimens for microbiology should be sent in both
a sterile tube (for Gram stain, acid- and alkali-fast bacilli and
culture of Mycobacterium tuberculosis) and blood culture bot-
tles to increase the microbiological yield
Combination treatment with intrapleural tissue-type plasmin-
ogen activator and DNase may be beneficial in patients with
pleural infection resistant to standard medical therapy
Heimlich valves allow ambulatory treatment for selected pa-
tients with pneumothorax
Amelia O Clive
Nick A Maskell
Pleural disease encompasses a wide range of pathological processes,
many of which are common and increasing in incidence. Patients with
pleural disease are encountered by both respiratory specialists and
general physicians, and a systematic approach to their management
helps in targeting investigation and optimizing patient care. Research
has led to recent advances in diagnostic strategies and therapeutic
techniques in these patients. This review focuses on the clinical
assessment, diagnosis and management of patients with pleural effu-
sions, malignant pleural disease, pleural infection and pneumothorax,
and provides practical suggestions regarding investigation and
Keywords Empyema; malignant pleural effusion; parapneumonic
effusion; pleural disease; pleural effusion; pneumothorax
Investigating pleural effusions
a heparinized syringe (to measure pH using a blood gas analyser)
and sent for the following tests:
? biochemistry e lactate dehydrogenase (LDH), total pro-
? microbiology e Gram stain, identification of acid- and
alcohol-fast bacilli (AAFB) and microbiological culture
Pleural effusions are a common medical problem (Table 1).
There are several underlying mechanisms, including:
? increased permeability of the pleural membrane
? increased pulmonary capillary pressure
? excess negative intrapleural pressure
? reduced tissue oncotic pressure
? obstructed lymphatic flow.
The differential diagnosis is wide, so a systematic approach to
investigation is necessary.1This should start with an accurate
history, including a drug history (Table 2), and examination.
Distinguishing pleural fluid exudate and transudate: in most
cases, a pleural fluid total protein of less than 25 g/litre represents
a transudate and more than 35 g/litre an exudate. However, if the
serum total protein is low or the pleural fluid protein concentra-
tion lies between these figures, differentiating the two can be
more difficult. In these cases, measurement of serum and pleural
fluid LDH and total protein allows Light’s criteria to be used to
distinguish exudates and transudates more accurately (Table 4).
Light’s criteria have good sensitivity and specificity (as high
as 98% in some series). However, a small number of patients
with malignancy will be categorized as having a transudate; in
addition, patients with cardiac failure taking diuretics may have a
higher fluid protein concentration, so the pleural fluid may be
mislabelled as an exudate.
Pleural aspiration: a diagnostic pleural fluid sample should be
collected using a fine-bore (21 G) needle and a 50-ml syringe,
using ultrasound guidance to locate a safe site to perform the
procedure (Table 3).1
The appearance and odour of the fluid should be noted. The
sample should be placed in sterile vials, blood culture bottles and
Oliver J Bintcliffe MRCP is a Specialist Registrar in Respiratory and
General Medicine and Clinical Research Fellow in pleural disease at
the University of Bristol, UK. His research interests include pneu-
mothorax and non-malignant pleural effusions. Competing interests:
Differential cell counts: a differential count of a pleural fluid
sample can be useful in narrowing the differential diagnosis, but
the results are not disease-specific. Lymphocytic effusions are
commonly seen in malignancy and tuberculosis (TB), after coro-
nary artery bypass graft and with cardiac failure and chronic
Neutrophilic effusions usually signify a more acute disease
process, such as pulmonary emboli (PEs) or parapneumonic
Amelia O Clive PhD is a Specialist Registrar in Respiratory and
General Medicine at North Bristol NHS Trust, UK. Her research
interests include the management of malignant pleural disease.
Competing interests: none declared.
Nick A Maskell DM FRCP is a Professor in Respiratory Medicine at the
University of Bristol, UK. His clinical and research interests include
malignant pleural disease and pleural infection. Competing interests:
Professor Maskell has received research funding from Care Fusion,
Roche and Novartis.
? 2016 Elsevier Ltd. All rights reserved.
Causes of transudative and exudative pleural effusions
Pleural procedures should not take place out of hours except in
Pleural aspirations and chest drain should be inserted in a clean
environment using full aseptic technique
Bedside thoracic ultrasound guidance is strongly recommended
for all pleural procedures involving pleural fluid
The preferred site for pleural interventions is the triangle of safety
Non-urgent pleural procedures should be avoided in anti-
coagulated patients until the international normalized ratio is
Pleural fluid aspiration should be stopped when no more fluid
can be aspirated or the patient becomes symptomatic, to reduce
the risk of re-expansion pulmonary oedema. The total amount
aspirated is often limited to 1.5 litres in the elderly.
Left ventricular failure
Superior vena cava obstruction
Benign asbestos effusion
Post-myocardial infarction syndrome
Yellow nail syndrome
Drugs (Table 2)
pH: a low pleural fluid pH (<7.2) can indicate pleural infection
requiring chest tube drainage. Other causes of low pH effusions
include advanced malignancy, rheumatoid arthritis, TB, collagen
vascular disease and oesophageal perforation. Pleural fluid
glucose concentration correlates with pleural fluid pH and can be
a useful alternative if pH cannot be measured.
Cytology: malignant effusions can be diagnosed from a single
pleural fluid cytology specimen in about 60% of cases. A second
cytology specimen increases the yield slightly. Certain malignant
cell types are diagnosed more readily by experienced cytologists,
using immunocytochemistry; a cytological diagnosis is more
likely in a malignant pleural effusion due to metastatic adeno-
carcinoma than in mesothelioma for instance.
Identify the ‘safe triangle for drain placement, as demarcated by
the outer border of the pectoralis major, the anterior border of the
latissimus dorsi and a horizontal line that meets the nipple
anteriorly. In general, the drain should be sited in the 4th or 5th
intercostal space within this triangle.
Pleural imaging: effusions greater than 200 ml can be detected
on a postero-anterior chest radiograph, although smaller vol-
umes can be detected using thoracic ultrasound. Ultrasound
scanning can also differentiate more clearly between pleural fluid
and thickening, assess septations and loculations within an
effusion and help to identify a safe site for pleural procedures.
Computed tomography (CT) can help to characterize pleural
abnormalities further. Contrast enhancement aids differentiation
between benign and malignant pleural thickening and is often
visualized more clearly if some pleural fluid is still present
(Figure 1). In addition, CT can identify other underlying causes of
a pleural effusion, such as PEs, infection or tumours. Up to 40%
of patients with PEs have a small pleural effusion with no specific
biochemical characteristics; a high index of suspicion is required
to make this diagnosis, and CT pulmonary angiography should
be requested if the diagnosis is considered.
Magnetic resonance imaging (MRI) is developing as an im-
aging modality for pleural disease and can be useful in selected
cases where clear soft tissue differentiation is required.
Drug causes of pleural effusion
Pleural fluid is an exudate if one or more of the following criteria
Pleural fluid protein:serum protein ratio >0.5
Pleural fluid LDH:serum LDH ratio >0.6
Pleural fluid LDH more than two-thirds of upper limit of normal
LDH, lactate dehydrogenase.
? 2016 Elsevier Ltd. All rights reserved.
failure of pleurodesis. Cytological analysis identifies tumour cells
in 60% of malignant effusions, so histology is often required for
diagnosis. This is particularly the case with suspected mesothe-
lioma, in which pleural fluid cytology is frequently non-
Blind pleural biopsies have a lower diagnostic yield and
higher complication rate than CT-guided biopsy and are now
rarely used. Use of local anaesthetic thoracoscopy is increasing
and allows for complete drainage of the pleural effusion, tissue
sampling for histology and pleurodesis in the same procedure. It
provides an alternative to VATS under general anaesthetic if a
less invasive approach is preferred, particularly for elderly pa-
tients for whom a general anaesthetic can be more risky. In some
cases, where the lung is tethered or the effusion heavily septated,
a surgical procedure via multiple ports may be needed to release
the trapped lung, break down septations and obtain tissue for
CT is mandatory for identifying the primary source and for
staging (Figure 1). The precise role of other imaging modalities,
such as MRI and positron emission tomography CT has yet to be
Figure 1 Contrast-enhanced thoracic CT of an exudative pleural
effusion, showing enhancement of the pleural tumour.
Pleural biopsy techniques
A pleural biopsy should be considered in patients who have a
pleural effusion of unknown cause after initial investigations,
particularly if malignancy or TB is suspected. The biopsy can be
performed percutaneously, or at thoracoscopy.
A blind pleural biopsy using an Abrams’ biopsy needle can be
considered if TB pleuritis is suspected, as the pleural abnormality
is more diffuse than in malignancy. However, at least four
samples should be taken to maximize the diagnostic yield. If TB
is suspected, the sample should be sent in saline for TB culture as
well as for histology.
If malignancy is suspected, however, pleural biopsy using an
image-guided cutting needle has a higher diagnostic yield than
blind pleural biopsy. Four samples should still be taken to opti-
mize the diagnostic accuracy.
Thoracoscopy is gaining popularity in the investigation and
management of pleural disease as it is both diagnostic and thera-
peutic.1It allows direct visualization of the pleura and can be per-
thoracoscopic surgery (VATS)) anaesthesia. The sensitivity for ma-
lignancy and TB is over 90%. During the procedure, all the pleural
fluid can be removed and pleurodesis performed if necessary.
The treatment modalities available to patients with malignant
pleural effusions are expanding and depend on patient choice,
clinical condition and availability.1Aside from treatment of the
underlying malignancy, management strategies focus on fluid
removal and prevention of reaccumulation. No current therapies
target the underlying problem of excess fluid production directly,
but this is the subject of continuing research. Treatment of the
underlying malignant process can help to reduce pleural fluid
production, particularly in chemoresponsive tumours such as
Thoracocentesis allows instant relief of symptoms, but reac-
cumulation frequently necessitates more definitive treatment.
Chest drain insertion and pleurodesis is a well-established
method of removing fluid and preventing recurrence. Talc is
the preferred agent in pleurodesis and is effective in about 70%
of patients. It can be given in the form of talc slurry through a
chest tube, or as a ‘talc poudrage’ during thoracoscopy. The ef-
ficacy of these procedures is the subject of a large, randomized
controlled trial (TAPPS). Pleurodesis is unlikely to be successful
when the lung is unable to fully re-expand (‘trapped lung’),
because of a visceral pleural ‘peel’ of tumour or endobronchial
Indwelling pleural catheters (Figure 2) are gaining popularity
in the management of malignant effusions, particularly in pa-
tients with trapped lung or those who wish to avoid hospital
admission.2The catheters are small chest tubes tunnelled under
the skin that allow regular pleural fluid drainage to be carried out
in the community. Spontaneous pleurodesis occurs in up to one-
half of patients, after which the catheter can be removed. The
combination of talc and an indwelling pleural catheter can in-
crease the rate of pleurodesis; this is the subject of a randomized
controlled trial (IPC-PLUS).
The role of prophylactic radiotherapy in mesothelioma to
prevent metastases along the procedure track following pleural
interventions is not established but is the subject of two large
multicentre randomized controlled trials (SMART, PIT).
Malignant pleural effusion
Malignant pleural effusion can result in disabling breathlessness
for patients with advanced malignancy and confers a poor
prognosis. It can be caused by mesothelioma (a primary pleural
tumour) or metastatic disease. Lung, breast, ovarian, haemato-
commonly metastasize to the pleura.
Other conditions associated with an underlying malignant
process can also cause a pleural effusion. These include PEs,
superior vena cava obstruction, nodal enlargement restricting
pleural fluid resorption and hypoalbuminaemia.
Initial assessment with blood and pleural fluid analysis assists
with diagnosis. Imaging using CT and ultrasound is also used.
Malignant pleural effusions are exudates in 90% of cases. A low
pleural fluid pH indicates extensive disease and helps to predict
? 2016 Elsevier Ltd. All rights reserved.
Figure 2 (a) An indwelling pleural catheter, commonly used for the management of recurrent, symptomatic, malignant pleural effusions. (b) Trocar
Parapneumonic effusions and empyema
choice of antibiotic. Prolonged courses of antibiotics may be
required to ensure complete resolution.
First-line antibiotic treatment for community-acquired pleural
infection should include an aminopenicillin (e.g. amoxicillin) to
cover organisms such as Streptococcus pneumoniae and Haemo-
philus influenzae, as well as metronidazole or a b-lactamase in-
hibitor (e.g. clavulanic acid), to ensure penicillin-resistant
aerobes and anaerobes are covered.1
In hospital-acquired empyema broader cover is required for
Gram-negative and anaerobic organisms.1
More than 65,000 patients develop pleural infection in the USA
and UK each year. Mortality is about 15%. Hospital-acquired
infection, particularly with Gram-negative bacteria, has a
particularly poor prognosis. The microbiology of hospital-
acquired infection also differs from that of community-acquired
empyema (Figure 3), and they should be considered as sepa-
rate entities in terms of epidemiology and recommended therapy.
Pleural infection can occur at any age, but is most common in
elderly patients and children. Men are affected twice as often as
women, and the incidence (particularly of infection caused by
Staphylococcus aureus) is increasing. The incidence is higher in
patients with diabetes, rheumatoid arthritis or coincidental
chronic lung disease, and in alcohol and substance abusers. Poor
dentition is associated with anaerobic infection.
In all suspected cases, pleural fluid aspiration and analysis
should be undertaken. Biochemical pleural fluid markers (low
pH, high LDH, predominant neutrophils, low glucose) are central
in establishing a diagnosis.
Gram staining and culture can aid antibiotic choice, although
40% of infected pleural effusions are culture-negative. Use of
blood culture bottles increases the microbiological yield over
universal containers alone and can aid assessment of poly-
A pleural pH <7.2 identifies effusions requiring chest tube
drainage. pH should be measured routinely in any potentially
infectedpleuralfluid sample,unless itis obviouslypurulent. A low
pleural fluid glucose concentration (<2.2 mmol/litre indicates the
Tuberculous effusions are usually unilateral and more than
50% will show evidence of parenchymal TB. These effusions are
usually sterile, unless secondarily infected. Smears for acid-fast
bacilli on pleural fluid are positive in only 5e10% of cases,
and only 25e50% are positive on culture. A pleural biopsy is
often required to confirm the diagnosis.
Antibiotics: the clinical setting, pleural fluid culture results and
local antibiotic prescribing policies help to inform the initial
? 2016 Elsevier Ltd. All rights reserved.
pleural fluid pH less than 7.2, septated appearances on ultrasound,
Seldinger tubes are as effective as larger ones and are more
comfortable for the patient; however, they need regular flushing
with sodium chloride 0.9% (20 ml 8-hourly) to prevent blockage.
Intrapleural fibrinolytics: there has been much debate about the
role of intrapleural fibrinolytics in pleural infection, to break
down fibrin septae and reduce the pleural rind, and thus improve
fluid drainage and lung expansion.
The MIST-2 trial, which assessed the use of intrapleural
tissue-type plasminogen activator and DNase, showed that
combined treatment improved drainage, reduced hospital stay
and decreased referrals for thoracic surgery.3This treatment can
have a role in patients who do not respond to standard therapy,
or in those not fit for surgery, although its precise role has yet to
be fully established.
Figure 4 A chest X-ray showing a left-sided primary spontaneous
line treatment and can prevent a hospital admission. However,
simple aspiration fails in 20e25% of patients, and insertion of a
chest tube is then warranted in those who are symptomatic.
Clinically stable patients with a large primary pneumothorax
can also be appropriate for conservative treatment without
aspiration; this hypothesis is the subject of a currently recruiting
trial in Australia and New Zealand.
Heimlich valves offer the potential for an outpatient-based
treatment of pneumothorax, which may be appropriate in
selected patients. These devices are the subject of a currently
recruiting randomized controlled trial (RAMPP study).
Recurrence of PSP occurs in about 40% of patients, usually
within 5 years of the first event. If a recurrence occurs, patients
should be referred to a thoracic surgeon for consideration of a
definitive procedure such as pleurodesis or pleurectomy to
prevent further events.4
Surgery: surgical referral may be necessary in patients with
continuing signs of sepsis or failure of the effusion to resolve
despite medical management. The aims of surgery are to treat
infection by draining any residual fluid completely and to allow
adequate lung re-expansion. Several surgical options are avail-
able, including open thoracotomy with decortication, mini-
thoracotomy, VATS and rib resection with open drainage (if
patients are not fit enough for a more definitive procedure).
Pneumothorax is defined as air in the pleural space and can be
spontaneous or traumatic (including iatrogenic). Recommended
management depends on the size of pneumothorax and patient
symptoms and whether the pneumothorax is primary or sec-
ondary (Figure 5). Chest radiographs confirm the diagnosis
(Figure 4) but do not accurately quantify pneumothorax size. CT
is sometimes required to differentiate a pneumothorax from a
subpleural bulla and confirm tube placement, particularly if the
radiographic images are obscured by surgical emphysema.1
Secondary pneumothoraces occur in the presence of underlying
lung pathology (particularly chronic obstructive pulmonary
disorder (COPD)); symptoms are often more severe than in PSP
because of a pre-existing impairment of respiratory function.
If the patient develops a small secondary pneumothorax
(<2 cm) and is asymptomatic, inpatient observation is reason-
able. If symptoms are minimal, simple aspiration can be
attempted, although this has a lower success rate than in PSP;
inpatient observation for at least 24 hours after the aspiration is
Many patients with a secondary pneumothorax need inter-
costal drain insertion. A small (<14 F) chest tube is usually
sufficient, but if there is a persistent air leak (continuous
bubbling of the drain >48 hours after insertion), significant
surgical emphysema or the patient is mechanically ventilated, a
larger bore chest tube may be indicated. Suction may also be
helpful if the pneumothorax is slow to resolve and should be
slowly titrated to a more negative pressure, depending on the
patient’s symptoms, down to ?20 cmH2O.
Primary spontaneous pneumothorax (PSP)
PSPs occur in individuals without underlying lung disease.
Subpleural blebs and bullae are found in up to 90% of patients at
thoracoscopy and are thought to have a role in the pathogenesis
of PSP. Smoking is a risk factor; the lifetime risk of PSP is 12% in
men who smoked heavily compared with 0.1% in non-smoking
men. Patients with primary pneumothorax tend to be taller
The aim of treatment is to reduce symptoms and prevent
recurrence. Administration of high-flow oxygen (10 litres/minute)
can accelerate resorption of the pneumothorax by reducing the
partial pressure of nitrogen in the pleural space. Observation alone
edge and chest wall) without significant breathlessness, as resorp-
tion will occur over time. If the patient is symptomatic or the
? 2016 Elsevier Ltd. All rights reserved.
Suggested management of pneumothorax
Known lung disease or
and clinical stability
Size >2 cm and/or
valve + ambulatory
management if available
Aspiration or observation.
(observe for minimum
Early outpatient review as required
Ongoing air leak
Figure 5 Adapted from the British Thoracic Society Pleural Disease Guideline 2010.
Tension pneumothorax: immediate intervention is necessary. A
large-bore cannula should be inserted promptly into the second
intercostal space in the mid-clavicular line and left in place until
a chest tube can be positioned.
Patients should be advised about smoking cessation and
should not fly until the pneumothorax has entirely resolved on
chest radiograph. Unless they undergo a definitive surgical pro-
cedure, patients should not dive.
Iatrogenic pneumothorax: the incidence of iatrogenic pneumo-
thorax is high and increasing. Percutaneous lung biopsy, trans-
bronchial needle aspiration, pleural biopsy, thoracocentesis and
central venous puncture are the principal causes. COPD and lung
fibrosis are important risk factors. In most patients, the pneu-
mothorax will resolve with observation alone, but others can
1 British Thoracic Society Pleural Disease Guideline Group. BTS
pleural disease guideline 2010. Thorax 2010; 65(suppl 2):
2 Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling
pleural catheter vs chest tube and talc pleurodesis for relieving
dyspnea in patients with malignant pleural effusion: the TIME2
randomized controlled trial. J Am Med Assoc 2012; 307: 2383e9.
3 Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue
plasminogen activator and DNase in pleural infection. N Engl J Med
2011; 365: 518e26.
4 Tschopp JM, Bintcliffe O, Astoul P, et al. ERS task force statement:
diagnosis and treatment of primary spontaneous pneumothorax.
Eur Respir J 2015; 46: 321e35.
Referral for surgery: open surgery with thoracotomy and pleur-
ectomy is an effective method to reduce recurrence rates, though
minimally invasive VATS with surgical talc pleurodesis or
mechanical abrasion is now usually the preferred approach on
account of reduced postoperative pain and shorter hospital stays.
Indications for a surgical referral for pneumothorax include:
? persistent air leak (patients should be referred early,
ideally within 5 days)
? second ipsilateral pneumothorax
? first contralateral pneumothorax
? bilateral spontaneous pneumothorax
? certain at-risk professions (e.g. pilots, divers).
Patients with recurrent secondary pneumothorax who are not
fit for surgery can be given alternative treatments including
chemical pleurodesis (although the recurrence rate is high) or an
ambulatory Heimlich valve.
Bintcliffe OJ, Hallifax RJ, Edey A, et al. Spontaneous pneumothorax:
time to rethink management? Lancet Respir Med 2015; 3: 578e88.
Clive AO, Bhatnagar R, Psallidas I, Maskell NA. Individualised manage-
Corcoran JP, Wrightson JM, Belcher E, DeCamp MM, Feller-
Kopman D, Rahman NM. Pleural infection: past, present, and future
directions. Lancet Respir Med 2015; 3: 563e77.
? 2016 Elsevier Ltd. All rights reserved.