# 13 - 305 Disorders of the Pleura

### 305 Disorders of the Pleura

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■FURTHER READING
American Thoracic Society/European Respiratory Society: 
Consensus classification of the idiopathic interstitial pneumonias. 
Am J Respir Crit Care Med 165:277, 2002.
Raghu G et al; ATS/ERS/JRS/ALAT Committee on Idiopathic 
Pulmonary Fibrosis: An official ATS/ERS/JRS/ALAT statement: 
Idiopathic pulmonary fibrosis: Evidence-based guidelines for the 
diagnosis and management. Am J Respir Crit Care Med 183:788, 2011.
Travis WD et al: Idiopathic nonspecific interstitial pneumonia: Report 
of an American Thoracic Society project. Am J Respir Crit Care Med 
177:1338, 2008.
Travis WD et al: An official American Thoracic Society/European 
Respiratory Society Statement: Ten decade update on IIP’s, poten­
tial areas for future investigation are proposed (ATS/ERS update of 
the international multidisciplinary classification of the idiopathic 
interstitial pneumonias. Am J Respir Crit Care Med 188:733, 2013.
Khalid Ismail, Hilary J. Goldberg, 

Rebecca M. Baron

Disorders of the Pleura
The pleural space lies between the lung and the chest wall and normally 
contains a very thin layer of fluid, which serves as a coupling system. 
This space is maintained around –3 to –5 cmH2O because of a constant 
balance between the elastic recoil of the lung, with its attached visceral 
pleura, and the counter expansion of the chest wall with attached parietal 
pleura. Invasion of this space with organisms, inflammatory or cancer 
cells, or introduction of air, blood, or chyle can lead to significant disease.
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■PLEURAL EFFUSION
A pleural effusion is present when there is an excess quantity of fluid 
in the pleural space.
Etiology 
Under normal conditions, fluid enters the pleural space 
from the capillaries in the parietal pleura and is removed via the lym­
phatics in the parietal pleura. Fluid also can enter the pleural space 
from the interstitial spaces of the lung via the visceral pleura or from 
the peritoneal cavity via small holes in the diaphragm. The lymphat­
ics have the capacity to absorb 20 times more fluid than is formed 
normally. Hydrostatic and oncotic pressures play a fundamental role. 
A pleural effusion develops when there is disturbance in hydrostaticoncotic balance, leading to pleural fluid formation that overwhelms 
fluid removal by the lymphatics. It is estimated that 1.5 million Americans 
per year develop pleural effusion. The most common presentation is 
that of shortness of breath and occasionally chest pain.
Diagnostic Approach 
Patients suspected of having a pleural effu­
sion should undergo chest imaging to evaluate its extent. Although 
chest x-ray with lateral decubitus films have been the standard diagnos­
tic modality (and remains so in some parts of the world), advances in 
chest ultrasound and computed tomography (CT) imaging have made 
them invaluable, for both identifying characteristics of the effusion and 
guiding pleural sampling and/or drainage. When a patient is found 
to have a pleural effusion, an effort should be made to determine the 
cause (Fig. 305-1). The first step is to determine whether the effusion 
is a transudate or an exudate, which requires thoracentesis. A transuda­
tive pleural effusion occurs when systemic factors (hydrostatic-oncotic 
pressures) that influence the formation and absorption of pleural fluid 
are altered. The leading causes of transudative pleural effusions in the 
United States are left ventricular failure and cirrhosis. An exudative 
pleural effusion occurs when local factors that influence the forma­
tion and absorption of pleural fluid are altered. The leading causes 

Pleural effusion
Perform diagnostic thoracentesis
Measure pleural fluid protein and LDH
Any of following met?
PF/serum protein >0.5
PF/serum LDH >0.6
PF LDH >2/3 upper normal serum limit
Disorders of the Pleura
CHAPTER 305
Yes
No
Exudate
Further diagnostic procedures
Transudate
Treat CHF, cirrhosis, nephrosis
Measure PF glucose
Obtain PF cytology
Obtain differential cell count
Culture, stain PF
PF marker for TB
Glucose <60 mg/dL
Consider: Malignancy
 
Bacterial infections
 
Rheumatoid
 
pleuritis
No diagnosis
Yes
Consider pulmonary
embolus (spiral CT
or lung scan)
Treat for PE
No
Yes
Treat for TB
PF marker for TB
No
Yes
Observe
SYMPTOMS IMPROVING
No
Consider thoracoscopy
or image-guided
pleural biopsy
FIGURE 305-1  Approach to the diagnosis of pleural effusions. CHF, congestive heart 
failure; CT, computed tomography; LDH, lactate dehydrogenase; PE, pulmonary 
embolism; PF, pleural fluid; TB, tuberculosis.
of exudative pleural effusions are bacterial pneumonia, malignancy, 
viral infection, and pulmonary embolism (Table 305-1). The primary 
reason for making this differentiation is that additional diagnostic 
procedures are indicated with exudative effusions to define the cause.
Transudative and exudative pleural effusions are distinguished by 
measuring the lactate dehydrogenase (LDH) and protein levels in the 
pleural fluid. Exudative pleural effusions meet at least one of the fol­
lowing criteria, whereas transudative pleural effusions meet none:
1.	 Pleural fluid protein/serum protein >0.5
2.	 Pleural fluid LDH/serum LDH >0.6
3.	 Pleural fluid LDH more than two-thirds the normal upper limit 
for serum
These criteria misidentify ~25% of transudates as exudates (“pseu­
doexudates”), often felt to be related to a “diuresed transudate.” If one 
or more of the exudative criteria are met and the patient is clinically 
thought to have a condition producing a transudative effusion, alterna­
tive criteria can be used. Serum to pleural fluid protein gradient (SPPG) 
and serum to pleural fluid albumin gradient (SPAG) >3.1 g/dL and

TABLE 305-1  Differential Diagnoses of Pleural Effusions
Transudative Pleural Effusions
1.	 Congestive heart failure
2.	 Cirrhosis
3.	 Nephrotic syndrome
4.	 Peritoneal dialysis
5.	 Superior vena cava obstruction
6.	 Myxedema
7.	 Urinothorax
Exudative Pleural Effusions
PART 7
Disorders of the Respiratory System
1.	Neoplastic diseases
a.	 Metastatic disease
b.	 Mesothelioma
2.	Infectious diseases
a.	 Bacterial infections
b.	 Tuberculosis
c.	 Fungal infections
d.	 Viral infections
e.	 Parasitic infections
3.	Pulmonary embolization
4.	Gastrointestinal disease
a.	 Esophageal perforation
b.	 Pancreatic disease
c.	 Intraabdominal abscesses
d.	 Diaphragmatic hernia
e.	 After abdominal surgery
f.	 Endoscopic variceal sclerotherapy
g.	 After liver transplant
5.	Collagen vascular diseases
a.	 Rheumatoid pleuritis
b.	 Systemic lupus erythematosus
c.	 Drug-induced lupus
d.	 Sjögren syndrome
e.	 Granulomatosis with polyangiitis (Wegener)
f.	 Churg-Strauss syndrome
6.	Post–coronary artery bypass surgery
7.	Asbestos exposure
8.	Sarcoidosis
9.	Uremia
10.	 Meigs’ syndrome
11.	 Yellow nail syndrome
12.	 Drug-induced pleural disease
a.	 Nitrofurantoin
b.	 Dantrolene
c.	 Methysergide
d.	 Bromocriptine
e.	 Procarbazine
f.	 Amiodarone
g.	 Dasatinib
13.	 Trapped lung
14.	 Radiation therapy
15.	 Post–cardiac injury syndrome
16.	 Hemothorax
17.	 Iatrogenic injury
18.	 Ovarian hyperstimulation syndrome
19.	 Pericardial disease
20.	 Chylothorax
>1.2 g/dL, respectively, together can identify pseudoexudates with 100% 
sensitivity in heart failure and 99% sensitivity in hepatothorax. Elevated 
pleural fluid cholesterol has also been used, especially when combined 
with elevated LDH, to favor a true exudate. In addition to describing the 

TABLE 305-2  Disease-Specific Pleural Fluid Tests
SUSPECTED DISEASE
TESTS
Pancreatic disease or esophageal 
rupture
Pleural fluid amylase
Drug-induced pleural effusion
Pleural fluid eosinophils
Congestive heart failure
Pleural fluid N-terminal pro-brain 
natriuretic peptide (NT-proBNP)
Chylothorax
Pleural fluid cholesterol and triglycerides
Hemothorax
Pleural fluid hematocrit
Rheumatoid disease
Pleural fluid glucose and pH
Amyloidosis
Congo red staining
Lymphoma
Flow cytometry
appearance of pleural fluid, the following pleural fluid tests should be 
obtained: glucose level, differential cell count, microbiologic studies, and 
cytology. More disease-specific diagnostic tests can be obtained depend­
ing on the clinical scenario (see examples in Table 305-2).
Effusion Due to Heart Failure 
The most common cause of 
pleural effusion is left ventricular dysfunction. Elevated left atrial 
pressure with elevated pulmonary venous pressure leads to increased 
amounts of fluid in the lung interstitial spaces exiting in part across the 
visceral pleura (a classic example of increased hydrostatic pressure), 
and this overwhelms the capacity of the lymphatics in the parietal 
pleura to remove the fluid. In patients with heart failure, a diagnostic 
thoracentesis should be performed if the effusions are not bilateral and 
comparable in size, if the patient is febrile, or if the patient has pleuritic 
chest pain, to verify that the patient has a transudative effusion. Other­
wise, the patient’s heart failure is treated. If the effusion persists despite 
therapy, a diagnostic thoracentesis should be performed. A pleural 
fluid N-terminal pro-brain natriuretic peptide (NT-proBNP) level 
>1500 pg/mL is suggestive of an effusion that is secondary to conges­
tive heart failure and correlates well with serum values.
Parapneumonic Effusion 
Parapneumonic effusions (PPEs) can 
be seen in up to 50% of patients with community-acquired pneumonia 
and are generally the most common cause of exudative pleural effusion 
in the United States. PPEs are usually reactive (i.e., no organisms iden­
tified on culture). In 10% of patients with PPE, infection of the pleural 
space sets in, leading to a complicated PPE or an empyema, which 
refers to a fibrinopurulent or grossly purulent effusion, respectively.
Patients with aerobic bacterial pneumonia and pleural effusion may 
present with an acute febrile illness consisting of pleuritic chest pain, 
sputum production, and leukocytosis. Patients with anaerobic infections 
can present with a subacute illness with weight loss, leukocytosis, mild 
anemia, and a history of some factor that predisposes them to aspiration. 
These patients can have minimal parenchymal infiltrates with a large 
effusion.
The possibility of a PPE should be considered whenever a patient 
with bacterial pneumonia is initially evaluated. Thoracentesis is usu­
ally indicated to exclude infection of the pleural space if significant 
pleural fluid is present. The presence of free-flowing pleural fluid 
can be demonstrated with a lateral decubitus radiograph, CT of the 
chest, or ultrasound (Fig. 305-2A, C). Traditionally, a minimum of 
10 mm of free fluid on a lateral decubitus film suggests the safety of 
thoracentesis. Presently, CT/ultrasound guidance permits a better 
determination, both for safety of thoracentesis as well as likelihood 
of a complicated PPE (usually indicated by loculation or septations in 
the fluid; Fig. 305-2B, D) that might make bedside thoracentesis more 
challenging. Factors indicating the likely need for evacuation of the 
pleural space by more advanced intervention (in increasing order of 
importance) include the following:
1.	 Loculated pleural fluid
2.	 Pleural fluid pH <7.20
3.	 Pleural fluid glucose <3.3 mmol/L (<60 mg/dL)
4.	 Positive Gram’s stain or culture of the pleural fluid
5.	 Presence of gross pus in the pleural space

R
A
∂
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C
FIGURE 305-2  A. CT scan from a patient with simple pleural effusion, demonstrating free-flowing fluid in the left pleural space (red arrow). B. CT scan from a patient with 
loculated pleural effusion, demonstrating two pockets of fluids (red arrows). C. Ultrasound image of a simple pleural effusion, demonstrating free-flowing fluid (arrow), 
atelectatic lung (#), chest wall (^), diaphragm (*), and liver (x). D. Ultrasound image of a complex pleural effusion, with loculations (yellow arrow) and septations (red arrows), 
diaphragm (*), consolidated lung (#), chest wall (^), and liver (x).
An elevated pleural fluid LDH (>900 IU/L) is another feature that 
suggests the need for pleural fluid evacuation.
Effusions can progress from exudative to fibrinopurulent to an 
organizing phase (pleural peel) (Fig. 305-3). If the fluid is fibrino­
purulent and cannot be completely drained by thoracentesis, consid­
eration should be given to insertion of a chest tube for drainage and 
possible instillation of the combination of a fibrinolytic agent (e.g., 
tissue plasminogen activator, 10 mg) and deoxyribonuclease (5 mg), 
or performing a thoracoscopy with the breakdown of adhesions if 
R
L
FIGURE 305-3  CT scan from a patient with empyema. Note thick pleural rind with 
that enhances with contrast (red arrows).

L
A
F
R
P
H
L
Disorders of the Pleura
CHAPTER 305
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B
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X
X
D
chest tube drainage does not completely evacuate the pleural space. 
Surgical decortication should be considered when these measures are 
ineffective.
Trapped lung (i.e., a lung that cannot re-expand) might develop if a 
fibrous restrictive peel forms around the visceral pleura, usually in the 
setting of long-standing pleuro-pulmonary pathology. Although mea­
suring pleural pressure at the time of thoracentesis (pleural manom­
etry) can help confirm trapped lung, a thick pleural rind, presence of 
air on chest imaging after thoracentesis (termed pneumothorax ex vacuo), 
and recurrence of effusion shortly after drainage are suggestive of a 
lung that will not re-expand without decortication.
Effusion Secondary to Malignancy 
Malignant pleural effusions 
are the second most common type of exudative pleural effusion. The 
three tumors that cause ~75% of all malignant pleural effusions are 
lung carcinoma, breast carcinoma, and lymphoma. Its presence usually 
portends poor prognosis (<6-month survival). Most patients complain 
of dyspnea, which is frequently out of proportion to the size of the effu­
sion. The pleural fluid is usually an exudate (although it can rarely be a 
transudate), and its glucose level may be reduced if the tumor burden 
in the pleural space is high.
The diagnosis usually is made via cytology of the pleural fluid. If 
the initial cytologic examination is negative, CT- or ultrasound-guided 
needle biopsy of pleural thickening or nodules can confirm the diag­
nosis. Ultimately, thoracoscopic biopsy is most definitive if malignancy 
is strongly suspected.
Patients with a malignant pleural effusion are treated symptom­
atically for the most part, since the presence of the effusion indicates 
disseminated disease, and most malignancies associated with pleural 
effusion are not curable with chemotherapy. If the patient’s lifestyle

is compromised by dyspnea and if the dyspnea is not relieved with 
a therapeutic thoracentesis, one of the following procedures should 
be considered: (1) insertion of a small indwelling catheter for regular 
home drainage (improves dyspnea) or (2) tube thoracostomy with the 
instillation of a sclerosing agent (chemical pleurodesis) versus thora­
coscopy with drainage of the effusion and surgical pleurodesis.

Mesothelioma 
Malignant mesotheliomas are primary tumors that 
arise from the mesothelial cells that line the pleural cavity; most are 
related to asbestos exposure. Incidence has dropped because of asbes­
tos remediation measures. Patients with mesothelioma often present 
with chest pain and shortness of breath. The chest radiograph reveals a 
pleural effusion, generalized pleural thickening, and a shrunken hemi­
thorax. The diagnosis is usually established with image-guided needle 
biopsy or thoracoscopy.
Hepatic Hydrothorax 
Pleural effusions occur in ~5% of patients 
with cirrhosis and ascites. The predominant mechanism is the direct 
movement of peritoneal fluid through small openings in the dia­
phragm into the pleural space. Ascites is common, and the effusion is 
usually right-sided and often large enough to produce severe dyspnea. 
Like ascitic fluid, it is usually low in protein (transudative) but can 
develop into a spontaneous bacterial empyema. Treatment is that of 
ascites, but if recurrent or persistent, pleurodesis, transjugular intrahe­
patic portosystemic shunt, or liver transplant might be required.
Effusion Secondary to Pulmonary Embolism 
The diagnosis 
most commonly overlooked in the differential diagnosis of a patient 
with an undiagnosed pleural effusion is pulmonary embolism. Dys­
pnea is the most common symptom. The pleural fluid is almost always 
an exudate. The diagnosis is established most often by CT angiography 
(Chap. 290). Treatment of a patient with a pleural effusion secondary 
to pulmonary embolism is the same as it is for any patient with pulmo­
nary emboli. If the pleural effusion increases in size after anticoagula­
tion, the patient may have recurrent emboli or another complication, 
such as a hemothorax or a pleural infection.
Tuberculous Pleuritis/Effusion (See also Chap. 183) 
In 
many parts of the world, the most common cause of an exudative pleu­
ral effusion is tuberculosis (TB), but tuberculous effusions are relatively 
uncommon in the United States. Tuberculous pleural effusions usually 
are associated with primary TB and are thought to be due primarily to 
a hypersensitivity reaction to tuberculous protein in the pleural space. 
Patients with tuberculous pleuritis present with fever, weight loss, 
dyspnea, and/or pleuritic chest pain. The pleural fluid is exudative 
and predominantly lymphocytic. The diagnosis is suggested by dem­
onstrating high levels of TB markers in the pleural fluid (adenosine 
deaminase >40 IU/L or interferon γ >140 pg/mL).
PART 7
Disorders of the Respiratory System
Diagnosis is established by culture of the pleural fluid for acid-fast 
bacilli, needle biopsy of the pleura, or thoracoscopy. Guided percutane­
ous needle biopsy has largely replaced closed needle biopsy, except in 
parts of the world where TB is prevalent. The culture yield of pleural 
biopsy is higher than that of pleural fluid. The recommended treatment 
of pleural and pulmonary TB is identical (Chap. 183).
Effusion Secondary to Viral Infection 
Viral infections are 
probably responsible for a sizable percentage of undiagnosed exudative 
pleural effusions. In many series, no diagnosis is established for ~20% 
of exudative effusions, and these effusions usually resolve spontane­
ously with no long-term residua. The importance of these effusions is 
that one should not be too aggressive in trying to establish a diagnosis 
for the undiagnosed effusion if the patient is improving clinically.
Chylothorax 
A chylothorax occurs when the thoracic duct is dis­
rupted and chyle accumulates in the pleural space. The most common 
cause of chylothorax is trauma (most frequently thoracic surgery), but 
it also may result from tumors in the mediastinum. Patients with chy­
lothorax may present with dyspnea, and a large pleural effusion is often 
present on the chest radiograph. Thoracentesis usually reveals milky 
fluid, and biochemical analysis reveals a triglyceride level that exceeds 
1.2 mmol/L (110 mg/dL). Patients with chylothorax and no obvious 
trauma should have a lymphangiogram and a chest CT scan to assess 

the mediastinum for lymphadenopathy. The treatment of choice for 
most chylothoraces is insertion of a chest tube plus the administration 
of octreotide and modification of diet to eliminate enteral fat intake. If 
these modalities fail, percutaneous transabdominal thoracic duct block­
age effectively controls most chylothoraces. An alternative treatment 
is ligation of the thoracic duct. Patients with chylothoraces should not 
undergo prolonged tube thoracostomy with chest tube drainage because 
this can lead to malnutrition and immunologic incompetence.
Hemothorax 
When a diagnostic thoracentesis reveals bloody 
pleural fluid, a hematocrit should be obtained on the pleural fluid. If 
the hematocrit is more than one-half of that in the peripheral blood, 
the patient is considered to have a hemothorax. Most hemothoraces 
are the result of trauma; other causes include rupture of a blood vessel 
or tumor. Most patients with hemothorax should be treated with tube 
thoracostomy, which allows continuous quantification of bleeding. If 
the bleeding emanates from a laceration of the pleura, apposition of 
the two pleural surfaces is likely to stop the bleeding. If the pleural 
hemorrhage exceeds 200 mL/h, consideration should be given to 
angiographic coil embolization, thoracoscopy, or thoracotomy.
Miscellaneous Causes of Pleural Effusion 
There are many 
other causes of pleural effusion (Table 305-2). Key features of some 
of these conditions are as follows: If the pleural fluid amylase level is 
elevated, the diagnosis of esophageal rupture or pancreatic disease is 
likely. If the patient is febrile, has predominantly polymorphonuclear 
cells in the pleural fluid, and has no pulmonary parenchymal abnor­
malities, an intraabdominal abscess should be considered. The diagno­
sis of an asbestos pleural effusion is one of exclusion. Benign ovarian 
tumors can produce ascites and a pleural effusion (Meigs’ syndrome), 
as can the ovarian hyperstimulation syndrome. Several drugs can 
cause pleural effusion; the associated fluid may be eosinophilic. Pleural 
effusions commonly occur after coronary artery bypass graft (CABG) 
surgery. Effusions occurring within the first weeks after CABG are 
typically left-sided and bloody, with large numbers of eosinophils, and 
respond to one or two therapeutic thoracenteses. Effusions occurring 
after the first few weeks of CABG are typically left-sided and clear yellow, 
with lymphocytic predominance, and tend to recur. Other medical 
manipulations that induce pleural effusions include abdominal surgery; 
radiation therapy; liver, lung, or heart transplantation; and complica­
tions of the intravascular insertion of central lines.
■
■PNEUMOTHORAX
Pneumothorax is the presence of gas in the pleural space. A spontane­
ous pneumothorax is one that occurs without antecedent trauma to the 
thorax. A primary spontaneous pneumothorax occurs in the absence 
of underlying lung disease, whereas a secondary pneumothorax occurs 
in its presence. A traumatic pneumothorax results from penetrating or 
nonpenetrating chest injuries. A tension pneumothorax is a pneumo­
thorax in which the pressure in the pleural space is positive throughout 
the respiratory cycle.
Primary Spontaneous Pneumothorax 
Primary spontaneous 
pneumothoraces are usually due to rupture of apical pleural blebs, small 
cystic spaces that lie within or immediately under the visceral pleura. 
Approximately one-half of patients with an initial primary spontaneous 
pneumothorax will have a recurrence. Conservative management with 
careful observation can be considered in adults who are asymptomatic 
or minimally symptomatic. Outpatient observational management is an 
option for low-risk patients with a good support system. Otherwise, the 
initial recommended treatment is needle aspiration or tube drainage. 
If the lung does not expand or if the patient has a recurrent pneumo­
thorax, thoracoscopy with stapling of blebs and pleurodesis is usually 
indicated. Thoracoscopy or thoracotomy with surgical pleurodesis is 
almost 100% successful in preventing recurrences.
Secondary Pneumothorax 
Most secondary pneumothoraces are 
due to chronic obstructive pulmonary disease, but pneumothoraces 
have been reported with virtually every lung disease. Pneumothorax 
in patients with lung disease can be more life-threatening than it is in 
normal individuals because of the lack of pulmonary reserve in these