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anti-inflammatory drugs. If the effusion is large and British Thoracic Society Standards of Care Committee Pulmonary
causes dyspnea, then it must be evacuated. Steroids Embolism Guidelines Development Group (2003) British tho-
may be added to limit inflammation and preclude racic society guidelines for the management of suspected acute
pulmonary embolism. Thorax 58: 470–484.
graft occlusion. Chan O and Hiorns M (1996) Chest trauma. European Journal of
Radiology 23: 23–24.
See also: Mesothelioma, Malignant. Pleural Effu- Cugell DW and Kamp DW (2004) Asbestos and the pleura. A
sions: Overview; Pleural Fluid, Transudate and Exudate; review. Chest 125: 1103–1117.
Pleural Fluid Analysis, Thoracentesis, Biopsy, and Chest Gallardo X, Castaner E, and Mata JM (2000) Benign pleural dis-
Tube; Malignant Pleural Effusions; Postsurgical Effusions; eases. European Journal of Radiology 34: 87–97.
Pleural Fibrosis. Pulmonary Thromboembolism: Pul- Goldhaber SZ (2004) Pulmonary embolism. Lancet 363: 1295–
1305.
monary Emboli and Pulmonary Infarcts.
Idell S (1995) Coagulation, fibrinolysis and fibrin deposition in
lung injury and repair. In: Phan SH and Thrall RS (eds.) Lung
Further Reading Biology in Health and Disease – Pulmonary Fibrosis, pp. 743–
776. New York: Dekker.
Abdel-Razek H, Qari M, Kristensen J, et al. (2004) GCC Throm- Landreneau RJ, Keenan RJ, Hazelrigg SR, Mack MJ, and
bosis Study Group: Guidelines for diagnosis and treatment of Naunheim KS (1995) Thoracoscopy for management of em-
deep venous thrombosis and pulmonary embolism. Methods in pyema and hemothorax. Chest 109: 18–24.
Molecular Medicine 93: 267–292. Parker C and Neville E (2003) Lung cancer 8. Management of
Ahmed N and Jones D (2004) Video-assisted thoracic surgery: malignant mesothelioma. Thorax 58: 809–813.
State of the art in trauma care. Injury 35: 479–489. Ziedalski TM, Sankaranarayanan V, and Chitkara RK (2004)
Beckh S, Bölcskei PL, and Lessnau K-D (2002) Real-time ultra- Thoracic endometriosis. A case report and literature review.
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Chest 122: 1759–1773. 1514.

PLEURAL SPACE

Y C G Lee, University College London, London, UK recruited efficiently during pleural inflammation or infection.
C A Clelland, John Radcliffe Hospital, Oxford, UK Cancer cells can invade the pleura and often lead to increased
N M Rahman, Oxford Centre for Respiratory Medicine, vascular permeability and accumulation of malignant effusions.
Oxford, UK
& 2006 Elsevier Ltd. All rights reserved.
Anatomy, Histology, and Structure
Abstract Introduction
The pleural cavity consists of a double-layered membrane lining The pleura is an intriguing tissue with significant in-
the inside of the thoracic cavity (parietal pleura) and the outside
terspecies variation: its precise structure and function
of the lung surface (visceral pleura). Each pleural membrane
consists of a layer of mesothelial cells lined with a brush border is not fully understood. In humans the pleural cav-
of microvilli, and several noncellular layers. The structure of the ities are separated by the mediastinum. Many other
mesothelial cell and the noncellular layers are variable according species, such as the mouse, do not have a complete
to the underlying tissue and the amount of movement of the mediastinal separation such that fluid and air can
chest wall. Absorption of pleural fluid occurs via the parietal
freely move between the left and right pleural cav-
pleura through direct communications (stomata) between the
pleural space and a complex underlying lymphatic network. ities. Some large animals such as the bison (American
These allow passage of large molecules, including cells, between buffalo) are also known to have a single pleural
the pleural space and the systemic circulation via the parietal cavity.
lymphatics. A constant layer of pleural fluid is maintained be- On the other hand, the elephant does not have a
tween the visceral and parietal pleura, allowing smooth lung
pleural cavity. While the fetal elephant has a normal
movement and elasticity within the thoracic cage. Fluid may
accumulate within the pleural space in pathologic states via a pleural space, in late gestation a sheet of dense con-
variety of mechanisms which either increase production of pleu- nective tissue replaces the parietal pleura and the two
ral fluid or decrease its absorption, or both. Air may enter the pleural membranes are separated by loose connective
pleural space (pneumothorax) from the lung via rupture of blebs tissue that allows sliding of the lung over the chest
through the visceral pleura; or from outside the chest cavity
wall. Such variations in the pleural structure in dif-
when the pleural space is penetrated accidentally or iatrogenic-
ally. The mesothelial cell is multipotent and is the predominant ferent species have not been explained.
cell type in the pleural cavity. In the normal state, there are few This article describes the anatomy and function of
leukocytes in the pleural cavity, but inflammatory cells can be the pleural cavity in humans.
398 PLEURAL SPACE

Macroscopic Anatomy 3. a thin superficial elastic layer, often merged with

the second layer;
The pleura consists of a double-layered serous mem-
4. a loose connective tissue layer, containing nerves,
brane overlying the inner surface of the thoracic cage
blood vessels, and lymphatics; and
and the outer surface of the lung. Between these two
5. a deep fibroelastic layer, often fused to the under-
delicate membranes lies the pleural cavity, a sealed
lying tissue (Figure 1).
space maintained B10–20 mm across.
In humans, the left and right pleural cavities are
separated from each other and from the pericardial Mesothelial cells Mesothelial cell is the predomi-
space. The pleural cavities contain the visceral pleura, nant cell type in the pleural cavity (see Mesothelial
overlying the entire lung surface, and the parietal Cells). No significant differences have been identified
pleura, overlying the inner surface of the entire thoracic between the mesothelial cells in the visceral or pa-
cage, including the mediastinum and diaphragm. The rietal pleura, or among those in the pleural, perito-
area of the entire pleura is estimated to be 2000 cm2 in neal, or pericardial cavities.
an average adult male. The two pleural membranes Mesothelial cells can vary in shape (from flat to
coalesce at the lung hilae, where they are penetrated by cuboidal) and in size, ranging from approximately
the major airways and pulmonary vessels. 10 to 50 mm in diameter and from 1 to over 4 mm in
The visceral pleura tightly adheres to the lung sur- thickness. Under electron microscopy, multiple pin-
face throughout the thorax and extends deep within ocytic vesicles can be identified within the mesothelial
the interlobar fissures. The parietal pleura is ana- cells, implying secretion and absorption processes. Ev-
tomically divided into four parts: idence of metabolic activity is apparent, with abundant
polyribosomes, glycogen granules, and mitochondria.
* costal pleura – overlying ribs, intercostal muscles, Each cell is covered at the pleural surface with a
costal cartilage, and sternum; carpet of microvilli, 0.1 mm in diameter and 3 mm
* mediastinal pleura; long (Figure 2). Their density varies according to
* cervical pleura – extending above the 1st rib by position within the thoracic cavity, with a high den-
2–3 cm over the medial end of the clavicle; and sity in the inferior parts of the thorax (i.e., the most
* diaphragmatic pleura. actively moving parts of the lung) and a higher den-
sity in visceral than in parietal pleura at the same
The inferior boundary of the parietal pleura mirrors thoracic level.
the lower border of the thoracic cage, but may ex- Mesothelial cells are adherent to one another at
tend beyond the costal surface, specifically at the the apical surface via tight junctions. At the basal
right lower sternal region and at the posterior junc- surface, the cells are more loosely associated, al-
tion of ribs and vertebra bilaterally. though the basal portions are often seen to overlap.
Several structures (e.g., the hilae and sometimes The cells slide over one another during the respira-
the great veins) within the thoracic cavity acquire a tory cycle; therefore, at full inspiration the overlap
double layer of parietal pleura during embryological disappears completely.
development. Such a double layer is pulled into the Mesothelial cells are multipotent with functions in
thorax by the developing lung, and extends from the extracellular matrix synthesis, phagocytosis, inflam-
lung hilum vertically downward to the diaphragm on matory cytokine production, etc. A detailed discus-
both sides – these form the pulmonary ligaments. sion of the biology of the mesothelial cells can be
They are of importance surgically as they may con- found in Mesothelial Cells (see also Tables 1 and 2).
tain lymphatics, tumor, or vessels. Their presence
may prevent torsion of the lower lobes.
Differences in pleural microstructure The parietal
Microscopic Anatomy
pleura demonstrates subtle alterations in its cellular
and noncellular structure according to position
Layers of the pleural membrane Both visceral and within the thoracic cavity, reflecting structure of the
parietal pleura in humans are approximately 40 mm underlying tissue and activity of the mesothelial cells.
thick. Between pleural surface and underlying tissue, In apical areas, where the pleura is statically ex-
five layers are identified histologically, consisting of a panded with relatively little movement, mesothelial
single-cellular layer and four subcellular layers, as cells are flattened with few microvilli and the sub-
follows: cellular layers are poorly developed and hence diffi-
cult to differentiate. In lower thoracic areas, where
1. a monolayer of mesothelial cells; the majority of chest-wall movement occurs, me-
2. the basal lamina and a thin connective tissue layer; sothelial cells are cuboidal, more numerous per unit
 PLEURAL SPACE 399

Figure 1 (a) Visceral pleura showing a surface layer of mesothelium with underlying connective tissue including a layer of elastic
tissue that is better displayed in (b), an elastic van Gieson stain. (c) The parietal pleura also has a covering of mesothelium and there is
generally more underlying connective tissue here than in the visceral pleura.

area, have a high density of microvilli, and well- the lung via bronchovascular bundles. There are
defined thick layers of collagen and elastic tissue. more lymphatic vessels in the dependent parts of the
Pleura overlying rigid tissues – such as rib, central lung, associated with higher intravascular pressures.
diaphragm, and intercostal muscles – contains flat Lymphatic plexuses within the parietal pleura are
mesothelial cells, few microvilli, and thin subcellular present in intercostal spaces and over the diaphragm,
layers. The fifth fibroelastic layer is fused with the but absent over ribs. The costal pleura drains ante-
underlying structure, such as the periosteum. Where riorly into the internal mammary nodes and poste-
pleura overlies looser substructures, such as the me- riorly into the intercostal lymph nodes posterior to
diastinum, mesothelial cells are cuboidal and prom- the rib heads. Pleura from the lung apex drain into
inent, subcellular layers are well defined, and the fifth the cervical chain, while pleura lining the diaphragm
fibroelastic layer is often absent. The fourth loose drain into the anterior and posterior mediastinal
connective tissue layer is often merged with the un- nodes.
derlying interstitial tissue.
Blood Supply
Lymphatic Drainage, Blood Supply, and The parietal pleura is supplied by the systemic arter-
Innervation ies, according to region. The costal pleura is supplied
by the intercostal and internal mammary arteries
Pleural Lymphatics
and the mediastinal pleura by the bronchial, upper
The visceral pleural lymphatic system consists of a diaphragmatic, internal mammary, and mediastinal
superficial network of lymphatic capillaries and col- arteries. The cervical pleura is supplied by the sub-
lecting vessels, forming a network along the pleural clavian artery, whereas the internal mammary artery
base of the secondary pulmonary lobule. Lymph and aorta (via posterior mediastinal and inferior
flows from lymphatic capillaries toward the hilae of phrenic arteries) supply the diaphragmatic pleura.
400 PLEURAL SPACE

drainage of the visceral pleura is mostly via the pul-

monary veins.

Innervation
It is noteworthy that only the parietal, but not the
visceral, pleura contains pain-carrying fibers. The
parietal pleura is supplied by the intercostal nerves;
any pain will be referred to the chest wall with the
corresponding innervation. The exception is the
central diaphragm, supplied by the phrenic nerve,
resulting in referred pain to the ipsilateral shoulder.
The visceral pleura is innervated by the vagus and
sympathetic trunk and contains no pain-carrying fib-
ers. Hence, pleuritic pain implies involvement of the
parietal pleura.

Transport from the Pleural to Systemic

Compartments
Small particles of o4 nm in size (including water) may
pass freely between cells of the mesothelial monolayer,
whereas moderate-sized particles are slowly but ac-
Figure 2 At electron microscopy the mesothelial cell surface is
tively transported across the mesothelial cell by pin-
covered by long slender microvilli with high length/diameter ratios
and desmosomes (arrowed) are present. ocytosis (e.g., carbon at 20 nm or ferritin at 11 nm).
Large particles of 41000 nm may become trapped
within mesothelial cells and are unable to cross the
Table 1 Maturation of mesothelial cells
basement membrane. Studies using radioactive-labe-
Low MW CK High MW CK Vimentin led red blood cells and protein molecules have shown
Surface mesothelium þ þ  that large molecules can move from the pleural space
Proliferating þ  þ into the systemic circulation rapidly. This implies the
submesothelial existence of a transport mechanism between pleura
cells and systemic circulation which is now known to be
Resting   þ
mediated by the parietal lymphatic system.
submesothelial
cells
The Pleurolymphatic Communication
MW, molecular weight.
The parietal pleura plays the major role in the forma-
tion and removal of pleural fluid. Direct communica-
Table 2 Immunoprofile of mesothelial cells vs. epithelial cells
tions, known as stomata, exist between the pleural
pan CK BerEP4 MOC31 CK5 Calretinin space and the underlying lymphatic network, allowing
Mesothelial cells þ   þ þ removal of large particles from the pleural space. Sto-
Epithelial cells þ þ þ   mata are unique to the parietal pleura. The stomata are
openings (2–6 mm in diameter) in the continuous sheet
of overlying mesothelial cells, and tend to cluster in
Venous drainage follows arterial supply into the groups of 10 or more. On average, there are 100 sto-
azygos vein and thence into the superior vena cava. mata per cm2 of pleura, but a higher density has been
The diaphragmatic pleura drains via the inferior observed in the anterior lower chest, the mediastinum
phrenic veins into the inferior vena cava. and the diaphragm. In specimens of parietal pleura
The arterial supply of the visceral pleura in from older animals, large openings of up to 10
50 mm
humans is controversial. In animals with thick vis- are seen where stomata are normally present, thought
ceral pleura similar to that of humans, the bronchial to represent areas where stomata have coalesced.
arteries provide the blood supply to the visceral Underlying each stoma is a network of inter-
pleura. This is believed to be the case for the visceral woven connective tissue bundles – the membrana
pleura in humans, although supply of the lung cribriformis. This network in turn forms the roof of a
apex and its convex surface is debated. Venous dilated lymphatic space, the lacuna. The lacunae
 PLEURAL SPACE 401

drain into lymphatic vessels via a system of valves to Pleural Inflammation and Fibrosis
ensure one way flow. During inspiration, the stomata
The pleural cavity is frequently invaded by undesir-
become stretched to over 10 mm allowing passage
able agents (e.g., bacteria), but the pleural cavity is
of large structures, and the lacunae similarly stretch
not under close surveillance by polymorphonuclear
open and fill. During expiration, the lacunae are
cells. In the normal state, there is only one leukocyte
compressed and empty into lymphatic capillaries,
in the pleural fluid to every 10 million mesothelial
with unidirectional flow maintained by valves. cells in the pleura. Mesothelial cells, therefore, form
Present in association with some collections of
the first line of defense in the pleural cavity. Exper-
stomata are modified cuboidal mesothelial cells,
imental evidence suggests that they are capable of
surrounded by aggregates of immune cells, includ-
releasing chemokines (e.g., interleukin 8) promptly
ing lymphocytes, plasma cell, and mononuclear cells,
and effectively to recruit inflammatory cells (e.g., ne-
around a central lymphatic vessel. These are known
utrophils), to initiate appropriate immune responses
as Kampmeier’s foci, visible on electron microscopy
to eradicate the pathogens.
as elevated mounds. Mesothelial cells in these areas
Chronic inflammation develops with many pleural
are in a state of activation, and the foci are thought diseases and results in pleural fibrosis and thickening.
to be analogous to Peyer’s patches in the gut, as a
While fibroblasts are conventionally regarded as
mechanism of local host defense.
the main cellular source of collagen and fibrosis, me-
sothelial cells are capable of producing collagen and
The Pleura in Health are likely to hold an important role in pleural fibro-
sis. Under appropriate circumstances, mesothelial
Normal Function and Content of the Pleura
cells can transform into fibroblast-like cells (a proc-
The pleural space is a real rather than potential space ess known as epithelial–mesenchymal transforma-
with experiments in sheep demonstrating no direct tion). The causes and pathology of pleural fibrosis
contact of the parietal and visceral pleura. The pleura are detailed in Pleural Effusions: Pleural Fibrosis.
permits friction-free movement of the lungs within
the relatively rigid thorax, and facilitates the devel- Pleural Effusion
opment of positive and negative intrapleural pressure
A wide range of pulmonary or systemic diseases can
during the respiratory cycle. Mesothelial cells, with its
affect the pleura, and commonly lead to the deve-
carpet of microvilli, vastly increase surface area and
lopment of pleural effusions (see Pleural Effusions:
allow secretion and maintenance of a film of glyco-
Pleural Fluid, Transudate and Exudate).
proteins and hyaluronic acid, acting as a lubricating
fluid layer between the two pleural surfaces. The
Pleural Malignancy
composition of the pleural fluid as well as its forma-
tion and turnover, in health and in disease states, has Cancer invasion of the pleural cavity is common in
been detailed in Pleural Effusions: Pleural Fluid, clinical practice, and often results in development of
Transudate and Exudate. Pleural structure alters ac- malignant pleural effusions (see Pleural Effusions:
cording to position within the thoracic cavity, reflect- Malignant Pleural Effusions). Metastatic pleural dis-
ing specialization in response to different degrees of ease accounts for most cases, with lung and breast
mechanical stress and different underlying tissues. being the most common primary cancer sites. Pleural
mesothelioma, a primary pleural malignancy, often
develops as a result of asbestos exposure. Metastatic
Pleural Disorders
carcinoma generally deposits first in the visceral
Pneumothorax pleura and migrates eventually onto the parietal sur-
face. This contrasts mesothelioma, which originates
Stretched-out visceral pleura in the statically expanded
from the parietal pleura before spreading to the vis-
lung apices are prone to bleb and bullae formation,
ceral pleura. The pathology of pleural malignancies
even in nonsmoking individuals. These are thought to
is further described in Pleural Effusions: Malignant
be an important factor in predisposition to primary
Pleural Effusions.
spontaneous pneumothorax. Due to the anatomical
boundaries of the parietal pleura, iatrogenic pneumo-
thorax may result from insertion of subclavian central
What Is the Role of the Pleural Space?
venous catheters, damaging the pleura above the first
rib. Due to pleural extension below the costal margin Interestingly, there is little evidence to support any
inferiorly, pneumothorax may occur during attempted essential role of the pleural space in humans. Al-
posterior access to upper abdominal organs. though the pleural space can act as an escape route
402 PNEUMONIA / Overview and Epidemiology

for unwanted substances (such as excess fluid in pul- date and Exudate; Pleural Fluid Analysis, Thoracentesis,
monary edema) in the lung parenchyma, it is unlikely Biopsy, and Chest Tube; Parapneumonic Effusion and
that the pleural space exists solely for such purpose. Empyema; Malignant Pleural Effusions; Postsurgical Effu-
Studies on pleurodesis, the iatrogenic obliteration sions; Pleural Fibrosis; Chylothorax, Psuedochylothorax,
LAM, and Yellow Nail Syndrome; Hemothorax. Pneumo-
of the pleural space to prevent recurrent effusions or
thorax.
pneumothoraces, showed no significant limitations
to pulmonary functions. Patients who received
talc pleurodesis over 22 years ago for spontaneous Further Reading
pneumothoraces showed a higher incidence of pleu-
Jones JS (2001) The pleura in health and disease. Lung 179: 397–
ral thickening but minimal restrictive changes in lung 413.
functions. Several small studies in humans and an- Lee KF and Olak J (1994) Anatomy and physiology of the pleural
imals also revealed no significant impairment in lung space. Chest Surgery Clinics of North America 4(3): 391–403.
volumes and gaseous exchange at rest or during ex- Lee YCG and Light RW (2001) How does pleurodesis affect lung
function? Journal of Respiratory Diseases 22: 706.
ercise following pleurodesis.
Miserocchi G (1997) Physiology and pathophysiology of pleural
The fact that obliteration of the pleural space does fluid turnover. European Respiratory Journal 10: 219–225.
not affect health and functioning supports the belief Mutsaers SE (2002) Mesothelial cells: their structure, function and
that the pleural space in humans serves no significant role in serosal repair. Respirology 7: 171–191.
role. Why the pleural space exists in the first place Peng MJ and Wang NS (2003) Embryology and gross structure. In:
and why it is preserved through evolution remain Light RW and Lee YCG (eds.) Textbook of Pleural Disease. pp.
3–17. Arnold Publishers.
unanswered. Sahn SA (1988) State of the art: the pleura. American Review of
Respiratory Diseases 138: 184–231.
See also: Mesothelial Cells. Mesothelioma, Malig- Wang NS (1998) Anatomy of the pleura. Clinics in Chest Medicine
nant. Pleural Effusions: Overview; Pleural Fluid, Transu- 19: 229–240.

Pneumoconiosis see Occupational Diseases: Coal Workers’ Pneumoconiosis.

PNEUMONIA
Contents
Overview and Epidemiology
Atypical
Community Acquired Pneumonia, Bacterial and Other Common Pathogens
Fungal (Including Pathogens)
Nosocomial
Parasitic
Mycobacterial
Viral
The Immunocompromised Host

Overview and Epidemiology bronchioles. Pneumonia results from the proliferation of mi-
croorganisms at these sites in combination with the host
R G Wunderink and G M Mutlu, Northwestern response to the presence of microorganisms. A variety of pneu-
University Feinberg School of Medicine, Chicago, IL, monia syndromes can be defined based on microbial etiology,
USA underlying host defenses, clinical presentation, and site of ac-
quisition. Because of the non-specific nature of the signs and
& 2006 Elsevier Ltd. All rights reserved.
symptoms, the diagnosis of pneumonia rests disproportionately
on the presence of an infiltrate on chest radiograph. The fre-
quent lack of a microbiologic diagnosis and the non-specificity
Abstract
of signs, symptoms, and radiographic infiltrates leads to fre-
Pneumonia is the infection of the distal lower respiratory tract, quent consideration of pneumonia in the differential diagnosis
principally the alveolar space, including the small bronchi and of many other pulmonary diseases. The etiologic spectrum of all