ACCP Pulmonary Medicine Board Review, 25e (August 17, 2009)_(0916609774)_(American College of Chest Physicians)


Чтобы посмотреть этот PDF файл с форматированием и разметкой, скачайте его и откройте на своем компьютере.
ACCP Pulmonary
Medicine
Board Review:
The American Board of Internal Medicine (ABIM) is not afÞ liated with, nor does it
endorse, preparatory examination review programs or other continuing medical edu-
cation. The content of the ACCP Pulmonary Medicine Board Review: 25th Edition is
developed independently by the American College of Chest Physicians (ACCP), which
has no knowledge of or access to ABIM examination material.
The views expressed herein are those of the authors and do not necessarily reß
ect the
views of the ACCP. Use of trade names or names of commercial sources is for informa-
tion only and does not imply endorsement by the ACCP. The authors and the publisher
have exercised great care to ensure that drug dosages, formulas, and other informa-
tion presented in this book are accurate and in accord with the professional standards
in effect at the time of publication. However, readers are advised to always check the


Copyright © 2009 by the AMERICAN COLLEGE OF CHEST PHYSICIANS.
Copyright not claimed on material authored by the US Government. All rights reserved.
No part of this book may be reproduced in any manner without permission of the publisher.
Northbrook, IL 60062-2348
Telephone: (847) 498-1400; Fax: (847) 498-5460


Contents
Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Lisa K. Moores, MD, FCCP
Pulmonary Vascular Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Lisa K. Moores, MD, FCCP
Lung Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
W. Michael Alberts, MD, MBA, FCCP
Hypersensitivity Pneumonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
W. Michael Alberts, MD, MBA, FCCP
Eosinophilic Lung Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
W. Michael Alberts, MD, MBA, FCCP
Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Cardiopulmonary Exercise Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Darcy D. Marciniuk, MD, FCCP
Hypercapnic Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Thoracic Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137


Other Pulmonary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Medical Statistics/Test-Taking Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
David W. Kamp, MD, FCCP
Acid-Base Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Drug-Induced Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
David W. Kamp, MD, FCCP
Hemodynamic Monitoring and Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Community-Acquired Pneumonia: Advances in Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
Ronald R. Grossman, MD, FCCP
Pneumoconiosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
David W. Kamp, MD, FCCP
Hospital-Acquired and Ventilator-Associated Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Ronald R. Grossman, MD, FCCP
Hypoxemic Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Curtis N. Sessler, MD, FCCP
Symptoms of Respiratory Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
Richard S. Irwin, MD, FCCP
Mechanical Ventilatory Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
Curtis N. Sessler, MD, FCCP
Unusual and Uncommon Pulmonary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Jay H. Ryu, MD, FCCP
Mediastinal and Other Neoplasms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
Jay H. Ryu, MD, FCCP
Pathology of Airway Disease and Organizing Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Henry D. Tazelaar, MD, FCCP
Pathology of Diffuse and Neoplastic Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Henry D. Tazelaar, MD, FCCP
Pleural Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
Steven A. Sahn, MD, FCCP
Pleural Pearls. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
Steven A. Sahn, MD, FCCP
Lung Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
Rare Interstitial Lung Diseases: Pulmonary Langerhans Cell Histiocytosis,
Lymphangioleiomyomatosis, and Cryptogenic Organizing Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
Joseph P. Lynch III, MD, FCCP
Tuberculosis and Other Mycobacterial Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
David Ashkin, MD


Idiopathic Pulmonary Fibrosis, NonspeciÞ c Interstitial Pneumonia/Fibrosis, and Sarcoidosis . . . . . . . . . . . . . . . 635
Joseph P. Lynch III, MD, FCCP
Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
WomenÕs Issues in Pulmonary Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
Occupational Asthma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723


Igor Aksenov, MD, PhD
Pulmonary and Critical Care Medicine Fellow
Division of Pulmonary, Critical Care and
Sleep Medicine
W. Michael Alberts, MD, MBA, FCCP
H. Lee MofÞ tt Cancer Center
Professor of Oncology and Medicine
Tampa, FL
David Ashkin, MD
Medical Executive Director,
A. G. Holley
State TB Hospital
cer,
Department of Health
Adjunct Assistant Professor, Division of
Pulmonary and Critical Care Medicine
Visiting Associate Professor, Division of
Pulmonary and Critical Care


vii
The American College of Chest Physicians (ACCP) remains strongly committed to providing the best available evidence-based
clinical information to participants of this educational activity and requires an open disclosure of any potential conß
ict of
interest identiÞ ed by our committee members. It is not the intent of the ACCP to eliminate all situations of potential conß
ict of
interest, but rather to enable those who are working with the ACCP to recognize situations that may be subject to question by
others. All disclosed conß
icts of interest are reviewed by the educational activity course director/chair, the Education Com-
mittee, or the Conß ict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary,
resolved. The ACCP educational standards pertaining to conß ict of interest are intended to maintain the professional auton-
omy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all ACCP
CME activities are ensured of independent, objective, scientiÞ cally balanced information. Disclosure of any or no relationships
The following authors of the Pulmonary Medicine Board Review: 25th Edition have disclosed to the ACCP that a relationship
does exist with the respective company/organization as it relates to their presentation of material and should be communi-
Ronald Grossman, MD, FCCP
Advisory committee: GSK, Bayer, Ortho McNeil, SanoÞ


Needs Assessment
Rely on the ACCP Pulmonary Medicine Board Review: 25th Edition to review the type of information you should know for
the Pulmonary Disease Subspecialty Board Examination of the American Board of Internal Medicine (ABIM). Designed as the
best preparation for anyone taking the exam, this comprehensive, exam-focused review will cover current critical care litera-
ture and management strategies for critically ill patients.
The ABIM Pulmonary Disease Subspecialty Board Examination tests knowledge and clinical judgment in crucial areas of criti-
cal care medicine. This premier course will review the information you should know for the exam. Course content mirrors the
content of the exam, as outlined by the ABIM, and includes the following topics:


Communications
, for specialists in pulmonology, critical care,
sleep medicine, thoracic surgery, cardiorespiratory
interactions, and related disciplines
Named one of the 100 most in
journals over the last 100 years in medicine
and biology.
Available at www.chestjournal.org
CHEST Physician,
the ACCP monthly news
publication, featuring current chest medicine
news from around the globe, plus updates on
ACCP matters and events.
Health-care Advocacy
A uni ed voice to policymakers on medical
and payment issues
Access to electronic tools for contacting
Congress about issues a
ecting your patients,
practice, and profession
Timely alerts on legislation that impact the
practice of medicine
Practice Resources
Coding and reimbursement education
Business of medicine resources
Patient education tobacco cessation products
ACCP Career Connection (online career service)
Educational Resources
Discounted tuition for all CME courses and
educational products
Board review courses and preparation materials
Hands-on clinical learning at the ACCP
Center for Advanced Clinical
Self-study tools, including ACCP-SEEK
Join the ACCP Today
Learn more about membership and apply online.


Participation Opportunities
Point. Click. Access.
Link to the resources you need


The CHEST Foundation is the philanthropic
arm of the American College of Chest Physicians
(ACCP), a 17,500-member international medical


Clinical Research Awards
Over $5 million conferred from 1998 to 2009 to
support promising clinical research
Distinguished Scholar awards to foster innovation
in clinical care to address public health related to
chest and critical care medicine
Eli Lilly and Company Distinguished Scholar
in Critical Care Medicine
GlaxoSmithKline Distinguished Scholar
in Respiratory Health
GlaxoSmithKline Distinguished Scholar
in Thrombosis
Clinical research awards in asthma, COPD,
critical care, pulmonary 
brosis, thrombosis,
and womens health
Roger C. Bone Award for Advances in
End-of-Life Care
The CHEST Foundation and ACCP Grant
in Venous Thromboembolism
Alpha-1 Foundation and The CHEST Foundation
Clinical Research Award in COPD
and Alpha-1 Antitrypsin De
ciency
The American Lung Association and CHEST
Foundation Clinical Investigator Award


1
 Compare actinomycosis and nocardiosis infections of the
 Discuss the treatment of actinomycosis and nocardiosis
 List the causes of bronchiectasis
 Discuss the therapeutic options for the treatment of
bronchiectasis
Nocardia species
are common natural inhabitants of the soil
throughout the world. Epidemics within the hos-
pital environment are rare, and person-to-
transmission has only rarely been suggested.
Although Nocardia can occur as a primary pul-
disease and can complicate surgery or trauma,
it is frequently recognized as an opportunistic
mediated immune de ciencies, including trans-
plantation (greatest frequency in those who have
undergone lung transplantation), lymphoma,
and AIDS. High-dose corticosteroids, cytomega-
lovirus infection in the past 6 months, and high
calcineurin inhibitor levels (cyclosporine or tacro-
limus) are independent risk factors for Nocar-
dia infection in organ transplant recipients. In
HIV-positive persons, nocardiosis most often pres-
100 cells/
L but can occur in patients with
250 cells/
Nocardiosis has also been reported to be asso-
ciated with pulmonary alveolar proteinosis, myco-
bacterial diseases, and chronic granulomatous
disease. Finally, nocardiosis is not uncommon in
patients with COPD receiving long-term cortico-
steroid treatment, but it is also increasingly being
seen in patients with COPD who have received
only a recent short course of corticosteroids for an
exacerbation. The disease has been reported world-
wide and is more common in men than women
(approximately 3:1). Most infections result from
the inhalation of bacilli. Lesions are characterized
by necrotizing abscesses that are not well encap-
sulated and spread easily. Granuloma formation
and  brosis are infrequent. Because of its propen-
sity for hematogenous dissemination, Nocardia


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)
The chest radio-
graphic patterns are variable. The most frequent
ally homogeneous, but occasionally patchy. Nod-
laments that
Cultures for Nocardia require special handling
Blood cultures require incubation aerobically for
up to 4 weeks. Advances in DNA extraction and
real-time polymerase chain reaction assays may
allow for identi cation of most Nocardia species
within hours. The isolation of Nocardia from
the sputum in a non-immunosuppressed patient
without radiographic abnormalities may repre-
sent colonization. However, a sputum culture that
is positive for Nocardia in an immunosuppressed
patient more often indicates disease. A number of
serologic tests have been evaluated, but the diver-


When they were  rst described, they were misclas-
ed as fungi. The word actinomycosis is derived
from the Greek terms
(the radiating appear-
disease). The classic clinical picture is a cervicofa-
cial disease in which the patient presents with a
large mass on the jaw. It is now recognized that the
organisms colonize in the mouth, colon, and
vagina. Infection results from mucosal disruption
and can occur at any site in the body. Infection is
characterized by a pyogenic response and necrosis,
brosis. Actinomycosis is dif-
cult to diagnose and is often confused with tuber-
culosis, lung abscess, or malignancy.
The organisms are
a normal inhabitant of the human oropharynx
and frequently are found in dental caries and at
the gingival margins of persons with poor oral
hygiene. Actinomycosis is most commonly caused
Actinomycotic infections
in the lung are, however, usually polymicrobial.
In tissue, actinomycotic infection grows in micro-
are yellow, they are often called
Actinomycosis of the respiratory tract is acquired
most commonly by aspiration, but direct exten-
sion of the disease from the head and neck or
abdominal cavity can occur. The peak incidence
is reported in the fourth and  fth decades of life;
nearly all series have reported a male predomi-
tutes only 15% of reported cases but has been as
(which might reveal early rib erosion). Actinomy-
cosis often is mistaken for pulmonary carcinoma;
the presence of an air bronchogram in the mass
plastic process. Actinomycosis also can present as
an endobronchial infection, which is often asso-
ciated with a broncholith or other foreign body.
Both actinomycosis and nocardiosis often are con-
fused with tuberculosis, cryptococcosis, anaerobic
pulmonary infection, bronchogenic carcinoma,
Actinomyces most com-
monly presents as a disease of the cervicofacial
region after dental extraction, with osteomyelitis
through the skin. Pulmonary actinomycosis usu-
ally presents with an indolent, progressive course.
The initial manifestations include a nonproductive
cough and low-grade fever, subsequently followed
by a productive cough, which can be associated
with hemoptysis. With chest wall involvement,
pleuritic pain will develop in the patient. Rarely,
a sinus tract may appear as a bronchocutaneous
stula. When this occurs, it is highly suggestive
may present with weight loss, anemia, and club-
A diagnosis of actinomycosis is
rarely suspected; in one series, it was suspected
7% of the patients in
nomycosis often mimics malignancy, diagnosis
may not be made until surgical resection. Because
these organisms are normal oropharyngeal 
isolation in specimens of sputum or bronchial
washings is not considered signi
cant, unless
sulfa granules are found. Actinomyces are fastidi-
ous bacteria that are dif cult to culture and, thus,
correlation with the clinical and radiographic


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)
presentation is essential. Bronchoscopy is usually
not diagnostic unless endobronchial disease is
present, and samples must be obtained anaerobi-
cally with a protected specimen brush and deliv-
ered to the laboratory under anaerobic conditions.
either transbronchial lung biopsy or open lung
biopsy may be necessary to con rm the diagnosis.
There is no reliable serologic test.
Treatment:
Untreated, actinomycosis is ulti-
mately fatal, but early treatment can result in cure
90%. Prolonged treatment with high
doses of antimicrobial agents is necessary. Peni-
cillin is the drug of choice. Regimens include IV
medical and surgical therapies. Patients with
bulky disease should probably not receive short
courses of therapy unless surgical debulking is
also performed. A comparison of the main fea-
tures of both actinomycosis and nocardiosis is
shown in Table 1.
Bronchiectasis
Bronchiectasis is a syndrome, with many


(on a high-resolution CT scan, it has parallel “tram
HRCT scan of the chest have been described in
complex (MAC).
Table 2.
Predisposing Factors for Bronchiectasis
Foreign-body aspiration
Mechanical airway obstruction
External compression
Necrotizing pneumonia
Diffuse
Kartagener syndrome
Young syndrome
Immune disorders
Hypogammaglobulinemia, IgG subclass de ciency, HIV, allergic
bronchopulmonary aspergillosis, post-lung transplant
Mycobacterial infections (tuberculous and NMTb*)
Viral (measles, adenovirus, in
uenza virus)
Rheumatoid arthritis, Sjögren syndrome, in ammatory bowel disease
Lung  brosis
Sarcoidosis, after radiation therapy
-Antitrypsin de ciency, yellow nail syndrome
*NMTb = non-tuberculosis mycobacteria.


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)
The most notable  nding in addition to bronchiec-
tasis is the presence of small nodular opacities or
the “tree-in-bud” appearance. Abnormalities most
often occur in the lower lung  elds. Treatment with
multiple antimicrobial agents may lead to the reso-
lution of these abnormalities, but prolonged therapy
for up to 18 months may be necessary.
There are an increasing number of immune
ciencies that have been associated with bron-
chiectasis. Ciliary disorders are considered to be
primary disorders of immune defense because
por-
tant component of barrier immunity. Acquired
view. Other  ndings include hyperin
ation and
air trapping, increased linear markings, rounded
opacities that represent areas of focal pneumonia,
and ring shadows that represent dilated airways


erential Diagnosis
tion of patients with suspected bronchiectasis: age


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)
corticosteroids in the treatment of this disorder.
Inhaled steroids have been suggested as alterna-
tive therapy and may be useful in some patients,
especially those with signi cant airway hyper-
reactivity. It has been shown that inhaled corti-
costeroids can reduce the levels of in
ammatory
mediators and improve dyspnea and cough. In
addition, inhaled corticosteroids appear to reduce
sputum volume and lead to improvements in
quality of life. However, a systematic review
found no signi cant improvement in pulmonary
function. Short courses of oral corticosteroid ther-
apy often are used during acute exacerbations.
Nonsteroidal antiin
ammatory agents, such as


Cystic Fibrosis


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)
increased basal and inducible airway in
ammation
independent of infection. Figure 2 summarizes the
Products of polymorphonuclear neutrophil and their effects on in
ammation of the airways in patients with CF.
Adapted from Ramsey BW. Management of pulmonary disease in patients with CF. N Engl J Med 1996; 335:179–188.
Increase in PMNs
Leukotriene B4 and IL-8
elastase
release of free
radicals
plugging of airway
structural damage;
bronchiectasis
cleavage of
complement receptors
and immunoglobulins
persistence of bacteria
increased IL-8


11
common mutations. The results of this test are
abnormal in the large majority of patients with
CF. A chloride level of
60 mEq/dL is usually
diagnostic for CF. However, the test must be
repeated at least twice, and an adequate sample
lected over a 30-min period. Approximately 1%
test results. Abnormal sweat test results are
seen in patients with other disorders (as listed
in Table 3). Therefore, a diagnosis should only
CF. The current diagnostic criteria for CF are
listed in Table 4.
3. Molecular diagnosis: Approximately 1,600 muta-
tions have been identi ed after sequencing the
entire gene in a research laboratory. Genotyping
at commercial laboratories usually can identify
This accounts for approximately 90% of CF
mutations in the general population.
4. PD across the respiratory epithelium: This is a
research tool that may be available at few cen-
ters to aid in the diagnosis of CF. The abnormal
PD across the nasal epithelium. The measure-
Nasal perfusion with amiloride hydrochloride
and with chloride-free solutions leads to char-
Nonpulmonary Clinical Manifestations
In the pancreas, dysfunction of the exocrine
tion. Glucose intolerance is present in as many as
Table 3.
False-Positive Sweat Test Results
Adrenal insuf
Anorexia nervosa
Glucose-6-phosphate dehydrogenase de
Hypoparathyroidism
Hypothyroidism (untreated)
Klinefelter syndrome


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)
have been reported. Women with CF are not infer-
tile, al though they may have dif
culty conceiving
tory cycles if their nutritional status is poor. Preg-
nancies can be successful, and pulmonary


obstructive airway disease is typically only
partially reversible because the underlying causes
include the chronic infection, in
ammation, and
resulting structural damage. Bronchodilator ther-
apy should be considered in patients who have
at least a 10% increase in FEV
in response to an
inhaled bronchodilator. In addition, bronchodila-
tors often are used in all patients with CF before
chest physiotherapy and immediately before the
c bron-
chial constriction. The role of these medications
in improving mucociliary clearance has not been


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)
improved lung function and a decreased number
of hospitalizations.
ammatory Agents:
There is a neutrophil-
predominant in
ammation in the airways of


15


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)
require bilateral lung transplantation using a


Davis JC, Alton E, Bush A. Clinical review: CF. BMJ
dence grading of management strategies in CF.
Davis PB. Centennial review: CF since 1938. Am J
Respir Crit Care Med 2006; 173:475–482
guished from celiac disease in 1938. The standardization of the
sweat test in 1959 allowed the identiÞ cation of milder cases. In
1983, chloride transport was identiÞ ed as the basic CF defect.
In 1989, the CF gene was discovered. This article is easy to
follow and explains concepts in an understandable fashion.


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)
Most current, comprehensive clinical review of pulmonary
McGeinness G, Naidich DP. CT of airways disease and
bronchiectasis. Radiol Clin North Am 2002; 40:1–19
This article discusses HRCT Þ ndings associated with
medium-sized and small airways diseases, focusing on bron-


19


Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)


21
thromboembolism (VTE)
Provide approaches to the diagnosis and treatment of
Discuss approaches to the prevention of VTE
hypertension (PAH)
List the recommended treatment regimens for PH
anticoagulation; hypercoagulable state; pulmo-
hypertension; thrombolytic therapy; venous thrombosis
VTE
Pulmonary embolism (PE) and deep venous
thrombosis (DVT) constitute the spectrum of one
disease: venous thromboembolism (VTE). Approx-
imately 79% of patients who present with PE also
will have concomitant DVT; conversely, only
approximately 50% of patients presenting with
of VTE in the United States is one episode per 1,000
patients. As many as 3,000,000 people die each year
in the United States from acute PE.
Risk Factors
Risk factors associated with VTE often are
inflammatory bowel disease; heparin-induced
thrombocytopenia (HIT); and myeloproliferative
disorders, such as polycythemia vera and hyper-
viscosity syndromes. Patients with a history of
VTE are at increased risk for recurrence. Con-
genital or hereditary hypercoagulable states
include the following: activated protein C resis-
tance (factor V Leiden mutation); antithrombin III
ciency (can also be acquired with the nephrotic
syndrome); protein C deÞ
ciency; protein S deÞ
ciency; dysfibrinogenemia; disorders of plas-
minogen and plasminogen activation; the presence
agulant; and hyperhomocysteinemia. Many
patients may present with multiple risk factors for
VTE that can further increase their likelihood of
this complication developing. Examples include
the elderly patient with congestive heart failure
who sustains a hip fracture and the patient with
a myelopro liferative disorder who is undergoing
major surgery.
Pathogenesis
The Virchow triad of venous stasis, endothelial
vascular injury, and hypercoagulability explains
how various processes can interact to overcome
antithrombotic defenses resulting in VTE. Vascular
stasis predisposes the patient to VTE by allowing
activated coagulation factors to remain undiluted
and in contact with the vascular endothelium.
Vascular trauma or injury, to include the presence


Pulmonary Vascular Diseases (Moores)
nation, is not recommended.
DVT
PE usually arises from the deep venous system
of the body as a complication of DVT. Although
DVT usually begins in the lower extremities, occa-
sional thrombi form in pelvic veins, renal veins,
upper-extremity veins, and the right heart. Most
thrombi originate in the soleal veins of the calf,
often at sites of decreased blood ß ow such as the
valve cusps or bifurcations. The majority of calf
thrombi resolve spontaneously, and PE is uncom-
mon. Approximately 20 to 30% of DVTs propagate
to the popliteal, femoral, or iliac veins. An addi-
tional 10 to 20% of all DVTs occur in proximal veins
without previous calf involvement. Iliofemoral
thromboses appear to be the source of most clini-
cally apparent PEs.
The occurrence of DVT can be self-limited, with
resolution of the clot in most cases; can embolize
resulting in PE; and/or the postthrombotic
syndrome of venous insufÞ ciency and the accom-
panying stasis changes can occur. The postthrom-
botic syndrome can occur in up to one half of
patients with acute DVT. Its frequency is likely
reduced by the use of compression stockings for 2
years after the initial event, but the underlying
predisposition for the disorder is very poorly
understood. Therefore, the prevention of DVT will
prevent these complications.
Detection of DVT
The clinical diagnosis of DVT of the lower
extremity is insensitive and nonspeciÞ
c, with DVT
rates ranging from 10 to 25% of those suspected of
having the disease. Even when the classic signs
and symptoms of thrombophlebitis are present,
only 45% of patients are found to have DVT by
venography. Therefore, patients presenting with
d-dimer level at this point in the evaluation further
es the approach and may obviate the need
ie,
semiquantitative rapid ELISA) have sufficient
Table 1.
SimpliÞ ed Clinical Model for Assessment of DVT (Wells Rule)*
Clinical Variable
Score
Active cancer (treatment ongoing or within previous 6 mo or palliative)
Paralysis, paresis, or recent plaster immobilization of the lower extremities
3 d or major surgery within the previous 12 wk
requiring general or regional anesthesia
Entire leg swelling
Calf swelling at least 3 cm larger than that on the symptomatic leg (measured 10 cm below the tibial tuberosity)1
Pitting edema conÞ ned to the symptomatic leg
Collateral superÞ cial veins (nonvaricose)
Previously documented DVT
*High probability if score is
3; moderate if score is 1 to 2; and low if score is


sensitivity and predictive value to rule out DVT in
patients with a low or moderate clinical probabil-
ity. The false-negative result rate is too high to be
useful in patients with a high clinical probability.
In those patients and in any patients in the low-risk
or moderate-risk groups who have an abnormal
d-dimer level, imaging of the extremity is
necessary.
The Ògold standardÓ imaging test for DVT is
compression ultrasound. The diagnosis of DVT
using compression ultrasonography is made by
ndings such as abnormal compressibility or lack
of compressibility of the vein and abnormal Dop-
pler color ß ow study results. Studies have dem-
onstrated that a lack of compressibility of a vein
95%) and speciÞ
c (
95%)
for proximal vein thrombosis. Ultrasound imag-
Table 2.
Diagnostic Tests for DVT of the Lower Extremities
TestInvasivenessComplicationsComments
Contrast venographyMost invasive
Phlebitis, allergic
reactions, renal failure
Reference or Ògold standardÓ
Radionuclide venographyLess invasive
Sensitive for proximal DVT, not


Pulmonary Vascular Diseases (Moores)
pacemakers, splenectomy, previous VTE, recurrent
VTE, malignancy, thyroid-replacement therapy,
and the antiphospholipid antibody syndrome.
Patients who experience a major central thrombo-
cant hemodynamic
compromise on presentation, a documented throm-
perfusion studies on follow-up may need to be
monitored more closely. Ventilation/perfusion
) scanning is the screening investigation of
choice because many chest radiologists are not
familiar with the distinguishing features of CTEPH
seen on CT angiography. Patients who are surgical
candidates should be referred to a specialty center
for the consideration of pulmonary endarterec-
tomy. All patients should receive life-long antico-
agulation therapy.
is often arrived at using an unstructured approach
presence or absence of identiÞ able risk factors (
surgery in the past, obesity, or previous VTE);
ndings (
eg,
tachypnea); the results of basic laboratory studies
hypoxemia); and the likely presence of alterna-
tive heart failure). As with DVT, there are now
prediction rules that can be applied. The two vali-
dated rules are shown in Table 3. It should be
emphasized that the tool or approach used is less
nding provides compelling evidence against the
patients with clinically suspected PE who had
nding, only 3 patients had
symptomatic VTE (PE, 1 patient) during a 3-month
follow-up period. When the PIOPED criteria are
used, a high-probability V
nding
accompanied with a high prescan clinical suspicion
is associated with conÞ rmed PE in
96% of cases.
scan patterns other than normal or high-prob-
ability patterns will require additional diagnostic
Spiral CT pulmonary angiography (CTPA) of
the pulmonary circulation has emerged as the
Table 3.
Clinical Prediction Rules for Acute PE*
Canadian (Wells) Clinical Prediction Score
Variable and score
Signs and symptoms of DVT, 3.0
PE as or more likely than an alternative diagnosis, 3.0
Heart rate
100 beats/min, 1.5
Immobilization or surgery in previous 4 wk, 1.5
Previous DVT or PE, 1.5
Hemoptysis, 1.0
Cancer, 1.0
Total score


25
Diagnostic algorithm for acute PE. From: Tapson VF. Acute pulmonary embolism. N Engl J Med 2008; 358:1037


Pulmonary Vascular Diseases (Moores)
Treatment of VTE
The goals of short-term treatment of VTE are
to reduce the short-term and long-term complica-
tions, such as extension of the thrombus, fatal PE,
early or late recurrence, postthrombotic syndrome,
and CTEPH. When patients present with acute
VTE, they should be administered parenteral anti-
rin (UFH) or subcutaneous low-molecular-weight
heparin (LMWH) or the pentasaccharide
ated on the Þ rst day of treatment. Treatment using
tive days (at which time the heparin or fondaparinux
therapy can be discontinued). Compared with
treatment of warfarin alone, overlap therapy with
heparin reduces the risk of recurrence. A validated
weight-based IV nomogram achieves a therapeutic
response more effectively than empiric heparin
dosing; thus, it is recommended that such a nomo-
is the activated partial thromboplastin time, which
sure heparin levels. Failure to achieve an adequate
anticoagulation response with heparin therapy (
activated partial thromboplastin time,
1.5 times
control) is associated with the increased recurrence
The LMWH preparations and pentasaccharides
share advantages over UFH, as follows: greater
bioavailability, more predictable dosing, and a
lower risk of HIT. These advantages negate the need
for monitoring in most instances, although measur-
a level in morbidly obese
cantly impaired
renal function can be considered. In patients with
suspected or documented HIT, treatment with a
direct thrombin inhibitor, such as argatroban or
lepirudin, should be considered. Treatment with


nary angiography. However, no proven effect on


Pulmonary Vascular Diseases (Moores)
cer, stroke with lower-extremity weakness, end-
stage renal disease, and bed rest. Many medical
patients have multiple risk factors. Unfortunately,
risk categories in medical patients has been
accepted and validated. Therefore, medical patients
are generally classiÞ ed as low risk if they are fully
mobile and have no additional risk factors for VTE.
All other medical patients are considered to be at
moderate risk and should receive thromboprophy-
laxis as noted previously.
Pulmonary Hypertension (PH)
ned by
a mean pulmonary artery pressure (PAP) of
25 mm Hg at rest or
30 mm Hg during exercise,
which is shared by many conditions. PH was pre-
viously categorized into primary or secondary PH,
based on the absence or presence of identiÞ
able
causes or associated conditions. A revised classiÞ
of disorders directly affecting the arterial tree from
disorders affecting the venous circulation or those
affecting the circulation by altering respiratory
function was proposed in 1998. A revision of this
cation was proposed at the Third-World
Conference on Pulmonary Hypertension, held in
Venice, Italy, in 2003 (Table 4). The major changes
noted in these revisions were as follows: (1) aban-
and (2) the
replacement of the term
(IPAH) or, when
of the BMPR2 gene often have an abnormal increase
in pulmonary artery (PA) pressures in response to
exercise and, given additional environmental or


PAH related to risk factors or associated condi-
Multiple-hit hypothesis of pathogenesis of PAH: BMPR-II, bone morphogenic protein receptor type 2. From Gabbay
E, Reed A, Williams TJ. Assessment and treatment of pulmonary arterial hypertension: an Australian perspective in 2006. Intern
Typical micrograph of a lung from a patient with
PAH. The patient has normal alveolar structures but a small
PA, in which the lumen is occluded by concentric Þ
brosis.
The artery also has increased medial smooth muscle and a
reactive adventitia. Dilated small vessels border the airway
above the artery. From Newman JH, Phillips JA, Loyd JE. Pul-
monary hypertension. Ann Intern Med 2008; 148:278283.


Pulmonary Vascular Diseases (Moores)
patients with an unexplained isolated reduction in
diffusing capacity). There are no early symptoms
of PAH, and thus, annual screening in high-risk
populations should be considered. Risk groups
thought to beneÞ t from screening include patients


vasodilators is deÞ ned as a decrease in mean PA
pressure of
10 mm Hg to reach a mean PA pres-
sure of
40 mm Hg, with an increased or
unchanged cardiac output. Very few patients
show a short-term response, but a negative chal-
lenge result will obviate a trial of calcium-channel
Measurement of Exercise Capacity
Formal assessment of exercise capacity is an
integral part of the evaluation. A 6-min walk test


Pulmonary Vascular Diseases (Moores)
capacity, hemodynamics and, in the case of epo-
prostenol, survival. In the NO pathway, sildenaÞ
strated improvement in exercise capacity, func-
oral nonselective endothelin receptor antagonist;
sitaxsentan and ambrisentan are selective endo-
thelin A receptor antagonists. These therapies have
been shown to improve exercise capacity, functional
Bosentan
has also been shown to improve hemodynamics.
Two studies have shown improved survival with
bosentan therapy compared with historical control
subjects. Although many of the trials that use these
medications. Multidrug treatment is appealing
because the three classes of medications approved
by the Food and Drug Administration exert their
effects by different mechanisms. The use of two or
more drugs may allow for dosing below the levels
that cause important side effects. A few small stud-
rmed this theory, but more data are
needed before Þ rm recommendations can be made.
Authors of the American College of Chest Physi-
cians evidence-based guideline published updated
Their overall recommended approach is shown in
Figure 4. If pharmacologic treatment fails, surgical
(the sixth line) treatment (lung transplantation or
atrial septostomy) should be considered.
Prognosis


33
Treatment algorithm for PAH. The recommended therapies presented in this algorithm have been evaluated mainly
in those patients with IPAH or PAH associated with connective tissue disease or anorexigen use. Extrapolation to other forms of
PAH should be made with caution. Country-speciÞ c regulatory agency approval status and functional class indications for PAH


Pulmonary Vascular Diseases (Moores)
This article is an update to the one before it, taking into
account the rapidly evolving Þ eld of therapeutic trials in
PAH. The authors give a nice review of the current evidence
use in patients with PAH.
sion: a tale of two circulations. Chest 2003; 123:562
Pulmonary involvement is common in patients with
portal hypertension and can manifest in diverse ways.
Changes in pulmonary arterial resistance, manifesting
either as the hepatopulmonary syndrome or portopulmo-
nary hypertension, have been increasingly recognized.
ned as an elevated


Venous ultrasonography is a valuable test for the diagnosis
and management of patients with suspected DVT or PE.
However, the following factors reduce the positive predic-


Pulmonary Vascular Diseases (Moores)
of follow-up than treatment for 6 months. However, there
was a trend toward a greater risk of major hemorrhage when
nitely.


prediction rules and d-dimer levels and applied these data in
Wood KE. Major pulmonary embolism: review of
a pathophysiologic approach to the golden hour of
hemodynamically signiÞ cant pulmonary embolism.
This is an extensive review of a pathophysiologic approach to
hemodynamically signiÞ cant PE. The article also discusses
risk gratiÞ cation in part based on right ventricular dysfunc-
tion. Thrombolytic therapy is acknowledged as a treatment
thrombolysis is contraindicated.


Pulmonary Vascular Diseases (Moores)


39
 Outline the various causes of lung cancer and the types of
clinical and radiographic presentations peculiar to each
 Review the paraneoplastic syndromes associated with lung
 Place in perspective the appropriate use of laboratory
studies, imaging techniques, and diagnostic approaches
 Review the results of various treatment modalities for both
dromes; screening; small-cell lung cancer; solitary pulmonary
nodule; staging; treatment
and 18.1% of women). Lung cancer is now more
prevalent in ex-smokers than active smokers.
The status of the treatment of lung cancer is no
more encouraging. The expected 5-year survival
for the diagnosis of lung cancer is 16% as compared
with 65% for colon cancer, 89% for breast cancer,
and nearly 100% for prostate cancer. Furthermore,
progress in treatment has been slow. The current


Lung Cancer (Alberts)


of lung cancer, and there appears to be a familial
correlation with the development of such respira-
tory disease. Inheritance of an abnormality in
of non-small cell bronchogenic carcinomas. Small-
cell carcinoma is generally regarded as a disorder
for which surgery is not indicated.
Microscopically, SCLC in made up of small,
round cells with large nuclei that stain blue when
hematoxylin and eosin is used. Histologically, they
are characterized by scant cytoplasm, 
ne chroma-
tin, and nuclear molding. “Crush artifact’ is com-
monly noted. SCLC arises from neuroendocrine
cells and stains positive for synaptophysin,
chromogranin A, and neuron-specific enolase.


smoking that such a diagnosis in a nonsmoker
All other cell types of bronchogenic carcinoma,
aged surgically with the potential for cure. Non-
small cell carcinomas are split into squamous cell
(29% of the total); adenocarcinoma, including
bronchioloalveolar cell carcinoma (32% of the
total), large-cell carcinoma (9% of the total), and
undifferentiated (11% of total). Non-small cell lung
carcinomas are believed to arise from lung epithe-
lial cells. They express cytokeratin in a distinct
and are commonly positive for thyroid transcrip-
Adenocarcinomas are the least closely associ-
never-smokers. BAC tumors grow in lepidic fash-
ion, spreading along the lining of alveolar air
spaces, and there is no invasion of the stroma,
pleura, or lymphatics. Where such invasion occurs,
the disease process is termed
adenocarcinoma mixed
type with a predominant BAC pattern
very slow growing and commonly spreads within
the lung through the airways. BAC is divided into
three subtypes: mucinous, nonmucinous, and a
Squamous cell carcinoma is characterized by
keratin formation, intercellular bridging, and a
nonglandular appearance. Squamous cell lung
cancer typically arises within the major bronchi
near the center of the chest. A total of 95% of
patients with squamous cell are smokers, and 60%


resembles the survival patterns for patients with


The IASLC recommends that the current N
descriptors should be maintained and that revi-
sions to should include grouping cases with malig-
nant pleural effusions and cases with nodules in
the contralateral lung in the M1a category, and


45


hypokalemia are more common. The potassium
3.0 mEq/L in 70 to 90% of patients.
Hyperpigmentation occurs in approximately 25
in 38 to 67% of all patients with lung cancer, but
SCLC is associated with the greatest frequency.
Calcitonin causes an immediate calciuresis, but it
does not produce symptoms.
Paraneoplastic Neurologic Syndromes:
Neuro-
myopathies are most commonly associated with
SCLC. The incidence of neuromyopathies for all


survival rate may be a function of earlier lead
A survival bene t, as opposed to a mortality
t, with screening compared with no screen-
ing may be anticipated because of several potential
inherent biases. Lead-time bias is de ned as appar-
ent improved survival by earlier diagnosis with
screening even when the outcome, death caused
by lung cancer, remains unchanged. Length-time
bias has the effect of improving apparent survival
by selecting cancers that, by their slow growth,
have a good prognosis compared with cancers
found by symptoms. Overdiagnosis bias improves
the apparent overall survival by the identi
of cancer that, in the absence of screening, would


graph. Granulomas and hamartomas constitute
40 to 60% of all SPNs and are the leading cause of
35 years of age. In older patients,


Flexible Bronchoscopy:
cally visible) cancer,  exible bronchoscopy is 90
to 95% sensitive (or greater). The main goal is to
establish a diagnosis and distinguish SCLC from
exible bronchos-
copy has a reasonable sensitivity (60 to 75%) if the
contamination with possible false-positive results.
The need to perform TBNA is predicated, at


biopsy of the pleura adds only approximately 8%
to the overall yield for malignancy, so it is gener-
ally not recommended as part of the approach to
a patient with a suspected malignant pleural effu-
logic studies of their pleural  uid, a thoracoscopy
should be done, because the true-positive yield
when malignancy is present is approximately 98
There is general agreement that
radionuclide scans of the bones are not warranted
during a preoperative evaluation unless symp-
toms, signs, or abnormal blood test results raise a
c 
ndings indicate the presence


51


liver disease, both for SCLC and NSCLC. In
ed preoperatively, it is essential to estimate
the likely postresection pulmonary reserve. The
amount of lung function lost in lung cancer resec-
scan or the number of segments removed. A pre-
40% indicates


an increased risk for perioperative complications,
including death, from lung cancer resection. Exer-
to further de ne the perioperative risks before
surgery.
Formal cardiopulmonary exercise testing is a
sophisticated physiologic testing technique that
includes recording the exercise ECG, heart rate
response to exercise, minute ventilation, and oxy-
perioperative complications can generally be
ed by V
max. Patients with preoperative
20 mL/kg/min are not at increased risk
min indicates an increased risk of perioperative
10
tive complications. Alternative types of exercise
testing include stair climbing, the shuttle walk, and
the 6-min walk. Although often not performed in
a standardized manner, stair climbing can predict
ve 
ights of stairs have V
20 mL/kg/min.
Conversely, patients who cannot climb one 
the shuttle walk and 6-min walk are limited, but


of equally effective non--cross-resistant combina-


however, have now shown that patients treated


apparent survival bene t, however, and signi
cant
neuropsychological de
cits may develop. Pallia-
ment of speci c symptoms, such as pain control,
hemoptysis, superior vena cava syndrome, and
in the 1980s were relatively ineffective, produc-
ing response rates of
15%. The combination of


theory, chemotherapy with a cytotoxic agent may


Lung Cancer (Alberts)


initiated by the binding of epidermal growth fac-
tor to cell surface receptors.
The initial trials of epidermal growth factor
receptor (EGFR)-blocking agents revealed that these
agents were not uniformly effective. A closer look at
the data indicated that patients with certain clinical


Lung Cancer (Alberts)


CT screening can identify lung cancers when they are
small and predominantly stage I. It is hoped that the ran-
domized controlled trials currently underway will pro-
vide evidence relating to the important issue of mortality


Lung Cancer (Alberts)


63
 Discuss the features of dusts and particulate matter that
 Identify the most common causes and the usual clinical
presentation of hypersensitivity pneumonitis
 Describe those clinical syndromes that are similar to
hypersensitivity pneumonitis but are clinically distinct
are exhaled in the expired gas.
HP is an immunologic-induced, non-
IgE-mediated in ammatory lung disease resulting
from the sensitization and subsequent recurrent


Hypersensitivity Pneumonitis (Alberts)


farmer’s lung) is an acute toxic lung injury caused
by the inhalation of nitrogen dioxide. Nitrogen
dioxide develops as a result of an interaction of
nitric oxide and freshly stored silage. This chemical,
when inhaled, will affect the terminal airways of
all who are suf ciently exposed, regardless of pre-
vious exposure or sensitization. This is, in essence,
a chemical burn manifesting as bronchitis, bron-
chiolitis, or acute respiratory distress syndrome.
Organic dust toxic syndrome (ODTS) is an
ammatory pneumonitis that develops when a
massive dose of organic dust is inhaled. This dis-
order was originally termed
in Wisconsin dairy farmers. The term
been described as “clumsy and ugly.” As a result,
some prefer to use the term
to
describe this and related illnesses. Clinically, ODTS
resembles HP with symptoms that are 
u-like and
dominated by fever and chills. ODTS, however,
does not require previous sensitization, and most
of the time this disorder will develop in subjects
who are suf
be 70% or greater, given suf
cient exposure. No
long-term effects have been documented, and


illness resembles the “24-h  u” with cough, dys-
pnea, tachypnea, diffuse end inspiratory rales,
chills, fever, malaise, diaphoresis, headache, and
myalgias. The clinical picture is often mistaken for
for 12 to 24 h, with a peak at 8 to 12 h after exposure.


radiographic changes, pulmonary function test
results, and immunologic test results. Of prime
importance is a high index of suspicion. In patients
with recurrent bouts of an in uenza-like illness or


more useful in establishing evidence of exposure
to speci c antigens. Serum precipitins are antigen-
c complement-
xing antibodies of the IgG
class, although IgM and IgA have also been
rather than transbronchial lung biopsy. Very few
biopsies have been performed during the acute
form of the disease. Where available, they have
shown alveolar and interstitial accumulation of
polymorphonuclear leukocytes,  uid, and macro-
phages. One of the most characteristic features is
More often, biopsies are conducted in the sub-
acute or chronic phases. At this stage of the disease,
biopsy specimens show a predominant lympho-
cyte, plasma cell, and macrophage in
ltration in
the alveolar wall and interstitium. Seventy percent
compact and less well de ned than those seen in
sarcoidosis. Sixty-five percent show varying
degrees of 
brosis. Foam cells are seen in 65%.
Foam cells are large foamy histiocytes representing
activated macrophages. Fifty percent of specimens
show bronchiolitis obliterans. Vasculitis and
eosinophils are distinctly unusual. The typical
of cellular bronchiolitis, a bronchiolocentric lym-
phocytic interstitial pneumonitis, and poorly
Inhalation challenge tests are rarely performed
challenge tests are not as well standardized, as is
ized. The test is not to be taken lightly, as the reac-
tion may be quite severe. Once a reaction is
established, bronchodilators are of little bene
t.
Corticosteroids must be used. Outside of research


with HP on chest radiograph or HRCT, (4) BAL
uid lymphocytosis, (5) histologic changes compat-
ible with HP, and (6) positive “natural challenge”
, reproduction of symptoms and laboratory
abnormalities after exposure to the suspected
environment). Minor criteria are (1) bibasilar rales,
(2) decreased diffusing capacity, and (3) arterial
In 2003, the Hypersensitivity Pneumonitis
Study Group attempted to develop a clinical pre-
diction rule for this diagnosis. Six signi
cant pre-
dictors were identi ed: (1) exposure to a known
offending antigen, (2) positive precipitating anti-
bodies to the offending antigen, (3) recurrent epi-
sodes of symptoms, (4) inspiratory crackles on
8 h after exposure, and (6) weight loss.
Treatment
The key is prevention and avoidance of reex-
posure is the top priority. This may require a job
change, discarding a hobby, or moving to a new
home. These changes may not be well received by
the patient. In one study, 75% of pigeon breeders
with disease were still breeding (pigeons, that is)
at a 10-year follow-up. Changes in industrial pro-
cedures have proven bene cial. For example, maple
bark stripper’s disease has all but vanished because
of the adoption of alternate work procedures. The
act of spraying bagasse with dilute propionic acid
has decreased the incidence of bagassosis. Improve-
ments in ventilation, air  ltering systems, or masks
may help in some circumstances.
For symptomatic relief of the in
ammatory


building syndrome). Speci c disorders are charac-
terized by well-defined signs, symptoms, and
ndings. A speci
c cause can be estab-
lished and a long recovery time is the norm.
Examples would include HP, humidifier fever,
asthma, and various respiratory tract infections.
Conversely, nonspeci c building-related disorders
are characterized by nonspeci
c symptoms and
variable signs. There are no characteristic labora-
tory  ndings, and no single cause can be identi
ed.
Symptoms appear soon after arriving at work,
worsen during the day, and dramatically disappear
Worldwide, it has been estimated that in 25%
of the investigations of apparent outbreaks of
building-related illness, a speci c cause can be
identified, such as microbial contamination of
humidification systems or the accumulation
of motor vehicle exhausts. The remaining 75% of
outbreaks are unexplained and are considered to
be due to the sick building syndrome. In a review
of 356 cases of building-related illness in the United
States, the National Institute for Occupational


Core symptoms of sick building syndrome are
be difÞ cult. The authors of the editorial suggest major and
minor criteria that should be present in a patient with this
disorder.
Silva CI, Churg A, Muller NL. Hypersensitivity pneu-
monitis: spectrum of high-resolution CT and pathologic
 ndings. Am J Roentgenol 2007; 188:334–344
There are several high-resolution CT Þ ndings that are typi-
cal of HP.
Pathology
ogy. Arch Pathol Lab Med 2008; 132:199–203


Burge PS. Sick building syndrome. Occup Environ


73
parenchymal eosinophils but did not necessarily
have peripheral blood eosinophilia. A lung biopsy
specimen was needed to identify these disorders.
Chronic eosinophilic pneumonia, as reported by
Table 1.
cation Scheme
Airway disorders
Eosinophilic bronchitis
Allergic bronchopulmonary aspergillosis
Bronchocentric granulomatosis
Interstitial disorders
Secondary (associated with known underlying disease
processes)
Bacterial infections (
brucellosis, mycobacterial)
Fungal infections (
Coccidiomycosis and Aspergillus)
Interstitial lung diseases
Idiopathic pulmonary 
brosis
Sarcoidosis
Systemic lupus erythematosus
Eosinophilic granuloma
Hypereosinophilic syndrome
AIDS-associated
Parasitic infections
Pulmonary vasculitis
Hodgkin disease
Drug reactions
Lung cancer
Primary (idiopathic eosinophilic pneumonia)
Simple pulmonary eosinophilia
Chronic eosinophilic pneumonia
Acute pulmonary pneumonia


The Eosinophil
cyte that is produced in the bone marrow. The


antigens resembles the response to other inhal-
ant allergens, such as house dust mite. Allergic
bronchopulmonary mycosis is an “infectious
fungal growth or colonization of the respiratory
tract. Both types of disorders can cause long-
Allergic Bronchopulmonary Aspergillosis:
Aller-
gic bronchopulmonary aspergillosis (ABPA)
is the most common type of allergic broncho-
pulmonary mycosis. ABPA is a complication of
allergic asthma in which the ubiquitous fun-
Aspergillus fumigatus
respiratory tract. Patients with cystic 
brosis are
particularly vulnerable. ABPA may be found in
up to 15% of patients with cystic  brosis and 2
to 28% of asthmatics. An ABPA-like disorder
Each of these organisms is capable of
hyphal growth at body temperature. The hyphae
persist in the airways and continually release
c IgG
sue damage may result in permanent damage,
as evidenced by proximal bronchiectasis and
irreversible airways obstruction.
Bronchocentric Granulomatosis:
Bronchocentric
granulomatosis (BG) is a rare granulomatous dis-
order characterized by granuloma formation and
necrosis centered on and limited to bronchi and
bronchioles. Vasculitis is not a major component.
c response to a number of
substances. A surgical biopsy specimen is required
for diagnosis. The disease is de ned by morpho-
ned clinical


anti-neutrophilic cytoplasmic antibody
Clinical features include asthma, a history of
atopic disease, fever, malaise, and weight loss.
upper airway involvement (sinusitis, rhinitis, nasal
plex; abdominal symptoms (pain, diarrhea,
bleeding); cardiac  ndings (heart failure, pericar-
ditis, hypertension); and microscopic hematuria.
Chest radiographs commonly reveal patchy and
ltrates, but large and small nodules
also have been reported. Thin-section CT 
include bilateral subpleural consolidation with
cially within the ground-glass opacity), or multiple
nodules, especially in association with bronchial
wall thickening. Pleural effusions may be noted in
one-third of cases. The effusions are exudative and
cant number of eosinophils.
cytosis with marked eosinophilia, a high percent-
age of BAL eosinophils, prolonged erythrocyte
often markedly increased and appears to correlate
with disease activity. In Churg-Strauss syndrome,
the prevalence of a positive serum ANCA result
ranges from 44 to 66%. The p-ANCA pattern is
often present as opposed to the c-ANCA observed
in Wegener granulomatosis.
Clinically, there are three distinct phases: (1) a
prodromal phase that may persist for many years,
consisting of asthma, often preceded by allergic
rhinitis; (2) a second phase of marked peripheral
trates resembling Loef er syndrome, or chronic
eosinophilic pneumonia, which may recur during
a period of years; and (3) a third, life-threatening
Survival is dramatically enhanced with treat-
ment. In the past, without treatment, 50% of


wheezing, fever, weight loss, and malaise. A his-
tory of residence in a  larial endemic region and a
nding of peripheral eosinophilia
should initiate a consideration of this disease.
Cases of tropical pulmonary eosinophilia typically
have been reported to masquerade as acute or
refractory asthma. The recommended treatment is
of the hypereosinophilic syndrome that may
respond to imatinib, a small molecule tyrosine
kinase inhibitor. Additionally, studies have
reported success in treatment with the use of
mepolizumab, which is a monoclonal antibody
Bronchogenic carcinoma occa-
invade the tumor, which suggests that eosino-
Pulmonary eosinophilic in ltrates may be noted
on biopsy specimen or BAL. Administration of
corticosteroids to patients early in their infection
can result in an acceleration of the infection with
possible fatal dissemination. In AIDS-associated
had BAL eosinophils
5%. A number of other
diseases have been reported to be associated
with pulmonary in ltrates and blood or alveo-
lar eosinophilia. They include bronchiolitis oblit-
erans organizing pneumonia, ulcerative colitis,
mycobacterial infection, Sjögren syndrome, and
brosis.
Parenchymal Disorders (Idiopathic)
er pneumo-
nally described by Loef er in 1932. This disorder
Respiratory symptoms are minimal or absent.
Malaise, fever, and cough may be noted. At times,
ned peripheral, nonsegmental, and relatively
homogeneous densities. By de nition, the disease
resolves within 4 weeks. Af icted patients have


Chronic Eosinophilic Pneumonia:
dromes. Both histologic and BAL studies strongly
the disorder. A recent study found strikingly
increased levels of IL-5, IL-6, and IL-10 in BAL
uid recovered from involved lung segments. No
such increase was noted in serum or uninvolved
lung segments. Furthermore, the presence of cir-
culating immune complexes, increased levels of
IgE, and a frequently positive rheumatoid factor
Chronic eosinophilic pneumonia (CEP) is a
serious disease that requires speci c treatment. The
disease usually affects middle-aged atopic women,
but it has been reported in both sexes and all ages.


Conclusion
In these disorders, teleologically, the eosinophil
may be: (1) a “good guy,” (2) a “bad guy,” or (3) an
“innocent bystander.” The eosinophil may be a
good guy. The “host defense” theory builds on the
of parasitic infections are associated with a striking
In vitro
studies have shown that
eosinophils can kill parasites. Conversely, the
eosinophil may be a bad guy. The eosinophil is
activated at sites of in ammation and thus may be
responsible for the actual tissue damage. Alterna-
tively, the eosinophil may be an innocent bystander.
The appearance of the cell may be part of the
body’s attempt to dampen or contain the effects of
ammation—the so-called
important to remember that the disease processes


Allergic Bronchopulmonary Aspergillosis
Lazarus AA, Thilagar B, McKay SA. Diagnosis and
treatment of allergic bronchopulmonary aspergillosis.
Mayo Clin Proc 2001; 76:930–938
More comprehensive review of the topic.
Vlahakis NE, Aksamit T. Allergic bronchopulmonary
aspergillosis. Dis Mon 2008; 54:547–564


81
 Understand the epidemiology of asthma and the con-
this group was published in 1991. It is often
referred to as the
The guidelines de ne asthma as
a chronic in ammatory disease of the airways
in which many cells play a role, in particular,
tion causes recurrent episodes of wheezing,
breathlessness, chest tightness, and cough, par-
ticularly at night and/or in the early morning.
These symptoms are usually associated with
widespread but variable air ow limitation that
is at least partially reversible either spontane-
ously or with treatment. This in
also causes an associated increase in airway


induce bronchoconstriction. A number of typical
histopathologic findings can be found in the
Histopathologic Findings
ltration of the airways by in
ammatory
cells such as mast cells, eosinophils, activated T
lymphocytes, and neutrophils can be demonstrated
by bronchial biopsies and inferred by demonstrat-
ing increased numbers of these cells in BAL 
The extensive bronchial wall in ltration by eosin-
ophils may be accompanied in severe cases by
eosinophilic in ltration of the alveolar septae and
cytes found in bronchial biopsy specimens has
been correlated with the number of local activated
c cytokines, most of which are products
of lymphocytes and macrophages, appear to direct
to release their mediators. For example, interleukin
(IL)-3, IL-5, and granulocyte-macrophage colony-
stimulating factor direct eosinophils to release a
number of mediators from their preformed gran-
ules. These mediators are major basic protein,
eosinophil cationic protein, eosinophil-derived
neurotoxin, and eosinophil peroxidase. All have
ammatory effects that contribute to the patho-
Mast cells, usually as a result of IgE-mediated
stimulation, also release preformed mediators,
such as histamine and proteases (
and further act as a regulator of in
ammation by
producing cytokines that promote eosinophil in
tration and activation. Several mast-cell products
(histamine, LTC
) are smooth-muscle
constrictors and, hence, induce bronchoconstric-


83
from asthmatic patients. There is a microvascular
component to airway remodeling in asthma, with
increased levels of vascular endothelial growth
factor in BAL  uid and sputum.
The structural changes that occur in the air-


Asthma (Braman)
ammation of the bronchial wall, however,
Acute bronchoconstriction
Bronchial wall edema
In ammatory cell in
Airway wall remodeling (
brosis)
Smooth-muscle hypertrophy
Uncoupling of elastic recoil forces


is trapped in airway mucus and is exposed to
underlying epithelial cells and resident dendritic


sex-linked mode of inheritance. This may be in


composed of several organic and inorganic com-
spores, mammalian dander, pollen grains, 
mites, and mite feces. Outdoor allergens include
pollens (mainly from trees, weeds, and grasses);
Air Pollution
to worsening asthma symptoms by triggering
bronchoconstriction, increasing BHR, and enhanc-
ing responses to inhaled aeroallergens. The two
main outdoor pollutants are industrial smog (sul-
with chronic stable asthma. There have also been
reports of asthma appearing for the  rst time after
an active infection with both of these organisms, as
cant improvement in lung function
and symptoms with antimicrobial therapy directed
to these organisms. In one prospective study,
was found in the air-
60% of a group of stable patients with
chronic asthma. Therapy with the macrolide anti-
biotic clarithromycin improved lung function and
decreased tissue expression of IL-5 in those patients
who were polymerase chain reaction positive to
these organisms. This  nding suggests that antibi-
may help to control the disease.
Allergic Rhinitis
Nasal and sinus diseases are common comor-
Allergic rhinitis


the development of asthma and atopy. For instance,
being underweight and being overweight are both
associated with an increased risk of the develop-
ment of asthma. There is some evidence that
ated with improved symptoms and lung function,
especially PEFR variability. Growing up on a farm
decreases the risk of atopy and allergic rhinitis in
adulthood, suggesting that environmental factors
may have a lifelong protective effect against the
development of allergy. In developing countries,
the move to cities is associated with a switch from
biomass fuels such as wood, charcoal, and animal
wastes to gas and electricity. The use of modern
fuels has been associated with an increased rate of
allergic sensitization and symptoms. Studies indi-


although remission from asthma is common in the
second decade, it is much less common in older age
groups, although it still may be as high as 20 to
30%. Asthmatic subjects who have severe symp-
toms, reduced ventilatory function, and a con-
comitant diagnosis of COPD are much less likely
to experience remission. Not infrequently, heavy


Asthma (Braman)


not rule out a severe attack. Cyanosis and signs of
acute hypercarbic acidosis, such as mental obtun-
dation, are absent in all but extreme cases. Acces-
sory muscle use and pulsus paradoxus are caused
by large negative changes in intrapleural pressure,
rapid, shallow breathing. They are reported to be
present in 30 to 40% of patients with acute
Objective Measures of Asthma
and Asthma Severity
The use of objective measurements of pulmo-
because the perception of asthma symptoms often
ndings on physical
examination may either overestimate or underes-
ow obstruction. The
following four tests of pulmonary function are
extremely useful for establishing the diagnosis of


It is believed that respiratory muscle fatigue
also contributes to respiratory failure and, in
extreme cases, sudden respiratory muscle failure
can result in acute cardiopulmonary arrest. Super-


modality is somewhat controversial. Indoor irri-


The LPMs are generally very safe, which has led
to more use in younger asthmatics, especially
years of age. The rare cases of Churg-Strauss vas-
culitis have occurred in patients with severe ste-
roid-dependent asthma who have had a recent
steroid taper. Because this form of vasculitis has
been seen in patients in whom inhaled steroids
have been substituted when oral steroids have
been tapered, the reaction may not be speci
c to
the LT-modifying agents.
nal antibody that inhibits the binding of IgE to mast
cells by forming complexes with circulating free
IgE, has been shown to be effective in the treatment
of patients with atopic asthma. The reduction of
free IgE in the circulation leads to a down-regula-
tion of basophil and mast-cell receptors. This fur-
ther reduces the potential for mast cell/basophil
activation and the subsequent release of in
tory mediators. Randomized, controlled trials have
severe asthma. The agent has been shown to reduce


Theophylline is an effective bronchodilator and
has antiin ammatory properties. It is available as
a sustained-release preparation and can be taken
once or twice daily. The monitoring of theophylline
blood levels is important to avoid toxicity, espe-
cially in the elderly, who are more prone to adverse
effects. GI side effects are seen with mild toxicity
Serious cardiac arrhythmias and seizures may
occur with blood levels in excess of this range.
A blood level of 8 to 15
g/mL is generally consid-
ered to be therapeutic.
Inhaled anticholinergic agents such as ipratro-
pium produce bronchodilatation by reducing vagal
tone and are widely used in patients with COPD.
-agonists
for a severe acute exacerbation of asthma. Their role
stitute bronchodilator when side effects preclude
-agonists, although it must be remem-
(Expert Panel Report 3) have offered two new treat-
ment plans. Treatment protocols use step-care
asthma symptoms and future risk as measures of
control and the clinical response to these interven-
tions. As symptoms and lung function worsen,
step-up or add-on therapy is administered. As
symptoms improve, therapy can be stepped
cation and
recommended treatment protocols are listed in
Table 2.
Asthma Control:
The classi cation of asthma
by severity has proven useful when decisions are
initial assessment of a patient. Asthma severity,
however, involves both the severity of the under-
lying disease and its responsiveness to treatment.
cation of severity is no longer recom-
mended as the basis for ongoing treatment deci-
sions in the new NAEPP guidelines. Instead, the
concept of asthma control has been suggested as
a basis for treatment decisions. The term
control
refers to control of the manifestations of disease,
including symptoms, effects on the quality of
daily living, and use of rescue medication. A peri-
odic assessment of asthma control is useful and
strongly recommended. The new classi
cation of
asthma control is listed in Table 3.
Table 2.
Asthma Treatment by Severity of Disease
2 times/wk nocturnal symptoms
2 times/mo FEV
80% of predicted; PEFR variability
Treatment: NEAPP guidelines call this step 1 therapy: inhaled SABA as needed
2 times/wk and
1 time/d; nighttime symptoms
2 times/mo; FEV
80% of predicted;
Treatment: step 2 therapy: Begin antiin ammatory therapy; low-dose ICS are preferred, or consider a LPM or cromolyn.
-agonist as needed for quick relief; however, increased use means need for additional controller therapy.
Severity: daily symptoms and daily use of rescue
2 exacerbations/wk and 1 nighttime exacerbation/mo;
and PEFR of 60 to 80% of predicted; PEFR variability
Treatment: Step therapy is advised in the 2007 NAEPP guidelines. Adding an LABA is given equal weight to increasing to
medium-dose ICS; if symptoms still persist, may increase dose of ICS or add LABA, whichever applies, or medium-dose
ICS with LPM or consider theophylline; continue a SABA for short-term relief. Step 5 is high-dose ICS plus LABA and
Severe persistent asthma
Severity: continuous symptoms; limited physical activity; frequent exacerbations; frequent nighttime symptoms; FEV
60% of predicted; PEFR variability
Treatment: high-dose ICS, LABA, possibly theophylline, oral corticosteroids, and consider omalizumab.


Step-down Care.
There are no hard and fast rules
on stepping down asthma care when asthma con-
trol is improved. Studies conducted by the Asthma
Clinical Research Centers have shown that patients
with mild persistent asthma controlled with a low
peak response 5 to 10 min after exercise. Often
in some patients, atypical presentations of chest
tightness or chest pain alone will occur. A cardiac
workup may often precede pulmonary testing in
such patients. The symptoms usually abate without
treatment, although the administration of a short-
Table 3.
ClassiÞ cation of Asthma Control in Youths
12 Years of Age and Adults
Controlled (All of
Not Well Controlled (Any
Measure Present in Any Week)
Very Poorly
Controlled
2 times/wk
Throughout day
Interference with normal activitiesNoneAnyExtremely limited
2 times/ mo
4 times/wk
Need for SABA (rescue treatment)
2 times/wk
80% of predicted or
60 to 80% of predicted or
60% of predicted
Validated questionnaire
, Asthma Control Test score)


rst. An intense warm-up period


this syndrome. The precise mechanism for this
syndrome is not known. The overexpression of the
enzyme LTC
synthase has been reported, and
some studies have described polymorphisms of
the LTC
synthase promoter region.
The prevalence of aspirin-induced broncho-
spasm in the population of asthmatic patients
depends on the population studied. Approximately
3 to 5% of hospitalized asthmatic patients report a
history of a reaction to aspirin. This number is
greater at highly specialized referral centers at
which patients with the most severe asthma are
cared for. The treatment is, of course, the avoidance
of aspirin and nonsteroidal antiin
ammatory drugs
with known cross-reactivity. For the occasional
patient who needs these drugs, oral desensitization
protocols using gradually increasing doses of aspi-
rin are effective. With the use of aspirin desensitiza-
tion, approximately two thirds of the patients report
cant improvement in their rhinosinusitis,
and approximately one half have improvement in
their asthma. The addition of LT inhibitors (
zileuton) and receptor antagonists (
montelukast)
as therapeutic options for asthma is important
rin-induced bronchospasm in sensitive patients.
Occupational Asthma
Asthma that is precipitated by a particular
occupational environment and not to stimuli out-
asthma that follows a latent period of exposure to
either a high-molecular-weight or a low-molecular-
follows exposure to workplace irritants. One form
reactive airways
dysfunction syndrome
, a condition that usually
results from the sudden inhalation of a large dose
of a highly irritating substance. Occupational
asthma associated with a latency period causes
asthma by immunologic events that affect only a
small proportion of exposed subjects.
Although some compounds induce asthma
through the production of speci
c IgE antibodies,
the immunologic mechanisms responsible for other
agents have not been identified. The reaction


Cough-Variant Asthma
At times, cough may be the sole presenting
manifestation of asthma, and the characteristic
ndings of variable air ow obstruction may not
be present. Such patients represent a subgroup of
patients who cough. As a result, cough-variant
asthma (CVA) is signi
cantly underdiagnosed.
Prospective studies have shown that asthma is
among the most common causes of chronic cough
There is evidence that cough receptors in the
airways are separate from bronchoconstrictive
receptors, and this may explain why such patients
do not wheeze. Cough receptors are more abun-
dant in the central airways. Patients with CVA
have demonstrated heightened sensitivity of
their cough reflexes, whereas those with the
typical form of asthma do not differ from healthy
volunteers when cough reflex sensitivity is


re
ux symptoms, 24-h pH monitoring has proven
re
ux to be present in
80% of patients. Even
when re ux symptoms are not present, re
ux can
time. Asthmatic patients have been shown to have
decreased lower esophageal sphincter pressures
when compared with healthy individuals. Medica-
-agonists can
lower the lower esophageal sphincter as can certain
olate, caffeinated beverages, alcohol, and pepper-
mint. In addition, the administration of prednisone
orally has been shown to increase esophageal acid


In fact, there is evidence that when the asthma
attack is sudden and respiratory failure occurs
within a few hours, recovery too is rapid. Improve-
ment occurs more rapidly than when the asthma
attack has been slowly progressive over days. The
explosive attacks. There is evidence that such
patients are immunohistologically different in that
their airways have a relative paucity of eosinophils
and a larger number of neutrophils compared with
the classic asthma picture. Typically, in patients
who die of asthma, the lungs are overin
ated, and
both large and small airways are  lled with plugs
consisting of a mixture of mucus, serum proteins,
ammatory cells, and cell debris. Microscopi-
cally, there is in ltration of the airway lumen and
is accompanied by vasodilation, evidence of micro-
The most commonly identi ed causes of near-
fatal asthma are listed in Table 4. Risk factors for
fatal or near-fatal asthma are as follows: (1) high
medication use (three or more medications), (2)
overuse of inhaled
of recurrent hospitalizations, (4) previous occur-
rences of life-threatening attacks, and (5) marked
uctuations in morning and evening peak 
ow rate
measurements. In addition, investigations have
shown that patients with near-fatal attacks have
abnormal respiratory control mechanisms such as
a blunted perception of dyspnea and a reduced
hypoxic ventilatory response to hypoxia. They are
also more likely to have a drinking problem, to
a nebulizer for symptomatic relief in the month
before death. Because blood levels of albuterol are
2.5 times greater in patients dying of asthma com-
pared with control subjects, closer supervision of
-agonist use should reduce asthma mortality.
Structured educational plans to teach management
may also offer improved mortality statistics in
Annotated Bibliography
Environmental allergen exposure
Upper respiratory viral infection
Aspirin and nonsteroidal antiin ammatory drug ingestion


ABPA,Ó and 7 patients were classiÞ
ed as having Òend-stage
ABPA.Ó


103


Asthma (Braman)


This article reviews the literature on asthma or use of anti-
asthmatic drugs during pregnancy.


In asthmatic patients, chronic inß
ammation of the airway
wall results in an abnormal repair process. Changes that
occur include subepithelial Þ brosis, smooth-muscle hyper-
plasia and hypertrophy myoÞ
broblast hyperplasia, epithelial


National Asthma Education and Prevention Program.
Expert panel report 3: guidelines for the diagnosis and


ne the historical and clinical features of vocal cord dys-


are the links? Curr Opin Allergy Clin Immunol 2005;


110


111


112


113
 Provide a brief overview of normal exercise physiology
and responses
shown to accurately predict important outcomes,


114
Cardiopulmonary Exercise Testing (Marciniuk)
Circulation and muscle blood 
(peripheral vascular resistance)
(capillary-tissue diffusion)
stores
(respiratory enzymes)
Venous O
Similarly, the removal of carbon dioxide (CO
),
Meanwhile, when the inspired CO
tion is negligible, the respiratory response to exer-
cise can be represented by the following
where V
is minute ventilation, the sum of alveolar
is the ratio of physiologic dead space to
tidal volume. These relationships are used to
understand the ventilatory response during exer-
are associated more closely
. Graphical representations of
how the respiratory and cardiovascular systems
Respiratory system responses during exercise.


115
is not brought about by a 20-fold increase in any
Cardiovascular system responses during exercise.


116
Cardiopulmonary Exercise Testing (Marciniuk)
of the most frequent reasons for testing in the
new equipment now produces
nary function testing equipment, exercise testing


117
procedures should be explained, and informed
consent should be obtained. A brief review of the
Measured and derived ventilatory measurements.


118
Cardiopulmonary Exercise Testing (Marciniuk)
responses and constraint. Both incremental and
endurance protocols may be used, and the results
from endurance exercise testing have been found
to be more responsive to a treatment effect than
either incremental exercise or 6-min walk testing.
If a thorough evaluation of exercise performance
is required, particularly in patients with multiple
dictated by the clinical question being addressed
and, in part, by responses demonstrated by the
Table 2.


119
A reduced peak V
is the starting point for


Cardiopulmonary Exercise Testing (Marciniuk)
Cardiovascular responses during exercise in different clinical situations.
Noninvasive estimations of the AT.


Oxygen Pulse
to HR is referred to as the
and is often used as a correlate of SV
during exercise. Although under ideal conditions
this relationship generally holds true (see equa-


Cardiopulmonary Exercise Testing (Marciniuk)
shown in Figure 5 (bottom left). The initial increase
has still not
increased) that typically occurs in concert with
Respiratory responses during exercise in different clinical situations.


; Fig 9:  ow vs volume). In
cant obesity and central airway obstruction also
demonstrate distinguishing responses.
of  ow-volume curves during exercise is also espe-
cially useful in helping to assess a therapeutic
response.
14,15
In these examples, the end-expiratory lung
volume, the inspiratory reserve volume, and the
presence/absence of 
tinguish the various disease states from normal,
these changes being unique and characteristic. The
value of  ow-volume curves during exercise is
Behavior of operational lung volumes during exercise.
Maximal and tidal  ow-volume curves at rest and during exercise.


Cardiopulmonary Exercise Testing (Marciniuk)
latter is rarely reproduced in the clinical laboratory.
A reduced Pa
with an abnormally widened
diffusion limitation, potentially accompanied by a
decrease in the mixed venous P
10 mm Hg at rest
but may normally increase to
20 mm Hg during
exercise. Values
35 mm Hg are abnormal and
indicate possible gas exchange abnormalities.
Occasionally, a less-than-optimal substitute, Sp
are not appreciably different during exer-
cise when compared with rest.
ciency. An increase in V
represents an
increased inef ciency of ventilation, which requires
an increase in V
is
highly dependent on the breathing pattern because
a rapid shallow breathing pattern increases V
is
calculated from the Pa
where the P
is the mixed expired CO
value of
directly by collecting expired gas and measuring its
concentration. This test can easily be performed
with a mixing chamber or, for breath-by-breath sys-


It should be understood that the variability
the speci c variable examined. However, it appears
reasonable to assume that differences in most mea-
surements obtained during CEPT should exceed
approximately 12 to 20% to be considered clinically
cant (
, twice the coef cient of variation)
and not caused by inherent variability alone.


Cardiopulmonary Exercise Testing (Marciniuk)
variables) while the ECG, BP, Sp
, and perceived
exertion (Borg scale) is monitored during a
maximal symptom-limited incremental exercise
should also be monitored to accurately assess/
understand the degree of ventilatory constraint.
Table 5.
Characteristic Patterns of Response During Exercise Demonstrated in Various Disease States*
Variable
Heart Failure
COPDILD
Vascular Disease



various responses, including exercise limiting
his expert assistance in the preparation and review
of the  gures and the manuscript.
References
1. Jones NL. Clinical exercise testing
delphia, PA: Saunders, 1997
2. Gallagher CG. Exercise and chronic obstruc-
tive pulmonary disease. Med Clin N Am 1990;
3. Palange P. The prognostic value of exercise testing.
Breathe 2009; 5:229234


Cardiopulmonary Exercise Testing (Marciniuk)


129
dioxide for each calorie expended. In patients with
limited ventilatory reserve, an increase in V
may
culminate in an increase in Pa
Reduced
Any disorder causing a reduction in V
will
increase Pa
. This occurs with three types of
(the product of respiratory rate and
reduced.
is reduced. Even if the overall V
or high, the portion of each breath that is dis-
increases, and
is reduced. If V
does not increase propor-
tionally, Pa
increases. This occurs commonly
in patients with rapid, shallow breathing pat-
increases, with normal or high V
Vt.
An extreme example would be a patient
xed V
embolism. Here, although V
remain the
same, the increase in V
that results from
the newly underperfused lung units reduces
and increases Pa
Disorders of Ventilation
Central Control
The medullary central controller sends signals


Hypercapnic Respiratory Failure (Rosen)
Ondine’s curse) and inborn failure of autonomic
control of breathing, linked to mutations in the
PHOX2B gene; (2) central sleep apnea; (3) over-
doses with narcotics or sedatives; (4) diseases of
the medulla (infarct, tumor); (5) hypothyroidism;
ammatory demyelinating
polyradiculopathy; others are acute motor and


treatments confers no additional bene
t. There is
no established role for therapy with corticosteroids
in this disorder.
Critical illness polyneuropathy (CIP) is an acute
sensory-motor disorder that mainly affects the
consequence of microcirculatory damage caused
by decreased perfusion or endothelial injury from
a systemic in ammatory cytokine response. Criti-
patients and that usually occurs with CIP. Because
CIP and CIM usually overlap, the term
ness polyneuromyopathy
tiorgan failure, and hyperglycemia often are cited
rmed because of


Hypercapnic Respiratory Failure (Rosen)
augmentation of muscle action potential with
The expiratory muscles (internal intercostal and
abdominal) are not used during resting breathing
because exhalation is passive. However, they con-
is increased and are essential
to the cough re ex. The internal intercostals depress
the ribs, and the abdominal muscles depress the
lower ribs and pull the abdominal wall inward.
Muscle Weakness
Weakness is de ned as a reduced capacity of a
rested muscle to generate an expected force. Weak-
ened inspiratory muscles may be incapable of
performing the work of breathing, leading to
hypercapnia. Expiratory muscle weakness impairs


hypercapnia. When acidosis impairs the contractile
force of respiratory muscles, a positive feedback
loop of respiratory muscle weakness and respira-
ation places the inspiratory muscles
at mechanical disadvantage, largely because of a
reduction in muscle length. Inspiratory muscle
ation is more pronounced
in acute disorders like severe asthma than in
COPD. With time, remodeling of sarcomeres
restores them to normal length, and the proportion
of slow-twitch muscle  bers increases. These adap-
tive responses improve contractile function and
increase resistance to fatigue. Also, many patients
with COPD lose weight; these patients have
increased circulating levels of tumor necrosis fac-
tor-
, which promotes muscle wasting and weak-
ness. The benefits of lung volume reduction
surgery (LVRS) in patients with severe COPD are
probably attributable to enhanced ventilatory
pump function; LVRS reduces hyperin
ation and
air trapping, improving diaphragm mechanics and
increasing V
Assessment of Respiratory Muscle Strength
In clinical practice, the strength of respiratory
muscles usually is measured with maximal pres-
sures at the mouth against a closed airway (maxi-
mum inspiratory pressure, maximum expiratory
pressure). The “gold standard” measurement, used
more in scienti
c investigations than in clinical
practice, is transdiaphragmatic pressure (Pdi) dur-
ing a maximal inspiratory effort. Pdi is calculated


Hypercapnic Respiratory Failure (Rosen)
gen consumption can be maintained by increased
cardiac output and augmented oxygen extraction
from capillary blood.
When respiratory muscles are fatigued, the
EMG power spectrum is shifted, with increased
low-frequency and decreased high-frequency com-
ponents. Dyspnea and tachypnea are common.
Respiratory alternans, the alternating recruitment
and derecruitment of the diaphragm and other


Concise summary of mechanisms, speciÞ c disorders, and
Neuromuscular Disorders


Hypercapnic Respiratory Failure (Rosen)
improvements in exercise capacity and maximum voluntary
ventilation, and patients with hypercapnia have reductions
improve.
Hypercapnia After Oxygen Administration
These studies exploring the mechanisms of hypercapnia after
shows that increased wasted ventilation is the major factor
whereas the latter holds that both increased dead space and
reduced total ventilation are responsible.


137
 Review the basic plain radiograph and cross-sectional
anatomy and pathology of the tracheobronchial tree, lobar
 Evaluate the role of CT pulmonary angiography in the
diagnosis of both acute and chronic pulmonary thrombo-
Tracheal Stenosis
Most tracheal stenoses are complications of
tracheal intubations. Narrowing occurs at the tho-


Thoracic Imaging (Shah)


in those who are intubated, a mucus plug is the
help identify the atelectasis and site of endobron-
chial obstruction. The major sign of lobar atelec-
tasis is opaci cation of the affected lobe due to
airlessness and displacement of the interlobar
fissure. Secondary signs of atelectasis include
displacement of the mediastinal structures, eleva-
tion of the hemidiaphragm, decrease in the dis-
tance of the intercostals spaces, displacement of
the hila, and compensatory overin ation of the
remaining lung. Discussion of the major and
minor radiographic features of the main lobar
atelectasis follow.
Right Upper Lobe Atelectasis
On the frontal chest radiograph, the right
upper lobe collapses superiorly and medially, cre-
hemithorax. The major  ssure is displaced anteri-
ssure is displaced upward.
carcinoma may produce a characteristic appear-
ance on the frontal chest radiograph, termed the
“reverse S-sign” of Golden. On the lateral projec-
Left Upper Lobe Atelectasis
When the left upper lobe collapses, the frontal
tion in the left perihilar area with partial obscura-


the lower extremities. Emboli are often multiple,
and they have predilection for the lower lobes of
the lung. This predilection is likely related to
increased blood  ow in the lower lobes.
CT Technique
In recent years, great advances have been made
in the CT technology. Because of its ability to
directly visualize PE noninvasively and with high


corresponds to the region of the anterior junction
line noted on the frontal chest radiographs. Nor-
mal structures that are present in this location
include the thymus gland, lymph nodes, and fat.
The differential diagnoses of lesions in this space
mic cyst); lymphoma; teratoma; aortic aneurysm;
momas account for the majority of the lesions in
this space. On CT, they appear as round or lobu-
lated soft-tissue density lesions. Most of them
istration and may contain calcification. Most
of the thymomas are encapsulated and conside-
red benign, but roughly 30% demonstrate inva-
sion through the fibrous capsule and are
considered malignant. Imaging features that sup-
sion of mediastinal structures, including the
superior vena cava and great vessels; (2) chest
wall invasion; and (3) contiguous spread along
pleural surfaces.
Cardiophrenic Angle
This region is situated anterior and to the right
of the heart. Typically, this region contains fat and
space are benign and include prominent fat,
lipoma, pericardial cyst, and Morgagni hernia.
Occasionally, they may contain lymph nodes from


including benign and malignant neoplasms,
administration
for up to 4 min at 1-min intervals. Attenuation of
the nodule is measured before and at the peak of
contrast enhancement. Those nodules that enhanced
15 Houns
eld units (HU) are strongly predictive
15 HU


include the following: (1) suspected diffuse lung
disease, (2) for possible prebiopsy workup, and
(3) assessment of disease activity. Knowledge of
ow of
lymphatics within the pulmonary interstitium are


Fraser RS, Pare PD. Diagnosis of diseases of the chest.
4th ed. Philadelphia, PA: W. B. Saunders, 1999
Webb WR, Muller NL, Naidich DP. High resolution CT
of the lung. 3rd ed. Philadelphia, PA: Lippincott, Wil-
liams and Wilkins, 2001
Tracheobronchial Tree
Gamsu G, Webb WR. Computed tomography of the
trachea and mainstem bronchi. Semin Roentgenol
nosis. Chest Surg Clin N Am 1996; 6:725–731
trachea and main stem bronchi: correlation of CT
with pathologic  ndings. Radiographics 1992; 12:647–


145


Thoracic Imaging (Shah)


147
ventilation. This section will review the general


cence. The obvious example is the com-
Table 1.
other health professionals when indicated.
6. A physician shall, in the provision of appropriate patient care, except in emergencies, be free to choose whom to serve, with
whom to associate, and the environment in which to provide medical care.
7. A physician shall recognize a responsibility to participate in activities contributing to the improvement of the community


other unit of resource fairly to all who would
qualify to receive it. At the same time, we should
advocate vigorously for rational health policies
that would provide proper care to those who need
what such care can provide.
consent from patients before initiating treatment,




Regardless of the process of extubation, there
is no evidence that increasing the dose of benzodi-
azepines and opiates before extubation with the
with a shorter time to death after extubation.




153
 Review the de
nition of COPD that describes this dis
ease
ammatory condition
 Explore the impact of COPD, including rates of morbidity
 Review the risk factors for COPD
 Explore the natural history of COPD from its earlier
 Explore the current understanding of the pathophysiology
mation and parenchymal lung destruction.
 Explore the systemic consequences of the disease and the
 Review the current state of pharmacologic and non-
pharmacologic therapy for COPD, including preventive
mea sures such as smoking cessation.
chronic bronchitis; COPD; emphysema; natural
history; risk factors; treatment
nition and Epidemiology
Internationally, the accepted definition of
COPD is as a disease state characterized by chronic
ow limitation attributable to chronic bronchitis
and emphysema. Chronic bronchitis has been
ned in clinical terms: the presence of chronic
productive cough for at least three consecutive
chronic productive cough must been ruled out.
by its pathologic description: an abnormal enlarge-
ment of the air spaces distal to the terminal bron-
chioles accompanied by destruction of their walls
and without obvious fibrosis. Contrary to this
traditional view, recent data have shown that
impact, there has been increasing interest in the
pathogenesis and management of COPD. It has
largest disease burden in the world, with projec-
fth by the year 2020.
In the United States, estimates from national inter-
views taken by the National Center for Health
16 million people are
icted with COPD; about 14 million are thought
to have chronic bronchitis, whereas 2 million have
emphysema. It is likely that these statistics under-
estimate the prevalence of COPD by as much as
50% because many patients underreport their
symptoms and remain undiagnosed.
tion Survey (NHANES) III the prevalence of COPD
tistics were derived using telephone surveys and
tion testing of randomly selected subjects. The
average number of days of restricted activities
reported by patients with COPD is very high,
ranking this condition among the highest chronic
conditions for this measure of morbidity in the
leading cause of disability-adjusted life-years in
COPD is a leading cause of hospitalizations in
talizations were attributed to COPD, and 7% of
pitalization. From 1995 to 2000, the trend in COPD
hospitalization rates was about the same for men
and women. However, the rates were slightly
greater among black than white patients during this
same period. In 2000, the COPD hospitalization
rates were 31.5 and 36.0 per 10,000 persons for white
and black subjects, respectively. More striking are
COPD statistics regarding the elderly. Nearly 20%
Chronic Obstructive Pulmonary Disease


Perhaps even more striking and ominous are
the magnitude and trend of the mortality rates for
as cardiovascular disease and stroke were decreas-
ing. During the same time period, the mortality
rate for COPD was increasing at an alarming rate.
For example, the US death rate for COPD rose
almost 33% during the years 1979 to 1991, resulting
in COPD becoming the fourth-leading cause of
death in this country. Although the death rate for
men has reached a plateau in recent years, among
women it has continued to increase. In 1998, 54,615
men and 51,377 women died from COPD. From
1995 to 1998, the death rate for COPD increased
time more women died from COPD than men.
The cost of COPD has also increased dramati-
cally. In 2002, it was estimated to be $32.1 billion.
Direct medical services accounted for $18.0 billion,
and the indirect cost of morbidity and premature
mortality was $14.1 billion. Medicare expenses for
COPD bene ciaries were nearly 2.5 times that of
the expenditures for all other patients. The cost per
patient in other countries around the world varies
depending on how health-care is provided and


 Bronchial hyperresponsiveness, the exagger-
ated bronchoconstrictive response to nonspe-
Table 1.


changes are not predictive, because only 15 to 20%
of these heavy smokers will develop an accelerated
decrease of their FEV
over time and clinically
evident COPD. The differences in susceptibility to
tobacco smoke injury are likely to be related to
have a reduced serum AAT level to approximately
20% of the normal level. Other rarely observed
phenotypes associated with very low levels of AAT
are Pi SZ, Pi null-null, and Pi null-Z. The normal
viduals with this phenotype have AAT levels of
150 to 350 mg/dL reported from most commercial
laboratories. Often the true laboratory standard
values are reported. Normal levels are 20 to
Most patients homozygous with the Z allele
are of northern European descent. Asian and Afri-


predicted of 35 to 49% had a slowing in their
decline in lung function compared with an un-
treated group. In addition to developing advan
ced
emphysema, hepatitis and cirrhosis, AAT defi-
ciency patients are at a 70 to 100% increased risk
of developing lung cancer.
Natural history of COPD. Accelerated decline in
whom the progressive disability of COPD develops.


of an aggressive smoking-intervention program
cantly reduced the decrease in their FEV
during a 5-year study period when compared with
those who continued to smoke. The inhaled bron-
chodilator ipratropium did not slow the decline of
lung function when given over the same time
The slowly progressive course of COPD is often
interrupted by a sudden change in symptoms and
lung function. These acute respiratory illnesses or
exacerbations are usually caused by viral or bacte-
rial infections and are heralded by an increase in
will often develop one to two exacerbations per
year; those with more severe disease are likely to
have many more. The exacerbations cause a
decrease in lung function for up to 90 days. There
is evidence that more frequent exacerbations play
a causal role in accelerating the development of
chronic air
ow obstruction.
Pathology and Pathophysiology
The pathologic changes in COPD are found in
the large and small (
2 mm) airways and in the
lung parenchyma (Fig 2). In advanced stages, there
are also changes in the pulmonary circulation, the
heart, and the respiratory muscles. Alveolar
hypoxia causes medial hypertrophy of vascular
layer into distal vessels that do not ordinarily con-
tain smooth muscle. Intimal hyperplasia also
occurs in advanced stages. These latter changes are
associated with the development of pulmonary
lar hypertrophy and dilation. Loss of vascular bed
the destructive alveolar processes. In some patients
with advanced COPD, there is atrophy of dia-


macrophages. Macrophages likely play an impor-
Table 3.
The Inß ammatory Cells of COPD
Neutrophils
trophils to airways
Increased numbers in sputum and BAL  uid, few in
Neutrophil numbers correlate with degree of air
obstruction


smoking. Increased quantities of certain proin
matory cytokines, including interleukin (IL)-8,
smokers and even further increased during an
acute exacerbation. Mediators found to be elevated
during a COPD exacerbation are listed in Table 4.
plays a key role in neovascularization and vascular
permeability and the in the expression of 
broblast
growth factors. Vascular remodeling changes have
also been inversely related to measures of lung
Other structural changes in the airways of
smokers include mucus hyperplasia, bronchiolar
edema and smooth muscle hypertrophy, and peri-
bronchiolar  brosis. These changes result in nar-
rowing of the small airways (
2 mm). Recent
studies suggest that the inflammatory cellular
ltrate, 
brosis, and muscle in the airway wall
show a progression worsening of pathologic
changes when nonsmokers, smokers with mild
COPD, and smokers with more severe disease are
compared, and there is a progression of the number


of compliance, nitrogen slope of the alveolar pla-
at low lung
75) are thought to re
ect small
airway narrowing. These pathophysiologic abnor-
2 mm have been referred to
as “small airway disease,” implying that it is a
distinct clinical entity. It is more important instead
to think of the early in ammatory changes in the
small airways as the first stage in a protracted
process that eventually leads to persistent air
obstruction and progressive decrease in the FEV
tive stress and proteolytic breakdown of connective tissue


Pathophysiology
The physiologic hallmark of COPD is the
limitation of expiratory  ow with relative preser-
vation of inspiratory  ow. Reductions in the FEV
/FVC percent are characteristic, whereas
the maximal inspiratory  ow rate is normal or near
normal. The degree of reversibility in COPD is
seldom brisk as it is in asthma. Differences in the
degree of reversibility in COPD and asthma may
many in ammatory mediators have been impli-
cated, including potent bronchoconstrictors such
as histamine, kinins, and prostaglandins. In con-
trast, there are few bronchoconstrictor mediators
released in COPD. One important in
mediator found in the sputum of patients with
tant for neutrophils. The term “partial reversibil-
has not been adequately de ned. Reversibility in
COPD patients can be acute, in response to bron-
chodilator drugs, mainly as the result of the release
of cholinergic tone. It also may be in response to
oral or inhaled corticosteroids, presumably as a
result of decreased in ammation. Studies have
small but signi cant degree of reversibility of air-
ow obstruction (de ned as a 12% and at least a
200-mL improvement in the FEV
dinal studies have suggested that increased revers-
ibility is associated with a greater risk of dying
from COPD, whereas others have suggested that
the presence of reversibility coupled with close
clinical treatment and follow-up is associated with


endothelin-1, IL-6, and circulating leukocytes
compared with normal subjects. Levels of VEGF,
mation, also have been shown to be increased in
tory cytokines in the blood of COPD patients
suggests that there is a persistent level of systemic
ammation, possibly caused by a “spill over”
of in ammatory from the in ammation that is
occurring in the airways, the lung parenchyma,
and the pulmonary vasculature. This latter theory
has not been proven. There is some evidence that
individuals with increased in
ammatory markers
such as fibrinogen and CRP are at risk for an
accelerated decrease in FEV
, greater rates of hos-
An analysis of the relative risk for systemic
disease in patients with COPD followed by general
practitioners has shown that patients with COPD
are at increased risk for glaucoma, angina, frac-
tures, myocardial infarction, osteoporosis, and
respiratory infection when compared with control
subjects without COPD. Anemia may occur in 10
to 15% of patients with severe COPD. Reduced
hemoglobin in patients on long-term oxygen
therapy has proven to be a strong predictor of
survival and is associated with a greater hospital-
ization rate and a longer cumulative duration of
hospitalization. In a nationally representative
sample of 47 million hospitalizations from 1979 to
2001, hospital discharges with a diagnosis of
COPD were more likely to be hospitalized with
pneumonia, hypertension, heart failure, ischemic
racic malignancies, and ventilatory failure when
compared with age-adjusted discharges without
COPD. Further, a diagnosis of COPD was associ-
ated with greater age-adjusted in-hospital rates of
mortality for pneumonia, hypertension, heart
failure, ventilatory failure, and thoracic malignan-
cies when compared with hospital discharges with
these comorbidities who did not have a diagnosis
COPD. These results suggest that the burden of
disease associated with COPD is largely underes-
timated because having a diagnosis of COPD is
associated with increase risk for hospitalization
and in-hospital mortality from other common
ammation, surfactant
protein D (SP-D), has been recently studied. SP-D
is a glycoprotein produced in the lungs. In addition
to regulating surfactant homeostasis, SP-D also has
a role in innate immunity and host defense
responses to microorganisms and inhaled particles.
Lung injury has been shown to increase levels of
be harmful. It has been associated with an increased
risk of atherosclerosis and poor clinical outcomes


the electrocardiograms of participants. The effects
of inhaled corticosteroids, newer antiin
tors, and statins on the cardiovascular and
overall rate of mortality of COPD patients are


patients with COPD and suspected PE, 19%
received a diagnosis of PE on pulmonary angiog-
raphy. Risk factors and symptoms were similar to
those with and without pulmonary embolus.
Recent studies have reported a 25% prevalence of
PE in a group of patients admitted to the hospital
for a severe exacerbation of COPD, but the study
results may not be generalized to most occurrences
of COPD because some patients in this study
were excluded if they had evidence of a potential
More recent evidence, which excluded the
diagnosis of PE on the basis of a normal
nostic imaging studies, showed a much lower
prevalence of pulmonary embolism. Only 6.2% of
suspicion, judged by emergency department phy-
sicians, were discovered to have PE. This study
showed that the prevalence of suspected PE in
patients presenting with a COPD exacerbation is
very low, and routine investigation for PE in this
group is not warranted. There are some important
lessons from these recent studies. When there is
no suspicion of infection, either viral or bacterial,
suspicion for PE in patients with a COPD exacer-
bation should be greater, especially in those
patients who are sick enough require hospitaliza-
tion as they my have more severe and debilitating
disease that predisposes them to PE. Other clues
that should increase clinical suspicion of pulmo-
nary embolism in COPD patients are a previous
history of malignancy and a decrease in the Pa
compared with baseline values. PE is a serious
comorbid condition in patients with COPD, and
a high clinical suspicion should be maintained in
Table 8.
GOLD Guidelines: ClassiÞ cation of Severity of COPD,
80% of predicted
With or without chronic symptoms (cough, sputum
production)
80% of predicted
III: Severe COPD
50% of predicted
IV: Very severe COPD
30% of predicted or respiratory/heart failure
Weight loss and anorexia


severity scoring on the basis of the severity of
ow obstruction: stage I is FEV
50% of pre-
35 to 49% of predicted, and
35% of predicted. Patients
with stage I disease usually have little impair-
ment in their quality of life. Patients with stage
II COPD have a signi cant impairment in the
quality of their lives, which results in a large per-
capita health-care cost. Patients with stage III
disease are profoundly impaired, are often hos-
pitalized with severe exacerbations of disease,
and therefore are frequent users of health-care
resources.
A new severity scoring system was introduced
by the GOLD guidelines (Table 8). It began staging
with an “at-risk” group, stage 0, to emphasize the
erentiation From Asthma
Table 9 lists the most common distinguishing


on COPD stated: “Some patients with asthma
cannot be distinguished from COPD with the
current diagnostic tests. The management of these
COPD: Outpatient Management
Once the diagnosis of COPD is established,
ing the disease. Pharmacologic intervention is
offered according to disease severity and the
patient’s tolerance for speci c drugs (Fig 4). The
goals of therapy are to induce bronchodilation,
decrease airway in ammation, and improve muco-
ciliary transport. Because COPD is basically an
irreversible condition, disease management of
life are most essential. The patient who still smokes
should be encouraged to quit. Preventive therapy
enza vaccine is recommended. Vaccination with
the  u shot has been shown to result in 52% fewer
uenza in
patients with COPD. Vaccinated patients also have
fewer outpatient visits for respiratory symptoms.
Smoking Cessation
Treatment plan from the GOLD guidelines.


COPD (Braman)


PR improves dyspnea, improves quality of life
scores, and reduces the number of hospitalizations
and days in the hospital; however, the effects on
survival are not de nite. PR has been shown to
help patients requiring long-term mechanical ven-
tilation by improving overall strength, weaning
Nutrition and COPD
Malnutrition occurs in one quarter to one third
of patients with moderate-to-severe COPD and is
an independent risk factor for mortality. Both fat
Noninvasive Positive Pressure Ventilation


subgroup analysis showed that those with upper-
lobe emphysema on CT scans and with low
exercise capacity at the beginning of the trial had
Given the potential risks of median sternotomy
and thoracoscopy, the usual surgical approaches
to LVRS, less-invasive procedures are being stud-
ied, including bronchoscopic LVRS, which is per-
formed with the placement of endobronchial
one-way valves. Preliminary studies have shown
improvement in exercise capacity and dynamic
hyperin ation with this procedure.
Resection of large bullae is occasionally neces-
sary for dyspnea, chest pain, or recurrent pneumo-
thorax. Other complications that can occur with
large bullae are bleeding and infection. The best
results occur when the bullae occupy more than
one third of the hemithorax. Factors that do not
favor surgical resection are the presence of multiple
small bullae and diffuse emphysema in the remain-
der of the lungs. No prospective clinical trials have
been performed. Case series have shown improve-
ment in dyspnea and even reversal of respiratory
failure after bullectomy. However, in those with
underlying emphysema there is a progressive


moderately severe COPD often show nonpatho-
Streptococcus viridans
sp, or
sp). Pathogenic bacteria include
Streptococcus pneumoniae
(10%), and
Moraxella catarrhalis
(9%). Sputum samples may
have limited validity considering the possible
environment are high. Small increases in SO
airborne particles have been shown to cause
increases in emergency room visits for COPD dur-
ing winter and summer seasons by 6% and 9%,
respectively. Whatever the cause of an acute exac-
erbation of COPD, it is clear that bronchial in
mation is enhanced during this event. Increased
levels of myeloperoxidase have been found in the
sputum, indicating neutrophilic activity, and high
trophil chemoattractants, are also seen. During
recovery, levels of sputum chemoattractants and
ammatory markers rapidly decrease. Risk fac-
tors associated with COPD exacerbations are listed
in Table 10.
Diagnostic and Therapeutic
Approaches
Often, patients present to a local emergency
of COPD. It is useful to do a chest roentgenogram.
The chest roentgenogram may be positive in
approximately 15% of cases, and in 25% of such
patients there is a change of management promp ted


on which to rely. The best indicators for the need
values on admission and the degree of change in
pH after initial oxygen therapy. Signi
cant predic-
body mass index, poor functional status before
admission, lower ratio of arterial partial pressure
) over the fraction of inspired oxy-
gen ratio, history of congestive heart failure, low
serum albumin, and presence of cor pulmonale.
Most therapeutic interventions for the treat-
ment of the acute exacerbation of COPD have been
studied through randomized controlled trials. In
general, mucolytic agents are ineffective in shorten-
ing the course and improving the outcome of
patients. Chest physiotherapy and mechanical
percussion of the chest are also ineffective and
cholinergic agents appear to be equivalent in their
usefulness and are superior to all parenterally


impaired mental status causing an inability to
by dividing weight (in kilograms) over height
). Values
21 kg
are associated with
increased rates of mortality. Functional dyspnea
lows: 0, not troubled with breathlessness except
with strenuous exercise; 1, troubled by shortness
of breath when hurrying or walking up a slight
because of breathlessness or has to stop for breath
for breath after walking approximately 100 m or
after a few minutes on the level; and 4, too breath-
less to leave the house or breathless when dressing
or undressing. A simple grading index, the BODE
index, has been proposed as a useful tool to grade
COPD severity and predict outcomes. The system
uses the body mass index (B), the degree of air
obstruction measured as the FEV
as percent pre-
dicted (O), dyspnea measured by the MRC dys-
pnea scale (D), and exercise capacity measured by
the six-minute walk test (E). Patients with greater
BODE scores were at greater risk for death. The
Table 11.
Outcome Measures for COPD (Morbidity/Mortality)
Exercise capacity


COPD (Braman)


els correlate with sputum cells counts of inß
ammatory cells.
The cell counts and cytokine levels do not predict the size
Biskobing DM. COPD and osteoporosis. Chest 2002;
This review discusses the problem of osteoporosis in advanced
COPD. Bone loss factors are diverse and include smoking,
vitamin D deÞ ciency, low mass index, hypogonadism, sed-
entary lifestyle, and the use of corticosteroids. Effective
strategies to prevent bone loss including calcium and vita-
min D are discussed. The use of calcitonin and bisphospho-
nate administration is also reviewed. Because up to 60% of
patients with advanced COPD have osteoporosis, the causes
and approaches to osteoporosis in COPD are extremely


produce the observed functional changes. Further studies are


irreversible obstructive changes occur. These changes may lead
and high rates of morbidity and
mortality. If the susceptible group stopped smoking, their rate


disease bene t from noninvasive positive-pressure
ventilation? A systematic review of the literature. Ann
This study examined selected randomized control trials
ity to standard care was shown in this systematic review to
decrease the rate of endotracheal intubation by 28%, length
of hospital stay 4.5 days, and reduce mortality rate by 10%.
The subgroup analysis shows that the beneÞ
cial effects
occurred only in patients with severe exacerbations (pH
7.30) and not in those with milder exacerbation).


these fractures is greatest in men who continuously use sys-
temic steroids.


COPD (Braman)


selected patients with advanced COPD. Finally, pulmonary
rehabilitation appears to beneÞ t patients with chronic lung


patients had shorter-duration exacerbations compared with


ammation in chronic obstructive pulmonary dis-
ease. Circulation 2003; 107:1514–1519


rate of mortality. Those with an FEV


185


COPD (Braman)


187

Important Considerations for Testing
The Patient
Testing is demanding, and results will be less
meaningful in patients who are not physically
capable of providing consistent, optimal effort. It
is recommended that testing not be performed
within 1 month of an acute coronary syndrome or
myocardial infarction.
Similarly, patients with
those with confusion or signiÞ cant dementia, are
likely to generate suboptimal test results.
Table 1.
¥ Evaluate symptoms, signs, or abnormal investigations
¥ Assess and monitor the effect of disease/intervention/
exposure on pulmonary function and respiratory


Pulmonary Function Testing (Marciniuk)
The Laboratory and Equipment
It is essential that unintended factors do not
contaminate the results and subsequently lead to
1. Proper hand-washing should be performed and
2. Reuseable mouthpieces, valves, mouthpieces,
and manifolds must be appropriately disin-
3. Disposable equipment, sensors, and devices
should be discarded, never reused, even if dis-
4. Sterilizing and disinfecting techniques should
be strictly adhered to and should be established
in consultation with the manufacturerÕs rec-
control divisions.
5. In patients with known or suspected transmis-
sible infectious diseases, additional precautions
(a)
the use of equipment solely reserved for use


for training courses are available. A period of men-
seasoned technicians is a crucial one for new staff.
Opportunities for ongoing professional develop-
ment should be availed to staff, ensuring that train-
ing and skills remain current, and upgraded when
appropriate. This development is particularly
important with alterations to equipment or changes
in pulmonary function testing standards. Although
manufacturers frequently provide training for new
equipment or signiÞ cant upgrades, laboratories
significant changes in pulmonary function can
occur while values still remain within the normal
of the most appropriate reference value regression
equations to use in the clinical laboratory.
In general, a number of observations regarding
lung function measurements in the population are
1. Male patients have larger lung function than
2. Lung function values plateau when patients
are 20 to 35 years of age.
decreases approximately 30 mL/yr.
4. Vital capacity decreases, whereas the residual
volume increases with age, leaving total lung
capacity the same. The diffusing capacity
decreases with age.
5. Taller individuals have larger lung volumes
and greater maximal ß
ow rates.


Pulmonary Function Testing (Marciniuk)
function test results, if serial testing is undertaken,
comparison with the patientÕs previous values is
more appropriate and meaningful.
c values for ÒnormalcyÓ are controver-
sial, but in general, there is a move toward report-
lower limit of
The basic variables of interest are the FVC and
, which both are expressed at body tempera-
ture, ambient pressure saturated with water vapor


191


Pulmonary Function Testing (Marciniuk)
Maximal Flow-Volume Curve
The maximal ß ow-volume curve is helpful in
tidal breathing at rest, is typically asked to
inspire to total lung capacity (TLC) and then
expire with maximal force until empty, down to
residual volume (RV), followed by a maximum
inspiration back up to TLC. Evaluation of the
efforts is the same as noted previously, although
the inspiratory portion of the curve is often
assessed only qualitatively. A volume vs time
plot and a flow vs volume plot for the same
maneuver are shown in Figure 2. Other measure-
ments also are possible (volume vs time
plot shown in Fig. 3, where measured volumes
are shown in clear bars and summed capacities
are shown in shaded bars).
The vital capacity (VC) is the volume of gas
that can be expelled from full inspiration to com-
Volume vs time and ß ow vs volume plots.
Reversibility Testing
bronchodilator is frequently undertaken in the
PFT laboratory. Baseline testing is followed by
administration of a short-acting bronchodilator,
after which repeat testing is repeated. Either a
g, with
repeat testing at least 10 min afterward) or anticho-
linergic (
, ipratropium, 160
g, with repeat testing
at least 30 min afterward) can be used.
Current
recommendations are for increased doses of the
bronchodilator (four puffs vs two puffs) as noted
previously, unless there is concern for the patientÕs


heart rate or tremor. An increase in either the FEV
12% and
200 mL is now consid-
ered a ÒpositiveÓ bronchodilator response.
It
should be recognized that the utility of a broncho-
L/s, whereas most portable monitoring instru-
ments display results in L/min. The measurement
(and derived/related variables) is highly depen-
dent on lung volume and effort. After achieving
ation, the patient should deliver the blow
without hesitation. A delay of as little as 2 s can
alter tracheal viscoelastic properties enough to
cause a reduction in the PEF by as much as
Work on the measurement and clinical utility
of the PEF are ongoing. These measurements are
but difÞ culties have been experienced with too
much trust in the measurement. There are many
other related and derived variables from the PEF
(Fig. 4), but they have not been proven to be equal
bution has largely been superseded by the FEV
and FVC and is now rarely measured. It may be


Pulmonary Function Testing (Marciniuk)
Lung Volumes
Measurement of absolute lung volumes is more
Peak expiratory ß ow and derived variables in ß


compressible gas within the thorax. In normal


Pulmonary Function Testing (Marciniuk)
may be used, although both tend to underestimate
lung volume when airway obstruction is present.
For nitrogen washout, the washout is satisfactory
1.5% for at least
3 successive breaths.
For He rebreathing, a typical
gas mixture inspirate is breathed until equilibration
is reached, when the change in He concentration
0.02% for at least 30 s.
If only room air is
added to the 10% He gas mixture, it is important
to ensure adequate O
replacement during the test.
Both measurements must be corrected to BTPS,
and the volume of the equipment dead space
using Capacity
The carbon monoxide diffusing capacity of the
the rate of carbon monoxide (CO) transfer from the
lungs to the blood, with values reported in
mL/min/mm Hg (standard temperature [0
C],
pressure [760 mm Hg], dry). A number of both
structural and functional properties inß
uence the
capacity of the lung to exchange gas across the
alveolar-capillary border. These include the
volume
and distribution of ventilation, mixing and diffu-
the alveolar membrane and lung parenchyma, the
tion and binding properties of hemoglobin (Hgb),
As a test of gas transfer, CO uptake by the lung
can be measured by a number of techniques
, steady-state, intrabreath, rebreathing, and
single-breath techniques), but the most commonly
) can affect CO uptake. Therefore, it is
as possible. Because a reduction in V
15% may
cantly reduce the measured


bin (COHgb), fraction of inspired oxygen, exercise
c adjustments should be
made for Hgb, COHgb, and fraction of inspired


Pulmonary Function Testing (Marciniuk)
Respiratory Muscle Pressures
Respiratory muscle strength can be assessed by
10 cm H
O. It must be emphasized
that testing is very dependent on a patientÕs effort
to the patient and by the use of a practice test. Other
potential sources of error in the measurements
include pressure gauge accuracy, the patient-device
The MEP measurement is similarly performed
except that the patient is instructed to inhale to
TLC and then blow out as hard and fast as he or
she can. In similar fashion to the MIP, the largest
positive pressure sustained for 1 s is recorded. After
resting for
1 min, the procedure is repeated for a
total of at least three times, with the intent of
obtaining repeat measurements with a variability
10 cm H
In both instances, the maximum value obtained
from the three suitable maneuvers should be
reported. DeÞ
nitive reference ranges for the MIP
and MEP have not been agreed on, although many
are available.
17,18
In general, a number of key
remarks are appropriate:
1. Values decrease with age, and are approxi-
mately one third lower in women when com-
pared with men.
2. In adults 18 to 65 years of age, the MIP should
65 years, the MIP should
3. In adults, the MEP should exceed 140 cm H
4. A MIP less than on third of normal predicts
hypercarbic respiratory failure.
5. A MEP
60 cm H
O predicts a weak cough and


Airway Challenges
Assessing airway responsiveness is most com-
suspected diagnosis of asthma, recognizing that
airway hyperresponsiveness (AHR) to exogenous
stimuli is a characteristic feature of the disease.
Testing can be performed by the use of a number
cally specific allergens, but uncommonly used
outside of the research laboratory) or nonselective
agents. Nonselective stimuli can be either direct


Pulmonary Function Testing (Marciniuk)
Table 9.
Obstruction
5th percentile of predicted
Reduced ß
ows at low lung volumes are not speciÞ
c for
small airways disease in individual patients.
A combined reduction in both FEV
commonly related to suboptimal effort. This pattern
may occasionally indicate airß ow obstruction, but
rmation requires absolute lung volume measurement.
Measurement of absolute lung volume measurement may
assist in diagnosing and assessing COPD and asthma.
5th percentile of predicted
assessment of acceptability and repeatability, inter-


201
Flow-volume curves in common respiratory disorders.
TLC assessed by gas dilution techniques will be


Pulmonary Function Testing (Marciniuk)
Flow-volume curves in physiologic central airway obstructions. A
variable intrathoracic obstruction; B
extrathoracic obstruction; C
physiologically Þ xed central airway obstruction.


schemas exist (see Table 10).
3133
It is therefore
recommended that clinicians choosing to use a
c classiÞ
cation system should recognize
procedure manual. 2nd ed. New York, NY: Ameri-


Pulmonary Function Testing (Marciniuk)


205
 Review the indications for 
exible and rigid bronchos-
 Review the diagnostic yield from various bronchoscopic
procedures
 Review the procedures available to the interventional
 Stress the need for speci c training in advanced proce-
dures
airway obstruction; bronchoscopy; hemoptysis;
interventional pulmonology; laser; lung cancer; pleuroscopy;
bronchoscopy.
that time, the flexible bronchoscope has been
tic tool for both diseases of the parenchyma and
central airways. With the miniaturization of elec-
tronic devices, the 
rst video bronchoscope was
introduced in 1987. This development allowed
endoscopic pictures to be printed out and shared
and, even more importantly, physicians no longer
needed to look through an eyepiece. Instead, the
endoscopic image could be projected onto moni-
tors, allowing everyone in the room to see what
was happening in the airway.
Little has changed in the appearance of bron-


Bronchoscopy and Interventional Pulmonology (Feller-Kopman)
segment of the right lower lobe), as well as the num-
, RB6) as initially proposed by Jackson
It is also important to
appreciate mediastinal anatomy, including intra-
thoracic vessels and lymph nodes, as well as their
relationship to endobronchial landmarks. These will
serve as reference points for transbronchial needle
aspiration (TBNA) and endobronchial ultrasound
(EBUS) and help avoid injury to the patient should
the bronchoscopist use therapy such as the Nd:YAG
laser or brachytherapy. The use of endoscopic
simulators has been associated with a more rapid
acquisition of bronchoscopic expertise.
Diagnostic Bronchoscopy
There are many indications for diagnostic
bronchoscopy. The most common indication is
for the diagnosis of suspected lung cancer. Other
indications include evaluation of diffuse lung dis-
ease, in ltrates in the immunocompromised host,
hemoptysis, and cough. Additionally, bronchos-
copy with bronchoalveolar lavage (BAL) and/or
brushing may be useful for the diagnosis of ventila-
tor-associated pneumonia.
15,16
Cancer Diagnosis and Staging
Lung cancer is the leading cause of cancer
approximately 161,840 deaths in 2008, more than
colon, breast, and prostate cancers combined.
is estimated that there were 215,020 new cases of
ber of lung cancer deaths continues to increase
Bronchos-
copy provides a minimally invasive approach
for the diagnosis tumors in the central airways.
parenchymal lesions, advances in navigation such
sampled next because this would be considered an
N2 node if involved with cancer. Only if sampling
proceed with addressing the left lower lobe mass.
working channel and make the TBNA a false-posi-
tive  nding, precluding the patient from curative
surgery.
There are several available tools by which to
obtain specimens during bronchoscopy, including
forceps biopsy, brushing, bronchial wash/lavage,
and TBNA. Electrocautery snare forceps is an
excellent tool for the removal of a pedunculated
also provide excellent tissue for the pathologist.
The choice of the aforementioned modalities


uid have been shown to closely correlate with the
ammatory nature of the entire lower respiratory
30,32–34
Transbronchial biopsy (TBBx), brushing,
and TBNA can also be performed for peripheral
The diagnostic yield of BAL for peripheral
cancer ranges from 4 to 68%.
35–37
Without advanced
guidance (discussed in the next paragraph), the
yield for TBBx ranges from 49 to 77%; for
brushing,
it is 26 to 57%. However, again, the combination
of all three increases the yield to 68%.
TBNA
of peripheral nodules has been shown to have
a greater diagnostic yield than other sampling
38,39
TBNA being introduced
25 years ago, it remains
an underused technique, with only 12% of pulmon-
ologists reporting its routine use for the evaluation
of patients with suspected lung cancer.
40,41
nique, however, is incredibly useful. A study of 365
the use of standard TBNA (without EBUS) would
preclude further invasive surgery in 29% of patients
42,43
The yield with TBNA has
lymphoma), lymph node size, and
The use of CT fluoroscopy to guide TBNA
and TBBx has several advantages over standard
uoroscopy. As opposed to standard 
uoroscopy,
which is typically only used in two dimensions, CT


Bronchoscopy and Interventional Pulmonology (Feller-Kopman)
use Parenchymal Lung Disease
Diffuse parenchymal lung disease describes a
group of infectious and in ammatory and 
brotic
disorders that may involve the interstitial, alveolar,
bronchial, and vascular structures of the tracheo-
bronchial tree. The most commonly used sampling
techniques for patients with diffuse disease include
BAL bronchial brushing, TBBx and, occasionally,
endobronchial biopsy and TBNA.
Although associated with a low morbidity
and mortality, TBBx should be used only when
the potential results will have an impact on treat-
ment decisions. Diseases in which TBBx can prove
cantly increase the diagnostic yield as compared
with less-invasive means include lymphangitic
carcinomatosis, sarcoidosis, rejection after lung
transplantation, hypersensitivity pneumonitis


The Immunocompromised Host
The early diagnosis and initiation of the appro-
priate antibiotic administration is the cornerstone of
successful treatment of the immunocompromised
patient with pneumonia. Additionally, it is impor-
present simultaneously in these patients
noninfectious conditions may have a similar pre-
sentation of cough, dyspnea, fever, and an in
ltrate
diagnosis in immunocompromised patients.
In
been shown to be roughly the same,
67,68
the combined use of both techniques may increase
The results of BAL have been shown
to change disease management in up to 84% of
Unfortunately, although bronchoscopy
changed disease management in patients who
have undergone bone marrow transplantation, the
rate of mortality has remained extremely high.
64,71
Bronchoscopy with BAL remains a safe procedure,
even in the immunocompromised host. Brushing
and TBBx have been associated with a greater
incidence of bleeding complications in patients
who are thrombocytopenic.
The “gold standard”
remains open-lung biopsy, which can yield a spe-
c diagnosis in 62% of patients and result in a
signi cant increase in survival.
Hemoptysis
There are many causes of hemoptysis, includ-
ing infectious and inflammatory, vascular, and
neoplastic processes.
Although one would think
that the use of bronchoscopy can often aid in the
patient who presents with hemoptysis, a broncho-
The incidence of cancer is increased in patients
who present with hemoptysis and normal chest
imaging if they are
40 years of age, are male,
40 pack-year smoking history.
75–77
As such, bronchoscopy is recommended in this
patient population. Although the appropriate
timing for bronchoscopy is controversial, there
is a greater likelihood of identifying the bleeding
source when performed within the  rst 48 h of
The combined use of bronchoscopy
and CT is also recommended.
If patients are
clinically stable, I would recommend performing
the CT  rst because it can serve as a road map to
guide bronchoscopy.
Therapeutic Bronchoscopy
exible bronchoscopy, the rigid
bronchoscope is the preferred tool in many situa-
80,81
The rigid bronchoscope provides an air-
way in which to oxygenate/ventilate the patient as
well as pass multiple devices, including large-bore


Bronchoscopy and Interventional Pulmonology (Feller-Kopman)
is approximately 150 mL, I consider any amount
100 mL in 24-h period as massive. By using a
cheal tube or bronchial blocker and providing some
therapeutic aspiration to protect the “good” lung.
All bronchoscopists should become familiar with
bronchial blockers (
, Arndt Bronchial Blocker;
Cook Critical Care; Bloomington, IN), which can
be passed in parallel to the bronchoscope. These
often more than that is visually appreciated at the
time of the procedure.
Cryotherapy
Cryotherapy is a safe and effective tool for a


211
Electrocautery
Electrocautery uses alternating current at high
frequency to generate heat, which cuts, vaporizes,
or coagulates tissue depending on the power.
Electrocautery is a contact mode of tissue destruc-


Bronchoscopy and Interventional Pulmonology (Feller-Kopman)


stereotactic radiosurgery.
Other techniques of
virtual bronchoscopic navigation are also being
developed that do not require the presence of an


Bronchoscopy and Interventional Pulmonology (Feller-Kopman)
should be required for the majority of procedures
considered essential to the interventional pulmo-
nologists. Clearly, it is not necessary to obtain a
formal additional year of training to become an
expert in any one technique, such as EBUS. To fully
understand the diagnostic approach and available
essary skills to anticipate, prevent, and manage
complications in patients with complex central
airway or pleural disease, it is best to obtain for-
pulmonology.
References
1. Zollner F. Gustav Killian, father of bronchoscopy.
Arch Otolaryngol 1965; 82:656–659
2. Killian G. Ueber direkte Bronchoskopie. Muench
Med Wochen 1898; 27:844–847
3. Becker HD, Marsh BR. History of the rigid bron-
choscope. In: Bolliger CT, Mathur PN, eds. Inter-
ventional bronchoscopy. Basel: Karger, 2000; 2–15
4. Miyazawa T. History of the 
exible bronchoscope.
In: Bolliger CT, Mathur PN, eds. Interventional
bronchoscopy. Basel: Karger, 2000; 16–21


215


Bronchoscopy and Interventional Pulmonology (Feller-Kopman)


217


Bronchoscopy and Interventional Pulmonology (Feller-Kopman)


219
 Review the types of pulmonary disorders that occur in
 Understand how demographic factors, the degree
of immunosuppression, and the application of anti-
In many urban communities, AIDS-related dis-
eases are still the leading causes of death among
young adults.
The lung is a frequent site of opportunistic
infection in immunocompromised patients, and
noninfectious pulmonary disorders associated
Pulmonary Complications of HIV Infection
Table 1.
HIV-Associated Respiratory Disorders
S pneumoniae
H inß
P aeruginosa
Staphylococcus aureus
Moraxella catarrhalis
R equi
M tuberculosis
Other nontuberculous mycobacteria
P jiroveci
C neoformans
H capsulatum
Aspergillus fumigatus
Coccidioides immitis
Blastomyces dermatitidis
Protozoal infections
Strongyloides stercoralis
Toxoplasma gondii
Viral infections
Adenovirus
Herpes simplex
Primary effusion lymphoma
Carcinoma of the lung
Other disorders
Bronchitis
Bronchiectasis
Lymphocytic interstitial pneumonia
Nonspeci c interstitial pneumonia
Cryptogenic organizing pneumonia
Immune reconstitution in
ammatory syndrome


occur in patients with HIV infection, and their
typical radiographic patterns are summarized in
Table 2.
HIV-Associated Pulmonary Disorders
The pulmonary disorders associated with HIV
infection range from asymptomatic and mild
opment of each of these disorders is strongly
uenced by the severity of immunosuppression,
the patient’s demographic characteristics, the place
Early in the course of HIV infection, when the
immune system is not severely compromised,
respiratory disorders occur that are generally
Opportunistic infections occur only with severe
ciency.
reliable surrogate marker for immune function, the
risk of opportunistic infection, and the risk of pro-
gression of HIV disease. The measurement of HIV
activity with serum HIV RNA (called the
is used routinely to assess the response to treatment
Table 2.


with severe immunode
ciency (
count,
100 cells/µL), including disseminated nontuber-
tions, CNS toxoplasmosis, and cytomegalovirus
(CMV) disease. Therefore, common respiratory
problems such as sinusitis and bronchitis may
count, and bacterial pneumonia
and tuberculosis (TB) often occur before AIDS-
ning opportunistic infections and neoplasms.
Decreasing immune function increases the risk for
all HIV-associated respiratory diseases.
Demographic Factors
The increasing proportion of injection drug
users in the HIV-infected population was accompa-
nied by the recognition of bacterial pneumonia and
TB as important HIV-associated infections. Bacterial
pneumonia occurs more frequently than
pneumonia (PCP) in all HIV-infected groups,
cantly
greater in injection drug users than in other persons
Residence
The place of residence strongly in
uences the
risk of the development of speci c infections. The
high incidence of PCP in the United States and
Europe contrasts sharply with that in Africa, where


disease because it is an independent predictor of
progression to AIDS and mortality.
Streptococcus pneumoniae
are the most frequent bacterial pathogens
(Table 1). Pneumonia caused by Mycoplasma,
to be relatively uncommon, especially in patients
with severe immunosuppression.
an aerobic Gram-positive acid-fast bacillus, may
cause focal consolidation, endobronchial disease,
50 cells/µL),
even in the absence of risk factors such as neutro-
penia, corticosteroid use, and hospital-acquired
Nocardia asteroides
may cause nodules,
consolidation, cavitation, pleural effusions, empy-
ema, and intrathoracic lymphadenopathy in HIV-
The diagnosis and treatment of bacterial pneu-
all respects the same as that for patients who are
not infected. Patients usually present with fever,
chills, productive cough, and localized areas of
consolidation on chest radiographs. Although this
clinical picture strongly suggests bacterial pneu-
tion. Conversely, patients with bacterial pneumonia
may have diffuse pulmonary opacities that resem-
ble PCP.
Polyvalent pneumococcal vaccine is recom-
mended for all HIV-infected people, although those
counts are less likely to mount an
adequate antibody response. A vaccine against
with HIV infection is limited because most
infections are caused by other strains. Although
administration of the influenza vaccine is also
reco mmended, there are no data indicating that
patients with HIV infection are at an increased risk
of contracting in uenza or that the illness is more
severe than in the general population.
Pneumocystis jiroveci
Pneumonia
P jiroveci
ed as
was the  rst opportunistic infec-
tion described in patients with AIDS and has
always been a major cause of illness and death. The
term PCP has been used for decades, and rather
than changing our terminology to PJP to re
ect the
new nomenclature, a consensus exists that PCP be
used to refer to the term PCP. Once thought to be
a parasite, genomic analysis revealed that
P jiroveci
is in fact a fungus that infects only humans,
whereas
cient rats. The organism cannot be cultured reli-
ably outside the lung, and its source is still not
ed; therefore, the precise route of transmis-
Although ART and effective prophylaxis for
PCP have existed for years, this infection still
occurs frequently for the following reasons: many
until an opportunistic infection develops, other
patients know that they have HIV but are not
receiving medical care, and some patients are
receiving care and are not prescribed PCP prophy-
laxis or ART. Adherence to complex regimens with
intolerable side effects often is problematic, and
the development of resistant strains of HIV is com-
mon. Some patients receive prophylaxis for PCP
but are still so profoundly immunocompromised
that it is ineffective.
Patients with PCP usually present with fever
and gradually increasing cough and dyspnea for


fungal infections. Oxygen desaturation with exer-
cise is a relatively sensitive and speci
c test in
patients who are suspected to have PCP, but it is
In lung scans are highly
sensitive indicators of PCP, but isotope uptake also
occurs in other pulmonary infections and therefore
they seldom are useful.
Microbiological Diagnosis
P jiroveci
cannot be cultured
in vitro
; therefore,
the diagnosis of PCP can be con rmed only by
demonstrating organisms in a lung-derived
tion of hypertonic saline solution or by bronchos-
copy. Although establishing a diagnosis is not
cult, many clinicians treat patients with sus-
pected PCP empirically, reserving bronchoscopy
for patients who do not respond to treatment. The
examination of BAL  uid establishes the diagnosis
90% of cases, and some centers have reported
that bronchoscopic lung biopsy increases the diag-
nostic yield not only for PCP but also for other
Mycobacterium tuberculosis)
and noninfectious disorders. The optimal approach
to the diagnosis of HIV-associated pulmonary


end- expiratory pressure. Survival after respiratory
failure in PCP seems to have improved since the
early days of the AIDS epidemic and is perhaps
related to improved strategies for mechanical
ventilation. However, the development of respira-
tory failure in patients after several days of appro-
priate therapy for PCP or of a pneumothorax while
receiving mechanical ventilation portend a poorer
prognosis.
Prevention
Prophylaxis can be discontinued safely in
patients who achieve a sustained increase in CD4
200 cells/µL after starting
ART. In those patients who have a suboptimal
response to ART, lifelong anti-Pneumocystis
therapy is recommended for all HIV-infected
200 cells/µL
or for patients with HIV-related symptoms, includ-
ing unexplained persistent fever (temperature,
100F [37.8C]) for 2 weeks, oropharyngeal can-
didiasis that is unrelated to antibiotic or cortico-
steroid therapy, and unexplained weight loss.
Prophylaxis with TMP-SMX is most effective but
is associated with more adverse events requiring
the discontinuation of therapy with aerosolized
SMX is also inexpensive and prevents other infec-
tions, including cerebral toxoplasmosis and
Current expert opinion recommends the adminis-


ed from sputum or bronchoscopic speci-
mens, patients should be treated presumptively
M tuberculosis
is identi ed, mainly because TB is more common,


Life-threatening pulmonary aspergillosis may
pression. The following two common patterns of
disease have been identi ed: an invasive paren-
chymal infection, which is usually fatal, and a
predominantly bronchial disease presenting with
dyspnea and airway obstruction. The classic risks
for Aspergillus infection, namely, prolonged neu-
tropenia and treatment with high-dose corticoste-
roids, often are absent. Aspergillosis probably
occurs in patients with advanced AIDS because of
defects in neutrophil or alveolar macrophage func-
cells/µL, and the previous use of corticosteroids
and neutrophil counts of
500 cells/µL increase
aspergillosis include upper-lobe disease with
cavitation and hemoptysis. This diagnosis has
traditionally required histologic proof, because
Aspergillus is ubiquitous, and its presence in naso-


approximately 10% of cases because of the focal
distribution of the lesions. Therefore, the diagnosis
of pulmonary parenchymal KS is usually inferred
graph  ndings, or CT scan  ndings that suggest
this disorder; visual con rmation of airway lesions;
and no evidence of opportunistic infection in BAL
fluid or bronchoscopic lung biopsy specimens.
Patients with parenchymal opacities who have
ed
pulmonary infection are assumed to have paren-
When KS involves the pleura, effusions are usu-
ally exudative and sanguineous, but the cytologic
examination is nondiagnostic. Closed pleural
biopsy specimens are rarely positive for KS due to
the focality of the pleural lesions and the predomi-
nant involvement of the visceral pleura, rather than


patients, although the ef cacy and toxicity of che-
motherapy and radiotherapy may be different.
Other Pulmonary Disorders
Obstructive Lung Disease
There is a propensity for the development of
chronic bronchitis and bronchiectasis in patients
100
cells/µL). Therapy with standard antimicrobial
agents is usually effective, but symptoms are likely
to recur, especially when
from the sputum. The role and ef cacy of therapy
with bronchodilators and antiin
ammatory agents
in patients with HIV-associated airway disease
HIV infection also appears to accelerate the


of cervical intrathoracic lymphadenopathy, pul-
monary infiltrates, pleural effusions, or other
tuberculous lesions develop in these patients
shortly after starting ART, which is associated with
the restoration of cutaneous reactivity to skin
test antigens. Respiratory failure caused by IRIS
was reported in several cases after the introduc-
tion of ART after the successful treatment of PCP.
Other patients had apparent exacerbations of
disease after the introduction of ART after or
during
infection with MAC, cryptococcosis, CMV,
herpes zoster, hepatitis B and C viruses, and
the agent that causes progressive multifocal
leukoencephalopathy.
gested by a compatible clinical syndrome in a
patient who is recovering from an infection and
has begun receiving ART in the prior several
cyte counts usually are improved compared with
prior measurements, but the circulating CD4
count may be unchanged because these cells are
tic consideration but, in the absence of a severe


UNAIDS. 2007 AIDS epidemic update. Available at:
http://data.unaids.org/pub/EPISlides/2007/2007_
epiupdate_en.pdf. Accessed April 30,2008
Provides a


231


Pulmonary Complications of HIV Infection (Rosen)


233
Pulmonary Complications of Cardiothoracic
Surgery and Trauma
Bruce P. Krieger, MD, FCCP
Table 1.
Thoracic Surgical Procedures
Indication Approach Procedures
Resectional Thoracotomy Pneumonectomy,
lobectomy,
segmentectomy,
wedge resection, rib
resection
Thoracoscopy Wedge resection,
lobectomy
Diagnostic Thoracotomy Biopsy of lung, pleura,
pericardium,
mediastinal
structures,
adenopathy
Thoracoscopy Biopsy of lung, pleura,
pericardium,
mediastinal
structures,
nodes; diagnose
diaphragmatic
Therapeutic Thoracotomy Control hemorrhage/
pneumothorax/pleual
effusion/empyemas/
granulomatous
infections; lung
transplanats; LVRS;
others*
Control

pneumothoraxpleural
effusion/empyema,
infection;
LVRS;
others*
*Others = pericardial window, ligation of thoracic duct,
esophageal surgery, vagotomy.


Pulmonary Complications of Cardiothoracic Surgery and Trauma (Krieger)
The decreases in lung function that occur after
thoracic surgery are more complicated than the
changes that occur following upper- abdominal or
cardiac surgery because a functional lung is removed.
Following laparotomy, there is an
approximately
50% decrease in FVC for the  rst few postoperative
days. There are similar predictable decreases in lung
function following cardiac surgery, as described
later in this article. The effect of thoracic surgery
permanent but also more dif
cult to predict since it
depends on the amount of viable lung parenchyma
that remains following surgery. If the patient has
limited pulmonary reserve preoperatively, further
worsening following lung resection can result in
postoperative atelectasis, pneumonia, prolonged
mechanical ventilator support (MVS), or even
function tests have been utilized to predict postre-
section pulmonary function and thus screen for
patients who are at increased risk for postoperative


FVC. Initially, an absolute lower limit of acceptable
0.8 L based on an accepted dictum that hyper-
carbia frequently occurred in patients with COPD
0.8 L. However, Olsen and
associates suggested that further accuracy could
be obtained by this technique if the predicted post-
was corrected for the patient’s age,
, based on percentage of predicted
Markos and coworkers prospectively studied
scanning, PFT based on percentage of predicted,


Pulmonary Complications of Cardiothoracic Surgery and Trauma (Krieger)
Pulmonary Complications Following
Cardiac Surgery
Pulmonologists are frequently asked to partici-
following median sternotomy for cardiac surgery.
Respiratory failure is one of the most feared compli-
edema. Rady and Ryan analyzed the hospital out-
come of 11,330 patients and reported the following
predictors of extubation failure: age
65 years;
the presence of COPD, pulmonary hypertension,
severe left ventricular dysfunction, or cardiac shock;
requirement for hospitalization preoperatively; sur-


for MVS. Preoperative renal failure or mechanical
ed patients
at risk for readmission to the ICU.


Pulmonary Complications of Cardiothoracic Surgery and Trauma (Krieger)
of the right lung has also been reported in a high
percentage (61%) of patients following CABG. In
frostbite injury
to the left phrenic
nerve was introduced to describe the phrenic
nerve palsy that was associated with the use of
cold (speci cally, ice slush) cardioplegic solutions
intraoperatively. However, phrenic nerve conduc-
patients with left-lower-lobe atelectasis following
sternotomy had evidence for phrenic neuropathy.
Even so, most surgeons use a protective insulation


239


Pulmonary Complications of Cardiothoracic Surgery and Trauma (Krieger)
biopsy and the therapeutic treatment of choice for
or empyema. In addition, as discussed elsewhere in
approaches to LVRS.
Chest Trauma
Trauma remains the major cause of accidental
death in the United States. Thoracic injuries account
for approximately 37,000 deaths per year and signif-
icantly contribute to another 37,000 trauma-related
deaths. Fatal hemorrhage or an inability to secure
an adequate airway are the major causes of death
in one third of these injuries. Other life-
threatening
conditions associated with chest trauma are listed
in Table 4. The severity of the injury relates to the
magnitude and duration of the applied force, the
velocity and contact area of that force, body com-
pression that occurs in blast injuries and falls, and
the hyperdynamic stress response that follows
trauma. This stress response is manifested by an
increase in cardiac output, V
ide production, along with a decrease in systemic
vascular resistance and oxygen extraction relative
to oxygen delivery. It is believed that the posttrau-
matic “stress” results from cytokine release from
macrophages that stimulates increased toxic oxygen
radical production, PMN activation, and the release
of endotoxin from ischemic tissues. The pulmonolo-
gist is often involved after the initial resuscitation
to deal with problems such as hypoxemia (Fig 2)
associated with fractures,  ail chest, and pulmonary
myocardial injuries or tracheobronchial tears.
Tracheobronchial Tears
Although uncommon, tracheobronchial tears
may be life threatening and are frequently over-
tent barotrauma and air leaks persist following
blunt chest trauma. Hemoptysis is usually, but not
always, present along with concomitant fracture of
the  rst and second ribs. The tear is usually within
Bronchoscopic findings include lacerations,
transections, and bared cartilage that may be hidden
below “heaped-up” mucosa. Early surgical repair
is usually required except for small tears (less than
one third the circumference of the bronchus or
trachea). Stabilization often requires placement of


exible and therefore are less frequently fractured
by the same degree of force compared to older vic-
tims’ ribs. When  rst or second ribs are fractured,
suspicion is raised for injury to great vessels or to the
acceleration/deceleration during motor vehicle
accidents, or blast injury from explosions, can
result in disruption of the lung parenchyma. This
disruption is ampli
ed if the glottis is closed at the
time that airway pressure is suddenly increased.
It causes disruption of alveolar-capillary mem-
branes, intraparenchymal hemorrhage, an increase
in ventilation/perfusion mismatch, shunt, and
dead space as well as increased permeability and
extravascular lung water. Pulmonary edema fol-
lowing terrorist incidents is often complicated by
other tertiary effects, such as crush, shrapnel, or
ARDS can occur early or late. The treatment for
pulmonary contusion is similar to treating other
forms of ARDS except that concomitant injuries,
such as barotrauma and neurological injuries, may
require modi
cation of ventilatory strategies (such
as having to avoid permissive hypercarbia) that


Pulmonary Complications of Cardiothoracic Surgery and Trauma (Krieger)
Outlines the basis for the recommended preoperative physio-
logic assessment of a patient prior to undergoing thoracotomy
as outlined in Figure 1.


243


Pulmonary Complications of Cardiothoracic Surgery and Trauma (Krieger)
polymorphisms were associated with a signiÞ
cantly higher
rate of prolonged MVS following a CABG procedure.
Thoracoscopy
Chest 1999; 116:1409–1415
Reviews the indications for VATS and quotes a procedure-
related mortality rate of 0.24% Òin experienced hands.Ó
Loddenkemper R. Thoracoscopy: state of the art. Eur
Respir J 1998; 11:218–221
Comprehensive review of the diagnostic utility of ÒmedicalÓ
thoracoscopy as performed by pulmonologists in Europe.


245
Understand the various neural processes that control sleep
Describe the physiologic changes that occur during
Review the rules related to the scoring of sleep stages and
respiratory events in adults
: circadian rhythm; polysomnography; sleep; sleep
Sleep is a complex reversible state characterized
by both behavioral quiescence and diminished
responsiveness to external stimuli. Sleep is gen-
the main CNS excitatory neurotransmitter;
(4) GABA, the main CNS inhibitory neurotransmit-
ter and the main NREM sleep neurotransmitter;
(5) glycine, the main inhibitory neurotransmitter in
the spinal cord and is responsible for REM sleep-
related muscle atonia/hypotonia; and (6) hypocre-
tin, the dysfunction of which is responsible for
narcolepsy.
Sleep-Wake Regulation
Two basic intrinsic components interact to
regulate the timing and consolidation of sleep and
the sleep-wake cycle, and circadian rhythm, which
processes in
uence sleep latency, duration, and
quality. In addition, the timing of sleep is also


both random distribution of sleep throughout the
day and night and a reduction in the duration of
There are two circadian peaks in wakefulness
(wake-maintenance zones), namely in the late
morning and early evening; there are also two
circadian troughs in alertness (increased sleep
propensity) in the early morning and early
Several afferent pathways provide inputs, both
photic and nonphotic, to the SCN. The main affer-


decreased glomerular 
ltration, and increase in
release of renin (during NREM sleep) and antidi-


SRBD; (3) follow-up after upper airway surgery or
dental devices for OSA; and (4) evaluation of nar-
colepsy, idiopathic hypersomnia, periodic limb
movement disorder (PLMD), atypical or injurious
parasomnias, and nocturnal seizures.
ed into
nography), level 3 (cardiorespiratory sleep studies


Each epoch is assigned a sleep stage that comprises
the greatest percentage of the epoch. Sleep among
Stage wake is scored when
50% of the epoch
has alpha EEG waves when eyes are closed. If alpha
waves are absent, stage wake is de ned by the
presence of vertical eye blinks, reading eye move-
Stage N1 sleep
is present if alpha waves are replaced by low ampli-
tude, mixed frequency (4–7 Hz) waves that occupy
50% of the epoch. Slow eye movements may be
present. Sleep spindles and K complexes are absent.
Tonic chin EMG levels are lower than stage
ned by low amplitude,
mixed frequency waves with the presence of K
complexes (not associated with arousals) or sleep
spindles during the  rst half of the epoch or during
the last half of the previous epoch.
Stage N3 sleep
is scored if at least 20% of the epoch is occupied by
over the frontal regions.
Stage REM sleep is char-
acterized by low amplitude, mixed frequency EEG
activity, REMs, and low chin EMG tone.
Scoring Respiratory and Movement Events
An apnea is defined by a decrease in peak
thermal sensor amplitude by at least 90% of
baseline for a duration of at least 10 s. Apneas can
be either obstructive, when inspiratory effort is
present throughout the entire event; central if
inspiratory effort is absent throughout the entire
by an obstructive event.
Hypopnea is a decrease in nasal pressure by at
accompanied by oxygen desaturation of at least
A respiratory effort-related arousal is charac-
terized by breaths associated with increasing
respiratory efforts for at least 10 s and 
attening of
the nasal pressure waveform. Event precedes an


Sleep Physiology (Lee-Chiong)


each 40 min in duration and performed at 2-h
intervals. The  rst nap trial is started about 1.5 to
dard monitoring leads include EEG, EOG and
to testing is not routinely indicated and should


Sleep Physiology (Lee-Chiong)


253
Differentiate the clinical and polysomnographic features
of obstructive and central sleep apnea
Describe the various effective therapies for OSA
Distinguish the causes of hypercapnic vs nonhypercapnic
 Identify the key features of the hypoventilation syn-
dromes
: central sleep apnea; hypoventilation; obstructive
sleep apnea; positive airway pressure therapy
Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) is characterized
is de ned by an AHI of at least 5 events/h plus the
presence of excessive sleepiness. It affects men
more commonly than women, in whom prevalence
increases with menopause.
Pathophysiology
collapsible cylinder, with air


Sleep-Related Breathing Disorders (Lee-Chiong)
Several factors might worsen hypoxemia
during obstructive respiratory events, including
increased percentage of total sleep time with
apneas or hypopneas, greater duration of apnea or
hypopneas, decrease in functional residual capac-
ity and expiratory reserved volume, comorbid lung
disorders such as COPD, or stage of sleep (more
severe oxygen desaturation during rapid eye
movement [REM] sleep compared with non-rapid
)Classi cation Based on Severity
The severity of OSA can be measured based on
the AHI as mild (5 to 15), moderate (16 to 30), or
severe (
30). In addition to the AHI, other factors
can in uence the clinical severity of OSA, such as
the degree of daytime sleepiness, nadir of Sa
severity of sleep fragmentation, presence of noc-
turnal arrhythmias, and the presence of comorbid
cardiovascular or neurologic disorders.
Risk Factors
Risk factors for OSA include a positive family
, muscle relaxants), and primary disorders, such
as untreated hypothyroidism (inconsistent data),
acromegaly, neuromuscular disorders, and stroke.
Androgen therapy has been shown to increase the
risk of OSA. Central obesity,
, waist-hip ratio, is
more important than general obesity.
c craniofacial and oropharyngeal fea-
tures predispose one to the development of OSA,
including increased neck circumference, namely
17 inches in men and
16 inches in women; nasal
narrowing or congestion; macroglossia; low-lying
soft palate; enlarged tonsils and adenoids; mid-face


degree of oxygen desaturation may be predictive
of the risk of pulmonary hypertension. There is a
greater likelihood of pulmonary hypertension in
persons with daytime hypoxemia and hypercap-
nia, morbid obesity, and comorbid COPD. Pulmo-
nary hypertension secondary to OSA is generally
mild. Other consequences of OSA include depres-


Sleep-Related Breathing Disorders (Lee-Chiong)


apnea that is primarily central in nature. The
devices generally are not recommended for
growing children. In addition, mandibular reposi-
equate or compromised dentition or in those with
cant temporomandibular joint dysfunction.
Complications associated with the use of oral
sive salivation, dental pain, undesirable dental
movements with mandibular repositioners, and
jaw or temporomandibular joint pain with man-
dibular repositioners.
Upper-Airway Surgery:
Upper-airway surgery
may be considered for persons with de
nitive cra-
niofacial or upper-airway abnormalities that are
responsible for OSA. Polysomnography is required
about a person’s degree of sleepiness. Moda
and armodafinil, wake-promoting agents, may
t persons who are excessively sleepy despite
PAP therapy. Consider reporting patients with
excessive sleepiness as the result of OSA to appro-
priate authorities if (1) there is a history of severe
car accidents related to untreated sleepiness; (2) if
prompt therapy for OSA cannot be provided; (3) if
the patient refuses, or is consistently nonadherent
with, therapy for OSA; (4) if the patient fails to
restrict driving until OSA has been adequately
controlled; or (5) if such situations are considered
reportable based on local legislation.
Upper-Airway Resistance Syndrome


Sleep-Related Breathing Disorders (Lee-Chiong)
present with insomnia or sleepiness or may be
Polysomnography
sis of CSA and demonstrates cessation of respira-
tion and ventilatory effort lasting at least 10 s, with
at least  ve central apneas per hour of sleep. Respi-


259


Sleep-Related Breathing Disorders (Lee-Chiong)


261
Describe the different causes of insomnia and excessive
sleepiness and the treatment options for each disorder
Identify the key features of the various parasomnias
Understand the clinical manifestations of restless legs
syndrome
Distinguish the main presenting symptoms of the different
circadian rhythm sleep disorders
: circadian rhythm sleep disorders; insomnia; nar-
colepsy; parasomnias; restless legs syndrome; sleepiness
The differential diagnoses of excessive sleepiness
is extensive and include the following: (1) narco-
lepsy; (2) idiopathic hypersomnia; (3) circadian
rhythm sleep disorders; (4) insufficient sleep
syndrome; (5) obstructive sleep apnea (OSA);
(6) periodic limb movement disorder (PLMD);
(7) posttraumatic hypersomnia (head injury);
(8) recurrent hypersomnia, including Kleine Levin
syndrome; (9) medical, neurologic and psychiatric
disorders; and (10) medication or substance use
or withdrawal. Transient insomnia can be a result
awakenings can be caused by advanced sleep
phase disorder, depression, or withdrawal from
short-acting hypnotic agents. There are many
tilation syndromes, diaphragm paralysis,
neuromuscular disorders, restrictive lung disease,
CHF, and high altitude.
Insomnia is characterized by repeated difÞ
culty
disturbance can present as difÞ culty falling asleep


Nonrespiratory Sleep Disorders (Lee-Chiong)
Consequences
Persons with insomnia have an increased risk
of psychiatric illness developing, such as major
depression. Other consequences of insomnia include
fatigue, cognitive impairment, impaired academic
and occupational performance, diminished quality
of life, and greater health-care utilization.
cation
Forms of insomnia can be classiÞ ed, based on
insomnia lasts only a few days, or chronic if it
1 to 3 months. Another useful distinction
es the causes of sleep disturbance into pri-
Adjustment Insomnia
In this syndrome, sleep disturbance is a result
of an identiÞ able acute stressor, such as a momen-
tous life event, change in the sleep environment,
or an acute illness. Sleep improves with resolution
of acute stressor or when adaptation to the stressor
This type of insomnia is not associated with
short-term benefits of these interventions are


comparable with pharmacologic therapy and,
unlike the latter, beneÞ cial effects are sustained
over time. At long-term follow-up, CBT is more
effective than pharmacotherapy. Effective CBT
techniques consist of cognitive therapy, paradoxi-
cal intention, relaxation techniques, sleep restric-
tion, and stimulus control.
2,3
Cognitive therapy addresses dysfunctional
es irratio-
nal expectations and excessive worry related to the
inability to sleep, challenges unrealistic concerns
about poor sleep, and provides a more appropriate
Paradoxical intention is designed to decrease


Nonrespiratory Sleep Disorders (Lee-Chiong)
adjustments are required; in cases of untreated
OSA; and in persons with severe obstructive and
restrictive ventilatory impairment.
The nonbenzodiazepine benzodiazepine recep-
tor agonists selectively bind to the BZ1 receptor
diate effect, and esopiclone having the longest
duration of action. Compared with conventional
benzodiazepines, this class of agents have a similar
hypnotic action; possess no muscle relaxant, anti-
convulsant, or anxiolytic properties; and are
less likely to cause rebound insomnia, with-
drawal symptoms or tolerance, or to alter sleep
architecture.
Ramelteon is a melatonin receptor agonist with
tonin receptor. Because of its short half-life, it is


of OSA and CSA, periodic limb movements dur-
ing sleep, REM sleep behavior disorder, and
depression.
Narcolepsy affects approximately 0.05% of the
US population. It may affect men more commonly
than women. Excessive sleepiness is usually the
taking scheduled naps during the day, and
avoiding driving until sleepiness is adequately
managed. Excessive sleepiness can be managed
nil, armodaÞ nil,


Nonrespiratory Sleep Disorders (Lee-Chiong)
Hypersomnia Caused by Medical Disorders
Many medical disorders can give rise to exces-
sive sleepiness, including hepatic encephalopathy,
hypothyroidism, Prader-Willi syndrome, renal
failure, CNS infections or tumors, head trauma,
Parkinson disease, stroke, atypical depression,
bipolar type II mood disorder, and seasonal affec-
tive disorder.
Hypersomnia Caused by Drugs or Substances
drawal from stimulants.
Evaluation of Sleepiness
comprehensive sleep history aided by sleep diaries
and/or actigraphy. Subjective tests of sleepiness,
such as the Epworth sleepiness scale, are com-
monly used. Polysomnography is necessary to
exclude OSA and PLMD. Multiple sleep latency
testing generally demonstrates a mean SOL of
8 min, and the Maintenance of Wakefulness Test
may show a mean SOL of
40 min.
Therapy for Sleepiness
Sleep extension should be recommended for
suspected insufÞ cient sleep syndrome. Scheduled
napping may be beneÞ cial for some patients, as
is caffeine intake, which has additive effects to
napping. Many patients, especially those with
moderate-to-severe sleepiness, will require stimu-
Parasomnias
Parasomnias are physical or experiential phe-


Medications that can cause nightmares include


Nonrespiratory Sleep Disorders (Lee-Chiong)
factors. Iron supplementation may be considered
if serum ferritin is
50 µg/L. Dopaminergic
agents, such as levodopa, pramipexole, or rop-
inirole, are the preferred first-line agents.
8,9
Adverse effects of dopaminergic agents include


Irregular Sleep-Wake Rhythm
There are no stable circadian sleep-wake rhythms
in this disorder. Rather, variable, inconsistent, and
multiple sleep and wake periods occur throughout
the day and from one day to another.
Nevertheless,
aggregate sleep time during a 24-h period is normal.
This disorder is most frequently seen in association


Nonrespiratory Sleep Disorders (Lee-Chiong)
insomnia and sleep fragmentation. Nocturnal
hypoxemia may develop as can nocturnal bron-
choconstriction, the latter occurring as a result of
either (1) circadian variability in airß ow, which is
lowest in the early morning; (2) sleep-related
changes in autonomic nervous activity,
, greater


271


Nonrespiratory Sleep Disorders (Lee-Chiong)


273
Describe the clinical syndromes of endemic mycosis
Show the various manifestations of aspergillosis and
Show different therapeutic strategies pertaining to fungal
aspergillosis; blastomycosis; candidiasis; coccidi-
. The organism is endemic throughout the
valleys. Heavy concentrations of the fungus are
found in excrement of chickens, pigeons, starlings,
and bats. A pulmonary infection will occur when
the mycelium is disturbed and aerosolized fungal
spores are inhaled.
Clinical Features
The primary
disease may have few or no symptoms. Even in
the asymptomatic patient, a chest radiograph may
show patchy areas of pneumonitis with or without
ipsilateral hilar adenopathy. Patients become symp-
tomatic around 14 days after exposure. In the event
of a very large inoculum, the symptoms may begin
sooner. The illness is an inß uenza-like disease with
fever, chills, myalgia, and nonproductive cough.
During the early nonimmune phase of the infection,
the fungus disseminates widely throughout the
body. With the advent of speciÞ
c T-cell
mediated
immunity, the infection is brought under control.
Patients who have been exposed to a very large
infective inoculum will present with a potentially


Pulmonary Fungal Infections (Sarosi)
ondary to respiratory compromise.
promised adults, in for whom the disease is a
the symptoms relate to weight loss. Physical
lesions along with hepatosplenomegaly. Histo-
pathologic examination shows well-formed
granulomas and only rare organisms.
In recent years, PDH has occurred primarily in
patients with signiÞ cant T-cell dysfunction, includ-
ing organ transplant recipients, patients receiving
glucocorticoids and/or cytotoxic drug therapy for
tion. In this latter group, PDH is frequently the
ning infection. The density of the organ-
isms in biopsy material is greater than that in other
immunosuppressed patients, helping materially
It is important to note that perhaps as many as
related to the lung. Especially in patients with
ness. Eventually, chest radiographic abnormalities
The incidence of PDH complicating untreated
HIV infections has resulted in the acknowledgment
mosis that were not known to harbor the fungus.
These areas include the entire Caribbean basin
extending all the way to the northern coast of South
ran Africa have identiÞ
ed patients with histoplasmo-
sis. The extent of the disease in Europe is not known.
Although in Europe most patients who present with
PDH come from endemic areas, a handful of cases
appear to have had no exposure outside of Europe.
The recent emergence of tumor necrosis factor
inhibitors has caused a clear-cut association
with PDH. All anti-TNF-
agents may lead to PDH,
but its occurrence is most frequent after the admin-
istration of inß iximab. In fact, PDH is the second most
common infectious complication after tuberculosis.
Diagnostic Tests
Histopathologic specimens reveal small yeasts
that are highly suggestive of histoplasmosis either
within macrophages or lying free in areas of necro-
sis. Although the organisms occasionally may be
visualized in routine hematoxylin-eosin
sections, as a general rule they are difÞ cult to visu-
alize unless special stains are applied. Most expe-
silver stains or the periodic acid-Schiff stain. The
organism is best visualized from biopsies of
adequate specimens for cultures. The availability
of the lysis-centrifugation system has increased our
ability to isolate the fungus from circulating blood,


whose serum is anticomplementary. The
availability
of the Histoplasma polysaccharide antigen is a
major step forward. The test is extremely useful in
diagnosing PDH, especially in immunocompro-


Pulmonary Fungal Infections (Sarosi)
and skin lesions. Other patients, especially
severely immunocompromised patients, will
present with a rapidly progressive extensive
infiltrate that leads to air exchange


1,500 mg. Fluconazole, an orally administered
azole, is frequently used by practitioners in the
endemic area for the treatment of acute coccidioi-
domycosis despite the fact that the efÞ cacy of this
treatment has never been established.
Residual thin-walled cavities usually require
no treatment. Resection with or without ampho-
tericin may be needed if hemoptysis develops or
if the cavities enlarge, move subpleurally, and
threaten rupture. The chronic Þ
brocavitary form
of pulmonary coccidioidomycosis requires treat-
ment. Although some patients respond to itracon-
azole or ß uconazole, more severely ill patients
will require amphotericin for effective treatment.


Pulmonary Fungal Infections (Sarosi)
digestion of 10% potassium hydroxide. The large,
single-budding organism is characterized by its
broad neck of attachment and its double refractile
cell wall. The organism is difÞ cult to see in stan-
dard hematoxylin-eosin-stained sections but is
readily visualized with periodic acid-Schiff- or
silver-stained sections. The organism is readily
recovered in cultures, although it is a somewhat
time-consuming process. Depending on inoculum
size, cultures may take up to 3 weeks before they
are recognizable.
There is no commercially available skin test,
and the serologic diagnosis in blastomycosis is
quite rudimentary. At present, even the presence
of a positive serologic test (measuring antibody)
result using one of the more recent ultrasensitive
assays does not confirm the diagnosis of
blastomycosisÑit merely points one in the direc-
tion of the infection. The recently available urine
antigen has performed well in preliminary studies.
Treatment
Acute pulmonary blastomycosis may not
require treatment in some patients; most patients
with acute pulmonary disease should be treated
with itraconazole, 200 mg bid, for at least 6 months.
In severely ill patients in whom gas exchange
abnormality forces the issue, amphotericin is used
until the patient reaches clinical, and this should
6 months. All patients with blas-
tomycotic meningitis should receive amphotericin;
there is no evidence that intrathecal amphotericin
administration improves prognosis. Because itra-
conazole reach high levels in CSF, high-dose ß
conazole is used as step-down therapy after
clinical stability is reached.
Cryptococcosis
produces a clinical illness. The organism exists
worldwide and is frequently associated with bird
droppings, especially from pigeons. Most patients
with significant cryptococcal disease have an
underlying immunocompromised state.
Clinical Features
discovered accidentally because most patients
have no symptoms. When symptoms are present,
fever is modest and a chest radiograph frequently
shows a large, localized lobar inÞ
ltrate. The usual


CSF are positive in 80 to 90% of patients. A blood
culture also should performed because it results
frequently are positive in immunocompromised


Pulmonary Fungal Infections (Sarosi)


administration of high-dose glucocorticoids.
Improvement is hastened and enlarged on by the
Chronic necrotizing aspergillosis and disseminated
or pyemic aspergillosis are treated with systemic
antifungal therapy.
activity against aspergillosis, but voriconazole is
favored. The new azole posaconazole is also active,
but it exists only in oral form, precluding its use in
critically ill patients. A new class of antifungal
agent is the echinocandin. Although they all have
activity against aspergillus, they are used primar-
ily as rescue therapy. Combination therapy with
two different classes of antifungal drugs has been


Pulmonary Fungal Infections (Sarosi)
The most recent guidelines for the treatment of coccidioido-


The ofÞ cial treatment guide of a very complicated topic.
breaks in Indianapolis and review of the literature.
A careful description of the largest outbreak ever studied.


Pulmonary Fungal Infections (Sarosi)


285
 Discuss the pathogenesis, clinical features, and treatment of
pulmonary disorders that occur in patients with sickle-cell
 Review the pathogenesis, clinical features, and treatment
 Review the pathogenesis and clinical features of pulmonary
 Discuss pulmonary injury caused by radiation therapy of
 Outline the pulmonary disorders that occur after thermal
adherence of these cells to endothelial surfaces is
an important feature of vasoocclusive crises. In
addition, the release of arginase and free hemo-
globin from hemolyzing RBCs leads to nitric oxide
(NO) dysregulation, endothelial dysfunction, and
ciated with a hypercoagulable state as the result
of thrombocytosis and the procoagulant effects of
thromboembolism does not appear to be increased
in these patients. The following three overlapping
pulmonary syndromes are described in patients
drome (ACS), fat embolism syndrome, and
chronic restrictive lung disease with pulmonary
Acute Chest Syndrome
Patients with SC disease frequently present
with a syndrome of chest pain, fever, and cough,


Because the pathogenesis of ACS is multifacto-
rial, each treatment is of uncertain benefit in a
c patient. Patients almost always are treated
with analgesics, are hydrated to prevent hemocon-
centration, and are given oxygen supplementation
to reduce sickling. Most patients receive antibiotics
empirically because it usually is impossible to
edly, recurrent fat embolization, infarction, and
infection all contribute to this syndrome. As the
disease progresses, increasing hypoxemia, radio-
graphic evidence of pulmonary fibrosis, and a
predominantly restrictive functional impairment
patients with SC disease. Mild PH, de ned as a
pulmonary arterial systolic pressure
35 mm Hg,
occurs in approximately 20% of adult patients and
severe disease (pulmonary arterial systolic pressure
45 mm Hg) in 10%. The presence of PH is also is
associated with a high risk of death. Hemolysis and
NO dysregulation play central roles in the develop-
produced by the conversion of
-arginine to citrul-
line and mediates pulmonary vascular tone through
the relaxation of smooth muscle and reduction of
the expression of endothelin-1 and endothelin
receptor. NO also reduces the endothelial expres-


Hypoxemia is caused by precapillary and capillary
anastomoses. The most common presenting symp-
tom is dyspnea, but the presence of stigmata of
chronic liver disease (spider nevi, clubbing) and
severe hypoxemia strongly suggest the diagnosis.
shortness of breath
while upright) because of increased shunting of
pulmonary blood to the systemic circulation
through spider nevi in the lung bases. Arteriove-


more often on the right side than the left. Sponta-
neous bacterial empyema may occur with or
without spontaneous bacterial peritonitis. The
initial treatment is directed at reducing the vol-
ume of ascites by the restriction if salt and the
Mechanisms of Oxygen-Induced Injury
The stepwise reduction of oxygen to water
produces free radicals that in turn are injurious to
tissues. These include the superoxide anion (-O
hydrogen peroxide (H
), and hydroxyl radical
). The latter is among the most reac-
Oxygen radicals have a bene cial role because they
are used by neutrophils during phagocytosis and
the killing of bacteria and may be important
mediators of vascular tone by interacting with NO.
However, unopposed hyperoxia promotes the
excessive production of these molecules (termed
oxidative stress
lysosomal membranes and in turn increasing cell
permeability, releasing lysosomal proteolytic
aging DNA. Thus, many cells that are exposed to
cient oxidative stress stop dividing and die,
ting “suicide,” others by oxidation-induced necro-
sis. This may be the case with ischemia-reperfusion
injury in patients with myocardial infarction and
stroke. The recruitment of neutrophils augments
tissue injury by releasing radicals when acti-
Oxidant injury is opposed by antioxidant
mechanisms. Intracellular enzymes that reduce
oxidant activity include superoxide dismutase


also potentiate hyperoxic injury. NO combines with
to form the peroxynitrite anion ONOO, which
is potentially extremely toxic.
Clinical Manifestations of Pulmonary Oxygen
Toxicity


4. Previous irradiation increases the risk.
5. Chemotherapy may potentiate radiation dam-
6. Withdrawal of therapy with corticosteroids
Radiation Pneumonitis
pnea (the most common symptom), dry cough,
ndings usually are normal.
A progression of chest radiographic 
ndings is
typical, manifesting as ground-glass opacities that
may progress to consolidation, coalescing to form
a sharply demarcated opacity corresponding to the
eld of radiation. Radiographic changes may occur
outside the radiation  eld, perhaps attributable to
a lymphocyte-mediated hypersensitivity reaction.
Pleural effusions are observed occasionally.
Most patients with radiation pneumonitis have
mild symptoms and require no therapy. Although
controlled studies in humans are lacking, animal
with corticosteroids is an effective treatment in
patients with more severe disease. The optimal
dose is unknown; prednisone, approximately
60 mg/d, is recommended, followed by a gradually
tapered dose. The disease may 
are during a ste-
roid taper. There is no effective treatment for
brosis.
Radiation Fibrosis
When lung injury is chronic,  brosis may occur.
This  brosis usually is not apparent until at least
6 months after exposure, may take up to 2 years to
evolve, and generally remains stable thereafter. The
brosis, ranging from no symptoms to severe dys-
brosis
may cause superior vena cava syndrome or con-
strictive pericarditis, and exposure of the coronary
arteries to the beam may cause obstruction. Severe
fibrosis may occur in the absence of clinically
apparent pneumonitis. The chest radiograph
typically shows volume loss in the affected areas.
Bronchiectasis and pleural thickening are common
ndings on CT scans. At times, con
uent 
brosis
may be dif cult to distinguish from the recurrence
of a tumor.
Smoke Inhalation
Smoke generated in a  re is a suspension of
particles and toxic gases in hot air. Fire victims


are also common in burn patients. Herpes simplex
tracheobronchitis is common, perhaps due to direct
extension from an oral source in patients who are
immunocompromised due to severe burn injury.
CO Poisoning
The inhalation of CO is the most common cause
of unintentional poisoning death in the United


Other Pulmonary Disorders (Rosen)


upright position correlated strongly with the presence of
Garcia N, Mihas AA. Hepatic hydrothorax: Patho-
physiology, diagnosis and management. J Clin Gastro-
enterol 2004; 38:5258
Useful review of current concepts.


Other Pulmonary Disorders (Rosen)


295
 Understand and analyze how well a clinical test “performs”
principles underlying medical statistics that are
clinically relevant as well as important for taking
pulmonary boards.
does not de ne “truth” but rather, when used cor-
rectly, it allows a sense of what the truth is based
tions underlying its validity. Although some sta-
tistical tests are fairly rigorous (
, insensitive to the
violation of assumptions), the results will be ques-
tionable if an incorrect statistical test is used. Study
aws (
use of appropriate controls, and double blinding)
will limit con dence in the results that have been
analyzed, even those that use the proper statistical
of 250 controlled tri-
ment had a 41% greater treatment effect compared
with those in trials with adequately concealed
treatment allocation and that studies that were not
double-blinded had a 17% greater treatment effect
compared with those in double-blinded studies. In


Medical Statistics/Test-Taking Strategies (Kamp)
with sepsis in an attempt to increase D
normal levels so as to improve V
. However,
these conclusions turned out to be incorrect based
De ning “abnormal” values of a test.


de ned as the value of X such that 50%
of the values are higher and 50% are lower.
is not as in uenced by data outliers. For sym-


Medical Statistics/Test-Taking Strategies (Kamp)
Hypothesis Testing
Statistics often are performed to assess samples


is calculated by choosing a numerical value for
and by using some reasonable estimates
from the available literature about the estimated


Medical Statistics/Test-Taking Strategies (Kamp)
are possible in the  ve groups in our example. For
cant. In contrast, a small study that is not
statistically signi cant may indeed provide a clini-
cally relevant bene
t of the new drug. CIs provide
a way to more easily judge the clinical relevance of
the  ndings while reporting the observed effect (
CI. The CI provides the following two useful pieces
of information: the point estimate, which is the
single value, based on the study, that is most likely


is a clinically relevant one when factoring in other
issues, such as the cost and side effects of the drug.
Table 2 shows how AR is calculated from a hypo-
information about the diagnostic test or treatment
response by combining data about the sensitivity
and specificity.
8,9
The LR informs how much a
positive or negative result alters the likelihood that
the patient would have the disease or treatment
response of interest. The LR of a positive test result
) is de ned as follows: sensitivity / (1 – spec-
city). The LR of a negative test result (LR–) is
ned as follows: (1 – sensitivity) / speci
city. A


Medical Statistics/Test-Taking Strategies (Kamp)
of cough while one is receiving therapy with val-
and therefore, treating 1/0.165, or 6.1 patients, with
a single case of drug-induced cough. The best index
to use in describing the data depends on that which
you are examining. Typically, the one that most
transparently re
ects the actual difference in event
rates is the ARR or the reciprocal of ARR, the NNT.
The RR and RRR obscure the actual change in rates
and may have widely different implications when
the actual data are assessed. The OR re
ects the
Medical Decision Making: Receiver
Operator Characteristic Curves


ROC curve analysis provides a global sense of how
well a test distinguishes patients with disease from
disease-free individuals. This distinction is par-
ticularly helpful when there are multiple tests that
exist for a given disease to decide which is superior.
ROC curve.


Medical Statistics/Test-Taking Strategies (Kamp)
probability of a test result in patients with the par-
ticular disease in question to the probability of that
same test in patients who are free of that disease.
The LR for a positive test result (
of PE. However, the value of d-dimer testing is in
its NPV, which in our illustrative example is 98%,
as calculated in Table 4. Thus, the posttest probabil-
ity of disease after a negative d-dimer test result


may not be clinically reassuring in stopping the
evaluation for PE. Indeed, this is precisely what
limits the predictive value of d-dimer testing
in patients who are deemed to be at very high risk
It is important to remember that no test is per-
, 100% sensitivity and 100% specificity).
Furthermore, even the “gold standard” test can be
wrong in a small percentage of cases (
, pulmonary
angiogram to diagnose PE has both FP results
[erroneous reading by a radiologist] and FN results
[sampling error or erroneous reading by a radiolo-
gist]). Thus, the sensitivity and speci city are insuf-
cient for informing clinicians about the utility of


Medical Statistics/Test-Taking Strategies (Kamp)
alarm); and (9) go to the bathroom before walking
into the examination room to avoid wasting any
Test-Taking Tips
Once a test is underway, there are also a num-
ber of helpful recommendations to optimize suc-
cess. (1) Read the directions carefully! Do not rush,
but rather pace yourself by reading the entire ques-
nding the key words. Always read the
whole question carefully and do not make assump-
tions about what the question might be. Simply not
following directions can result is a loss of many
easy points on questions to which you actually
knew the answers. (2) When you  rst receive your
test, do a quick survey of the entire test so that you
deep breaths to relax, then move to a portion of the
test with which you are more comfortable. If you
do not know an answer, skip it, go on with the rest
of the test, and come back to it later. Perhaps on


answer after reading all the answers. Look for the
central idea of each question. What is the main
point? (2) Come up with the answer in your head
before looking at the possible answers. In this
way, the choices given on the test will not throw
you off or trick you. (3) Eliminate the answers that
you know are not right. (4) Avoid answers that
begin with always, never, none, except, most, or
least. Underline these or other key words on the
test paper. (5) Because there is no guessing pen-
alty on the pulmonary boards, always make an
educated guess, and select an answer. If you have
to guess, the following guidelines are helpful:
(A) because the length of choices can be a clue,
choose the longest; (B) if two choices are simi-
lar, choose neither; (C) if two choices are oppo-
sites, choose one of them; and the most general
alternative is usually the right answer. (6) Do not
choice is usually the right one, unless you have
incorrectly read the question. (7) In “all of the
above” and “none of the above” choices, if you
are certain one of the statements is true, do not
choose “none of the above.” Likewise, if one of
the statements is false, do not choose “all of the
choice, if you see at least two correct statements,
then “all of the above” is probably the answer.
(9) A positive choice is more likely to be true than
a negative one. (10) If there is an “all of the above”
option, and you know that at least two of
the choices are correct, select the “all of the above”
choice. (11) The correct answer is usually
True/False Test Tips
There are a number of common sense recom-
mendations to consider when answering true/false
questions. The basic ground rule for answering
true/false items is that if any part of the statement
is not true, then the student should select false as
the answer. (1) Usually, there are more true answers
are more dif cult to construct as looking correct.
Thus, if you are guessing on a true/false question,
there is a
50% chance of being right with a true
answer. (2) As with multiple choice questions, read
through each statement carefully and pay attention
to the qualifiers and keywords. Qualifiers like
“never,” “always,” and “every” mean that the
statement must be true all of the time. Usually,
these types of quali ers lead to a false answer.


Medical Statistics/Test-Taking Strategies (Kamp)
A succinct overview of statistical terminology that also
provides a logical approach for selecting the appropriate


309
 Define terminology used in describing acid-base
 Diagnose simple and complex acid-base disorders
Acid-Base Disorders
Table 1.


normal functioning of lungs and kidneys, and
failure to develop a compensatory response de
nes
the presence of a second primary disorder.
approach requires assessment of all the indepen-
This chapter will primarily review the more
traditional analysis of acid-base problems using
. However, some
correlates of Stewart’s approach will be mentioned
De
The following de nitions are used:
an increase in H
and a decrease in arterial pH;
, a decrease in H
, a process that, if unopposed, will lead
to a decrease in pH; and
, a process that, if
unopposed, will lead to an increase in pH.
Acid-Base Disturbances
The development of an acid-base disorder is
traditionally identi ed by changes in the bicar-


311
can be found in hypoaldosterone states, ammonium
chloride administration, and type 4 distal RTA.
A decreased AG implies an increase in unmea-
sured cations or a decrease in unmeasured anions.


: Increased cerebral blood 
ow; decreased
Hyperventilation with rapid and/or
deep respiration (Kussmaul respiration); increase
in pulmonary vascular resistance.
Potential decreased myocardial
contractility; arrhythmias; potential decreased
responsiveness to catecholamines; arterial vaso-
Table 5.


313


Clinical Manifestations
The clinical manifestations of acute respira-
tory acidosis depend on the absolute increase in
increase, and severity of
associated hypoxemia. Intentional hypoventilation
(permissive hypercapnia) is well tolerated and has
circumstances, intubation and mechanical ventila-
tion are necessary to support alveolar ventilation.
for acute respiratory


Clinical Manifestations
Acute respiratory alkalosis results in neuro-
respiratory alkalosis, mild hypokalemia (from
intracellular shift) and hyperchloremia (from renal
Table 7.


considerations are one system that may be useful
Adrogue HJ, Madias NE. Management of life-threaten-
ing acid-base disorders: second of two parts. N Engl J
Med 1998; 338:107–111
Review of adverse consequences and management of severe
Dubose TD. Acid-base disorders. In: Brenner BM, ed.
Brenner and Rector’s the kidney. 6th ed. Philadelphia,
PA: WB Saunders, 2000; 925–997


Kellum JA. Disorders of acid-base balance. Crit Care Med
A review of quantitative and traditional approaches to acid-


Acid-Base Disorders (Zimmerman)


319
 Appreciate the diverse clinical syndromes of drug-induced
 Understand the general approach to the patient with sus-
pected drug toxicity
 Review the common abnormalities associated with speci
 Comprehend the typical manifestations of pulmonary
acute lung injury; drugs; hypersensitivity pneu-
brosis
Drug-induced lung diseases have challenged
1880, William Osler described a patient with pul-
monary edema associated with opiate exposure
and suggested that there was a pathophysiologic
relationship. In 1972, Edward Rosenow
sively reviewed this topic and identi ed 20 drugs
that clearly caused pulmonary toxicity. A decade
later, Cooper and colleagues
expanded the list
to 37 drugs. Since then,
350 drugs have been
ponents of the respiratory system including the
airways, parenchyma, pleura, pulmonary circula-
tion, mediastinum, vocal cords, and respiratory
muscles (Table 1). The number of drugs that cause
lung disease will undoubtedly continue to grow
as new agents and biological response modi
are developed.
Although the clinical syndromes associated
with certain drugs are well de ned, the full scope
of the epidemiology of drug-induced lung disease
is not  rmly established, partly because of the fact
and tumor). Notably, there are no pathognomonic
clinical, laboratory, physiologic, radiographic, or
ndings. Also, most reactions are idio-
syncratic, without any clear relationship to dose or
time of exposure. Indeed, some drugs can cause
toxicity years after exposure (
cyclophosphamide).
With few exceptions, the risk factors for drug-
induced lung diseases are poorly de
ned. More-
over, confounding variables such as the use of
other drugs, oxygen, or radiation therapy, each of
tive effects (
, bleomycin and oxygen), often
cated drug is rarely performed because effective
alternative agents are nearly always available.
drug-induced pulmonary symptoms must obtain
a thorough drug exposure history, maintain a high
index of suspicion, and use a systematic diagnostic
approach that is reviewed herein.
The management of patients with drug-induced
pulmonary side effects is largely supportive. Typi-
cally, therapy with the implicated drug is with-
drawn, and a trial of corticosteroids is considered,
Drug-Induced Lung Diseases
David W. Kamp, MD, FCCP
Table 1.
Major Clinical Syndromes of Drug-Induced
1. Chronic pneumonitis/
brosis*
2. Hypersensitivity-type lung disease*
3. Acute noncardiogenic pulmonary edema*
4. Bronchiolitis obliterans with organizing pneumonia
5. Alveolar hypoventilaton
6. Bronchospasm
7. Cough
8. Concentric bronchiolitis obliterans
9. Pleural effusions
10. Venous thromboembolism
11. Pulmonary vasculitis
12. Pulmonary hypertension
13. Drug-induced SLE
14. Alveolar hemorrhage
15. Pulmonary renal syndrome
16. Alveolar proteinosis
17. Mediastinal abnormalities (
, adenopathy, lipomatosis,
18. Panlobular emphysema
19. Pulmonary calcinosis
20. Pseudosepsis syndrome


supported by anecdotal reports rather than well-
designed controlled studies.
Major Clinical Syndromes of Drug-
Induced Pulmonary Disease
Chronic Pneumonitis/Fibrosis
A wide array of drugs has been implicated in
causing chronic interstitial pneumonitis and/or
brosis, making them the most common manifes-
tations of drug-induced lung disease. Some of the
agents implicated are listed in Table 2. There is a
small increase in antidepressant use, especially
tricyclic-related agents and selective serotonin
receptor inhibitors, in patients with idiopathic
pulmonary  brosis (IPF; odds ratio [OR], 1.52; 95%
dence interval 1.24 to 1.86).
These patients
Hypersensitivity-Type Lung Disease
Virtually any drug can cause a generalized
hypersensitivity-type reaction with respiratory
symptoms that are associated with pulmonary
ltrates and eosinophilia (PIE). The agents com-
monly implicated are listed in Table 3. Patients can
present with Loef er syndrome, consisting of an
Table 2.
Some Drugs That Cause Chronic Pneumonitis/Fibrosis
 Azathioprine Amiodarone*
 Anti-TNF-
Table 3.
Some Drugs That Cause Hypersensitivity-Type
Chemotherapeutic Nonchemotherapeutic
 Azathioprine  Antibiotics (
 Bleomycin sulfa-containing)*


be similar to ARDS. Several mechanisms have been
implicated in causing drug-induced noncardio-
genic pulmonary edema. First, some drugs increase
ltration coef
cient of the respiratory mem-
brane, making it more permeable (
, overdose
of narcotics/sedatives). Second, certain agents
depress the CNS, resulting in neurogenic pulmo-
nary edema. Finally, some drugs cause an idiosyn-
cratic reaction resulting in noncardiogenic
pulmonary edema within hours of absorption. The
prognosis varies depending on the offending
with an overdose of salicylates is potentially
reversible with appropriate management, whereas
patients with carmustine-induced pulmonary
edema generally have a poor prognosis.
Cryptogenic Organizing Pneumonia
rheumatoid arthritis (RA), a disease that can also
cause COP. Thus, it may be dif
cult to distinguish
drug-induced COP from the patient’s underlying
collagen vascular disorder. Management requires
a high clinical suspicion, lung biopsy, prompt
withdrawal of therapy with the implicated drug,
and the administration of corticosteroids. The
pathic COP.
Alveolar Hypoventilation
Alveolar hypoventilation is caused by drugs
that induce respiratory depression or block respira-
tory muscle function. Patients with underlying
pulmonary or neuromuscular disorders are par-
ticularly prone to the development of acute hyper-
carbic respiratory failure. Some of the agents
implicated in causing neuromuscular blockade or
motor neuropathies/myopathies are listed in Table
6. Aminoglycoside-induced neuromuscular block-
ade is a rare but potentially life-threatening adverse
effect that has been described in patients who have
been exposed to neomycin, streptomycin, tobra-
mycin, gentamicin, amikacin, kanamycin, and
Table 4.
Pulmonary Edema
Chemotherapeutic Nonchemotherapeutic
 Azathioprine  Amiodarone
 Cytosine arabinoside 
Aspirin and NSAID overdose
 Gemcitabine  Cocaine
 G-CSF  Opiate overdose (
, heroin)
 IL-2  Sedative/hypnotic drug


Drug-induced bronchospasm is caused by
various agents (Table 7). Patients generally present
Isolated Cough
Cough, which is one of the most common
manifestations of drug-induced lung disease, is a
vagus nerve-mediated re ex caused by various
where within the upper and lower respiratory
tracts. Cough often occurs in patients with drug-
induced bronchospasm or drug-induced interstitial
lung disease. However, angiotensin-converting
productive cough without associated broncho-
spasm or parenchymal lung disease in nearly 10%
of patients receiving any type of ACE inhibitor.
Pleural E
Although a number of drugs can cause a pleu-
ral effusion (Table 8; see also Dr. Sahn’s chapter on
less than those that involve the lung parenchyma.
Table 6.
Neuromuscular blockade
 Aminoglycosides
 Opiates (
heroin)
 Cocaine
 Polymixins
 Gamma-hydroxybutyrate  Sedative/hypnotic
drugs
Motor neuropathies or myopathies
 Amiodarone
 Isoniazid
 Captopril
 Phenytoin
 Corticosteroids
 Procainamide
Table 7.
Some Drugs That Cause Bronchospasm
 Aspirin and NSAIDs


Pulmonary Vascular Disease
Drugs that affect the pulmonary vascular cir-
culation by causing venous thromboembolism
(VTE), pulmonary hypertension, vasculitis, or
pulmonary venoocclusive disease are listed in
Table 9. Oral contraceptives and other estrogen-
are relatively small in patients using second-gen-
eration and third-generation oral contraceptives
compared with nonusers (15, 30, and 5 per 100,000
patients treated, respectively).
There is an impor-
suppressants. Oral contraceptives and other
estrogen-containing agents have also been asso-
ciated with an increased risk of pulmonary
ammatory vasculitis has been noted in
conjunction with a generalized hypersensitivity
reaction in patients exposed to busulfan, nitrofu-
rantoin, or illicit drugs such as cocaine and heroin.


of the vasculitis, and (3) use in steroid-naïve
very rare adverse effect reported after exposure to
various agents (Table 9).
Miscellaneous Drug-Induced Pulmonary
Reactions
Table 10.
ConditionImplicated Drugs
Drug-Induced SLEHydralazineProcainamide


failure, diffuse alveolar in
ltrates, and progressive
decline in hemoglobin levels within hours to 2 days
after the  rst dose of abciximab. Bevacizumab, a
based on the presenting clinical syndrome review ed
above as well as by the presence of localized or
diffuse in ltrates (Table 11). In some instances, the
patient may have minimal or absent symptoms and
findings but demonstrate abnormalities on the
chest radiograph or PFT results. A high level of
clinical suspicion is required because drug-induced
disease may occur years after initial exposure and
Diagnostic Approach
Because drug-induced pulmonary toxicity has
a profound impact on patient management, it is
important to establish a  rm diagnosis as soon as
clinical syndromes caused by various agents com-
bined with the prudent use of noninvasive studies
and invasive procedures. Evaluation of the chest
radiograph, PFT results and, on occasion, chest CT
scan help narrow the differential diagnosis. Non-
invasive studies that may be useful include the
following: (1) an echocardiogram to assess cardiac
, Gram stain, culture, direct
uorescent antibody for
or
ture); and (3) immunologic studies to exclude col-
lagen vascular disorders and vasculitis.
If a  rm diagnosis is not established, then the
judicious use of invasive diagnostic procedures is
warranted. Typically,  beroptic bronchoscopy with
BAL and transbronchial lung biopsy is the next


Although this procedure has an excellent diagnos-
tic yield for infections and malignant lesions
(approximately 70 to 90%), it has a lower diagnos-
tic yield for interstitial inflammatory lesions,
including those caused by drug-induced toxicity.


radiation increase the risk of BCNU-induced lung
injury; however, a synergistic interaction has not
been documented. In regard to preexisting lung
disease, patients with preexisting symptomatic
pulmonary disorders, especially with a reduced
, are typically excluded from
receiving BCNU. A reduced D
radiographic abnormalities occurs in patients
receiving BCNU.
Although there are no prospective studies to
guide the timing of PFT monitoring, PFTs are
typically performed during BCNU therapy to
tently for the long term, given the extended latency


common, occurring in approximately 11% of those
patients treated. Patients typically present with a


Cyclophosphamide
Cyclophosphamide, an alkylating agent that
causes pulmonary toxicity less frequently than
busulfan, is widely used to treat malignant diseases
, lymphomas, breast carcinoma, and ovarian
carcinoma) and nonmalignant diseases (
gen vascular disorders, IPF, and Wegener granu-
effects is
for cyclophosphamide and its frequent use in con-
junction with other cytotoxic drugs increases the
monologists. Although cyclophosphamide alone
induces pulmonary toxicity in humans relatively
infrequently,


Drug-Induced Lung Diseases (Kamp)


patients with chronic lymphoproliferative disor-
ders, can cause chronic pneumonitis/
brosis as
well as a hypersensitivity-type reaction in nearly
9% of patients that is often responsive to therapy
with corticosteroids.
Although older chemotherapeutic agents
induce a wide array of pulmonary toxicity in nearly
10% of patients, there is less information concern-
ing the frequency as well as the clinical manifesta-
tions resulting from exposure to the newer
7,42
Gemcitabine, an agent that is increasingly
cysteinyl leukotriene receptor 2, and T-cell T box.
A similar syndrome occurs with other nonsteroidal
ammatory drugs (NSAIDs). Agents that
do not block the cyclooxygenase pathway, such


ents with multiple medical problems, or intention-
ally in individuals attempting suicide. These
patients will often present with dyspnea, tachy-
pnea, altered mental status, and a chest radiograph
revealing diffuse alveolar in ltrates. Most patients
will manifest with a simple respiratory alkalosis
in the management of chronic in
conditions, most notably RA but also pemphi-
gus, psoriatic arthritis, bronchial asthma, and
and the IM (gold sodium thiomalate) prepara-
tions can induce chronic pneumonitis/interstitial
brosis. Bronchiolitis obliterans, in the presence
or absence of organizing pneumonia, occurs
less frequently. Interstitial lung disease caused
by gold therapy can be distinguished from the
patient’s underlying rheumatoid lung disease by


The incidence of penicillamine-induced bron-
1% of patients with RA receiving this
therapy. There are no clear risk factors. Patients


Symptoms consist of dyspnea, cough, fever, chest
. There is
an elevated erythrocyte sedimentation rate (ESR)
and peripheral blood eosinophilia in most patients.
ltrative pattern but is normal in 18%
of patients. One third of patients have a small
pleural effusion. PFT results typically reveal a
restrictive pattern with a reduced D
the diagnosis is generally made clinically, a lung
biopsy specimen and BAL  uid should be obtained


that are not mutually exclusive have been impli-
cated, including the following: (1) direct cellular
logic injury, (4) ROS-induced damage, (5) alterations
in membrane properties, (6) increased intracellular
of G proteins, and (8) inhibition of pulmonary
phosphatase. More recent studies show that amio-
darone causes lung epithelial-cell mitochondrial
dysfunction, ROS production, and mitochondria-
regulated apoptosis that can be blocked with the
58,59
Amiodarone has a large volume of distri-
Thus, the antiarrhythmic effects as well as the
adverse effects of amiodarone will persist for
weeks to months after the drug is withdrawn from
therapy. Amiodarone is an iodine-containing phos-
liver. This blockade results in the accumulation of
a feature that is seen in virtually all patients receiv-
ing the drug.
The histologic features of amiodarone-induced
mulation of foamy macrophages with characteris-
tic lamellated inclusions in the interstitium and
ltration of lymphocytes, plasma cells, eosino-
phils, and neutrophils. Edema, intraalveolar 
thelial cells, bronchiolar epithelial cells and type II
cells, and  brosis can also occur.
amiodarone-induced pulmonary toxicity include
brosis,
(2) ARDS, (3) COP, (4) mass lesions that can
cavitate, (5) eosinophilic pneumonia, (6) diffuse
alveolar hemorrhage, and (7) pleural effusions.
Uncommon reactions include hypersensitivity
pneumonitis, alveolar hypoventilation, and bron-
chospasm. The patients typically present with an


treated for at least 6 months to reduce the likeli-
hood of relapse. Recurrent amiodarone pulmonary
toxicity can also occur. If amiodarone is the only
effective agent in a patient with life-threatening
arrhythmias, the dose must be reduced to the
minimum that is effective (ideally
400 mg/d)
and corticosteroids added to therapy.
of patients receiving any type of ACE inhibitor.
The cough generally appears from 1 to 2 months
up to 1 year after initiating therapy. Patients
without asthma in whom ACE inhibitor-induced
cough develops, compared with those patients


morbidity and mortality. Statins inhibit cholesterol


complications of crack cocaine use include PIE;
COP; pulmonary hypertension; and alveolar
hemorrhage/hemoptysis, and barotrauma
, pneumothorax, pneumomediastinum, and
pneumoperitoneum). Barotrauma is likely caused
by the Valsalva maneuver that is performed to
enhance alveolar-capillary cocaine absorption.
is either normal or mildly reduced
75,76
The reason for the reduction in D
is unclear,
but it may re ect a loss of alveolar-capillary sur-
face area.
75–77
that crack users have increased lower respiratory
tract iron and ferritin levels that may contribute
Foreign-Body Granulomatosis:
Foreign-body gra-
nulo matosis is caused by the IV injection of insolu-


transthoracic echocardiogram 
ndings generally
are normal. Management involves supportive
care and diuresis. The prognosis is generally
tion required in
Sirolimus (Rapamycin):
Sirolimus is an immuno-
suppressive agent that is used in organ-transplant
patients in the presence or absence of cyclosporine.
The frequency of pulmonary toxicity varies from
“rare” to approximately 11%.
84,85
Of 24 patients
with sirolimus-associated pneumonitis, symptoms
occurred within 5 months of initiating therapy
and consisted of cough (96%), fatigue (83%), fever
84,85
pathologic patterns include COP (79%), ground-
glass attenuation (17%), and, less commonly, inter-
stitial  brosis, alveolar proteinosis, necrotizing
vasculitis, and pleural effusions.
84,85
BAL 
ndings
show a lymphocyte predominance (CD4
CD8)
with occasional eosinophils and rarely (8%) diffuse
alveolar hemorrhage. Sirolimus withdrawal results


Drug-Induced Lung Diseases (Kamp)


341


pulmonary capillary blood volume in the lung.
78. Janjua TM, Bohan AE, Wesselius LJ. Increased
lower respiratory tract iron concentrations in alka-
loidal (“crack”) cocaine users. Chest 2001; 119:422–
79. Pare JP, Cote G, Fraser RS. Long-term follow-up of
drug abusers with intravenous talcosis. Am Rev
80. Hauggaard A. Non-cardiogenic pulmonary
ionic contrast media. Acta Radiol 1996; 37:823–825


343


Drug-Induced Lung Diseases (Kamp)


345
 Understand the indications, complications, and use of pul-
be considered for use when hemodynamic informa-
tion is needed for optimum care of the patient that
that PAC data are more accurate than clinical


from insertion to the right atrium is approximately
10 cm from a subclavian approach, 10 to 15 cm from
the right internal jugular, and 35 to 45 cm from the
femoral site. The PA is usually reached within 50
to 55 cm from the internal jugular or subclavian
vein and within 65 to 70 cm from the femoral vein.
Greater insertion lengths may indicate coiling in
waveforms and pressures are obtained during
passage through the right atrium, right ventricle,
and PA (Table 3, Fig 2). Atrial pressure waves can
usually be recorded from the right atrium and the
PA occlusion position. The a-wave is absent in
If particular waveforms are not seen, place-
Table 1.
Indications for PAC Monitoring
Evaluate cardiac function


ation, a characteristic PA pressure waveform
should be apparent. If a PA pressure tracing is not
present, continued occlusion of the pulmonary
vessel (“overwedging”) is possible and requires
repositioning of the PAC to prevent pulmonary
infarction. A chest radiograph should be obtained
after the procedure to evaluate proper positioning.
can be directly measured. Normal values for these
measurements are listed in Table 4. In general,
trends in these measurements over time are more
useful clinically than single values. From these pri-
mary measurements, other physiologic variables
values are listed in Table 5.
Large variations in intrathoracic pressure due
to labored spontaneous respiration (
, severe bron-
chospasm) or mechanical ventilation, especially
with positive end-expiratory pressure (PEEP),
Table 3.
Components of Hemodynamic Waveforms
Waveform
Atrial pressure and PAOP
end of or after QRS in PAOP tracing.


more than end-expiration will be averaged. Visual
assessment of the pressure tracing allows more
PAOP
The measurement of PAOP is a major reason
for PAC. Accurate measurement is essential for
Table 4.
Normal Values Obtained From PAC
Variables
Right atrial pressure, mm Hg
pressure, mm Hg
pressure
PA pressure, mm Hg
PAOP, mm Hg
diastolic PA pressure)
Table 5.
Physiologic Data Derived From Invasive Monitoring*
Cardiac index:
CO/BSA (normal range, 2.4 to 4.4 L/min/m
Systemic vascular resistance:
(MAP
Pulmonary vascular resistance
(MPAP
PAOP)/CO
Stroke volume index
Stroke volume index
SV/BSA
Left ventricular stroke work index
(MAP
PAOP)
Right ventricular stroke work index
(MPAP
0.003) [normal approximately 19.5 mL/dL]
Arteriovenous oxygen content difference
Pulmonary shunt (veno-arterial admixture)
 3 to 5%]
*BSA
body surface area; Ca
);
cardiac index; CO
cardiac output; Cv
mixed venous oxygen content; CVP
central venous pressure; Hb
heart rate; MPAP
mean pulmonary artery pressure; SV
stroke volume; SVI
stroke volume index.


pressure. The pulmonary vascular system distal to
the physiologic assumptions. The PAOP is a com-
mon measurement that is obtained to re ect left ven-
tricular  lling pressure (left ventricular end-diastolic
pressure). Balloon occlusion of a branch of the PA
interrupts  ow and allows transmission of pressure
back from the pulmonary veins and, ultimately, the
left atrium. In general, the PAOP approximates left
atrial pressure in the absence of any mechanical
disruption of the large pulmonary veins. Pressures
within the left atrium are a re ection of the pressure
Wedge pressure (PW) may be associated with dif-


on lung and chest wall compliance. Usually, PEEP
causes a decrease in left ventricular transmural
pressure despite an increase in measured PAOP.
Overall, measured PAOP will overestimate left
ventricular end-diastolic pressure with PEEP,
(3) inject the solution over 2 s at the same phase of
respiration, which preferentially is end-expiration;
(4) use of room temperature injectate except for
patients who are severely hypothermic (
C)
who require iced injectate; a temperature difference
C is necessary for accurate measurements; and
(5) inspect graphic display of cardiac output ther-
modilution curve for rapid upstroke and gradual,
the presence of tricuspid regurgitation and falsely
elevated results in the presence of intracardic


breathing patients reduces the accuracy of the car-
diac output estimation. Inaccurate measurements
also result with low minute ventilation, high shunt
fraction, and high cardiac output.
Pulse Contour Analysis
Analysis of the arterial pressure waveform is
used to compute stroke volume with or without
initial calibration of cardiac output by transpul-


of in-hospital adverse events. The bene t of PAC
in cardiogenic shock has not been evaluated in
PAC or less invasive techniques may be helpful
in the diagnosis of shock not due to myocardial
infarction. Characteristic hemodynamic patterns
lling pressures, cardiac output, and/or
SVR are usually suf cient to distinguish cardio-
genic, distributive, hypovolemic, and obstructive
Mitral Regurgitation
Chronic mitral regurgitation is best diagnosed
by noninvasive echocardiography. In acute decom-
pensation, as may occur in myocardial infarction,
PAC information will often distinguish mitral
regurgitation from other complications if echo-
cardiography is not readily available. Elevated
left atrial pressure and PAOP are noted, and tall,
peaked v-waves are seen in the PAOP tracing. A
d PA waveform composed of the PA systolic
wave and the v-wave may be seen. Regurgitant
flow makes accurate assessment of the PAOP
cult if not impossible. In such circumstances,
the a-wave on the PAOP tracing can be used to
estimate left ventricular end-diastolic pressure.


prominent systolic x-descent and blunted y-descent
on the right atrial pressure tracing. The right atrial
pressure declines in inspiration in contrast to right
ventricular infarction and constrictive pericarditis.
Constrictive Pericarditis
Constrictive pericarditis produces equalization
pressures similar to cardiac tamponade. In addi-
tion, constrictive pericarditis usually produces an
early diastolic dip followed by a pressure plateau
in the right and left ventricular pressure tracings.
An inspiratory increase in pressure (Kussmaul
along with a systolic x-descent and prominent early
Restrictive Cardiomyopathy
The hemodynamic pattern in restrictive car-
diomyopathy is similar to constrictive pericarditis.
Differentiation of the two conditions may be very
cult. Left-sided 
lling pressures tend to be
higher than right-sided  lling pressures in restric-
tive cardiomyopathy. In addition, the diastolic
pressure plateau is usually less than one third of
the right ventricular systolic pressure.
Shock
Shock is a syndrome of impaired tissue oxy-
genation and perfusion that results from one of
the following mechanisms: an absolute or relative
decrease in oxygen delivery; ineffective tissue
perfusion; or impaired utilization of delivered
oxygen. Shock results when the oxygen balance
is disturbed and oxygen demands exceed supply.
Although hypotension is often present in shock
states, BP may be normal or even slightly increased
due to compensatory vasoconstriction. Additional
clinical manifestations in shock are related to tis-
sue hypoperfusion, the compensatory responses
Table 8.
Type of Shock
SVRCOCVPPAOPSvO
or N* (rarely
Neurogenic

Cardiogenic

Obstructive
Cardiac tamponade

Pulmonary embolism

cardiac output; CVP
central venous pressure;
increase;
decrease.
Table 7.
cation of Shock
Hemorrhagic (trauma and GI bleed)
Nonhemorrhagic (
redistribution)
Adrenal crisis
Neurogenic (spinal shock)
Thyroid storm
Cardiogenic
ischemia, cardiomyopathy)
Arrhythmias
Obstructive
Tension pneumothorax
Cardiac tamponade
Constrictive pericarditis


Hemodynamic Monitoring and Shock (Zimmerman)


(3 recommendations); infection issues (15 recom-
mendations); hemodynamic support (13 recommen-
dations); adjunctive therapy (9 recommendations);
and supportive therapy (33 recommendations).
Recommendations of particular interest are listed
below. Recommendations with a grade of 1 are
strong recommendations, and those with a rating
Reassess the antibiotic regimen daily to optimize
cacy, prevent resistance, avoid toxicity, and
decrease costs. Grade of recommendation, 1C
ceptibilities are known. Grade of recommenda-
Implement source control measures as soon
as possible after initial resuscitation. Grade of
recommendation, 1C
Hemodynamic Support
uid resuscitation.
Grade of recommendation, 1B
Maintain MAP at
65 mm Hg. Grade of recom-
Norepinephrine and dopamine are the initial
vasopressors of choice. Grade of recommen-
Epinephrine, phenylephrine, or vasopressin
should not be the initial vasopressor. Grade of
recommendation, 2C
agent to be used when BP is poorly responsive
to norepinephrine or dopamine. Grade of recom-
Adjunctive Therapy
Consider therapy with IV hydrocortisone when
hypotension responds poorly to adequate 
resuscitation and vasopressors. Grade of recom-
An adrenocorticotropic hormone stimulation
test is not recommended to identify patients who
Table 9.
Vasoactive Agents in Shock: Adrenergic Effects
Drug
Dopaminergic
Dopamine1–2
Dobutamine2–30
Norepinephrine0.5–80
Phenylephrine20–200
Vasopressin
0000


should receive hydrocortisone. Grade of recom-
Consider therapy with activated protein C in
patients with sepsis-induced organ dysfunction
(APACHE [acute physiology and chronic health
evaluation] II score of
25 or multiple organ
failure) if there are no contraindications. Grade
of recommendation, 2B
Patients with severe sepsis and a low risk of death
(APACHE II score of
20 or single organ failure)
should not receive activated protein C. Grade of
recommendation, 1A
Supportive Care
After initial resuscitation, transfuse RBCs when
hemoglobin concentration decreases to
7 g/dL


A comprehensive review of the quality and outcomes of clinical
trials of PAC use.
Hollenberg S. Vasopressor support in septic shock. Chest
A review of the evidence and experience with speciÞ
c vasopres-
sors in treating patients with septic shock.
toring in the intensive care unit. Crit Care Clin 2007;
A review of newer noninvasive monitoring techniques and


Wiedemann HP, Matthay MA, Matthay RA. Cardiovas-
cular-pulmonary monitoring in the intensive care unit:
part 2. Chest 1984; 85:656–658
Still a classic series covering PAC technique, complications,
and physiologic correlates of measurements.


359
 Identify the common pathogens causing community-
acquired pneumonia
 Identify the risk factors for mortality to improve site-
of-care decisions
 Improve antibiotic selection in the empiric therapy of
community-acquired pneumonia
 Recognize the risk of avian in uenza and community-
the presence of comorbidities, and the likelihood
for drug-resistant
(DRSP), enteric
Gram-negative organisms, and
Not every patient should be considered at
risk for infection with DRSP. Speci
c risk factors
have been identi ed, and there are regional differ-
ences in resistance rates. The role of enteric Gram-
negative organisms in CAP is controversial, but
these organisms do not need to be considered
c risk factors are present; one of these
risk factors includes residence in a nursing home.
and it may even account for pneumonia in patients
who have no pathogen identi ed by routine diag-
nostic testing (Table 1). Although the incidence of
DRSP is increasing, available data show that the
rate of mortality in patients with CAP is adversely
affected by drug-resistant pneumococci only when
minimum inhibitory concentration values to
penicillin are
The impact of organisms
at lower levels of resistance remains uncertain.
Community-Acquired Pneumonia:
Advances in Management
Ronald R. Grossman, MD, FCCP
Table 1.
Organisms Associated with Community-Acquired
Patient Type


Community-Acquired Pneumonia (Grossman)
failures when patients with drug-resistant strains
are treated with antibiotics that do
in vitro
activity against the pathogen.
Treatment failures have been described among
patients with infection treated with macrolides
when pneumococci exhibit macrolide resistance
and  uoroquinolones when pneumococci exhibit
uoroquinolone resistance.
8,9
The mechanism of
macrolide resistance does not appear to in
the risk of macrolide failures.
All patients with CAP could potentially be
, and
Legionella sp (the “atypical” pathogens), either
alone or as part of a mixed infection; thus, all
patients should receive therapy to account for this
possibility.
replace, this process.
18–20
In general, hospitalization


361
have more severe illness and should be considered
for admission to the ICU. These criteria include
respiratory rate
30 breaths/min, diastolic BP
60
7.0 mmol/L (
, CURB [confusion, elevated urea,
increased respiratory rate, decreased BP]). The
ed ATS rule achieved a sensitivity of 69%
city of 97% in predicting admission to
city of
93% for predicting mortality.
were used to predict outcome, the BTS-CURB cri-
ed
ATS rules.
Patients should initially be treated empirically
of care, although when culture results become avail-
able, organism-speci c therapy may be possible for
some patients. All populations should be treated
(Table 2). For outpatients or non-ICU inpatients
with risk factors for these other organisms, therapy
-lactam/macrolide com-
uoroquinolone
alone (Table 2). Although both regimens appear
therapeutically equivalent, particularly among
inpatients, in the outpatient treatment of the
more complicated patient, an antipneumococcal
uoroquinolone may be more convenient than a
-lactam/macrolide combination.
All admitted patients should receive their 
Although 4 h has been the
recommended standard, it is not clear that every
patient must be treated that quickly because the
lish and treatment should not be started until other
ICU-admitted patient, current data do not support
uoroquinolone
either a macrolide or fluoroquinolone, using a
regimen with two antipseudomonal agents in
appropriate, at-risk patients (Table 3). The more
Table 2.
Outpatient Treatment*
1. Previously healthy and no use of antimicrobials within the previous 3 mo
A macrolide


Community-Acquired Pneumonia (Grossman)
combination antibiotic therapy was superior
to monotherapy but only for severely ill patients.
 Antibiotics administered in a timely way,
 Oxygen assessment or therapy within 8 to 24 h
 Blood specimen for culture drawn before the
 Administration of antibiotics with activity
against all likely causative pathogens, prefer-
cacious regimen;
 Counseling patients regarding smoking cessa-
 Switching from IV to oral antibiotics if the
patient is clinically improving and hemody-
namically stable, with discharge within 24 h of
 Chest radiography within 24 h of hospital
Table 3.
Inpatient Treatment*
A respiratory 
uoroquinolone
-lactam plus a macrolide
-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin (level II evidence) or a respiratory
uoroquinolone (for penicillin-allergic patients, a respiratory  uoroquinolone and aztreonam are recommended)
-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus
either cipro oxacin or levo oxacin (750 mg); or
-lactam plus an aminoglycoside and azithromycin; or
-lactam plus an aminoglycoside and an anti-pneumococcal  uoroquinolone (for penicillin-allergic patients,
substitute aztreonam for above


tive organisms (such as
S aureus
had greater associated mortality rates. An
episode of CAP in young adults without signi
cant
comorbidity is not a predictor of poor medium-
Increasing age, comorbid cerebro-
vascular and cardiovascular disease, an altered
mental status, and increasing blood glucose are
independent predictors of decreased medium-term
Treatment failure rates with guideline-driven
empiric therapy have been reported as high as
Risk factors for treatment failure that have
been identi ed include liver disease, pneumonia
risk class, leukopenia, multilobar CAP, pleural
effusion, and radiographic signs of cavitation.
of treatment failure include in
uenza vaccination,
initial treatment with fluoroquinolones, and a
concurrent diagnosis of COPD. Failure of empiric
therapy increases the rate of mortality in patients
with CAP 11-fold after adjustment for risk class.
cation of these risk factors is possible and
should encourage prospective randomized trials.
Emerging Threats
cient human genes to be easily transmitted from
person to person. Such an event would mark the
start of an influenza pandemic. In published
series, symptoms of fever, sore throat, cough and,
in several of the fatal cases, severe respiratory
distress secondary to viral pneumonia devel-
Previously healthy adults and children
and some with chronic medical conditions were
affected. Antiviral drugs, some of which can be
used for both treatment and prevention, are
clinically effective against influenza A virus
strains in otherwise-healthy adults and children


Community-Acquired Pneumonia (Grossman)
Newer Studies


decrease of
90% in CRP levels in 7 days were both
associated with an increased risk of having received
inappropriate empiric antibiotic treatment. Con-
secutive CRP measurements may be useful in the
rst week in follow-up of antibiotic treatment for
severe CAP, and delayed normalization of CRP
levels is associated with a greater risk of having
received inappropriate antibiotic treatment.


Community-Acquired Pneumonia (Grossman)
Clinical, laboratory, and functional data were
prospectively collected on 1,813 adults with CAP
uenza season.
The cohort consisted of 352 vaccine recipients and
352 matched control subjects. In
uenza vaccination
was associated with a 51% reduction of mortality
outside in uenza season. Adjustment for age, sex,
and comorbidities did not alter these findings.


367


Community-Acquired Pneumonia (Grossman)


369
 Review the epidemiology, pathophysiology, and clini
manifestations of silicosis and coal worker’s pneumo-
 Understand the pulmonary manifestations of asbestos-
induced diseases of the lung (asbestosis and rounded
atelectasis) and of the pleura (effusions and plaques)
 Discuss the malignancies associated with asbestos expo-
sure (bronchogenic carcinoma and mesothelioma)
Silicosis
De
Silicosis is a chronic lung disease that is caused
by the inhalation of crystalline silica (usually
quartz and, less commonly, cristobalite, tridymite,
coesite, and stishovite) and is characterized by
progressive parenchymal nodules and pulmonary
brosis. Silica or silicon dioxide is the most abun-
dant mineral in the crust of the earth and is used
in a wide range of industrial products. Amorphous
and vitreous silica) are relatively less 
brogenic,


decreased the number of deaths caused by silicosis.
However, the number of silicosis-associated deaths
among persons 15 to 44 years of age has not
decreased signi
cantly in the United States.
4,5
Fur-
This history is particularly important given the


typically are scattered throughout the upper lung
zones, sparing the majority of the lung parenchyma
and thereby causing minimal symptoms (Fig 2).
chronic silicosis, can become complex silicosis as
the nodules expand, affecting the bronchioles and
vasculature and eventually coalescing into large
masses (progressive pulmonary 
brosis [PMF])
that can undergo necrosis (Fig 3). However, the
presence of central cavitation should raise concern
about tuberculosis (TB). The adjacent lung may
brosis is unclear,
but quartz, cristobalite, and tridymite are more
brogenic than amorphous silica. Silica particles
A,
Figure 2.
Simple silicosis.
Progressive massive pulmonary 
brosis due to
silica exposure.


that are 5
distal alveoli, where they are ingested by alveolar
macrophages (AMs), which are the first line of
alveolar defense. Silica-activated AMs subsequently
release reactive oxygen species (ROS), reactive
nitrogen species,  bronectin, and various cytokines
and growth factors. In particular, silica and other
particulates activate the expression of transforming
growth factor-
, resulting in excess extracellular
matrix deposition. Silica also can directly injure
damage occurs, as seen with intense exposure to
high levels of silica, surfactant production and
processing are altered, resulting in acute silicosis.
PMF, which can occur with both silica and coal
exposure, may ensue over time but may also occur
Figure 5
depicts some of the key pathogenic
events leading to silicosis and highlights the over-
lapping molecular pathways that are activated by
precise mechanisms underlying the distinct clinical
manifestations of each mineral dust are unknown
but likely relate in part to the differences in the
, chest radiograph from a patient with silicosis showing left hilar adenopathy with egg-shell calci


for patients with atypical occupational exposure
or chest radiograph  ndings. Silicotic nodules are


silicosis who present with active pulmonary TB
with cavities and have smears positive for acid-fast
bacilli, the recommended treatment duration is for
11 months rather than 9 months. TB prophylaxis
alone or for 4 months if a four-drug regimen con-


bituminous, and anthracite. Bituminous coal
accounts for nearly 43% of the US coal reserves; it
is contaminated with low levels of silica and, in
the Pittsburgh area, surface-active iron (0.119
mg/100 mg), which may account for its greater
pathogenicity.
Underground miners, compared with surface
or strip miners, have the greatest risk for the devel-
opment of CWP. In the 1950s and 1960s, there was
an increase in mortality rate among coal miners in
part because of CWP.
1,2,16
The extensive dust-control
measures invoked in the 1960s through the 1970s
in the United States and in other industrialized
countries resulted in a substantial reduction in the
prevalence and mortality rate of CWP. It is esti-
100,000 workers currently are em-
States and that the estimated prevalence of CWP,
ned as an ILO chest radiograph abnormality
of 1/0 or greater, varies from 3 to 14%, depending
on the mining region, with the highest prevalence
30 years of mining
2,16
Fortunately, complicated CWP or PMF
0.5% of workers with CWP.
The risk
for PMF is directly proportional to the radiographic
profusion score and the levels of quartz in the coal
Pathology
The initial lung tissue reaction to coal dust is
the formation of a coal macule and, when combined
with surrounding focal emphysema, de
nes simple
CWP. Coal macules are typically up to 4 mm in size
and tend to form at the junctions of respiratory
bronchioles in the upper lungs (Fig 1,
The
macule, consisting of coal dust–laden macrophages
and  broblasts, enlarge, loosen the connections
of the alveolar walls to the bronchioles, and thereby
cause focal areas of emphysema. Unlike the con-
the nodules associated with CWP have haphazardly
arranged collagen bundles  lled with dark-staining
anthracotic pigment and lack the birefringent
particles found in silicosis tissue, which can be seen
with polarized light. However, coal-induced mac-
ules are similar to silicosis in that they can enlarge
and coalesce, resulting in masses that encroach on
the alveolar ducts and alveoli. In patients with either
CWP or silicosis, when these masses are
1 cm
radiographically, the PMF label can be used.
Pathogenesis
Table 2.
Frequency
 OSHA
Preplacement; every 5 years if
20 years of exposure; every 2 years if
20 years of exposure;
 WHO
Preplacement; then after 2–3 years of silica exposure; then every 2–5 years of silica exposure
and thereafter
 ACOEM
Preplacement; every 3 years if
10 years of exposure; every 2 years if
10 years of exposure;
 OSHA
Preplacement; every 5 years if
10 years of exposure; every 5 years if
10 years of exposure
up to age 35 then every 2 years up to age 45; then annually thereafter or at employment
0.1 
ber/cm
exposure
 WHO
Preplacement; every 3–5 years if
10 years of exposure; every 1–2 years if
exposure; annually if
20 years of exposure
Adapted from Schwerha JJ. Occupational Medicine Forum. J Occup Environ Med 2008; 50:101–104.


The prevalence of CWP is greater in anthracite coal
miners than in bituminous coal miners in part
because of the greater levels of crystalline silica and
in part because of the greater levels of carbon-cen-
tered free radicals. Coal mine dust fractured by
grinding contains more free radicals than unfrac-


infections that occur in both diseases. An unex-
in coal miners is lower, but in patients with silico-
sis, the risk is greater than that in the general
population when adjusted for age and smoking
Premature death is limited to patients with
complicated CWP or PMF. A 23-year follow-up
of 8,899 coal miners who were initially


a fourfold excess of pleural mesotheliomas. As


various proteins involved in tumor suppression,
cell cycle arrest, apoptosis, and cell survival.
Benign Asbestos Pleural E


risks, advising the patient of the importance of
chest radiograph (Table 1).
Diffuse pleural plaques are a more widespread
form of pleural  brosis involving the visceral and


A diagnosis of mesothelioma begins with a strong
clinical suspicion based on the appropriate expo-
sure history. Pleural  uid cytology is diagnostic in
video-assisted thoracoscopic surgery is occasion-
A panel of immunohistochemical
Adenocarcinomas, with which mesothelioma
is often confused, show periodic acid-Schiff-posi-
tive vacuoles and stain positively with carcinoem-
ndings of these stains typically are negative in
mesotheliomas. However, mesothelioma cells gen-
erally stain positively for vimentin. Mesotheliomas
may also elevate pleural fluid hyaluronic acid
levels, but this test is not always readily available.


of asbestos  bers. There is a latency period of at
least 20 to 40 years from the time of initial exposure
to the development of respiratory symptoms. The
earliest symptom of asbestosis is insidiously pro-
gressive exertional dyspnea that often progresses
inexorably regardless of further asbestos exposure.
Cough with sputum production is generally attrib-
is frequently obtained because of its greater sensi-
tivity. The characteristic HRCT scan 
ndings of
asbestosis, although nonspeci c, include the fol-
lowing: (1) subpleural linear densities parallel to the
pleura; (2) parenchymal bands 2 to 5 cm in length,
often contiguous with the pleura; (3) thickened
ndings, HRCT scan
ndings consistent with asbestosis were noted in
57 patients (33.7%). These workers also had reduc-
and an
increased dyspnea score in comparison with workers
with asbestosis demonstrate restricted lung vol-
lco,


233 workers who died, 20% died from asbestosis,
39% died from lung cancer, 9% died from meso-
thelioma, and 32% died from other causes. Given


Pneumoconiosis (Kamp)


Pathophysiology
Acute beryllium pneumonitis is caused by
direct acute lung injury resulting from the inhala-
lium also incites an antigen-specific immune
response that can cause a noncaseating granulo-
matous in ammatory reaction that is histopatho-
logically similar to that seen in patients with
sarcoidosis. Persistent low-level beryllium expo-
sure results in chronic berylliosis, which is mani-
fested by chronic interstitial  brosis, often with
bullous changes, as well as systemic involvement
in the skin, liver, spleen, lymph nodes, myocar-
dium, kidney, bones, and salivary glands. T lym-
phocytes from the lung and blood of patients with
berylliosis proliferate when exposed
in vitro
to
This reaction serves as an important early marker
brosis.
2,73
Up
to 16% of beryllium workers are sensitized to
beryllium as assessed in the lymphocyte prolif-
Clinical Features/Management
Acute beryllium disease is now relatively rare


Pneumoconiosis (Kamp)
nitis with features of hypersensitivity pneumonitis;
and (3) chronic diffuse interstitial  brosis that can
progress to end-stage  brosis. Patients with cobalt-
induced chronic interstitial 
brosis present with


Occupations involving iron exposure (
to siderosis. It is often a relatively benign condition,
usually noted as an incidental  nding or as an
abnormality on a chest radiograph with dense
linear opacities in an asymptomatic iron worker.
Occasionally, iron can induce respiratory symp-
toms, restrictive pulmonary physiology, and pul-
monary fibrosis in heavily exposed workers.
Pathologic  ndings range from the characteristic
iron dust macule to interstitial  brosis. There is no
c treatment other than the prevention of
further iron exposure.
genesis of asbestosis and silicosis. Am J Respir Crit
Care Med 1998; 157:16661680


11. Wang X-R, Christiani DC. Respiratory symptoms
asbestos, and coal mine dusts. J Occup Environ
12. Greenberg MI, Waksman J, Curtis J. Silicosis: a
review. Dis Mon 2007; 53:394416
A relatively current review of silicosis. Includes 79
references.
cancers: clinical spectrum and pathogenic mecha-
nisms. Clin Occup Environ Med 2002; 2:753778


35. Nicholson WJ, Perkel G, Selikoff IJ. Occupational
exposure to asbestos: population at risk and pro-
jected mortality; from 1980 to 2030. Am J Ind Med
1982; 3:259311
36. Kamp DW. Asbestos-induced lung diseases: an
update. Transl Res 2009; 153:143152.
A recent review emphasizing epidemiology and patho-
genesis. Includes 106 references.


Pneumoconiosis (Kamp)


391
 Identify the key respiratory pathogens causing hospital-
acquired pneumonia/ventilator-associated pneumonia
 Develop a systematic approach to the diagnosis of
hospital-acquired pneumonia/ventilator-associated
 Improve the initial therapeutic choices for the management
of hospital-acquired pneumonia/ventilator-associated
clinical pulmonary infection score; hospital-
acquired pneumonia;
aureus;
ventilator-associated pneumonia
48 h after admis-
ned as
hospital-acquired
Ventilator-associated pneumonia
(VAP) refers to pneumonia that occurs
48 to 72 h
after endotracheal intubation among patients


Hospital-Acquired and Ventilator-Associated Pneumonia (Grossman)
P aeruginosa, Escherichia coli, Klebsiella


of inspired oxygen), and microbiologic data into a
single numerical result to improve the speci
good correlation with positive quantitative culture
ndings of bronchoscopic and nonbronchoscopic
BAL  uid specimens was observed. These 
ndings
have not been reproduced by other investigators,
but the accuracy of the CPIS score is improved if
a Gram stain of a deep respiratory tract culture is
51,52
These  ndings suggest that the presence of
abnormal radiographic  ndings, can be used for
initial screening for VAP. However, the lack of
should be collected before changes of antibiotic.
Samples can include an endotracheal aspirate,
BAL  uid sample, or protected specimen brush
A sterile culture of respiratory secre-
72 h virtually rules out the presence of bacterial
infection are
of infection, an extrapulmonary site of infection
A reliable tracheal aspirate Gram stain can be
used to direct initial empiric antimicrobial therapy
and may increase the diagnostic value of the CPIS.
The presence of a new or progressive radiographic
ltrate and at least two of three clinical features
38°C, leukocytosis or leukopenia, and


Hospital-Acquired and Ventilator-Associated Pneumonia (Grossman)
and length of stay for patients with HAP, and
antibiotic-resistant organisms are the pathogens
most commonly associated with inappropriate
therapy.
who have recently received an antibiotic, an effort
should be made to use an agent from a different
antibiotic class because recent therapy increases
the probability of inappropriate therapy and
can predispose to resistance to that same class of
Initial antibiotic therapy should be
administered promptly because delays in admin-
istration may add to excess mortality resulting
from VAP.
68,71,72
Empiric therapy of patients with severe HAP
or VAP requires the use of antibiotics at optimal
doses to ensure maximum ef
cacy.
Initial therapy
should be administered IV to all patients, with a
with a good clinical response and a functioning
as the quinolones and linezolid, may be easily
nation therapy should be used if patients are likely
have documented the superiority of this approach
compared with monotherapy, except to enhance
the likelihood of initially appropriate empiric
therapy. If patients receive combination therapy
with an aminoglycoside-containing regimen, the
responding patients.
agents can be used for patients with severe HAP
and VAP in the absence of resistant pathogens.
Patients in this risk group should initially receive
combination therapy until the results of lower
respiratory tract cultures are known and con
that a single agent can be used. If patients receive
an initially appropriate antibiotic regimen, therapy
can be shortened from the traditional 14 to 21 days
to periods as little as 7 days, provided that the
Table 2.
Initial Empiric Antibiotic Therapy for HAP or VAP in
Patients With No Known Risk Factors for MDR Pathogens, Early


renal insuf ciency or are receiving other nephro-
toxic agents, but more data are needed. Antibiotic
restriction can limit epidemics of infection with


Hospital-Acquired and Ventilator-Associated Pneumonia (Grossman)
after major heart surgery.
CASS was a safe proce-
dure that reduced the use of antimicrobial agents
in the overall population and the incidence of VAP
48 h). The cost
for the conventional tube. This is more evidence to
support the use of these more expensive endotra-
cheal tubes, at least in patients undergoing major
heart surgery.
In a prospective observational study involv-
ing 105 consecutive patients receiving mechanical
ventilation and undergoing BAL, BAL 
uid soluble
triggering receptor expressed on myeloid cells-1


pneumonia in the critically ill patient. Am J Respir
Crit Care Med 1999; 159:12491256


Hospital-Acquired and Ventilator-Associated Pneumonia (Grossman)
41. Craven DE, Steger KA. Nosocomial pneumonia in
ogy and prevention in 1996. Semin Respir Infect
1996; 11:3253


pneumonia. Crit Care Med 2000; 28:27372741
65. Campbell GD. Blinded invasive diagnostic proce-
dures in ventilator-associated pneumonia. Chest
2000;117:207S211S
66. The Canadian Critical Care Trials Group. A rando-
mized trial of diagnostic techniques for ventilator-


Hospital-Acquired and Ventilator-Associated Pneumonia (Grossman)
86. Michel F, Franceschini


401
 Examine the causes of hypoxemic respiratory failure
 Review the pathophysiology, diagnostic criteria, clinical
features, and epidemiology for acute lung injury (ALI) and
 Examine management strategies for ALI/ARDS, including
mechanical ventilation, medical management, and rescue
therapy for refractory hypoxemia
acute lung injury; ARDS; hypoxemia; mechanical
Hypoxemic Respiratory Failure
Pulmonary Gas Exchange
The disruption of gas exchange, as a result of
one or more of numerous pathophysiologic mech-
anisms, can cause a signi cant elevation in Pa
, hypercapnia, and/or a reduction in Pa
age as a result of the loss of effective alveoli during
advancing age and can be approximated from the
years). This equation assumes the individual is
breathing ambient air and is near sea level. Pa
will decline progressively with increasing altitude
greater than sea level as a result of decreasing
In fewer cases, hypoxemia is the result of true
genated blood, producing hypoxemia. These con-


Hypoxemic Respiratory Failure (Sessler)
Clinical Manifestations and Causative
Conditions of Hypoxemia
Table 1.
Common Clinical Conditions Associated With
Hypoxemic Respiratory Failure
Diffuse alveolar hemorrhage
Chronic bronchitis
Bronchiolitis


form the basis for the American European consen-
sus conference de
of which are displayed in Table 2. It is noteworthy
that exclusion of left atrial hypertension as the
ple, measurement of pulmonary capillary wedge
pressure (PCWP), or more properly
pulmonary
artery occlusion pressure
, is performed infrequently
in current practice, and elevations in PCWP may
re
Table 2.
American European Consensus Criteria for ALI and
All features must be present:


Hypoxemic Respiratory Failure (Sessler)
prone position, CT may demonstrate migration of
consolidation and in ltrates to the ventral lung
units which are now in a dependent position.
Causes of ALI/ARDS
The causes of ALI/ARDS often are categorized
based on the mechanism of injury: direct (or epi-
thelial) or indirect (or vascular). The more common
causes are listed in Table 3 using this categoriza-
tion. When one considers comprehensive epidemi-
ology studies, sepsis, pneumonia, trauma, and
gastric aspiration account for the majority of
Pathophysiology of ALI / ARDS
The acute phase of ALI/ARDS is characterized
by the accumulation of protein-rich edema 
as a result of increased permeability of the alveolar
capillary endothelium and the alveolar epithelium,
Further, surfactant is inactivated and diluted. As
epithelium is sloughed, hyaline membranes are
ammatory injury. Neutro-
phils migrate from the vasculature into interstitium
and alveoli, where they release inflammatory
mediators, proteases, and oxidants. Neutrophils
are recruited and activated in part because of
release by alveolar macrophages of cytokines such
as tumor necrosis factor-
and IL-8. Other cellular sources of mediators also
are important, because ALI/ARDS occurs in neu-
tropenic patients. Additionally, fibroblasts are
activated to produce extracellular matrix. Fibrin is
prolonged inflammation and fibrosis. Many
patients quickly progress to a recovery phase char-
acterized by phagocytosis of apoptotic neutrophils,
clearance of sodium by the sodium pump of
type II epithelial cells, and water ef ux via aqua-
porins. The presence of alveolar and interstitial
edema,  brosis, and in ammation contributes to
stiff poorly compliant lungs. Many alveoli are not
functional gas exchange units because they are
lled with  uid and/or in ammatory exudates, or
are prone to collapse, and thus contribute to shunt-
like gas exchange resulting in refractory hypox-
emia. The reader is referred to excellent reviews by
Ware and Matthay for further information.
Epidemiologic estimates of the incidence of
ALI and ARDS vary widely from 1.5 to 75 per
100,000 annually but are highly dependent on the
population studied, the definitions used, and
other factors. Some of the best data regarding US
cases comes from studies conducted in Seattle, in
Direct causes
Pulmonary infection
Aspiration injury (gastric contents, near drowning, blood,
Inhalation injury (smoke, toxins)
Trauma (contusion)
Embolism (amniotic  uid, fat, air)
Re-expansion injury
Reperfusion injury
Indirect causes
Severe sepsis
Nonpulmonary trauma
Transfusion-related lung injury
Cardiopulmonary bypass
Medications (opioids, salicylates, amiodarone, tocolytics,
Acute pancreatitis


cases arising after sepsis or gastric aspiration. An
analysis of published reports suggests that mortal-
ity rates for ALI/ARDS have declined approxi-
mately 1% per year from 1994 to 2006. Mortality
rates in recent large RCTs of patients with ALI,
performed primarily in AMCs, reveal 30- to 60-day


Hypoxemic Respiratory Failure (Sessler)
Table 4.
0.20.30.40.50.60.70.80.91
without
ARDS
PaO2
(mmHg)


407
PBW was used and the PEEP was increased accord-
ing to the Table 5
as long as the pressure plateau
(Pplat) remained
30 cm H
O. A word of caution
regarding the more aggressive PEEP approach of
0.30.40.50.60.70.80.91.0
PEEP, cm H
O5101018182020202022222224
*PEEP is adjusted upwards according to the table, unless Pplat
30 cm H
O while the patient is receiving volume-assist con-
trol ventilation with V
= 6 mL/kg PBW. PEEP is increased in increments of 2 cm H
by 0.1. Note that a trend for greater
180 mm Hg; thus, this strategy is
recommended for ALI without ARDS
Female
Predicted
body weight
6 ml/kg
tidal
volume
(in kg)(in ml)
581476015245.5
601526215750
621576416354.7
641636616859
661686817364
681737017868.5
701787218373
721837418878
741887619382


Hypoxemic Respiratory Failure (Sessler)
improvement in lung compliance will result in
larger, and potentially excessive, V


this was rarely present) is presented in Table 6. Of
study were when the patient was “stable,”
, nor-
uid by diuresis. Work
by other investigators suggest that the addition
of albumin infusion to patients with ALI and low
5 mg/dL) serum protein as they are receiving
furosemide diuresis leads to improved oxygen-
ation,  uid balance, and hemodynamics.
ALI/ARDS is an
ammatory disorder in which oxidants also
play a role in lung injury. Altering the fatty acids
that are incorporated into tissue lipids can modify
the nature of lipid in ammatory mediators that
are subsequently released. The arachidonic acid
demonstrated the lack of bene t of high-dose,
short-duration corticosteroids in
preventing
the
development of ARDS in high risk patients. Dur-
ing the past two decades, four studies addressing
the administration of corticosteroids early in the
course of ALI/ARDS suggest that corticosteroids
may be bene cial in reducing mortality but did not
reach statistical signi cance (odds ratio 0.48, 95%
dence interval, 0.40 to 1.09) when pooled. A
CVP range,
mm HgShock Present
OliguricNonoliguric


Hypoxemic Respiratory Failure (Sessler)


411
administration of INO to patients with ALI/ARDS
improves chances of survival or reduces ventilator
time. Thus, the role of INO is largely as rescue
therapy for refractory and life-threatening hypox-
emia. Potential adverse effects of INO include


Hypoxemic Respiratory Failure (Sessler)
and high PEEP, and sedatives and opioids were associated


in hypoproteinemic patients with acute lung injury.
Crit Care Med 2005; 33:16811687


Hypoxemic Respiratory Failure (Sessler)
lung compliance without increasing barotrauma. Although
there are technical concerns regarding accuracy of esopha-


415
 Address the symptoms of respiratory disease commonly
encountered by the pulmonologist
 Review the physiology, pathophysiology, complications,
differential diagnosis, pathogenesis, diagnosis, and treat-
 Review the physiology, differential diagnosis, pathogenesis,
 Review the pathogenesis, differential diagnosis, diagnosis,
and treatment of hemoptysis
 Review the physiology, differential diagnosis and patho-
physiology, diagnosis, and treatment of dyspnea
Respiratory symptoms are among the most com-
mon reasons for which patients seek medical care.
The National Ambulatory Medical Care Survey,
showed that respiratory
system-related symptoms were the most common
ce visits
in 1998, accounting for approximately 12% of the
total. Other common system-related symptoms
are shown in Table 1. Of all symptoms reported,
cough of undifferentiated duration was the single
most common complaint for which patients sought
medical care of primary care physicians. Of the
ce-based phy-
sicians in the United States from 2001 to 2002,
3.1%, or 34.1 million visits, were for cough. Because
iction of
usually self-limited cough, it is likely that the great-
est majority of the coughs seen by primary care
physicians are acute in duration. With respect to
the pulmonologist, referrals of patients with per-
sistently troublesome chronic cough of unknown
Cough
Healthy people rarely cough during waking
do, it is essentially devoid of any clinical impor-
tance. The lesser frequency of cough during sleep
compared with wakefulness in normal subjects as
well as in patients with chronic bronchitis and
emphysema is likely the result of greater thresholds
However, when
cough is present and persistent, it can assume great
clinical importance. Cough can be an important
defense mechanism that helps clear excessive
Symptoms of Respiratory Disease
Richard S. Irwin, MD, FCCP
Table 1.
Spectrum/Frequency of Symptoms by System for Which


Physiology/Pathophysiology of Cough
There are usually three phases involved in the
active cough mechanism. Cough is usually pre-
This initial inspiration is important in producing
an effective cough by permitting both expiratory
pressure and  ow to be maximal during the ensu-
ing expiration. This high lung volume allows
maximal expiratory  ow rates. During the second
compressive phase, intrathoracic pressure is
increased suf ciently to produce  ow rates neces-
sary for effective cough during the expiratory
is, the removal of undesired material from the
lower respiratory tract.
Although dynamic changes are taking place in
, vocal cords separate and vibrate, and
the width of the glottis narrows at the aryepiglottic


is being readied. It has been shown that patients
with ventricular  brillation, asystole, or heart block
according to the duration of cough into acute, sub-
acute, and chronic types. Acute cough is one that
3 weeks and is most commonly transient
however, it can occasionally be potentially life
threatening (
heart failure, or pneumonia). Subacute cough lasts
from 3 to 8 weeks. It is most commonly caused by
such as asthma and COPD. Chronic cough lasts
weeks and is persistently troublesome. Because
there are patients with respiratory infections (
pertussis) more severe than the common cold who
3 weeks and have it spon-
taneously disappear by 8 weeks, it is reasonable to
lows an obvious respiratory infection for 8 weeks.
However, when cough lasts
3 weeks and does
not follow an obvious respiratory infection, the
workup for cough should not wait 8 weeks. Finally,
because acute cough may become chronic, the
categories are not mutually exclusive.
Table 2.
CardiovascularArterial hypotension; loss of consciousness; rupture of subconjunctival/nasal/anal
veins; massive intraocular suprachoroidal hemorrhage during
vitrectomy;


With respect to the pathogenicity of cough,
there are limited data that do not appear at this
time to support one common mechanism. For
example, although excessive mucus production
may lead to cough by mechanically stimulating the
afferent limb of the cough re ex and extraluminal
masses by compressing/distorting submucosal
airway receptors, an increased sensitivity of the
afferent limb of the cough re ex appears to be an
that the cough eventually resolves, seemingly on
it own; however, on occasion, the resolution of the
corticosteroids, inhaled corticosteroids, or ipratro-
In adults, during outbreaks of
tion, the frequency of postinfectious cough increases
to 25 to 50% in selected series. Although up to 28%
of the cases reported to the Centers for Disease
Control and Prevention on an annual basis occur
in adults, it is clear that this is an underestimation
because the disease is underappreciated. Whooping
cough should be considered in all subjects who
present with a cough-vomit syndrome even if the
, the stridorous noise heard during
inspiration following a prolonged 
t of coughing)
c serum acute IgA


UACS
17,18
and loratadine plus pseudoephedrine
in one study,
were found to be ineffective in treating
the nonhistamine-mediated acute cough associated
controlled trials. The older antihistamines are prob-
ably effective because of their anticholinergic
properties. Other treatment options include intrana-
sal corticosteroids and ipratropium; however, data
on their use are limited.
On the basis of numerous controlled clinical
trials in allergic rhinitis, there is good reason to
believe that avoidance of allergens, intranasal cor-
ticosteroids and cromolyn, and all antihistamines
will be ef cacious for the treatment of the cough
caused by histamine-mediated UACS. Allergen
Streptococcus pneumoniae
and
Other organisms include
anaerobes, Streptococcal species,
Moraxella catarrh-
(especially in children), and
Staphylococcus
aureus.
Therapy includes antibiotics, intranasal
corticosteroids to decrease inflammation, and


the most troublesome symptom. In prospective,
descriptive studies of patients with chronic cough
attributable to asthma, cough has been the only
symptom from 6.5 to 57% of the time. This is called
diagnosis of asthma should
be considered in the differential diagnosis of all
patients with chronic cough because it is a common
cause. Usually, patients with isolated cough do not
ow obstruction at the time of
presentation. The diagnosis of cough-variant
asthma is suggested by the presence of airway
hyperresponsiveness in a patient with chronic
rmed when cough goes away
with asthma medications. The treatment of cough-
variant asthma should be the same as that of
asthma presenting with other symptoms. The most
t is likely to be obtained with corticosteroids,
steroids if the symptoms are very severe, or with


, unless it can be de nitively shown to apply,
should be replaced by the more general term
reß
, so as not to mislead the clinicians into thinking
that all patients with cough caused by GERD
should improve with acid-suppression therapy.
The Committee also recommends empiric therapy
for GERD when patients  t the following clinical
pro
le that has been prospectively validated to be
92% accurate in predicting that cough will improve
or disappear with antire
ux therapy:
8 weeks in duration
Not exposed to environmental irritants or a
present smoker
Not receiving an ACEI
Chest radiographic  ndings are normal or
show nothing more than stable, inconsequen-
Symptomatic asthma has been ruled out:
Cough has not improved with asthma
therapy or


Bronchiectasis
As a cause of chronic cough, bronchiectasis has
been diagnosed in prospective studies
with a
frequency of approximately 4%. Its diagnosis is
established by compatible clinical history, chest
radiographs, high-resolution CT scans of the tho-
c ther-
apy. Cough associated with  ares of the disease
can be treated successfully with a combination of
chest physiotherapy, drugs to stimulate mucocili-
ary clearance, and systemic antibiotics. Aerosolized
antibiotics have been shown to be effective in cys-
tic  brosis (CF) patients with bronchiectasis, but
their use in non-CF patients has not been proven
Bronchogenic Carcinoma
Bronchogenic carcinoma is not a common cause
of chronic cough (0 to 2%). It is very unlikely in
phy, sputum cytology, and 
exible bronchoscopy
are the most important initial tests to consider in
evaluating for this entity. The chest radiograph is
the most important initial diagnostic test for pre-


Chronic Interstitial Pulmonary Disease
In series of patients, this is an uncommon
cause of chronic cough. In patients with chronic
cough, before diagnosing interstitial lung disease
Figure 1 is the suggested algorithm for managing
adult patients with an acute cough. The most
important initial clinical decision is to decide
tions. Figure 2
ography, the most important initial clinical deci-
xD gninetaerhtefilnoN
xD gninetaerhtefiL
History,
URTILRTIAsthma
UACSCOPD
15 years of age with cough lasting
3 weeks. Dx
LRTI
lower respiratory tract infection; PE
pulmonary embolism; UACS
upper airway cough syndrome; URTI
respiratory tract infection.


integrative evaluation, the following systematic,
diagnostic approach that has been validated in
and treat
suoitcefnitsopnoN
suoitcefnitsoP
History,
Workup
Bronchitis
serious diseases
15 years of age with cough lasting 3 to 8 weeks.
acute exacerbation of chronic bronchitis; NAEB
nonasthmatic eosinophilic bronchitis; UACS
upper airway cough
syndrome.
Table 5.
Testing Characteristics of Diagnostic Protocol*
Tests
Sensitivity, %
Speci city, %
PPV, %
NPV, %
BaE 48–92 42–76 30–63
100 66–100 89–100
Bronchoscopy


cytology;  exible bronchoscopy; chest CT scan;
ACE-1
A cause of
and treat
History,
response to
optimal RX
response
tooptimalRX
Upper airway cough syndrome (UACS)
Empiric treatment
Asthma
Chronic cough algorithm for the management of patients
15 years of age with cough lasting
8 weeks.
antihistamine/decongestant; BD
bronchodilator; HRCT
high-resolution chest CT; ICS
inhaled corticosteroid;
LTRA
leukotriene receptor antagonist; PPI
proton pump inhibitor.


multiple causes from 18 to 62%. Multiply
caused cough has been the result of three dis-
3. Although most smokers have a cough, they
have not been the group of patients who most
4. In adults of all ages and the elderly, UACS,
asthma, and/or GERD are the three most
common causes of chronic cough.
5. In prospective studies,
chronic cough in
by six disorders: UACS, asthma, GERD,
chronic bronchitis, noneosinophilic bronchi-
tis, and bronchiectasis.
6. Cough has been shown in prospective stud-
asthma, nonasthmatic eosinophilic bronchitis,
�and/or GERD) 99% of the time in nonsmok-
ing adults who are not receiving an ACEI and
7. Cough can be the sole clinical manifestation
the time, respectively, and nonspeci
c bron-
choprovocation challenge testing and 24-h
to be extremely useful in making a diagnosis
8. Unless the chest radiographic 
ndings are
abnormal, and this is an uncommon occur-
r�ence (no 7%),  exible bronchoscopy will
have a very low diagnostic utility (approxi-
9. The principal strength of the diagnostic pro-
tocol is in ruling out suspected possibilities.
result cannot necessarily be relied on to estab-
been shown to predict a favorable response to
speci c therapy (Table 5).
Schematic representation of the anatomy of the
cough re ex. This representation comes from an amalgama-
iological results in experimental animal studies.


Wheeze
Wheeze is a continuous musical sound that lasts
80 to 100 ms.
The pathophysiologic mechanism(s)
that generate wheezing are still not known.


can be physiologically differentiated. The three
areas include the following: (1) the extrathoracic
upper airway that includes the nose, mouth, phar-
ynx, larynx, and extrathoracic trachea; (2) the
thoracic trachea and bronchi down to the level of
the 2-mm airways; and (3) the small airways that
are
Spectrum and frequency of causes of wheeze in patients referred to a pulmonary clinic. PNDS is now referred to as


during maximal inspiratory effort (Fig 7).
Because the extrathoracic airway will dilate dur-
ing expiration, the maximal expiratory flow
The effect of transmural pressure changes during inspiration and expiration on the severity of obstruction at differ-
Top:
extrathoracic upper airway obstruction. During expiration, intrapleural pressure (Ppl) and subsequently
intratracheal pressure (Ptr) are greater than atmospheric pressure (Patm). Therefore, the site of the obstruction widens. Durin
inspiration, because Ppl and Ptr are less than Patm, the site narrows.
intrathoracic upper airway obstruction. During
expiration, because Ppl is greater than Ptr, the site narrows. During inspiration, because Ptr is greater than Ppl, the site widens.


If the upper airway obstruction is 
xed (
does not allow the airway to respond to normal
transmural pressure changes), it cannot be localized
that the obstruction is in large rather than small
airways (Fig 7). Air ow will be uniformly impeded
during inspiration and expiration because there will
Schematic  ow-volume loop con
tions in a spectrum of airway lesions.
, variable extrathoracic upper airway obstruction;
xed upper airway obstruction; and
obstruction.


physician should, in stepwise fashion, address
ated in a physiologically oriented manner when
common causes do not explain the patient’s
Hemoptysis
Hemoptysis is the spitting of blood derived
from the lungs or bronchial tubes. Hemoptysis may
be scant, producing the appearance of streaks of
bright red blood in the sputum; or profuse, with
expectoration of a large volume of blood. Massive
hemoptysis is de ned as the expectoration of 600
mL of blood within 24 to 48 h and may occur in 3
Gross or
frank hemoptysis produces a quantity smaller than
massive hemoptysis and greater than blood streak-
ing. Dark red clots may also be expectorated when
blood has been present in the lungs for days.
Pseudohemoptysis is the expectoration of
blood from a source other than the lower respira-
patients cannot clearly describe the source of their
may occur when
blood from the oral cavity, nares, pharynx, or
tongue drains to the back of the throat and initiates
the cough re ex; when blood is aspirated into the
lower respiratory tract in patients who have
hematemesis; and when the oropharynx is colo-
nized with the red, pigment-producing, aerobic,
Gram-negative rod,
Serratia marcescens.
have received broad-spectrum antimicrobial agents
and mechanical ventilation. Other rare causes of
pseudohemoptysis are self-inflicted injuries or
other bizarre tactics in the malingering patient
seeking hospitalization, and rifampin overdose
(red man syndrome).


Symptoms of Respiratory Disease (Irwin)
Table 7.
Distinguishing Features
UACS
History of postnasal drip, throat clearing, nasal discharge; physical examination shows


37%, bronchogenic carcinoma in 19%, tuberculo-
sis in 7%, pneumonia in 5%, and bronchiectasis in
200 mL/d


Symptoms of Respiratory Disease (Irwin)
caused by bronchiectasis, and 4% were caused by
sporotrichosis. In a series
from Duke University,
had cancer and only 8 patients (19%) had bron-
chitis, bronchiectasis, or tuberculosis as a cause.
Idiopathic hemoptysis is less frequent in patients
5% of cases.
Rupture of a pulmonary artery complicates
Table 9.
Cardiovascular
Arteriobronchial 
Congestive heart failure
Pulmonary arteriovenous 
Diffuse intrapulmonary hemorrhage
Diffuse parenchymal disease
Iatrogenic
Malposition of chest tube
Pulmonary artery rupture
Tracheoartery 
Aspergilloma
Bronchiectasis
Bronchitis
Lung abscess
Sporotrichosis
Tuberculosis
Bronchogenic carcinoma


Pathogenesis
The bronchial arteries are the chief source of
blood for the airways (from mainstem bronchi to
terminal bronchioles), for the supporting frame-
monary lymphoid tissue, and the large branches
of the pulmonary vessels, and for the nerves in
the hilar regions. The pulmonary arteries supply
the pulmonary parenchymal tissue, including the
Arteriographic studies in patients with active
hemoptysis have shown that the systemic circula-
tion is primarily responsible for the bleeding in
approximately 92% of cases.
if the lesion is endobronchial, the bleeding is from
the bronchial circulation; if the lesion is parenchy-
mal, the bleeding is from the pulmonary circula-


lymph node erodes the wall of a bronchus because
of pressure necrosis, the patient may cough up
blood as well as the calci ed node (broncholith).
In endobronchial tuberculosis, hemoptysis may
result from acute tuberculous ulceration of the
bronchial mucosa. In healed and 
brotic parenchy-
mal areas of tuberculosis, bleeding may arise from
irritation of granulation tissue in the walls of bron-
chiectatic airways in the same areas.
In traumatic rupture of the pulmonary artery


too large a dose or recurrent pulmonary embolism
from too small a dose. The possibility of pulmonary
embolism should always be considered when a
patient who presents with hemoptysis has been at
increased risk for deep venous thrombosis. The
possibility of traumatic rupture of a pulmonary


a systemic disease associated with diffuse paren-
chymal disease. While there is simultaneous evi-
dence of clinical involvement of the lungs and
kidneys in 33% of cases of Goodpasture syndrome,
there can be clinical lung involvement without
renal disease in 33% and clinical renal involvement
logic disorder that is primarily responsible for the
ing from another disease. The ECG may help sug-
gest the presence of a cardiovascular disorder.
routine posteroanterior and lateral radiographs
When pulmonary tumor or infection is not read-
ily apparent, other radiographic signs that may
suggest the cause and source of bleeding include
radio-opaque foreign bodies that may give rise to
hemoptysis even years after entry into the lungs;
the disappearance of a calci ed mediastinal lymph
node after it has eroded the bronchial wall and is
expectorated as a broncholith; aortic or pulmonary
aneurysms that by dissection may erode into the
bronchial tree; single or multiple pulmonary cavities
that suggest pulmonary tuberculosis, fungal dis-
ease, parasitic disease, acute or chronic lung abscess,
74,75
with a  exible bronchoscope, and in up to 86% with
the rigid instrument.
When the procedure is done
within 48 h, localization of bleeding can drop to
When bronchoscopy is done after bleeding
has ceased, accurate localization is likely to be
reduced even further. Although the 
exible bron-
choscope is usually the instrument of choice in
diagnosing lower respiratory tract problems, rigid
bronchoscopy is preferred in cases of massive
uncontrolled hemorrhage because patency of the
airway is maintained more effectively during this
procedure. There are data that show that obtaining
a high-resolution chest CT before bronchoscopy
may enhance the yield of bronchoscopy. With the
exception of tracheoartery  stula, the tracheobron-
chial disorders that can be diagnosed by a bron-
choscopic examination are listed in Table 8.


Bedside bronchoscopy should not be per-
formed to rule in the diagnosis of tracheoartery
tysis, bronchoscopy should be performed to rule
out other causes, such as bleeding from suction
ulcers, tracheitis, or lower respiratory tract disor-
ders. If no other cause for hemoptysis can be found
ward pressure on the cannula on the stomal site or
ation of the tracheostomy balloon slows
down or stops the bleeding, a surgical consultation
should be sought immediately and the patient
brought to the operating room for examination in


tuberculosis and fungal diseases. Pulmonary cap-
illaritis with hemorrhage has been reported in an
ever-increasing number of conditions. The diagno-
and ruling out other diseases (Table 8).
It is important to be aware that diseases may
be considered (and therefore evaluated) in more
than one category. For instance, the case of a patient
agulation may be evaluated in three categories: (1)
a hematologic disorder that may cause (2) localized
and (3) diffuse parenchymal disease. A patient with
chronic bleeding from the tracheobronchial disor-
der of diffuse bronchial telangiectasis could present
with diffuse as well as localized parenchymal dis-
ease (aspiration hemosiderosis). A patient with
cardiovascular disorder might present with diffuse
pulmonary hemosiderosis, whereas a patient with
acute pulmonary edema usually presents with dif-
erential Diagnosis
In evaluating patients with hemoptysis, it is
necessary to rule out the causes of pseudohemop-
tysis. Unless the cause of pseudohemoptysis is


antibiotic therapy is administered for acute infec-
nitive CareÑMassive Hemoptysis:
with massive hemoptysis, treatment is directed not
c cause but also at abrupt cessa-
tion of bleeding. Death from massive hemoptysis
is predominantly caused by asphyxiation, and the
likelihood of death appears directly related to the
rate of bleeding. Urgent management in all cases
of massive hemoptysis must emphasize protecting
the uninvolved lung from aspiration of blood and
artery  stula may be present, the following steps
should be considered:
and profuse, there may be time only to overin
site at the balloon, and apply downward and
forward pressure on the top of the tracheostomy
the stoma. If the arterial rupture is at the cannula
tip, these efforts will not be helpful. If bleeding
stops or slows either by these efforts or spontane-
ously, an endotracheal tube should be placed distal
diate surgical consultation requested. Ideally, an
experienced surgeon should be present when
the tracheostomy tube is removed; should crisp
bleeding start again, the surgeon can attempt to
nger tamponade/compress the bleeding artery
sternum to the vessel. The vessel, once reached,
can be compressed against the back of the ster-
can be gently suctioned from the distal trachea
and the patient taken to the operating room for
nitive repair.
When bleeding originates from below the pri-
mary carina, the bleeding lung should be kept
blood. Numerous techniques have been advocated
to help minimize aspiration and have proved help-
ful. A bronchoscopically positioned endobronchial
balloon may provide effective tamponade. Hemop-
tysis caused by bleeding from all but the right
sion. Placement of a Carlen tube that intubates each
mainstem bronchus separately is helpful, but the
tube can be dif cult to place; once in position, its


while the patient is stabilized to minimize the
chance of air embolism while receiving positive
pressure ventilation.
Survival from iatrogenic rupture of the pulmo-
nary artery has been reported.
Several urgent
maneuvers may prove helpful, and balloon tam-
ponade and selective intubation should always be
attempted. Balloon tamponade of the ruptured ves-
sel with the Swan-Ganz balloon has been helpful.
With the balloon de


When corticosteroid therapy is administered
serum anti-glomerular basement membrane anti-
body levels. If pharmacologic doses of corticosteroids
control severe pulmonary hemorrhage and the plas-
mapheresis and cyclophosphamide therapy makes
circulating anti-glomerular basement membrane
antibody disappear, bilateral nephrectomy is unnec-
essary. On the basis of favorable case reports in life-
threatening situations, consider recombinant
activated factor VII as a temporizing measure in
Dyspnea
Dyspnea is a distressing sensation of dif
labored, or unpleasant breathing. The word
tressing
nition because
labored or dif cult breathing may be encountered
by healthy individuals while exercising, which
perceived as distressing. The sensation is often
Physiology
The physiology of dyspnea remains unclear
40 years of active investigation. What is
clear, however, is that a simplistic single neural
pathway theory has been superceded by a com-
Because
the respiratory system is extremely complex and
redundant in its control mechanisms, it is quite
likely that there are multiple stimuli, receptors,
nerves, and neural pathways that mediate the
arise caused by abnormalities in the afferent path-
ways, the efferent pathways, or the central control
centers of the respiratory system (Fig 8). Because
afferent pathways feed back to the CNS from virtu-
ally all levels of the efferent pathway, afferent
dyspneic information from virtually all thoracic
and upper abdominal organs (including the phar-
ynx, larynx, airways, lung parenchyma, esopha-
On the basis of the vagus nerve, muscle affer-
ent, and chemoreceptor experiments, it appears
that hypercapnia, hypoxemia, and muscle afferent
data that relate to load, effort, and impedance are
the major dyspnogenic stimuli. An important role
for vagal afferents has not been ruled out. With
respect to the central integration of the afferent and
efferent systems, it appears that the intensity of
dyspnea can be modulated by learning, experience,
erential Diagnosis of Dyspnea
As with cough, a multiplicity of causes located


(2) pulmonary, (3) psychogenic/hyperventilation,
(4) GERD, and (5) deconditioning disorders.
Approximately two thirds of cases, chronic dyspnea
will be caused by four diseases: COPD, asthma,
interstitial lung disease, and cardiomyopathy.
Pathophysiology of Dyspnea
The mechanism by which diseases produce
dyspnea varies with the disease. Some affect
Table 12.
Differential Diagnosis of Dyspnea According to
Cardiac
Pregnancy
GIPulmonary
HematologicPsychiatric
InfectiousRenal
Larynx/upper airwayRheumatologic
NeuromuscularVascular
Schematic representation of the afferent and efferent motor nerves serving the respiratory system. The cortex inte-
grates sensory afferent (
) and efferent (
) data with experience and produces sensations of dyspnea, effort, fatigue,
and weakness. Reprinted with permission from Curley.
Representative spectrum and frequency of causes
of chronic dyspnea evaluated in an outpatient pulmonary
clinic. The 64 respiratory disorders included asthma in 25
UACS in 6 cases, bronchiectasis in 2 cases, tracheal stenosis
in 1 case, kyphoscoliosis in 1 case,  brothorax in 1 case, cos-
tochondritis in 1 case, lung cancer in 1 case, bronchiolitis ob-
literans in 1 case, and unilateral hyperlucent lung syndrome
in 1 case. Upper respiratory tract disorders accounted for
LRT
lower respiratory tract; URT
upper respiratory tract.


afferent pathways, others affect efferent pathways,
and others affect the central integrative sensory
pathways. In most diseases, the precise mechanism
ied. Virtually all studies performed to elucidate the
pnea in asthma reveal that mechanical, blood gas,
and psychological factors probably all play a role.
The intensity of dyspnea does not appear to cor-
relate well with the degree of obstruction. It has
most recently been shown
that asthmatic patients
with a history of near-fatal attacks had a reduced
response to hypoxia and a reduced sensation of
Compared with asthma, Pa
appearto play a greater role in COPD, whereas the
mechanical effects are similar.
probably caused by abnormal gas exchange,
impaired muscle function, or andactivation of
intrapulmonary vagal afferents.
Compression of
the tracheobronchial tree and laryngeal dysfunction
probably cause dyspnea by creating airway obstruc-
tion similar to COPD and perhaps by triggering
vagal afferent pathways.
Compression of lung
tissue by pneumothorax, tumor, or pleural effusion
likely leads to dyspnea by stimulating vagal affer-
wall deformities may alter gas exchange and
muscle length-tension relationships.
Cardiac diseases probably cause dyspnea by
activating afferents, muscle efferents, and/or by
anism by which GERD causes dyspnea (it has
been reported to do so 2 to 5% of the time
96,97,98
) is
not known. Because patients may have normal
lungs, exercise capacity, muscle strength, and gas
exchange, dyspnea in patients who do not have
laryngospasm and who do not aspirate may be
attributable to the stimulation of vagal afferents.
a history and performing a physical examination
threatening conditions 
rst (
, acute asthma,
pulmonary embolism, pulmonary edema states,
Guidelines for Evaluating Chronic Dyspnea of


mouth pressures, and 
ow-volume loops
Noninvasive cardiac studies to include ECG,
echocardiography, and stress testing
ed barium esophagography and/or 24-h
Comprehensive exercise tolerance test
Other more invasive tests such as cardiac cath-


study,
the results of speci c treatment yielded the
following results: (1) chronic dyspnea improved in
76% of patients; (2) all patients with asthma, UACS,
hyperventilation syndrome, deconditioning, and
GERD improved; (3) 33% of patients with COPD,
cardiomyopathy improved; (4) patients with inter-
stitial lung disease and cardiomyopathy all contin-
ued to have some dyspnea despite treatment; and
dyspnea, therapy was helpful in only 12% of
c treatment of asthma, COPD, and inter-
stitial lung disease will be discussed by other
authors in this volume; see the section on cough for
recommendations for treatment of GERD. With
respect to the hyperventilation syndrome, the
authors of controlled studies
100
suggest that breath-
disorders, the only two controlled clinical trials
103,104
improved in COPD patients. Although the results
of studies with systemic narcotics are con
randomized controlled trials do not support use of
105,106
or acupuncture in nonmalignant
breathlessness.
107
Finally, although a small double-
blind randomized controlled clinical crossover
108
suggests that inhaled furosemide may
COPD, the results must be con
rmed in a larger,
multicenter study before this can be routinely rec-
Annotated References
Cough
1. Schappert SM, Burt CW. Ambulatory care visits
to physicians’ of ces, hospital outpatient depart-
ments, and emergency department: United States,
Vital Health Stat 2006; 13:1–66
This survey summarized data from an estimated 1.1
which patients sought medical care.
2. Irwin RS, Corrao WM, Pratter MR. Chronic persis-
tent cough in the adult: the spectrum and frequency
c ther-
apy. Am Rev Respir Dis 1981; 123:413–417
This prospective, descriptive study was the Þ rst to use
and validate the anatomic, diagnostic protocol. It stud-
Table 13.
Predictive Values of Diagnostic Tests in the Evaluation of Chronic Dyspnea*
Test
PPV, %
NPV, %


Symptoms of Respiratory Disease (Irwin)


asthma, and GERD and not chronic bronchitis.
16. Pratter MR. Chronic upper airway cough syn-
drome secondary to rhinosinus diseases (previ-
ously referred to as postnasal drip syndrome):
ACCP evidence-based clinical practice guidelines.
This provides a comprehensive discussion of the upper
airway cough syndrome and justiÞ cation for changing
the name from PNDS.
17. Gaffey MJ, Kaiser DL, Hayden FG. Ineffectiveness
This randomized, controlled, clinical trial showed that a
18. Berkowitz RB, Tinkleman DG. Evaluation of oral
terfenadine for the treatment of the common cold.
Ann Allergy 1991; 67:593–597
This randomized, controlled, clinical trial showed that a


This document is the most comprehensive and up-to-
32. Bolser DC. Cough suppressant and pharmacologic
protussive therapy: ACCP evidence-based clinical
A comprehensive, evidence-based review of nonspeciÞ
tive are identiÞ
Wheeze
33. Pasterkamp H, Kraman SS, Wodicka GR. Respi-


47. Kaminsky DA, Irvin CG. Anatomic correlates of
reversible restrictive lung disease. Chest 1993;
This publication provides convincing data that diseases
can present with reversible restrictive lung disease that
is clinically indistinguishable from asthma.
48. Hudgel D, Cooper D, Souhrada J. Reversible
restrictive lung disease simulating asthma. Ann
This is another publication that reports that patients can
have a reversible restrictive lung disease that is like asthma
and responds to conventional asthma medications.
49. Smyrnios NA, Irwin RS. Wheeze. In: Irwin RS, Cur-
ley FJ, Grossman RF, eds. Diagnosis and treatment
of symptoms of the respiratory tract. Armonk, NY:
Futura Publishing Company, 1997; 117–153
This chapter is a comprehensive, extensively referenced


aspects of tracheoartery Þ stula as a complication of
tracheostomy except for describing the surgical opera-
tions to correct the complication.
61. Lyons HA. Differential diagnosis of hemoptysis
and its treatment. Basics of respiratory disease
This article reviews the spectra and frequencies of
62. Rath GS, Schaff JT, Snider GL. Flexible 
beroptic
bronchoscopy: techniques and review of 100 bron-
This study also includes idiopathic hemoptysis as a spe-
ciÞ c cause of hemoptysis.


Even rigid bronchoscopy has an excellent chance of
localizing the speciÞ c site of bleeding in hemoptysis if
the procedure is performed early.


and critically reviews all aspects of dyspnea.
93. Fedullo AL, Swineburne AJ, McGuire-Dunn C.
Complaints of breathlessness in the emergency
pital. NY State J Med 1986; 86:4–6
This study provides data on spectrum and frequency of
causes of dyspnea evaluated in an emergency depart-
94. Pearson SB, Pearson EM, Mitchel JRA. The diagno-
tal with acute breathlessness. Postgrad Med 1981;
This study provides data on spectrum and frequency of
95. Mustchin CP, Tiwari I. Diagnosing the breathless


breathlessness? A single-blind, placebo-controlled
crossover study. Chest 2004; 125:1783–1790
Although there have been very few studies assessing
the efÞ cacy of acupuncture for dyspnea relief, this
study failed to demonstrate that acupuncture is efÞ


Symptoms of Respiratory Disease (Irwin)


457
ventilation delivery, computerized integration
of physiologic measurements and gas-delivery


Mechanical Ventilatory Support (Sessler)
is certainly inter-related, approaching the issues
separately can be useful to emphasize key elements.
Hypoxemia is a common component of respiratory
failure, and the most straightforward solution is
to increase the fraction of inspired oxygen (F
Adjustments in airway pressure can have an
larly for patients who have extensive parenchymal
mismatching with a large component of underven-
tilated or shunt-like alveoli contributes greatly to
hypoxemia and is often responsive to increases in
airway pressure through alveolar recruitment and


459
pressure
time
Adjust max
flow rate &
pattern,
inspiratory
time
- Pressure or
-
volume
Select mode,
all breaths are
controlled or
assisted
(Cycling)
initiated)
initiated
P
ressure


Mechanical Ventilatory Support (Sessler)
sensors are positioned inside the ventilators and,
thus, the pressure or  ow signal is dampened by
c V
. The inspiratory pressure (Pi) and the
Mode of ventilationAC Mode
Mandatory breathsYes
Yes
Spontaneous breaths*No
Yes
Yes
Volume or pressureEither
spontaneous: pressure only
Pressure
Unreliable ventilation if there is


Table 2.


Mechanical Ventilatory Support (Sessler)
The AC and SIMV modes differ in the num-
ber of mandatory breaths permitted. With the
AC mode, a minimum frequency (for example,


ventilator support. Patient comfort can be impaired
in this mode as well, with the patient receiving three
different breath types.
Spontaneous Ventilation/PSV
—Spontaneous
ventilation requires patient effort for the initiation
of all breaths. Additionally, the termination of all


Mechanical Ventilatory Support (Sessler)


hosts, postextubation respiratory distress caused
by upper-airway obstruction, and persistent
wea ning failure with extubation to NPPV. It is
important to recognize that patients who require


Mechanical Ventilatory Support (Sessler)
Ineffective triggering patient-ventilator dyssynchrony. Graphic display of  ow and pressure over time demonstrates two
conventional breaths followed by an ineffective trigger in which patient inspiratory effort (arrows) does not trigger a breath.
Double-triggering patient-ventilator dyssynchrony. Graphic display of  ow and pressure over time demonstrates three
conventional breaths followed by a double-triggered breath (arrows). See text for de


and hemodynamic compromise. Hyperin
ation
can overdistend alveoli, increasing the likelihood
of rupture as well as compressing the alveolar cap-
space. Additionally, hyperin
ation can place the
diaphragm in a  attened, mechanically disadvan-
, which
in turn promotes tachypnea, thus exacerbating
air trapping by further reducing exhalation time.
Auto-PEEP is also a common cause of ineffective
triggering patient-ventilator asynchrony because
the patient must overcome the auto-PEEP with
decrease in intrathoracic pressure of sufficient
magnitude to be sensed by the ventilator. When
extreme, hypotension can progress to frank shock
and even to cardiopulmonary arrest, typically
with pulseless electrical activity. Mechanisms
exhalation time and progressive hyperinflation
and auto-PEEP. Another situation is the use of very
1s), such as with APRV,
in which even mild bronchospasm or respiratory
exhalation persisting up to the next positive pres-
sure breath, respiratory efforts (chest movement)
ings of ineffective trigger on ventilator graphics,
ation on chest radiograph, or a decrease in
if the patient is receiving positive-pressure
Pulmonary barotrauma: air leak
Pneumomediastinum/pneumopericardium/subcutane-
Dynamic hyperin ation and auto-PEEP or intrinsic PEEP
Hemodynamic compromise
Alveolar overdistention
Altered diaphragm/chest wall position and function,
VALI
Volutrauma
Multiple organ dysfunction
Ventilator-associated pneumonia
Tracheomalacia
Trauma and dysfunction of vocal cords


Mechanical Ventilatory Support (Sessler)
to trigger a breath. The magnitude of inspiratory
effort by the patient can be measured by the use
pleural pressure during these efforts.
Ventilator-Associated Lung Injury
There is considerable experimental evidence
from animal models and accumulating evidence
from patients that MV can be injurious, produc-
response. It is hypothesized that excessive alveo-
lar volume coupled with increased transalveolar
pressure results in shearing forces that disrupt
Acute Lung Injury
Adverse Effects of
Mechanical Ventilation
Systemic
Pulmonary
Alveolar
Capillary
Proteinrich
Pulmonary
Surfactant
Dysfunction
Persistent
Inflammation &
Fibrotic Repair
Alveolar
Collapse
Reduced Lung
Compliance
Barotrauma,


Patient-Focused MV
The goals of MV include improving hypoxemia
and hypercapnia, relief of suffering and distress
such as dyspnea, providing respiratory support
during circumstances in which the patient experi-
ences an impaired drive to breathe (
thesia), and applying evidence-based strategies
to promote survival and timely recovery. Lung-
protective strategies and permissive hypercapnia
One can conceptualize stages of respiratory failure
and MV support as stabilization, maintenance, and
recovery.
MV may be required when there is a failure of
oxygenation or ventilation. Life-threatening respi-
ratory distress or cardiopulmonary arrest requires


Mechanical Ventilatory Support (Sessler)
the lungs of patients with ARDS reveals a small
the notion of “baby”-sized lungs in ARDS. Some
earlier RCTs demonstrated improved outcomes in
ARDS when patients were ventilated with lower
s (and other ventilatory adjustments) compared
difference was found.
In 2000, publication of the result of the ARDS
s. In one study in which three
centers were examined, only 16% of patients had
8 mL/kg predicted body weight (PBW), and
virtually none were
tion include lack of willingness to relinquish ven-
tilator control, recognition of ARDS, and concerns
for contraindications, discomfort, and impaired
gas exchange. Improved compliance with low V
ventilation was strongly associated with use of a
written protocol in a one study.
On the basis of an earlier study by Amato and
coworkers, more recent smaller studies by Ranieri
Table 4.
Variables
Severe Air
Obstruction


471


Mechanical Ventilatory Support (Sessler)
ventilation, while increasing the WOB that the
patient undertakes until it is judged that the patient
is capable of breathing independently, at which
complications (unplanned extubation, prolonged
ventilation, reintubation, and tracheostomy).
This protocol incorporated daily screening of all
mechanically ventilated patients by respiratory
therapists for hemodynamic stability, cessation
PEEP level, adequate cough, and adequate respi-
ratory muscle strength as judged by f/V
105
while breathing without support. Patients who
successfully passed this screening protocol under-
went a 2-h spontaneous breathing trial (SBT) with
O CPAP or T tube. Those who passed were
extubated. This protocol has served as a basic tem-
plate for many weaning protocols (speci
c criteria)
and structured approaches (daily performance by
respiratory therapists and nurses). Most, but not
all, published reports of such protocols have dem-
ICU length of stay (LOS), cost savings, and/or
other bene ts. It is worth noting, however, that
strict adherence to overly conservative criteria can
December 2001, a collective task force composed
of representatives from the American College of
Chest Physicians, American Association for Respi-
Table 5.
Values for Table 4*
Variables
0.30.40.40.50.50.60.70.70.80.91.01.0


(3) hemodynamic stability (no active myocardial
cant hypotension); and
(4) capability to initiate an inspiratory effort. These
recommendations serve as a solid basis for current
recommendations; however, newer data allow us to
was superior to SBT alone. The combination of poor
cough, high sputum volume, and poor mental status
is a particularly worrisome combination, even if the
patient is capable of passing an SBT. In one study,
The SBT is widely considered to be the
low-level ventilatory support intended to overcome
Although T tube, “ ow-by,” CPAP, or PSV is often
tube compensation (ATC) is emerging as a form of
“smart” PSV. ATC is designed to provide enough PS
to overcome the resistance of breathing through an
cial airway. This pressure is recalculated every


Mechanical Ventilatory Support (Sessler)
stridor tend to be sicker, have longer duration in-
tubation, and are more likely to have had a dif
ating the
three SBTs, in regards to duration of MV, ICU LOS,
and hospital LOS. However, one must carefully
consider reasons for SBT failure and troubleshoot
potential causes before using this approach.
Tracheostomy
Tracheostomy has been available for many
years as a surgically placed arti cial airway that
permits longer-term placement compared with an


475
Table 7.
Recommendations for Evaluation of the Ability To Tolerate Discontinuation of Ventilation and Extubation*
Screening Criteria
1. Is patient hemodynamically stable (not in shock, no more than minimal vasopressor requirement)?
2. Is underlying cause of respiratory failure improving?
3. Is the patient alert or have easy arousal (opens eyes to voice) and cognition (follows simple commands)?
Perform daily interruption of sedation in patients in whom this is feasible.
1. Does patient tolerate breathing on minimal support for 60 min? Consider using ATC as mode of ventila-
tory support during SBT, if available
*All intubated patients receiving MV should undergo screening. Those who satisfy the criteria but fail men-
tal status testing (screening criterion 3) should have sedation interrupted (
opioid drugs) and repeat testing for screening criteria. Patients who satisfy the screening criteria should
undergo a cuff-leak test. If the cuff leak is
15%, MP should be administered (four doses of 40 mg IV
every 6 h or 20 mg IV every 4 h). Patients who satisfy the screening criteria and who pass the cuff leak test
should undergo SBT testing; if patients pass the SBT, they should be extubated.
Table 8.
able Factors Related to Failure of Weaning From MV
Unresolved precipitating process
ow obstruction
Increased endotracheal tube resistance


Mechanical Ventilatory Support (Sessler)
This study concludes that SIMV is not a preferred weaning


pulmonary disease: Cochrane systematic reviews and


Mechanical Ventilatory Support (Sessler)
acute respiratory failure: cardiorespiratory responses
cially increased ventilatory demand. Crit Care
PAV, even when combined with an automatic tube compensa-


479
 Discuss several unusual and uncommon pulmonary
disorders
 Describe clinical manifestations and facilitate recognition
of these disorders
 Discuss management options for these disorders
BirtHoggDubé syndrome; constrictive
bron
chiolitis; IgG4 sclerosing disease; pulmonary alveolar
proteinosis; pulmonary amyloidosis; spontaneous pneumo-
Rare (orphan) disease is de
ned as a disease or
condition affecting
200,000 persons in the United
An estimated 25 million people in the
6,000 rare diseases.
The failure to diagnose a rare or unusual disease
is generally attributable to the failure to consider
rst place.
The diagnosis of unusual pulmonary disorders
is facilitated by considering a broad differential
It is now known that IgG4-related sclerosing dis-
ease can be localized to one or two organs or pres-
2,3
IgG4-related sclerosing disease manifests
similar histopathologic  ndings in different organs
and is characterized by diffuse lymphoplasmacytic
infiltrate consisting of extensive IgG4-positive
brotic
Other histopathologic features may
include eosinophilic in ltration and obliterative
Quantitatively, IgG4 is the smallest subclass of
normal serum. The IgG subclasses exhibit differ-
ences in their effector functions. Involvement of
related sclerosing disease, but exactly what role
ogy of this disorder remains unclear.


Unusual and Uncommon Pulmonary Disorders (Ryu)
uorodeoxyglucose uptake is observed in pan-
creatic and extrapancreatic lesions.
Serum IgG4 levels and immunostaining of the
biopsy specimen with anti-IgG4 antibody are useful
Although the serum IgG4
level was initially reported to be increased in nearly
all patients with autoimmune pancreatitis,
the
prevalence of increased IgG4 levels appears to be
lower in patients presenting with various extrapan-
creatic lesions of IgG4-related sclerosing disease.
In patients with intrathoracic abnormalities
associated with extrathoracic inflammatory or
brotic lesions, particularly pancreatitis, the diag-
nosis of IgG4-related sclerosing disease should be
considered. Even in the absence of extrathoracic
manifestations, some unusual cases of intrathoracic
lesions such as mediastinal  brosis and focal in
matory lesions may be IgG4 related in origin.
IgG4-related sclerosing disease responds well
to corticosteroid therapy.
2–4
The starting dose of
prednisone is typically 30 to 60 mg/d for 1 to 2
, 10 mg/d. In the absence of recur-
rent disease, corticosteroid therapy is eventually
Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP), also
pulmonary alveolar phopholipoproteinosis
is a rare parenchymal lung disease that is charac-
terized by accumulation of lipoproteinaceous
material in the alveoli. Most cases (90%) are idio-
pathic; the remaining cases consist of congenital
and secondary forms of PAP.
5–7
The congenital form
is caused by mutations in the genes encoding sur-
factant proteins or the receptor for granulocyte-
macrophage colony-stimulating factor (GM-CSF).
Secondary PAP occurs in association with hema-
tologic or immunode ciency disorders, inhalation
of chemicals or inorganic dusts (
, silica), or cer-
tain pulmonary infections. PAP results from


brosis may occur in some cases.
ammatory cells are seen in the lung tissue. Sur-
gical biopsy is now less frequently required to
con rm a PAP diagnosis.
The treatment standard for PAP is whole-lung
lavage, during which repeated instillation and
drainage of the lung with aliquots of isotonic saline
solution (up to a total volume of 20 to 30 L) is per-
formed until the run off is clear.
5,6,10
This procedure
is performed via a bronchoscope passed through
a double-lumen endotracheal tube with the patient
under general anesthesia. Chest percussion is per-
formed during the lavage procedure to facilitate
removal of the lipoproteinaceous material. The
main indication for treatment is limiting exertional
dyspnea associated with hypoxemia. Approxi-
mately 85% of patients show improvement after
t is approximately 15 months. Eventually, 60 to
70% of patients require repeat lavage. Lung lavage
is associated with improved survival.
5,6
with its proposed importance in surfactant clear-
ance, preliminary experience with GM-CSF admin-
istration in PAP has shown favorable responses in
the characteristic apple-green birefringence with
polarized microscopy after staining with Congo
red.
14,15
Tracheobronchial and diffuse parenchymal
forms of pulmonary amyloidosis can be diagnosed
by bronchoscopy, although the endoscopist must


Unusual and Uncommon Pulmonary Disorders (Ryu)
be prepared for potential patient bleeding. Lung
nodules are diagnosed by needle aspiration biopsy
or surgical resection. Diagnosis of pulmonary
amyloid deposition, if it is not already known, as
The treatment of amyloidosis varies with dif-
ferent types of pulmonary involvement and the
underlying cause of amyloidosis. Treatment of
diffuse parenchymal amyloidosis associated with
AL (primary) amyloidosis is directed against the
underlying plasma cell dyscrasia. This is also true
for hilar/mediastinal adenopathy. The progno -
sis is poor for patients with primary systemic
amyloidosis who have pulmonary involvement.
Symptomatic tracheobronchial involvement with
localized stenosis can be treated with broncho-
scopic laser or surgery. Recently, external beam
therapy has been reported to be effective in the
treatment of tracheobronchial amyloidosis.
growth factor antibody, has been reported to be
effective in managing refractory pleural effusions
Treatment of AL systemic amyloidosis involves
Birt-Hogg-Dubé Syndrome
Birt-Hogg-Dubé (BHD) syndrome is a rare,
inheritable disorder (autosomal dominant) that is
Recent reports suggest that BHD may
be an underdiagnosed cause of pneumothorax.
BHD was  rst described in 1977 and is character-
brofolliculomas
and skin tags, along with a propensity for renal
) gene that lies on chromosome 17 and
encodes a tumor-suppressor protein, folliculin.
20,21


managed accordingly,
, consider pleurodesis.
These patients also need to be screened for renal
Constrictive Bronchiolitis
Constrictive bronchiolitis (also called oblitera-
tive bronchiolitis or bronchiolitis obliterans) is a
form of obstructive lung disease that results from
bronchiolar scarring and narrowing.
26,27
Bronchi-


Unusual and Uncommon Pulmonary Disorders (Ryu)
usually consist of chest pain and/or dyspnea. Other


485


Unusual and Uncommon Pulmonary Disorders (Ryu)


487
 Discuss the anatomic compartments of the mediastinum
 Discuss the diagnostic approach to mediastinal lesions and
 Discuss uncommon intrathoracic neoplasms
carcinoid; germ-cell tumors; hamartoma; lymph-
neurogenic tumors; salivary gland type carcinoma
Mediastinal and Other Neoplasms
Jay H. Ryu, MD, FCCP
Table 1.
LocationDisorder
AnteriorThymoma and other thymic tumors
Lymphomas
Thyroid goiter and other thyroid tumors


Mediastinal and Other Neoplasms (Ryu)
are malignant, with a higher risk in those masses
appearing in the anterior mediastinum and in
children.
Symptomatic patients are also more
likely to have a malignancy (50%) compared with
Patients with
mediastinal masses may experience localized
symptoms (related to compression or invasion of
ed based on the type of neoplastic cells
present; polygonal-cell type, spindle-cell type, and
mixed-cell type. Precise histologic subclassi
cation
ultrasound or CT-guided core needle biopsy or
surgical excision.
3,6
observed in approximately one third of cases, but
lymph node and hematogenous spread are rela-
tively rare. Anatomic staging of thymoma is based
on assessment of capsular invasion at the time
of surgery and on microscopic examination.
Thymomas can be classi ed into three categories


based chemotherapy and radiotherapy are
generally poor, with 5-year survival rates of
approximately 30%.
Thymic carcinoid is a rare, malignant neuroen-
clinical and radiologic presentation as for thymic
carcinoma.
11,12
Approximately one third of patients
experience ectopic hormone production, including
Cushing syndrome (most common), multiple
endocrine neoplasia syndrome type I, syndrome
excision of an enlarged lymph node or extranodal
mass. Core needle biopsy may also yield adequate
tissue. Treatment of mediastinal HD consists of
radiotherapy and/or chemotherapy; both treat-
ment modalities usually are instituted in the treat-


Mediastinal and Other Neoplasms (Ryu)
homogeneous mass. Fine-needle aspiration biopsy
is often adequate to make the diagnosis. Pure
seminomas are very radiosensitive, but if non-
, embryonal carci-
noma, are present, these tumors tend be more
aggressive and do not readily respond to radiation
therapy. Patients with locally advanced disease
may be treated with chemotherapy, followed by
resection of residual tumor. At the time of diagno-


common. Bronchogenic cysts are lined with ciliated
respiratory epithelium and contain serous 
uid,
mucus, blood, or purulent material. Bronchogenic
cysts typically are found in adults.
24,25
Patients are
commonly asymptomatic at presentation, although
symptoms can be produced from airway compres-
sion or communication of the cyst with the airway.
These cysts are most commonly located in the
subcarinal or paratracheal regions but are occasion-
ally in the lung. Radiologically, bronchogenic cysts
variable attenuation depending on the composition
tive diagnosis can be obtained by CT-guided,
bronchoscopic, or endoscopic aspiration of the cyst
24,25
Most bronchogenic cysts are surgically
excised, but  uid aspiration and observation are
24,25
Enteric cysts are lined by enteric or strati
ed
squamous epithelium and are usually seen in the
The majority
of enteric cysts are encountered in children. They
may cause symptoms by compression of the tra-
chea or esophagus, as well as mucosal ulceration,
hemorrhage, or cyst rupture if the cyst contains
gastric or pancreatic mucosa.
Surgical excision is
the treatment of choice.


Mediastinal and Other Neoplasms (Ryu)
a posterior spinal nerve root. Radiologically,
schwannomas and neuro bromas are well-circum-
scribed, round, or lobular posterior mediastinal
Associated abnormalities may be seen in
the ribs, vertebral bodies, and neural foramina as
the result of pressure and erosion caused by the
enlarging mass. The treatment of choice is surgical
resection. Combined thoracic and neurosurgical
approach may be needed for dumbbell tumors.
are rare spindle-cell sarcomas (
5% of nerve
sheath tumors) and include malignant neuro
bro-
sarcomas, malignant schwannomas, and neuro-
brosarcomas. Approximately one half of
these are associated with neuro
bromatosis.
Pain
and enlarging mass are common presenting man-
ifestations of this tumor, which appears radiologi-


Among these, more frequently encountered tumors
include the carcinoid tumor, salivary gland-type
carcinomas (mucoepidermoid carcinoma and
adenoid cystic carcinoma), and hamartoma.
Carcinoid
Bronchial carcinoid tumors are malignant neo-
plasms with neuroendocrine differentiation and
42,43
There
is no clear association with smoking. Carcinoid
ed into
typical (more common) and atypical types.
39,42
Atypical tumors have greater mitotic activity and
necrosis.
Patients with typical bronchial carcinoids usu-
ally present in the  fth decade of life, whereas
those with atypical carcinoids present later.
39,42
The majority of carcinoid tumors are central or
perihilar in location. Patient often present with
symptoms related to bronchial obstruction (
recurrent pneumonias or wheezing) or vascular-
Bronchial
carcinoids are occasionally associated carcinoid
syndrome caused by release of serotonin and
other vasoactive substances into the systemic
circulation.
Rarely, biopsy or manipulation of a
bronchial carcinoid results in acute carcinoid
syndrome. Bronchial carcinoids can also cause
Cushing syndrome and acromegaly as a result of
the ectopic production of adrenocorticotrophic
hormone and growth hormone-releasing factor,
respectively.
42,43
Radiologically, bronchial carcinoids may


Mediastinal and Other Neoplasms (Ryu)
Adenoid cystic carcinomas (previously called
cylindroma) also arise in the trachea or a major
bronchus in most cases. It occurs in adults, most
commonly in the  fth decade of life.
45,47
cough wheeze, and hemoptysis are the most com-
mon presenting symptoms. Surgical resection is
the treatment of choice; however, this tumor has a
transthoracic needle aspiration biopsy, bronchos-
copy, or thoracoscopy.
References


sternotomy required? Thorac Cardiovasc Surg


Mediastinal and Other Neoplasms (Ryu)


497
 Review the morphologic characteristics of COPD
 Summarize the pathology of disease affecting small and
large airways
 Review the histopathologic features of asthma
 Review the complex constellation of histologic abnormalities
in patients with allergic bronchopulmonary fungal disease,
including bronchocentric granulomatosis, and mucoid
impaction of bronchi
 Review and contrast the histologic characteristics of
organizing pneumonia and constrictive (obliterative)
bronchiolitis
allergic bronchopulmonary fungal disease; ob-
structive airway disease; obliterative bronchiolitis; organizing
Obstructive Pulmonary Disease
Emphysema
ned as “a condition of the
lung characterized by abnormal, permanent enlarge-
ment of airspaces distal to the terminal bronchiole,
accompanied by destruction of their walls, and with-
brosis.”
Involves destruction of entire acinus.
Lower lobes most affected initially.
ow obstruction.
most destroyed.
Paracicatricial Airspace Enlargement (So-Called
Irregular or “Scar” Emphysema):
Airspace enlargement next to foci of 
brosis.
May not have clinical correlate depending on
, Langerhans’ cell histio-
: Air within the visceral pleural layers, so
really being a misnomer here by the
aforementioned de
1 cm in diam-


Pathology of Airway Disease and Organizing Pneumonia (Tazelaar)


Chronic bronchiolitis
c patho-
logic term used to describe the presence of chronic
ammation and/or  brosis around and in wall of


Pathology of Airway Disease and Organizing Pneumonia (Tazelaar)
separate and distinct entities with different clinical,
radiographic, and morphologic features.
In certain circumstances, such as lung trans-
plant recipients, silo  ller’s disease and, occasion-
ally, rheumatoid arthritis, there is evidence to
suggest that intraluminal organization localized to
membranous and respiratory bronchioles can
cause obstructive airways disease and can “prog-
ress” to a lesion that is indistinguishable from the
late stage of constrictive bronchiolitis.
[Note to participants regarding references:
There are some primary sources quoted, but the
textbooks have additional photographs worth
References
1. Snider G, Keinerman J, Thurlbeck W. The de
workshop. Am Rev Respir Dis 1985; 132:182


501
organizing includes proliferating/reactive type
broblasts with
focal airspace organization. (These areas may
look like typical organizing pneumonia.) Acute
and organizing thrombi within vessels are com-


Pathology of Diffuse and Neoplastic Disease (Tazelaar)
honeycomb appearance. Microscopic 
alveolar macrophages, as seen in
respiratory
bronchiolitis
(DIP), are common.
Honeycomb changes are most advanced at the
bases and periphery.
Work by some investigators
10,11
Table 1.
Clinical and Pathologic ClassiÞ cation of Idiopathic Interstitial Pneumonias*
AIP, Hamman-rich disease idiopathic diffuse alveolar
IPF, cryptogenic 
brosing alveolitis
Respiratory bronchiolitis
Nonspeci c interstitial pneumonia
Nonspeci c interstitial pneumonia: cellular and 
brotic
Cryptogenic organizing pneumonia (formerly idiopathic
bronchiolitis obliterans organizing pneumonia)
Organizing pneumonia
Lymphocytic interstitial pneumonia
Lymphocytic interstitial pneumonia


c interstitial pneumonia; 
brosis is
geographically and temporally more uniform; (4)
accelerated idiopathic pulmonary  brosis; foci of
diffuse alveolar damage are present.
1315
Accelerated Idiopathic Pulmonary Fibrosis
13–15
Underlying UIP can be recognized clinically
(previous history of slowly progressive interstitial
brosis with characteristic features of IPF), radio-
graphically, and/or on the basis of  ndings at the
time of surgical lung biopsy. Wedge lung biopsy
will show underlying UIP with DAD or, likely as
the result of sampling, either just DAD or just UIP.
In some cases, only organizing pneumonia is
c Interstitial Pneumonia/Fibrosis
Findings for nonspeci c interstitial pneumo-
brosis
16,17
include geographic homogeneity
(looks same from  eld to 
eld), 
brosis and inter-
stitial thickening with in ammation, and is NOT
RB-ILD
2023
is a diagnosis of exclusion, as the
histology of RB may be seen in any active or past
smoker. Microscopic 
ndings include RB (pig-
mented alveolar macrophages in and around
respiratory bronchioles) and a lacks of signi
fibrosis, interstitial inflammation, or germinal
Differential Diagnosis:
RB-ILD and DIP repre-
sent points along a spectrum, and some cases fall


Pathology of Diffuse and Neoplastic Disease (Tazelaar)
Langerhans Cell Histiocytosis
Microscopic 
ndings of Langerhans cell his-
1,3,5
include (1) bronchiolocentric nodu-
lar to stellate lesions; (2) variable  brosis; and (3)
, Langerhans cell with convo-
luted nuclei (kidney-bean shaped, grooved,
resemble buttocks). They usually are admixed
with some eosinophils and smoker’s macro-
ndings include
S100 protein
On electron microscopy, Birbeck granules (pen-
diagnostic biopsy is related to the number of
specimens obtained, and the best results require a
or 3 disease and as many as 10 in patients with
Microscopic findings (berylliosis looks iden-
Granulomatous in ammation without bron-
Compact, well-circumscribed collections of
giant cells surrounded by a rim of lympho-
brosis;
Central necrosis (
Distribution along lymphatic routes (broncho-
 Multinucleated giant cells may contain a vari-


Differential diagnosis of disease with small
granulomas is discussed in Table 4.
Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP)
1,3,5,33,34
due to a defect in alveolar macrophage function
caused by granulocyte/macrophage colony-stim-
airspaces with thin walls involving upper and
lower lobes. The main pathology includes a disor-
derly proliferation of smooth muscle cells, cystic
portion of their walls, and hemosiderin laden
macrophages that may be present within air spaces
as the result of pulmonary hemorrhage. Immuno-
for HMB45, actin, desmin, melan A, and estrogen
and progesterone receptor protein
Other pathology includes micronodular pneu-
mocyte hyperplasia, or circumscribed prolifera-
a pattern resembling bronchioloalveolar adenocar-
Table 4.
Differential Diagnosis of Diffuse Lung Disease With Small Granulomas*
Hypersensitivity PneumonitisSarcoidosisHot Tub Lung
Chronic bronchiolitis
Well formed
Single giant cells
Necrosis
Organizing pneumonia
Cultures
intracellulare
rare;
prominent feature.
Table 5.
ClassiÞ cation of PAP
Primary PAP
Secondary PAP
Immunocompromised patients, hematologic disorders
(polycythemia vera, leukemias, idiopathic thrombocyto-
penic purpura, multiple myeloma),
Infections, Nocardia,
Environmental inhalants, dusts (silica, aluminum), toxins
(solvents, insecticides, cleansers)


Pathology of Diffuse and Neoplastic Disease (Tazelaar)
In acute eosinophilic pneumonia, there is dif-
fuse alveolar damage with prominent tissue
1,3,5
Wegener Granulomatosis
Necrotizing granulomatous in
ammation with
geographic borders (appears more like paren-
chymal necrosis than a true granuloma since
the foci usually lack signi cant numbers of epi-
Centrally in foci of necrosis there is amor-
remnants of necrotic neutrophils and other
in ammatory cells (so-called
dirty necrosis
mas” and microabscesses;
Palisading granulomas are tiny granulomas
thelioid histiocytes that either radiate around
a central point or surround a central eosino-
philic structure resembling a collagen bun-
dle. As the palisaded granulomas enlarge,
they become more microabscess-like;
 Necrotizing segmental (involving portion of
 Randomly dispersed, darkly staining multinu-
 Common variants include: (1) presentation
lung; (2) hemorrhage with or without capillari-
tis (vasculitis involving capillaries recognized
by presence of neutrophils in alveolar walls);
(3) bronchocentric; (4) organizing pneumonia
 c-ANCA titers are
positive in approximately
90% of patients with active generalized disease,
60 to 85% of patients with active limited disease,
and 30 to 35% of patients with quiescent disease.
Positive p-antineutrophil cytoplasmic antibody
titers generally representing autoantibodies
directed against myeloperoxidase are less spe-
c but have been reported to be positive in
some patients with Wegener granulomatosis.
Pneumoconioses
Asbestos-related reactions (Table 7): the pneu-
5,37
is “asbestosis.” Macroscopically,
rm, 
brotic lungs with areas of honeycomb change
can be found, whereas microscopically, marked
interstitial fibrosis with minimal inflammatory
ltrate are found, as well as UIP-like reactions.
The presence of asbestos bodies, 
brosis, and expo-
sure history are needed for a de
nitive diagnosis.
Asbestos bodies are iron-encrusted 
bers (one
type of ferruginous body, which is a more generic
term) that typically are beaded and dumbbell shaped
with a thin translucent core. There are no generally
accepted criteria de ning how many asbestos bodies
must be identi ed in any given case for a diagnosis
of asbestosis, but the presence of even a single
asbestos body in a routine tissue section usually
signi es “above-background” asbestos exposure.
Table 6.
Associations and Causes of Chronic Eosinophilic
Allergic bronchopulmonary fungal disease
Connective tissue disease, especially rheumatoid arthritis


Silicosis
Gross  ndings of silicosis (Table 8) include 
rm,
Table 8.
Morphologic ClassiÞ cation of Silicosis
Silicotic nodules
1 cm
Upper lung zones
Conglomerate nodules
1 cm
Upper and middle lung zones
Acute silicosis (silicoproteinosis)
Alveolar proteinosis
Silicotuberculosis
Table 9.
Variables
HistoCocciBlastoCryptoAsperMucorCandida
Tissue reaction
Necrotizing granulomas
YesYesYesYes/noNoNoNo
Vascular invasion/infarct
NoNoNoNoYesYesNo
AC in
NoNoYesNoNoNoYes
Budding yeast
YesNoYesYesNoNoYes
Lavage size, microns
330–608–154–7
OvalNoRoundIrregularHyphaeHyphaeDimorphic
Spherules/endospores
NoYesNoNoNoNoNo
Thick cell wall
NoYesYesNoNoNoNo
Mucin-positive capsule
NoNoNoYesNoNoNo
NoRareNoNoYesYesRare
Size, microns
3–510–15
YesNo
45°90°
NoNoNoNoNoNoYes
*Data are from Katzenstein and Askin.
AC = acute; Histo
Aspergillus; Mucor


Pathology of Diffuse and Neoplastic Disease (Tazelaar)
three cells thick and is composed of small round,
Grade 2, mild acute rejection: frequent
perivascular in ammatory cell in
ltrates
surrounding venules and arterioles. In
ltrates
are readily recognizable and are usually 
ve
ltration is found by
ammatory cells into the adjacent alveolar
Table 11.
Frothy ExudateCystsSporozoites
Yes
Yes
Table 12.
Morphology of Selected Viral Pathogens
Variables
Adenovirus
Virus
Tissue response
Interstitial pneumonia
Yes
Necrotizing bronchopneumonia
Yes/no
Yes
Yes
Yes
Bronchiolitis
Rare
Yes
Yes
Yes
Tracheobronchitis
Yes
Yes
Yes
Yes/no
Yes
Giant-cell pneumonitis
Yes
Yes
Yes
Yes
Cowdry A
Yes
Yes
Ground glass
Yes
Yes
“Smudge” cells
Yes
Table 10.


Grade 3, moderate acute rejection: all of the
histologic features of mild acute rejection.
ammatory cell in ltrate extends into peri-
vascular and peribronchiolar alveolar septae
Grade 4, Severe acute rejection: diffuse peri-
vascular, interstitial, and airspace in
of in ammatory cells, including neutrophils.
ciated with necrosis, airspace hemorrhage,
entire lobe and show preservation of underlying
architecture with large pools of mucus within air-
spaces. Microscopic  ndings include nonmucinous,
mucinous, and mixed variants. The epithelium is
well differentiated, uniform, and grows along intact
alveolar walls, and there is no invasion into underly-
ing stroma. Multifocality with microsatellite lesions
is common. The differential diagnosis: atypical
adenomatous hyperplasia, (1) cytologic atypia is less
0.5 cm.
Small Cell Carcinoma
A total of 70% of cases present as perihilar mass.


Pathology of Diffuse and Neoplastic Disease (Tazelaar)
glandular differentiation; 10% show squamous
differentiation.


511


Pathology of Diffuse and Neoplastic Disease (Tazelaar)


513
 Understand the pathogenesis of pleural  uid (PF) formation
 Appreciate the clinical presentation, radiographic features,
and the most common causes of pleural effusions
 Appreciate the diagnostic value of PF analysis
 Understand the management of patients with pleu-
ral effusions, especially malignant and parapneumonic
effusions
 Understand the pathogenesis, causes, clinical features,
effusions; empyema; exudates; malignant pleural
Pathogenesis of Pleural E
Normal Pleural Fluid
In the normal pleural space, there is approximately
uid (PF).
Normal PF is clear, with
500 nucleated cells/
the differential is approximately 2% neutrophils,
0% basophils, 7 to 11% lymphocytes, 61 to 77%
macrophages, and 9 to 30% mesothelial. PF pH
has been reported in the range of 7.60 to 7.64, and
there is a biocarbonate gradient (PF minus serum
1,2
Anatomy
and subsequently lymphatic ducts and well-formed
lymphatic channels and ultimately into mediastinal
lymph nodes. A clinically-relevant pleural effusion
develops when PF formation exceeds resorption.
The mechanisms for PF formation and clinical
examples are shown in Table 1.
Assessment of the Patient with a
Pleural E
Symptoms of Pleural E
The patient may present with symptoms such
, most patients with a benign asbestos
pleural effusion (BAPE). When patients with a
pleural effusion are symptomatic, dyspnea and
chest pain are the most common 
ndings. Dyspnea
may be caused by a large or massive pleural effu-
effusion in patients with some underlying lung
disease, and a small-moderate effusion in patients
with severe lung disease. A large effusion causes
ipsilateral mediastinal shift, depression of the
Pleural Disease
Steven A. Sahn, MD, FCCP
Table 1.
MechanismClinical ExampleClassi
Increased
failure
Transudate
Decreased peri-
Transudate
Decreased P
HypoalbuminemiaTransudate
Increased capillary
permeabilityPneumoniaExudate
Impaired lymphatic
Yellow nail
syndromeExudate
hydrothoraxTransudate
rupture
ChylothoraxExudate
Duropleural 
stulaTransudate
pleural effusion of extravascular origin;
microvascular pressure; P
oncotic pressure.


ipsilateral diaphragm, outward movement of the
ipsilateral chest wall, and lung compression when
there is no endobronchial lesion or 
xed mediasti-
num. Dyspnea is perceived by the patient with a
large-to-massive pleural effusion because of its
effect on the previously mentioned structures with
input from neurogenic receptors in the lung and
Patients with a pleural effusion may present
pleural in ammation. Pleuritic chest pain has been
by deep inspiration, cough, or sneezing. Any
maneuver resulting in chest wall splinting, such as
manual pressure over the chest wall, will minimize
the pain. However, a splinting maneuver will not
pleural effusion.
lished “de nitively” by PF analysis are shown in
Table 2.
5,6
Virtually all patients with a newly discovered
pleural effusion should have a thoracentesis per-
ment. Exceptions would be a secure clinical
diagnosis, such as typical congestive heart failure
uid as with
viral pleurisy. Observation is warranted in the
aforementioned examples; however, if the clinical
Table 2.
by PFA*
DiseaseDiagnostic PF Tests
esophageal rupture
Presence of LE cells; ANA
uid/serum
Tuberculous effusionPositive acid-fast bacilli stain or
culture
Esophageal ruptureHigh amylase (salivary), low PF
pH; presence of food particles
Fungal effusionPositive potassium hydroxide stain
or culture
Triglyceride
110 mg/dL (high
likelihood); presence of chylomi-
crons de
uid/blood
Creatinine (pleural 
uid/serum
Protein (
0.5 g/dL) and pleural
 uid/ serum glucose ratio
30 mg/dL and
1,000 IU/L (highly likely
if empyema excluded); character-
istic cytology de
Duropleural 
Presence of
GlycinothoraxGlycine in PF (complication of


515
80% lymphocytes limits
the possibilities of the exudative pleural effusion
(Table 4). The most common of these diagnoses
worldwide is a tuberculous pleural effusion.
Although these diagnoses do not always have
80% lymphocytes, when this degree of lympho-
cytosis is present, one of these diagnoses is virtu-
ally always present.
PF eosinophilia is defined as a PF eosino -
10% of the total nucleated cells
(Table 5). Interleukin-5 appears to be an impor-
tant chemotactic factor attracting bone marrow-
produced eosinophils into the pleural space. In
patients who require thoracotomy for spontaneous
pneumothorax, eosinophilic pleuritis is commonly
encountered within hours of the pneumothorax.
the pleural space after a pneumothorax, after a
Interestingly, PF eosinophilia is associ-
after a traumatic hemothorax that does not resolve
Table 3.
Pale yellow (straw)Transudate, some exudates
Malignancy, BAPE, PCIS, or
pulmonary infarction if trauma
White (milky)Chylothorax or cholesterol
effusion; EVM of CVC with
Brown
Long-standing bloody effu-
sion; rupture of amoebic liver
Aspergillus niger
Yellow-green
Color of enteral tubeFeeding tube has entered pleural
Feeding or centralEVM of CVC
Venous line infusate
Greenish tint
Viscous
Turbid
ammatory exudates
Anchovy pasteRupture of amebic liver abscess
Satin-like sheenCholesterol effusion
Looks like waterDuropleural 
Looks like urineUrinothorax
Anaerobic empyema
*See Table 2 for abbreviations not used in the text.
Table 4.
Lymphocyte-Predominant (
80%) Exudative Pleural
Tuberculous effusionusually 90 to 95% lympho-
cytes; acutely, may be
neutrophil-predominant
Lymphoma
are lymphocytes; diagnostic
Yellow nail syndromeA cause of benign persistent
effusion; protein discordant
Chronic rheumatoid
Sarcoidosis
90% lymphocytes;
effusion in
2% of sarcoid
patients; discordant exudate
(by protein only)
Post-CABG effusions
2 mo) including PCIS
Acute lung rejectionPF may be 
rst manifestation
of rejection
80%; other exudates rarely
have 80% lymphocytes. NHL


PF Glucose and pH
PF glucose and pH should be measured on all
exudative effusions because: (1) they can narrow
the differential diagnosis; (2) in a parapneumonic
effusion, they provide information helpful in man-
agement strategies; and (3) in malignant effusions,
it provides information relating to extent of pleural
involvement with tumor, ease of diagnosis, prog-
The  nding of a pleural
effusion with a pH
7.30 signifies substantial
accumulation of hydrogen ions in the pleural
the pH to decrease.
ral effusions and chronic rheumatoid pleural effu-
sions, the mechanism of low pH and glucose is
related to an abnormal pleural membrane that
inhibits the ef ux of CO
and lactate from the pleu-
Table 5.
pleural effusion
Pulmonary embolismAssociated with infarction and
hemorrhagic effusion
Parasitic diseaseParagonimiasis, hydatid disease,
Fungal diseaseHistoplasmosis,
Drug-inducedDantrolene, bromocriptine,
nitrofurantoin, valproic acid,
Carcinoma5 to 8% with PFE
Churg-Strauss
syndrome
Pleural effusions in 30% with
LymphomaHodgkin disease (rare)
Tuberculous pleurisyRare
Table 6.
Diagnoses Associated With Pleural Fluid Acidosis (pH
DiagnosispH Incidence (%)Glucose (mg/dL)
4.50–7.29 (~100)0–40
Esophageal rupture5.50–7.00 (~100)0–59
Chronic tuberculous
6.90–7.05 (100)0–30
Chronic rheumatoid
7.00 (~100)0–30
Malignancy6.95–7.29 (30)30–59
Tuberculous
effusion
7.00–7.29 (20)30–59
Lupus pleuritis7.00–7.29 (20)30–59
complicated parapneumonic effusion.


diagnostic accuracy compared with the Light cri-
teria: PF protein concentration
3.0 g/dL; PF/
serum protein ratio
0.5; PF LDH greater than
two-thirds the upper limits of normal of serum
LDH; PF/serum LDH ratio
0.6; PF cholesterol
45, 54, 55, or 60 mg/dL; PF/serum cholesterol
0.3; and albumin gradient
1.2 g/dL.
In a receiver operating characteristic analysis
of 200 consecutive patients with pleural effusions,
a PF LDH of 163 IU/L (serum upper limits of nor-
0.82) was the best cutoff point for
an exudate (area under the curve, 0.89), followed
by PF/serum total protein ratio of 0.5 (area under
If serum tests are not available,
single tests or test combinations that rely only on
PF results can be used with an excellent diagnostic
accuracy. A Bayesian approach with application of
the PF protein and LDH may reach “exudative”
levels after diuresis, which can be con
with
use of the serum- PF albumin gradient (
1.2 sup-
The diagnosis of pleural effusions from CHF is
presumptive with the compatible clinical presenta-


Pleural Disease (Sahn)
Table 8.
Causes of Exudative Pleural Effusions
Tuberculous
Nocardia, Actinomyces
Subphrenic abscess
Rupture of amebic liver abscess
Viral hepatitis
Spontaneous esophageal rupture
Carcinoma
Lymphoma
Sarcoma (angio, Kaposi)
In ammatory and others
Pancreatic disease (acute; pancreaticopleural 
Uremic pleuritis
Sarcoidosis
Churg-Strauss syndrome
Wegener granulomatosis
Lymphatic abnormalities
Yellow nail syndrome
Noonan syndrome
Lymphangiectasia
Movement of  uid from abdomen to pleural space
Acute pancreatitis
Pancreaticopleural 
Meigs syndrome
Carcinoma
Lymphoma
Cholesterol effusion (TB; rheumatoid pleurisy)
CABG Surgery
Hypothyroidism
Ovarian hyperstimulation syndrome
Iatrogenic
Esophageal instrumentation
Esophageal sclerotherapy


The diagnosis is presumptive in the proper


Trapped Lung
Trapped lung, the end stage of an infectious or
ammatory pleural effusion, presents as a per-
sistent transudative effusion months to years after
the acute pleural process. It is a relatively uncom-
mon cause of a pleural effusion, representing
5%
of effusions in the Medical University of South
Carolina database of
1,000 patients. Trapped
lung is one of the three forms of an unexpandable
lung; the other two causes of an unexpandable
lung are an endobronchial lesion, usually second-
ary to carcinoma of the lung, and chronic atelec-
tasis, which may eventually resolve over time
without intervention. Trapped lung is caused by
visceral pleural restriction when a 
brous mem-
brane covers a portion of the visceral pleura,
preventing lung expansion to the chest wall.
The increased negative intrapleural pressure
favors PF formation until a new steady state is
Patients with trapped lung may present with
an asymptomatic pleural effusion seen on a rou-
months to years after the acute pleural injury.
plicated parapneumonic effusion or empyema,
hemothorax, tuberculous pleural effusion, uremic
pleuritis, rheumatoid pleurisy, and after CABG
surgery. During a therapeutic thoracentesis,
patients often develop severe, anterior, substernal
chest pain as a result of the decrease in pleural
pressure, which is quickly resolved by allowing


bilateral effusions with a normal heart size. On
PFA, the clinician will  nd paucicellular levels (ie,
500 total nucleated cells/
L) that are predomi-
nantly mononuclear. PF pH is 7.45 to 7.55, and the
PF glucose is equivalent to the serum glucose. LDH
and protein are clearly in the transudative range.
Hypoalbuminemia-induced pleural effusions are
a clinical diagnosis in a patient with a very low
serum albumin and when other possible causes of
the effusions have been excluded. The treatment
is to maximize nutrition and prevent protein loss
either through the GI track or kidneys.
Continuous Ambulatory Peritoneal Dialysis
Small right-sided, or less commonly, bilateral
pleural effusions develop in approximately 2% of
patients on continuous ambulatory peritoneal
dialysis (CAPD). Acute, massive, right-sided pleu-
ral effusions may occur, usually in women in
1 month (range 1 day to 2 years) after starting
The pathogenesis of these
effusions is peritoneal to pleural movement of 
uid
through diaphragmatic defects that become
enlarged from acute increases in peritoneal pres-
sure during dialysis. Multiparity and peritonitis
are risk factors for the development of pleural effu-
The majority of these patients are asymptom-
atic, but some with enlarging effusions have


difference, an increase in PF pH, and rapid resolu-
tion of the pleural effusion.
Exudates
Parapneumonic E
A parapneumonic effusion is defined as a
pleural effusion associated with pneumonia or
lung abscess. An uncomplicated parapneumonic
effusion is a small-to-moderate effusion that re-
sequelae. A complicated parapneumonic effusion
requires pleural space drainage for resolution of
pleural sepsis. An empyema, or pus in the pleural
space, represents the end stage of a complicated
parapneumonic effusion and always requires pleu-
ral space drainage. A parapneumonic effusion is
the most common cause of an exudative effusion.
A total of 40 to 57% of patients with bacterial pneu-
monia will develop parapneumonic effusions.
However, only a small percentage (10 to 15%) have
complicated effusions, and empyema develops in
The stages of a parapneumonic effusion are as
brinopuru-
lent or bacterial invasion and fibrin formation
stage, which tends to occur after 7 days up to
2 weeks; and (3) the organizational or empyema


most patients; PF is usually not sampled. The
majority of institutions are not equipped to per-
form viral cultures and, therefore, these effusions
are typically not recognized. However, a pleural
effusion develops in approximately 40% of patients
with adenovirus 3 and 7. Adenovirus infection is
endemic throughout the year and occurs in all age
groups, although it is more common in school-aged
children.
The PF is a paucicellular exudate with a pre-
dominance of mononuclear cells. In the acute
phase, there may be an increased number of neu-
trophils. The diagnosis is established by document-
ing increasing complement fixation titers or
culturing the virus from the 
Hantavirus, which has been reported pre-
dominantly from the Four Corners area of the
, New Mexico, Arizona, Utah, and
Colorado) is the virus transmitted to humans via
contact with deer mice. Pleural effusions are caused
by either cardiac dysfunction or increased vascular
permeability. The  uid can be either transudate in
the initial phase with cardiac dysfunction or an
exudate with vascular leak. Chest radiograph
ltrates
with blood tests documenting thrombocytopenia,
a left shift in the myeloid series, and enlarged
can develop bronchopneumonia involving one or
multiple lobes. A small pleural effusion occurs in
nding speci
c antibody titers or by isolating
from the PF. Positive polymerase
chain reaction results from PF samples are associ-
ated with the abnormality observed on chest
Macrolides are the drug of choice,
and no speci c treatment is necessary for the pleu-
ral effusion.
Malignant Pleural E
usions (Carcinoma,
Lymphoma )
Malignant pleural effusions are the second
most common cause of exudates. Lung and breast
carcinoma represent approximately 60% of all
malignant pleural effusions, with lymphoma
representing approximately 10%.
46,47
Malignant
pleural effusions in lung cancer result from ipsi-
lateral tumor invasion into the pulmonary artery


contralateral shift, the most likely diagnosis is
lung cancer with obstruction of the ipsilateral
mainstem bronchus. The classic triad of lym-
phangitic carcinoma is ipsilateral mediastinal
adenopathy, Kerley B-lines, and a pleural
effusion.
PFA is variable in a malignant pleural effu-
sion. The  uid may be serous or grossly hemor-
rhagic and is typically a concordant exudate.
Approximately 10 to 14% of patients with a
malignant pleural effusion will have an elevated
ally diagnostic of adenocarcinoma of the lung in
geal perforation. A low PF pH and glucose in a
malignant pleural effusion is associated with
poorer survival, a greater yield on initial PF cytol-
ogy, and poorer response to chemical pleurodesis
than those with normal pH malignant pleural
effusions.
7,46–48
A malignant pleural effusion is diagnosed by
nding malignant cells either in PF or on pleural
biopsy. The yield of cytology and pleural biopsy
depends on the stage of the disease, with the more
advanced disease being associated with greater
sensitivities; therefore, the sensitivity of cytology
ranges from 45 to 90% and percutaneous pleural
biopsy from 30 to 50% with thoracoscopy being
the most sensitive diagnostic test with yields of
95 to 100% depending on the expertise of the
operator.
Treatment of patients with malignant pleural
effusion is palliative; outpatient therapeutic thora-
centesis for patients with far-advanced disease and
contralateral mediastinal shift is appropriate.
Chemical pleurodesis with talc poudrage or slurry
for refractory effusions with dyspnea relieved by
thoracentesis is an additional option. An indwell-
The epithelioid variant is
tially replaced electron microscopy as the gold
standard for diagnosis. Pathologists typically use
a panel of markers to con rm the diagnosis. Cal-


There are no speci c biomarkers in PF for the
diagnosis of malignant mesothelioma. The effu-
sions are typically exudative with protein concen-
4 g/dL and are lymphocyte predominant.
PF LDH levels often are
advanced disease present with extensive pleural
involvement and a low PF pH and glucose, por-
tending a poor prognosis as well as a poor response
to pleurodesis. Other poor prognostic factors at the
time of diagnosis include thrombocytosis, leuko-
cytosis, anemia, fever, sarcomatoid or mixed histol-
ogy,
65 years of age, poor performance status,
and male gender.
50,52
strated some evidence of antitumor activity with
tabolites. Pleurodesis may be effective early in the
course if lung entrapment is not present. Pleurec-
tomy has been shown to be more successful than
talc pleurodesis in reducing the recurrence of the
pleural effusion. There are some long-term survi-
vors after extrapleural pneumonectomy, when
there is a component of a multimodality treatment
suggesting that this procedure may alter the
natural history of the disease in appropriately
selected patients who are in early stages.
Other
approaches to treatment are still in clinical trials


occurring in up to 10% of untreated puri
ed pro-
tein derivative (PPD) converters. These effusions
develop when a subpleural focus of tuberculosis
ruptures into the pleural space followed by a cell-
mediated immune response to the tuberculous
antigens. A tuberculous pleural effusion can occur
A combination of histology and culture of the
pleural biopsy tissue, culture of PF, and sputum
culture establishes the diagnosis in up to 86% of
cases (Table 9).
A high PF adenosine deaminase
40 to 60 U/L supports the diagno-
sis if rheumatoid arthritis and empyema are unlikely.
An ADA level
40 U/L has a high negative predic-
tive value for tuberculous pleural effusions. An
ADA
50 IU/L with a lymphocyte/neutrophil ratio
75% makes a tuberculous effusion highly
likely.
Treatment is the same as for pulmonary tuber-
; however, because the organism load is
low with a tuberculous pleural effusion, 6 months
of isoniazid and rifampin appears to be effective
therapy.
A tuberculous effusion usually resolves
in 4 to 6 weeks with treatment or spontaneously
but can persist for up to 16 weeks. Untreated, the
recurrence rate is 65% within 5 years, mostly pul-
monary without a pleural effusion.
Therefore,
predominant exudate and positive PPD skin test
needs to be treated with isoniazid prophylaxis if
Corticosteroids
are effective in resolving severe symptoms and in
causing more rapid resolution of the pleural effusion
but has no effect on residual pleural thickening.
Pancreatic Disease (Acute Pancreatitis, Chronic
Pancreatic E
usion [Pancreatopleural Fistula])
Approximately 3 to 17% of patients with acute
pancreatitis will develop a left pleural effusion.
Table 9.
Diagnosis of Tuberculous Pleural Effusion*
Tests
Sensitivity, %
Percutaneous pleural biopsy
Culture
uid culture
effusion on CXR)
Pleural  uid acid-fast bacilli smear
VATS pleural biopsy
chest radiograph; N-PCR
nested polymerase chain
reaction; VATS
video-assisted thoracoscopic surgery.


Pleural effusions are much less common in patients
with chronic pancreatitis. Those with acute pan-
creatitis develop a pleural effusion from transdia-
phragmatic passage of amylase-rich PF into the
pleural space with resultant increased capillary
permeability from in ammatory mediators. The
PF to serum amylase ratio is
1 and is explained
by the rapid renal clearance of amylase and poor
amylase clearance from the pleural space. A
chronic, large recurrent pleural effusion is associ-
ated with chronic pancreatitis and pseudocyst
formation. Pseudocysts develop in approximately
10% of patients with acute pancreatitis, and 50%
pleural effusion.
The pleural effusion occurs
when a  stulous track develops from the pseudo-
the pericardial sac.
Patients with acute pancreati-
tis virtually always have abdominal symptoms and
occasionally pleuritic pain and dyspnea. The major
symptom with a chronic pancreatic effusion is
dyspnea attributable to the large pleural effusion;
chest discomfort and cough are typical in these
patients who do not have abdominal symptoms
68,69
The chest radiograph in acute pancreatitis is a
small left-sided pleural effusion in 60% of cases but
tion, there is usually an elevated left diaphragm


usually without fever. Patients with rheumatoid
pleurisy typically have high serum rheumatoid
factors and presumably high levels of CCP anti-
bodies. The chest radiograph typically shows a
small-to-moderate unilateral effusion with a nor-
standing lung entrapment and a cholesterol pleu-
ral effusion. The fluid typically contains a few
hundred mononuclear cells (mostly lymphocytes)
if there is an unexpandable lung without active
disease, up to 15,000 mostly neutrophils/
L in
acute rheumatoid pleurisy or with a cholesterol
effusion with chronic inflammation. When the
30 mg/dL, a pH of 7.00,
1,000 IU/L, the clinical diagnosis is
highly likely as long as infection is excluded.
Approximately 65% of patients on presentation
with rheumatoid pleurisy will have a PF glucose
Table 10.
Differentiating Features of Pleural Effusions From Acute and Chronic Pancreatitis
Clinical FeaturesAcute Pancreatitis
Chronic Pancreatitis (Pancreaticoplueral Fistula)
Incidence3–17%Uncommon
Presenting symptomAbdominal painDyspnea
Size of effusionSmallLarge to massive
SiteUsually left sidedUsually left sided, can be bilateral or right sided
PF amylase, IU/L500–10,000
Increased vascular permeabilityDirect  stulous communication from pancreatic pseudocyst
Speci c treatment not required50% require surgical intervention, percutaneous drainage or
Table 12.
Type of Amylase Isoenzyme
Pancreatitis, pancreaticopleural 
Pancreatic
Carcinoma of the lung (usually adenocarcinoma)Salivary (most common cause of salivary amylase-rich effusion)
Adenocarcinoma of ovary
Lymphoma
Macroamylase/salivary
Esophageal rupture
Chronic lymphatic leukemia
Ruptured ectopic pregnancy
Probably salivary
Table 11.
Tests Useful in the Differential Diagnosis of Amylase-Rich Pleural Effusions
Tests
Acute PancreatitisChronic Pancreatic EffusionEsophageal RuptureMalignancy
uid amylase
Extremely elevated
Pleural  uid /serum amylase10:1
uid amylase
Pancreatic
Pancreatic
uid pH
Serum lipase
Normal to minimally increasedNormal


30 mg/dL, and 80% will have a glucose
50
mg/dL. PF complement is decreased, immune
complexes are present, and rheumatoid factor is
1:320. Cytology is diagnostic by 
large, elongated tadpole-shaped cells with multi-
nucleated giant cells with a background of granu-
The cytologist should be advised that
rheumatoid pleurisy is a possibility. The diagnosis
is presumptive with the characteristic PF triad in
a presenting manifestation of SLE in 5% of patients.
At autopsy, 67% of patients with SLE will have
effusions (Table 13).
Pleuritis and pleural effu-
sions result from a local immune response with
ponents found in PF. In addition, PF anti-DNA
complexes may be involved. A speci
c immuno-
uorescent pattern of nuclear staining of pleural
77,78
are of SLE. Patients are virtually always symp-
tomatic with pleuritic chest pain (86 to 100%),
pleural rub (71%), cough (65%), dyspnea (50%),
and fever. The symptoms are similar in both native
and drug-induced lupus. The chest radiograph
typically shows small-to-moderate bilateral effu-
sions; however, unilateral massive pleural effu-
sions have been reported. Alveolar infiltrates,


7.30 in approximately 20% of
patients. The presence of lupus erythematosus (LE)
cells is diagnostic. A PF/serum antinuclear anti-
1 and decreased comple-
78,79
However, LE
cells are not found in the PF of all patients with
lupus pleuritis and are usually associated with the
presence of serum LE cells, which may diminish
the value of pleural LE cell positivity. Moreover,


is hemorrhagic with a low number of nucleated
cells, which are predominantly lymphocytic. The
majority of post-CABG effusions resolve over
weeks to months; however, some patients may
require 1 to 3 therapeutic thoracenteses; less com-
monly, some progress to trapped lung with severe
restriction requiring decortication.
29,82–84
Chylothorax
When the thoracic duct or one of its major
tributaries ruptures, chyle  ows into the surround-
ing tissues. If the mediastinal pleura remain intact,
chyle  lls the mediastinum and forms a “chyloma”
over the next several days before rupturing into
of the pulmonary ligament. The thoracic duct,
which has its origin in the cisterna chyli, is situated
in the midline anterior to the  rst and second lum-
bar vertebrae. The thoracic duct travels through
the aortic hiatus of the diaphragm approximately
at the level of the tenth to twelfth thoracic vertebrae
to the right of the aorta. Approximately at the 
posterior mediastinum and eventually joins the
venous circulation where the left subclavian and
internal jugular veins merge.
Therefore, disruption of the thoracic duct
whereas injury to the duct above this level re-
sults in a left chylothorax. However, signi
cant
anatomic variation exists in the path of the thoracic
Chyle is
normally transported from the intestine to the
14 carbon units) and
ingested fats are transformed into chylomicrons
and low-density lipoproteins in the intestines and
12 carbon units) are directly absorbed
into the portal vein without entering intestinal


PFA shows  uid that is typically white and
opalescent if fat is present; however, the 
uid can
for 12 h or hemorrhagic if there is concomitant
clear after centrifugation. The primary cells in chyle
are T lymphocytes, which typically represent
80%
count ranges from 400 to 6,800/
L. PF protein has
been reported from 2.2 to 5.9 g/dL (Table 15).
In contrast to a cholesterol pleural effusion, the
cholesterol levels in chyle are substantially lower
and range from 65 to 220 mg/dL.
110 mg/dL, there is a high likelihood
that the patient has chylothorax. Conversely, if the
50 mg/dL, it is highly
unlikely that a chylothorax is present.
However,
triglyceride concentration may be falsely low. If
chylomicrons are present, the diagnosis is estab-
nitively. Chylous 
uid has been reported
to have a pH from 7.40 to 7.80 and a glucose con-
Measurement of
the PF/serum glucose ratio assists in differentiat-
ing a chylous effusion (ratio
1.0) and pleural
accomplished by various techniques. Second, pro-
longed drainage of a chylothorax should be
avoided to prevent immunosuppression and mal-
nutrition. Patients with a traumatic chylothorax
are typically managed with chest tube drainage,
bowel rest, and parenteral nutrition to minimize
the  ow of chyle and maintenance of 
uid and
electrolyte balance. Because most traumatic chylo-
thoraces resolved within 10 to 14 days, protein loss
and immunosuppression are usually minimal. If
1,500 mL for
cant weight
loss or progressive loss of protein despite nutri-
tional therapy, surgical intervention is indicated.
Table 15.
Differentiating a Chylothorax and a Cholesterol Effusion
CharacteristicsChylothorax
Cholesterol Effusion
Rare
Lymphoma, trauma, surgery, LAM


a reported range of 39 to 76%, is one of the highest
monly the presenting event that leads to the


Pleural Disease (Sahn)


brosis. Water-soluble contrast agents are
tory reaction; however, the limitations are related
to hypertonicity. Therefore, aspiration of these
compounds into the tracheobronchial tree can cre-
cant in
ammation and precipitate pul-
monary edema. On chest CT, if air is found in the


simply represents peripheral atelectasis contiguous
to the most signi cant pleural 
brosis and merely
represents a form of peripheral lobar collapse.
108
Uremic Pleural E
At autopsy, 20% of uremic patients have 
109,110
In patients undergoing decortica-
tion for restriction from uremic pleuritis, both the


thyroid enlargement, hypothyroidism, and goiter.
Of 97 patients, 6 (6%) developed malignancies.
Hypogammaglobulinemia and nephrotic syn-


effusions are small and respiratory drives may be


Drugs that produce pleural thickening include
amiodarone, the ergolines, cyclophosphamide, and
Drug-induced pneumothorax can
occur in patients with rheumatoid nodules, pri-


Pleural Disease (Sahn)
Table 16.
Drug
Presentation
Chest RadiographPFA
Procainamide1 yr (1 mo–8 yr) of treat-
polyarthralgias, fever,
and effusion in 67%
ltrates and
effusion
Nonspeci c exudateAlso exudative effusion
ANA and anti-histone
NitrofurantoinAcute: previous drug
exposure; hours to
days after drug; acute


have life-threatening hypoxemia, and hypotension
occurs in 15%. The symptoms of SSP do not resolve
spontaneously. A suspicion of pneumothorax should
remain heightened in the COPD patient with dys-
pnea and unilateral chest pain. The presence of
cation
of the visceral pleural line problematic. A supine
radiograph can show pneumothorax gas juxtacar-
diac or in the costophrenic sulcus and may produce
diagnose a SSP. The arterial blood gas in patients
with a SSP shows signi
comitant hypercapnia (Table 19). Virtually all
patients with SSP require chest tube drainage
because the hypoxemia, hypercapnia, and respira-
tory distress can lead to an untoward event.
133
The
management of SSP is discussed in Table 19.
Table 16.
Drug
Presentation
Chest RadiographPFA
BleomycinEffusions have occurred
effusions associated
Not reported
Effusions resolve when
treated with steroids
Valproic acidFever, chest pain or
present
effusions; no paren-
1,000; IU/L
Lymphoplasmacytic
in ltrate and eosino-
phils on pleural biopsy.
Effusions resolve over
several weeks after drug
*Abbreviations as in Table 9.
Table 17.
Classi cation of Pneumothorax
Types of PneumothoraxCauses
Traumatic


pleural pressure exceeds atmospheric pressure
during the entire respiratory cycle. It develops
when there is unidirectional  ow of air from the
nism. Experimental data suggest that circulatory
collapse in tension pneumothorax is related to
decreased tissue oxygen delivery from hypoxemia
As soon as the patient is stabilized, a standard chest
Iatrogenic Pneumothorax
Causes of iatrogenic pneumothorax include
Table 19.
Immediate OptionsComments
Results in fourfold increase in
ObservationSmall PSP, asymptomatic, no
progression in 6 h
Simple aspirationSuccessful in 70% of patients with
Chest tube drainageFor virtually all patients with SSPs
Table 20.
Prevention of Recurrence of Spontaneous
Therapeutic OptionsComments
Chemical pleurodesis via
Reduces recurrence rate; talc
slurry (most effective) and
Video-assisted thoraco -
scopic surgery
Stapling of large bleb with talc
or partial pleurectomy


11. Heffner JE, Brown LK, Barbieri C. Diagnostic value


Pleural Disease (Sahn)


545


Churchill Limitis; 1884
101. Parkin G. The radiology of perforated esophagus.
102. Anderson R. Rupture of the esophagus. J Thorac
Surg 1952; 24:369–388


547
Understand the causes, pathophysiology, clinical presentation,
Understand the clinical presentation, pathophysiology,
syndrome
Understand the epidemiology, pathogenesis, clinical pre-
mechanical cause for the persistent fluid-filled
pleural space. The pleural ß uid in trapped lung
typically has low total protein and lactate dehy-
drogenase (LDH) concentrations consistent with a
transudative ß uid; however, depending on the


entrapment and differs from the single mechanism
In patients with trapped lung, there is no other
explanation for the mechanical visceral pleural
restriction of lung expansion or for the persistence
of the pleural effusion. In contrast, with intense
ammation, as with empyema, there are other
pathophysiologic mechanisms that produce pleural
uid in addition to the ß uid induced by the hydro-
static imbalance. Lung entrapment, as can be pres-
ent with malignancy, causes a pleural effusion by
two mechanisms: a hydrostatic mechanism caused
wall because of visceral pleural tumor involvement
and a capillary leak or lymphatic obstruction as a
ltration. In contrast,
a pleural effusion from trapped lung is solely
caused by failure of lung expansion that results in
hydrostatic imbalance. It follows therefore that a
trapped lung would be a transudate and lung
entrapment an exudate. A trapped lung, in reality,
is the end stage of lung entrapment when the
inß ammatory process has resolved (Fig 1).
Pathophysiology
The generation and removal of pleural ß
uid in
a trapped lung are operative under conditions
found in the normal pleural space with intact
hydrostatic and oncotic pressure gradients. The
uid from a trapped lung exists because
the forces promoting generation and removal of
uid are in equilibrium. The loss of lung
volume decreases pleural pressure and leads to
decreased thoracic volume on the affected side.
Moderate decreases in lung volume, such as with
lobar atelectasis, lobectomy, or interstitial lung
disease, usually do not result in a pleural effusion;
more volume loss, results in a pleural effusion
requires explanation.
After lobectomy, the remaining lung expands,
the diaphragm may be displaced upward, and the
pleural space assumes its usual width with the
remaining lung assuming the shape of the thoracic
cavity. However, in trapped lung, the Þ
broelastic
membrane usually involves only the dependent
lung, although the entire lung may be involved. The
affected lung is not only prevented from expanding
brous membrane but also is restricted to
conforming to the shape of the thoracic cavity. The
unaffected lung expands normally during breathing
and therefore will expand into any void left by the
portion of lung that is unexpandable. For the effu-
sion caused by the trapped lung to persist when it
is only partially unexpanded, the shape of the


ciently different from
from the thoracentesis.
After thoracentesis, reaccumulation of ß
uid to
beroptic bronchoscopy should be
considered to exclude endobronchial obstruction.


At thoracoscopy, a thin, resilient membrane is
seen covering the lung surface and preventing
reexpansion. On histologic examination, mature
brosis is evident with few inß ammatory cells. If
chronicity and stability over time has been dem-
onstrated, a diagnosis of trapped lung can be
established with reasonable conÞ
dence. These
ral effusion for months to years. The effusion


551


Therapy is usually symptomatic. Local steroid
injection and oral vitamin E have been reported to
be successful in treating the yellow nails. After
thoracentesis, ß uid recurs over weeks to months.
Chemical and surgical pleurodesis have been suc-
cessful in those with symptomatic pleural effu-
5,6
After pleurectomy in a single patient, there
was remission of the yellow nails. Spontaneous


(73%) of 110 cases, catamenial hemothorax in 15
Pathogenesis
A number of hypotheses have been proposed


Pleural Pearls (Sahn)
volume averaging. In addition to tuberculous


empyema, the differential diagnosis of empyema
necessitatis includes bacterial empyema, lung
Pleural Fluid Analysis
The deÞ nitive diagnosis of tuberculous empy-
ema is established at thoracentesis by finding
purulent ß
and subsequently cultures
M tuberculosis.
Tuberculous empyemas typically have nucleated
L, with virtually all the cells
being neutrophils. The pleural ß uid is acidic, with
7.20, and has a low glucose concen-
20 mg/dL. Pleural ß
uid protein
5 g/dL, and the
1,000 IU/L. Anaerobic and aerobic cul-
tures should be performed because, on occasion,
there is concomitant bacterial and mycobacterial
Complications
chronic tuberculous empyema include pleural
phoma), superior vena cava syndrome, and pleural
aspergillosis.
Treatment
The principles of treatment, pleural space
drainage and antimicrobial chemotherapy, are the
same for both bacterial and tuberculous empyema.
However, problems speciÞ c to chronic tuberculous
empyema include the inability to reexpand the
age and to achieve therapeutic drug levels in pleu-
ral fluid, which can lead to drug resistance.
Several patients have been described in whom
chemotherapy for tuberculous empyema was com-
plicated by progressive, acquired drug resistance.
It is believed the mycobacteria are exposed to sub-
in the emergence of resistant strains.
There is a single report of successful nonsur-
gical treatment of tuberculous empyema with
serial, space-emptying thoracenteses and 24


Pleural Pearls (Sahn)


parapneumonic effusion, esophageal rupture,
carcinoma, rheumatoid pleurisy, tuberculosis, and
Treatment
Relief of obstruction results in rapid reversal
uid/serum creatinine ratio and
resolution of the effusion over several days without
Clinical Pearls
¥ A urinothorax is typically an ipsilateral urine
collection in the pleural space due to obstruc-
tive uropathy.
¥ Urinothorax is the only single cause of a low-
¥ A pleural ß
uid/serum creatinine ratio
1.0 is
¥ The pleural ß
uid/serum creatinine ratio
urinary tract obstruction is relieved.
¥ The effusion resolves rapidly over a few days
after the relief of obstruction, and there are no
References


Chest Radiograph
Shortly after the development of a DPV, the
chest radiograph may be normal. Effusions range
from small to massive depending on the size and
duration of the Þ stula. Mediastinal widening may
stula should
be considered.
Pleural Fluid Analysis
Pleural ß uid in nontraumatic DPF is clear and
looks like water. The nucleated cell count is low
and the pleural ß uid glucose value is approxi-
mately 0.6 of the serum glucose. An important
feature of the transudative effusion is that the total
protein is consistently
1.0 g/dL (if precisely
measured should be
0.05.); the LDH is also
transudates with total protein consistently
1.0
g/dL include urinothorax, peritoneal dialysis, and


¥ Spontaneous resolution is rare, and most patients
require surgical closure for deÞ
nitive treatment.
References
1. Lloyd C, Sahn SA. Subarachnoid pleural Þ
origin of the elevated pleural ß uid cholesterol has
been attributed to local degeneration of pleural
nucleated cells and RBCs. The lipoprotein pattern
of a cholesterol effusion shows a shift of cholesterol
binding towards the high-density lipoproteins,
most likely occurring as the cholesterol is seques-
tered in the pleural space and undergoes a change
in lipoprotein binding characteristics. Cholesterol
in these effusions may be complexed with triglyc-
erides and proteins.
These chronic, inß
ammatory effusions result
in ÒpermanentÓ lung entrapment that causes per-
sistence of the effusion as a result of hydrostatic
tory process continues, as evidenced by a pleural
fluid total protein and LDH in the exudative
range with concomitant neutrophilia.
brosis progresses and large cholesterol
deposits are often demonstrated on histologic
The high triglyceride concentration noted in
some cholesterol effusions cannot be explained by
local cellular degeneration and supports the
hypothesis that plasma lipoproteins move into the
Causes
A literature review published in 1999 revealed
175 cases of cholesterol pleural effusions, with
78% in men (age range, 17 to 81 years). The major-
ity of the cases were attributable to tuberculosis;
rheumatoid pleurisy was a distant second in fre-
quency. Other causes include paragonimiasis,
lung cancer, empyema, hemothorax, and trauma
(Table 1).
Table 1.
Causes of Cholesterol Effusions*
Chronic tuberculous pleural effusion (most common)
Trauma


The cardinal feature of these effusions is
a high cholesterol concentration, which is inde-
pendent of the serum cholesterol. A cholesterol
pleural effusion may be differentiated from a
observation with reassurance is indicated. Decor-
tication should be considered for the symptomatic
patient with restrictive physiology as long as the
underlying lung is relatively normal. However, the
presence of an active inß ammatory process would
appear to make the prospect of successful decorti-
cation less likely.
Clinical Pearls
¥ A cholesterol effusion is distinct from a chylo-
thorax and is a consequence of chronic pleural
inß ammation and lung entrapment.
¥ Lung entrapment causes hydrostatic imbal-
ance, whereas pleural inß ammation leads to a
capillary leak and with high total protein and
¥ The most common causes reported are chronic
tuberculous empyema and rheumatoid pleurisy.
¥ The diagnosis can be suspected by observing
uid with a satin-like sheen and diagnosed if the
cholesterol concentration is
200 mg/dL and
cholesterol crystals are seen micro scopically.
¥ If the effusion does not resolve with treatment
be considered for the symptomatic patient with
restrictive physiology.
References
1. Coe JE, Aikawa JK. Cholesterol pleural effusion.
Arch Intern Med 1961; 108:163Ð174
Table 2.
Differentiating a Cholesterol Effusion From Chylothorax*
ConditionChylothorax
Cholesterol Effusion
IncidenceUncommon
Rare
CausesLymphoma, trauma, surgery, lymphangioleiomyomatosisLung entrapment; tuberculosis, rheumatoid


2. Agrawal V, Sahn SA. Lipid pleural effusions. Am J
3. Hillerdal G. Chylothorax and pseudochylothorax.
Eur Respir J 1997; 10:1157Ð1162
4. Hamm H, Pfalzer B, Fabel H. Lipoprotein analysis in
a chyliform pleural effusion: implications for patho-
5. Garcia-Zamalloa A, Ruiz-Irastorza G, Aguayo FJ,


Pleural Pearls (Sahn)


563
ne the indications for lung transplantation
 Review the guidelines for recipient selection for lung
 Describe the relative and absolute contraindications to lung
 Describe outcomes after transplantation, including survival
and physiologic results
 Review the complications after lung transplantation
 Give an overview of the immunosuppressive medications
acute rejection; cytomegalovirus; immunosuppres-
sion; lung transplantation; obliterative bronchiolitis
During the last 2.5 decades, lung transplantation
(LT
) has become a successful therapeutic option
for patients with end-stage pulmonary parenchy-
mal and vascular diseases. Dr. James Hardy at the
rst LT
in 1963. However, the patient survived for only 18
days. Subsequent attempts at LT were complicated
by bronchial anastomotic dehiscence and early graft
failure, resulting in limited survival. Advances in
donor and recipient selection, improved surgi-
cal techniques, new immunosuppressive drugs,
recipients, much of the subsequent follow-up care
is now conducted by the referring pulmonologist
insurance company mandates. This section will
attempt to concisely review the topic of LT for the
Indications for LT
Heart-Lung Transplantation
One of the original successful LT procedures,
performed primarily in the late 1980s and early
1990s, was heart-lung transplantation (HLT). Cur-
rently, HLT is performed at only a few transplant
centers and should be reserved for patients who
cannot be treated by LT alone. The most frequent
indications for HLT are Eisenmenger syndrome
with a surgically uncorrectable cardiac anomaly
or severe end-stage lung disease with concurrent
severe heart disease.
Bilateral LT
Bilateral LT (BLT) is performed in patients with
, cystic
brosis [CF] and bronchiectasis). In fact, 28% of all
BLTs are performed as treatment for CF. Initially,
double-lung transplantation was the procedure
level of the trachea; however, the rate of ischemic
airway complications was prohibitive. Now, BLT
(essentially, sequential single-lung transplanta-
tion [SLT]), in which the anastomoses are per-
formed at the level of the mainstem bronchi, is
the preferred surgical technique. Many centers
also recommend BLT for younger patients with
severe COPD (secondary to tobacco use [24% of
BLTs] or
-antitrypsin de ciency [9% of BLTs])
from the increased reserve provided during times
prefer to perform a BLT procedure in patients with
Lung Transplantation


Lung Transplantation (Levine)
primary pulmonary hypertension (PPH; 6% of
BLTs). Although a single-lung allograft with nor-
mal pulmonary vasculature can accommodate the
entire right ventricular output without elevation
of pulmonary artery pressures, in times of graft
compromise, such as rejection or infection, severe
Overall, BLT procedures are now being performed
more than SLT procedures.
SLT
SLT is performed for the treatment of obstruc-
sema secondary to tobacco use or 1-antitrypsin
ciency (50% and 7%, respectively, of all SLTs
are performed for these indications). SLT was
initially thought to be a poor choice of procedure
for the treatment of patients with COPD as the
result of concerns of preferential ventilation to
the compliant native lung, but these concerns
have proven to be largely unfounded. Other
indications for SLT include idiopathic pulmonary
fibrosis (28% of all SLTs), familial pulmonary
fibrosis, drug-induced or toxin-induced lung
disease, occupational lung disease, sarcoidosis,
limited scleroderma, lymphangioleiomyomato-
sis, eosinophilic granuloma, and other disorders
resulting in end-stage  brotic lung disease. SLT
is rarely performed for pulmonary vascular dis-
1% of SLTs
cult because of the large
volume of blood  ow going to the transplanted
Table 1.
Transplantation*
CriteriaDescription
Untreatable end-stage obstructive
or restrictive pulmonary paren-
cant medical
Ambulatory with rehabilitation
Satisfactory psychosocial pro
le and
Systemic or untreated extrapulmonic
Colonization with resistant bacteria,
Symptomatic osteoporosis;
Severely limited functional status
70% or
30 kg/m
, renal
[creatinine clearance,
50 mg/mL/min]);
Hepatitis C biopsy-proven liver


Age
limit of 65 years as, generally, but not 
rmly, the
upper limit regardless of procedure type. Although
this limit is somewhat arbitrary, numerous patients
with end-stage pulmonary disease are young to
middle aged, and there is a relative lack of available
what poorer outcome than younger patients.
Relative Contraindications
Transplantation
is not contraindicated in patients with systemic
diseases that are limited to the lungs such as sclero-
sitis, and rheumatoid arthritis. These cases should
be considered on an individual basis. Patients with


Lung Transplantation (Levine)
cancer greater than Duke A stage, renal carcinoma,
or melanoma greater than or equal to level 2, the
waiting period should be at least 5 years. Restaging
is suggested before transplant listing.
Table 2.
c Criteria for Lung Transplantation*
DiseaseCriteria
7 or at least one of the following:
20% predicted (nonreversible) and
diffusing capacity
20% or homogenous
emphysema on HRCT;
50 mm Hg;
-dependent hypercapnic patients (refer early)
5 (refer to lung transplant center)
IPFDiagnosis of usual interstitial pneumonitis with
Diffusing capacity
39% predicted;
A decrease in FVC of
10% in 6 mo of follow-


A 1998 analysis
of transplant survival data
a signi cant improvement in quality of life (QOL),
but a clear survival bene t with transplantation
term supplemental oxygen therapy, if the criteria


Lung Transplantation (Levine)
of postoperative ventilator days, the length of
hospital stay, and the number of days receiving
antibiotic therapy, the incidence of bronchitis and
indicate the necessity for a bilateral procedure, or
to look for focal nodules that were not apparent on
plain chest radiographs. Renal and liver functions
are assessed by 24-h creatinine clearance and liver
function tests, respectively. Serologies for hepatitis
and HIV should also be obtained. The majority of
these investigations can be performed at the refer-
ring center. In those patients being evaluated for
SLT, a ventilation/perfusion scan with quantitation
may suggest the preferred side to be transplanted if
there is unequal distribution of perfusion.
While awaiting transplantation, patients
ter or their referring physician for both physiologic
and emotional support. In those patients who are
antibiotic regimen in the immediate postoperative
period. Those patients who are able to should be
involved in a rehabilitation program before under-
Donor Allocation


not by necessity. In the spring of 2005, the system
for donor allocation for lungs was revised, and the
assigned priority for lung offers became based on
the lung allocation score (LAS), which is calcu-
lated using the following measures: (1) waiting
list urgency measure (
survival measure (
lived during the  rst year after transplant); and
t measure (
transplant survival measure minus waiting list
urgency measure).


Lung Transplantation (Levine)
pulmonary vein undergo anastomosis 
rst, fol-
lowed by the bronchial anastomosis, and 
the arterial anastomosis. BLT is usually performed
through a transverse thoracosternotomy (clam
shell incision or median sternotomy). Cardiopul-
monary bypass may be required in cases of pulmo-
nary hypertension. Organ preservation remains a
major area of research in LT. Currently, the lung can
only be preserved for a period of approximately 4
cant ischemia/
reperfusion injury. Newer preservative agents may
increase this time period and permit a larger area
Management After the Postoperative
Period
Patients are typically discharged from the hos-
pital within 7 to 14 days after surgery. Follow-up
is in the outpatient clinic on a weekly, biweekly,
and  nally monthly basis. After this time, patients


to the transplanted lung. BLT procedures usu-


(line sepsis, pneumonia,
tracheobronchitis)
(Aspergillus,
(Pneumocystis carinii)
incidence with treatment for chronic rejection
mo
3rd
6th
9th
12th
18th
The common complications after LT and the typical time periods in which they develop. Reprinted with permission from Melo J, Levine SM. Lung transplantation for the
referring pulmonologist. Pulm Crit Care Update 1999; 13:lesson 16.


patients in whom primary graft failure developed.
A study
from a different large transplant center
ed cardiopulmonary bypass as a risk factor
for PRR and also observed prolonged mechanical
PRR. It did not observe a difference in survival


Lung Transplantation (Levine)
transplantation that are either recurrent (
, more
than two episodes) or persistent (failure to resolve
with standard therapy). Acute rejection is usu-
ally not seen as frequently after the  rst year after
transplantation. Risk factors for acute rejection are
poorly de ned, but HLA mismatches and gastro-
esophageal re ux may have a correlation.
Clinically, patients with acute rejection present
with cough, shortness of breath, malaise, and fever.
Occasionally, the presentation is asymptomatic,
and some centers advocate surveillance bronchos-


non-CMV infection; older donor age; and bron-
chiolitis obliterans with organizing pneumonia.
The most consistently identified risk factor is
acute rejection, particularly in those patients who
experience recurrent, high-grade episodes of acute
rejection. It is probable that lymphocytic bronchi-
olitis and CMV pneumonitis are also important
Other risk factors are being
ed. In the past several years, gastric aspira-
tion and gastroesophageal re ux disease (GERD)
have been recognized as an important cause and/
pulmonary dysfunction after LT, particularly BOS.
for BOS. Clinically, OB can manifest as an upper
respiratory tract infection and can be mistakenly
treated as such. Other patients present without
clinical symptoms but with gradual obstructive
dysfunction seen on pulmonary function test
results. FEV
bronchioles by transbronchial biopsy, the ISHLT
This
staging system is based on a reduction in FEV
comparison with a posttransplant baseline FEV
OB. This staging system was revised by the ISHLT
in 2002, and the new system includes an earlier
and/or mid- ows compared with posttrans-
values; and/or forced expiratory 
ow, midexpira-
75% of baseline values; Table 3).


Lung Transplantation (Levine)
of predicted FEV


be dif cult and often requires invasive procedures
such as bronchoscopy with BAL 
uid, quantita-
tive sterile brush sample, and/or transbronchial
biopsy.
Atypical pneumonias
such as Legionella, Mycobacteria, and Nocardia
species are uncommon in patients undergoing
LT but have been reported to occur in 2 to 9% of
recipients. The numbers of viral infections, such
as those attributable to herpes simplex virus, have
cantly reduced with the common use
of acyclovir or ganciclovir prophylaxis. Candidal


Lung Transplantation (Levine)


EBV serology before transplantation and receive
an organ from an EBV-positive donor resulting
in seroconversion are at a significantly greater
risk for the development of a PTLD. Children
are at greater risk because of their frequent EBV-
The clinical features of PTLD in LT recipients
rst posttransplant
year, involvement of the allograft, and radiographic
ndings of solitary or multiple pulmonary nodules.
Disseminated disease has also been reported. Treat-
ment includes the anti-CD20 monoclonal antibody
rituximab, a reduction in immunosuppression, as
well as consideration for adjunctive treatment with
antiviral therapy, radiation, chemotherapy, surgery,
and adoptive immunotherapies extrapolated from
the bone marrow transplant population. Mortal-
ity may be signi cant with high-grade PTLD. An
increased incidence of other nonlymphomatous
malignancies has been reported in the LT popula-
tion, and careful screening is recommended.
Miscellaneous Complications
The recurrence of primary disease has been
described in patients who have received trans-
plants for the treatment of sarcoidosis, lymphan-
desquamative interstitial pneumonia, idiopathic
pulmonary hemosiderosis, bronchioalveolar carci-
noma, eosinophilic granuloma, alveolar proteino-
sis, and diffuse panbronchiolitis. However, disease
recurrence may be an incidental 
nding in some of
these patients, particularly those with sarcoidosis.
Pleural effusions may develop because of the
fact that the lymphatics are not reanastomosed


Lung Transplantation (Levine)
these drugs and, to some degree, in nearly 100%
of patients with long-term use. Acute renal toxicity
is usually related to dose and typically is revers-
ible. In addition, other potentially nephrotoxic
For example, use of the azoles results in a signi
cant increase in cyclosporine and tacrolimus levels
therapy with azole agents without increasing the
dose of cyclosporine or tacrolimus can result in
an acute and life-threatening drop in therapeutic
levels of these drugs. Interactions with macrolide
motility drugs have also been reported. Levels of
both agents are decreased with the use of rifampin
Azathioprine inhibits nucleic acid synthesis
and suppresses the proliferation of lymphocytes.
Toxicities of this drug include cytopenias such as
leukopenia and thrombocytopenia. Macrocytic
creatitis and cholestatic hepatitis have been well


and


Lung Transplantation (Levine)


This article gives an excellent overview of the mechanisms of
action of the immunosuppressive agents commonly used in LT.


Lung Transplantation (Levine)


585
 Describe the salient epidemiologic, clinical, physiologic,
and radiographic features of Langerhans cell histiocytosis
genic organizing pneumonia (COP)
 Compare and contrast the salient features seen on high-
resolution CT scans in these disorders
 Review the characteristic histopathologic features of each
of these disorders and the role of immunohistochemical
 Review the differing therapeutic strategies for these disorders
bronchiolitis obliterans organizing pneumonia;
cryptogenic organizing pneumonia; cystic lung diseases;
Langerhans cell granulomatosis; Langerhans cell histiocy-
tosis; lymphangioleiomyomatosis; pulmonary eosinophilic
Pulmonary Langerhans cell histiocytosis (LCH;
Langerhans cell granulomatosis
) and
lymphangioleiomyomatosis (LAM) are rare and
poorly understood chronic lung disorders char-
acterized by extensive cyst formation within the
lung parenchyma. These disorders share certain
features, but LAM affects exclusively women,
whereas pulmonary LCH (PLCH) may affect either
sex. Cryptogenic organizing pneumonia (COP),
bronchiolitis obliterans organizing
(BOOP), is a rare disease of unknown
organs.
However,
20% of adults with PLCH
More
importantly, LCH predominantly affects children,
whereas isolated PLCH is a rare occurrence in
children.
The clinical and radiographic features of
PLCH overlap with those of myriad chronic ILDs.
However, CT scans are highly characteristic and
may distinguish PLCH from idiopathic pulmonary
 brosis and other chronic ILDs.
The prevalence of PLCH is estimated at two to
ve cases per million persons.
5% of cases of ILDs.
in adults 20 to 50 years of age; children are rarely
affected.
PLCH is almost exclusively seen in


Rare Interstitial Lung Diseases (Lynch)
LCH. Posteroanterior chest radiograph demonstrat-
ing  nely nodular densities throughout the lung parenchyma,
with a predominance in the middle and upper lung  elds, in a
44-year-old man with pulmonary LCH.


radiographs in discerning the cystic nature of the
The combination of cystic
and nodular lesions, with a proclivity to involve
the upper lobes, strongly suggests PLCH.
There
is no central or peripheral predominance. Mul-
tiple thin-walled cysts are observed in
85% of
These cysts are usually round and
10 mm but may coalesce, occasionally exceed-
Nodules ranging in size from
1 to 15 mm are a prominent component of PLCH;
they are found in approximately two thirds of
The nodules surround small bronchi-
oles and represent peribronchiolar granulomas. As
the disease progresses, the nodules are replaced by
LCH. Posteroanterior chest radiograph demonstrat-
ing far advanced cystic and nodular changes throughout the
lung parenchyma. A persistent right pneumothorax is evident,
despite the presence of a right thoracoscopy tube. Surgical clips
are from prior thoracotomies for attempted pleurodesis.
LCH. Posteroanterior chest radiograph demonstrating
nely nodular densities throughout the lung parenchyma and
ation in a 38-year-old woman with pulmonary LCH.
LCH. HRCT scan from the patient in Fig 3 reveals nu-
merous cysts of various sizes throughout the lung parenchyma.
Multiple small nodules can also be seen dispersed throughout
the peribronchial regions and alveolar interstitium.
LCH. HRCT scan of the upper lobes from a 56-
year-old man with progressive cough and dyspnea. Note the
multiple well-de ned cystic spaces and coalescence of blebs
in the medial aspect of the right apex. A few tiny, scattered
peribronchiolar nodules are also present. Transbronchial lung
biopsy specimens demonstrated typical histologic features of
LCH. S100 stains were also positive.


Rare Interstitial Lung Diseases (Lynch)
uent. The extent
of nodular opacities on HRCT correlates with the
ammatory lesions
in lung tissue; cystic lesions on CT correlate with
and  brotic) on biopsy.
Serial studies of individual
patients indicate that lesions evolve from nodules
These cysts or nodules are
associated with areas of intervening normal lung
The cystic radiolucencies resemble LAM,
addition, LAM affects all lung zones, including
the basilar regions. The cysts of PLCH lack the
nary  brosis (Fig 6, 7).
Ground-glass opacities
but are rarely dominant. When
GGOs are prominent, concomitant respiratory
bronchiolitis-ILD often is present.
Pleural effu-
sions and hilar adenopathy are rare.
However,
mediastinal or paratracheal lymphadenopathy
Idiopathic pulmonary  brosis. HRCT scan from the
patient in Fig 6 (lower lobes). Foci of honeycombing are noted
throughout both lungs. Note the peripheral (subpleural) distri-
bution of honeycomb cysts, with relative sparing of the central
regions. In addition, prominent septal lines, bands, or 
brosis
are apparent. This pattern differs from the more uniform dis-
brosis. HRCT scan from a
55-year-old woman with usual interstitial pneumonia (UIP)
(documented by thoracoscopic lung biopsy) demonstrates
extensive honeycombing throughout both lungs (upper lobes).
Note that the cysts are distributed preferentially in the periph-
eral (subpleural) regions of the lung, with relative sparing of
the central regions. This pattern differs from the more uniform


thoracoscopic lung biopsy, but transbronchial biop-
sies may be adequate provided the salient features
are present.
Early in the course of the disease, the
proliferation of atypical histiocytes (histiocytosis X
Later, granulomatous
ammation ensues. Fibrosis is the end result of the
chronic in ammatory cellular lesions. In individual
patients, several histologic features may be present
, histiocytic proliferation, granulo-
ammation, 
brosis, healing, and repair).
power microscopy by numerous peribronchiolar
nodules, numerous cysts, and a distinctive stellate
or star-shaped pattern of 
brosis.
tern of  brosis was observed in 84 of 100 cases of
PLCH reported by Friedman and colleagues.
stellate border re ects extension of the cellular in
trate into adjacent alveolar interstitium. Numerous
Photomicrograph of a subpleural granulomatous
areas within the nodule correspond to in
ammatory cellular
ltrates. The process extends into the alveolar interstitium.
Photomicrograph of pulmonary LCH. Scattered
atypical histiocytes (LCs) are present within a cellular nodule.
LCs are moderately large cells with pale eosinophilic cytoplasm
and an indented, clefted nuclei (hematoxylin-eosin, oil immer-
sion). From Lynch JP III, Raghu G. Major disease syndromes


Rare Interstitial Lung Diseases (Lynch)
destroyed by the granulomatous process.
As the
process evolves, bronchioles and alveolar walls are
destroyed and replaced by 
brotic connective tis-
sue. Dilated and distorted bronchioles and alveolar
parenchymal cysts result. Dense 
brosis (consist-
ing of mature collagen) and intraluminal 
brosis
(consisting of young, organizing connective tissue
within lumens of bronchioles and alveoli) may
resemble COP.
Thus, the histopathologic features
of PLCH overlap with those of other chronic ILDs.
cation of large numbers of LCs is the key to
the diagnosis. However, late- or end-stage PLCH
may be relatively acellular, with
5% LCs and
context, distinguishing PLCH from other end-
stage chronic  brotic lung disorders is dif
cult,


T-cell mitogens, stimulate macrophage cytokine
production,
and induce epithelial cell produc-
, granulocyte-macrophage
stimulating factor and transforming growth
factor-
that recruit LCs and up-regulate lym-
The number of pulmonary LCs is increased


Rare Interstitial Lung Diseases (Lynch)
and essential component of therapy; the role of
pharmacological agents has not been studied
For multisystemic LCH


patients with PLCH treated with IV epoprostenol
Lung transplantation has been successfully
accomplished in PLCH patients with severe respi-
ratory failure refractory to medical therapy.


Rare Interstitial Lung Diseases (Lynch)
LAM. HRCT scan from a 33-year-old woman with
a history of recurrent pneumothoraces shows numerous well-
ned cysts scattered throughout the lung parenchyma.
Figure 11.
LAM. Posteroanterior chest radiograph demonstrat-
ing modest hyperin ation and some cystic and emphysema-
tous changes in a 42-year-old woman with LAM. Surgical clips
are present in the left lung from a previous thoracotomy for the
treatment of recurrent pneumothorax.
LAM. CT scan from the same patient demonstrating
with several large con uent cysts. Note that cysts are scattered
relatively evenly throughout the lung, with neither peripheral
nor central predominance. A nodular component is lacking.


regions or lobes.
Cavitation is not a feature of
brosis, or
irregular lung-pleural interfaces—features com-
monly observed in other chronic ILDs—are absent
or a minor feature in LAM.
GGOs were not cited
in early reports of HRCT in LAM
but were noted
of patients in
two more recent series. GGOs may re
ect foci of
alveolar hemorrhage, pulmonary hemosiderosis, or
diffuse proliferation of smooth-muscle cells (Figs 15
LAM. Posteroanterior chest radiograph from a 41-
year-old woman with a history of recurrent pneumothoraces
LAM. HRCT scan in a 44-year-old woman with
LAM demonstrates multiple, thin-walled cystic radiolucencies
bilaterally. Note the two large lesions, representing con
cysts. From Lynch JP III, Raghu G. Major disease syndromes
LAM. CT scan (upper lobes) from a 36-year-old
woman demonstrating small (1 to 3 mm) round cysts through-
out both lung  elds, which is consistent with early changes in
LAM. A diffuse background haze (ground-glass opaci
is present, which is consistent with alveolar hemorrhage. She
had a 12-month history of intermittent hemoptysis. Transbron-
chial lung biopsy specimens demonstrated hemosiderin-laden
macrophages (which is consistent with previous hemorrhage)
and clusters of smooth-muscle cells (positive for HMB45),
LAM. CT scan from the patient in Fig 13 demonstrat-
ing multiple thin-walled cystic radiolucencies throughout lung
parenchyma consistent with LAM. Note that both the central
and peripheral regions of the lungs are involved.


Rare Interstitial Lung Diseases (Lynch)
tative analyses of extent of disease by thin-section


blood gases, and alveolar-arterial gradient do not
predict survival.
The rate of progression of air-
ow obstruction is highly variable, ranging from a
few years to more than two decades.
A review
cited a mean decrease in FEV
of 118 mL/year, but
Photomicrograph of LAM. Open-lung biopsy speci-
men demonstrating the proliferation of atypical smooth-muscle


Rare Interstitial Lung Diseases (Lynch)
ltration of
LAM cells, are a predictor of death and time to
Immunohistochemical Stains and Ancillary
Diagnostic Techniques
Smooth muscle cells in pulmonary LAM
are similar histologically and by immunohisto-
chemical analysis to AMLs, which are benign
71,75,113
Immunohistochemical stains are positive for
c actin, desmin, and human mela-
75,114
HMB-45 produces
114
HMB-45 immunoreactivity in smooth muscle is
highly speci c for LAM, AMLs, and clear cell
tumor of the lung but is never found in normal
75,114
The speci city of HMB-45
may allow a diagnosis of LAM by transbronchial
lung biopsy, provided the immunohistochemical
The immunohistochemical
reactivity of LAM cells is localized more fre-
quently in the large epithelioid cells.
LAM cells contain increased amounts of matrix


Renal or abdominal AMLs (HMB-45 positive)
have been noted in 15 to 54% of patients with
71,76,97,113
In one study, uterine
leiomyomas were cited in 41% of patients with
AMLs often are incidental  ndings on CT,
but the growth of these smooth muscle tumors may
pression of contiguous structures.
75,76,113
A study of
12 AMLs from women with LAM demonstrated
positive estrogen receptor immunoreactivity in
10 (83%); all expressed progesterone receptors
A previous study noted positive PRs in
55% of AMLs associated with TSC but in only 7%
AMLs are hyperechogenic on ultrasonography
and reveal fat attenuation on CT.
is the best screening test to assess the presence,
size, and extent of renal or intra-abdominal cystic
or angiomyolipomatous lesions in patients with
97,113
In one prospective study,
80 patients with LAM underwent chest and
nography.


Rare Interstitial Lung Diseases (Lynch)
113
Early prevalence studies cited pulmo-
nary lesions indistinguishable radiographically
and histopathologically from LAM in 1 to 4% of
However, subsequent
studies suggest that the prevalence of LAM among
In one prospective study, screening HRCT
scans were performed in 48 patients with TSC who
had no pulmonary symptoms, no previous history
of LAM, and normal PFTs.


growth, lymphatic or vascular spread, and tissue
destruction.
Course and Prognosis of LAM
ultimately die of respiratory failure. However, the
pace of the disease is extremely variable. Early


Rare Interstitial Lung Diseases (Lynch)
gonadotropin-r
14),
6), and oophorectomy (n
Among 34 patients with serial PFTs, FEV
improved
15% in only 4 patients; 19 patients stabilized


603


Rare Interstitial Lung Diseases (Lynch)
syndrome,
Wegener granulomatosis,
lower respiratory
, legionellae, viruses, and Myco-
toxic fume inhalation; radiation
therapy,
chemotherapy,
malignancy,
lung cancer,
or bone marrow,
transplants. It can also
occur as a reaction to pharmacologic or exog-
organizing pneumonia, a disorder in which no


corticosteroids compared with other radiographic
Pleural effusions, cavitation, and intra-
thoracic lymphadenopathy are not features of
COP. However, multiple nodular mass lesions,
have
HRCT scans depict the salient features of
COP more clearly than conventional chest radio-
but are not essential for diagnosis or
management. Typically, multiple segmental or lobar
dense alveolar opacities with air bronchograms are
seen in the peripheral regions of the lungs.
some cases, a feeding vessel or bronchus leading
into the area of consolidation or nodular opacity
BOOP.
Top
: posteroanterior chest radiograph
from a 75-year-old woman with a 6-month history of recurrent
tion. A patchy left lower lobe in ltrate is also present.
: posteroanterior chest radiograph from the same patient as
alveolar in ltrates; a patchy right lower lobe in ltrate is also
present. A transbronchial lung biopsy specimen demonstrated
the classic features of BOOP. Following the initiation of therapy
BOOP. Posteroanterior chest radiograph demon-
ltrates in the left lung and
a patchy in ltrate in the right lower lobe in a 58-year-old man.
The open-lung biopsy specimen was consistent with BOOP.
After 4 weeks of therapy with prednisone, 60 mg/d, he was


Rare Interstitial Lung Diseases (Lynch)
Photomicrograph of BOOP. Open-lung biopsy
specimen demonstrating a plug of organizing granulation
tissue within a respiratory bronchiole. A peribronchiolar
mononuclear inflammatory cell infiltrate is also evident
cation). From Neagos
GR, Lynch JP III. Making sense out of bronchiolitis obliterans.
Photomicrograph of BOOP. Open-lung biopsy
the bronchioles. A peribronchiolar inflammatory cellular
ltrate is present extending into the alveolar interstitium
edema, the alveolar architecture is preserved
and  brosis is absent. The lesions in COP appear
to be of uniform age, suggesting a stereotypic
response to prior injury. By contrast, constrictive
bronchiolitis, also termed OB, lacks the organizing
pneumonia component of COP and is associated
with a distinctly worse prognosis.
In OB, the
small airways and bronchioles are obliterated
by transmural  brosis and in ammation, but a
prominent in ammatory component is lacking.
The airway lumens are narrowed by a concentric
deposition of collagen and  brous connective tis-


complication of rheumatoid arthritis, toxic fume
inhalation, bone marrow or lung transplantation,
and diverse exposures.
In contrast to COP,
OB is associated with a poor prognosis and low rate
of responsiveness to corticosteroids or cytotoxic
agents. The course is characterized by progressive
ow obstruction, eventually resulting in respi-
ratory failure and death. This entity is beyond the
scope of this chapter.
The histologic features of COP overlap with
those of several other entities, including DIP,
chronic eosinophilic pneumonia, hypersensitiv-
brosis,
infectious
Photomicrograph of BOOP. Open-lung biopsy
the bronchioles. A peribronchiolar inflammatory cellular
ltrate is present extending into the alveolar interstitium
(hematoxylin-eosin, low-power magni
cation). From Clini-
cal pulmonary medicine. Boston, MA: Little Brown, 1992;


Rare Interstitial Lung Diseases (Lynch)
sources of MMP-9. It is possible that MMP-2 pref-
erentially degrades collagens and that TIMPs play
a role in remodeling after parenchymal damage.
211


oral macrolides are logical therapeutic agents for


Rare Interstitial Lung Diseases (Lynch)


611
with eosinophilic granuloma. J Clin Invest 1990;
45. Zeid NA, Muller HK. Tobacco smoke induced lung
nary Langerhans cells. Pathology 1995; 27:247–254
46. Wells AU, Nicholson AG, Hansell DM. Challenges
in pulmonary  brosis. 4: smoking-induced diffuse


Rare Interstitial Lung Diseases (Lynch)


Silva CI, Churg A, Muller NL. Hypersensitivity
pneumonitis: spectrum of high-resolution CT and
ndings. AJR Am J Roentgenol 2007;


Rare Interstitial Lung Diseases (Lynch)


615


Rare Interstitial Lung Diseases (Lynch)
(Herceptin) therapy for breast cancer. Eur Respir J


semi-quantitative evaluation using computed
tomography and positron emission tomography.


Rare Interstitial Lung Diseases (Lynch)


619
 Become familiar with the epidemiology of tuberculosis
 Review the pathogenesis and clinical presentation of
tuberculosis
 Address issues concerning the prevention of tuberculosis,
including the diagnosis and treatment of tuberculosis
 Review issues concerning the diagnosis and treatment of
tuberculosis disease
 Outline pertinent topics concerning mycobacteria other
than tuberculosis (
multidrug-resistant tuberculosis; nontuberculous
mycobacteria; tuberculosis
Tuberculosis
At the turn of the 20th century, tuberculosis
(TB) was one of the leading causes of death in the
United States. After the discovery of effective
chemotherapy, the rate of TB significantly
decreased at an average rate of 8% per year
rate and total number of TB cases ever documented
since national reporting began in the United States.
The highest numbers of cases have been reported
in California, Florida, New York, and Texas, which
ally. It is estimated that approximately 15 million
people are infected with TB in the United States,
making for a large potential reservoir of disease in
the population. The infection rate among foreign-
born individuals in the United States is approxi-
mately seven times greater than that for the
US-born population. Although the number of cases
in the United States has been decreasing, the
proportion of cases in the foreign-born population
has increased from 27% in 1992 to 59% in 2008. In
addition, 82% of the reported multidrug-resistant
cases in the United States occurred in foreign-born
Worldwide, the rate of TB has not decreased as
it has in the United States. According to the most
recent statistics from the World Health Organiza-
approximately 9.27 million worldwide, with a total
prevalence of 13.7 million cases of TB disease.


Causative Agent of TB
TB is caused by a group of closely related
mycobacteria (MTB, Mycobacterium bovis, M


indication that infection has taken place. Individu-
als with LTBI but not active disease are not infec-
tious and thus cannot transmit the organism.
destroying the CD4 cells of the host’s immune
system, HIV allows dormant TB to activate and
rapidly cause disease. In response to the reactiva-
to replicate. This activation further renders the CD4
cells that are vulnerable to invasion by the HIV and
allows the virus to further replicate within these
cells, leading to a vicious cycle of increasing viral
Table 1.
ClassiÞ cation of TB
cationDescription
No TB exposure, not infected
TB exposure, no evidence of infection


immigrants and refugees developed by the Centers
for Disease Control and Prevention (CDC). The
purpose of this classi cation is to identify new arriv-
als that are at high risk for TB and evaluate them to
try to decrease the risk of active TB. It may be impor-
these categories because they may be asked to assist
Diagnosis and Treatment of LTBI
contact investigations, the evaluation of recent immi-
grants, and sequential testing surveillance programs
for infection control (
, those for health-care work-
ers). In addition, the requirement of one visit to draw
the specimen (as opposed to two visits needed for
conducting the TST and then subsequently to read
the reaction) and a more reproducible result are also
proposed advantages of the IGRA. However, the


improve the speci city according to the
individual’s
risk of true TB infection and the risk of the active
An induration measurement of 5 mm is con-
sidered to be indicative of TB infection in patients
with a high probability of infection or a high risk
of disease when infection is present (
, recent close
infection, patients with organ transplants, patients
blockers have been prescribed,
and other immunosuppressed patients adminis-
tered the equivalent of
15 mg of prednisone each
1 month). Many reports suggesting an
increased risk of progression of TB infection to
administered TNF blockers for conditions such as
rheumatoid arthritis or in ammatory bowel dis-
ease. As such, it is generally recommended that
patients who are prescribed these agents 
rst be
tested for LTBI and treated if found to have a reac-
Indurations measuring 10 mm are considered
to be a positive result for individuals with a
moderate-to-high probability of TB infection (
recent arri vals [
5 years] from endemic areas, resi-
to react to TSTs because of cutaneous anergy
associated with progressive HIV immunosuppres-
sion. However, the usefulness of anergy testing to
Injection drug use


follows: “the decision to tuberculin test is the deci-


The key element in the diagnosis of TB is to
have a high degree of suspicion, especially in those
groups of persons who are at high risk. Early rec-
transmission; however, no single clinical, radio-
ment is required. A careful history to elicit the most
, fever,
productive cough, weight loss, wasting, night
sweats, shortness of breath, and occasionally
hemoptysis) should be obtained. The systemic
nature of many of these symptoms is caused by the
cytokine release associated with the in
response by the host to the organism. These symp-
toms are usually present for a prolonged period,
characteristically weeks to months. A history of
possible TB exposure risk (
, previous exposure,
history of homelessness, or prolonged stay in a
lymphocytes, are negative for acid-fast bacilli
(AFB), and are positive on culture in only 50 to
60% of cases. The addition of pleural biopsy for
histologic studies and culture increases the yield
to approximately 80%.
Pulmonary TB that develops as a result of the
endogenous reactivation of LTBI in immunocom-
 Unexplained cough (for
 Unexplained cough with fever (
 Unexplained pleuritic chest pain, hemoptysis, and/or
 Unexplained fever, night sweats, and weight loss
*From Pitchenik AE, Brooks R. The most common clinical
mistakes in prevention, diagnosis and therapy of tuberculo-
sis. In: Tuberculosis in Florida: the clinician’s desktop refer-
ence. Gainesville, FL: Florida TB Control Coalition, 1999.


be immediately isolated if they are admitted to a
for
AFB smear and culture; recent recommendations
acid ampli cation to attempt to establish the diag-
nosis microbiologically. A quality sputum speci-
patient is unable to produce an adequate specimen,
sputum induction and/or bronchoscopy should
be considered (with proper infection control pre-
Sputum smears, the time-honored test for the
diagnosis of TB, only yield a positive result for TB
in approximately 50% of active cases. The advan-
The reason for its low sensitivity is the need for
10,000 to 100,000 organisms in 1 mL of specimen.
In addition, the smear is not speci c because other
Patients with smear-positive sputa are more likely
to transmit infection to contacts compared with
those with smear-negative studies, although this
latter group has clearly been shown to transmit
Culture  ndings are positive in approximately
80% of cases, but unfortunately organisms take a
prolonged time to grow, up to 8 weeks for solid
media and 1 to 3 weeks for liquid media. At least
500 organisms per milliliter need to be present in
the specimen to obtain a positive culture result.
on all initial isolates) may take another 1 to 3
ogy are now becoming available that could shorten
the turn around time for susceptibility studies to
Fifteen to twenty percent of diagnosed cases
cannot be con rmed microbiologically and are
considered to be culture-negative or clinical TB. In
presence of symptoms, positive TST results, a
an improvement in clinical status after treatment
with antituberculous therapy, despite negative
studies that use BAL and transbronchial biopsy,
which are performed with appropriate infection
control precautions, may help to establish the
mend the use of multiple) specimens to improve
active TB disease; however, the clinician must be
aware that a negative test result does not rule out
the possibility of TB and that a positive test result
Since the advent and utilization of effective


discontinued. After 2 months of therapy, pyrazin-
amide is stopped, and isoniazid and rifampin are
patients who are at increased risk of relapse. If
culture 
ndings are not negative after 2 months of
therapy and cavities are present on chest radio-
graphs, then treatment should be extended for at
least 4 months after negative results are achieved.
This regimen can be administered effectively either
daily or intermittently by the use of directly
observed therapy (DOT; Table 5). It may also be
Table 5.
TB Treatment Options for Adults and Children With Culture-Positive Pulmonary TB Caused by Drug-Susceptible Organisms*
RegimenDrugs
(Minimal Duration)RegimenDrugs
Range of Total
Duration)HIV
1INH
1aINH/RIF7 d/wk for 126 doses
182–130 (26 wk)A (I)A (II)
1bINH/RIFTwice weekly for
92–76 (26 wk)A (I)A (II)
INH/RPTOnce weekly for 18
74–58 (26 wk)B (I)E (I)
2INH
2aINH/RIFTwice weekly for
62–58 (26 wk)A (II)B (II)
INH/RPTOnce weekly for 18
44–40 (26 wk)B (I)E (I)
3INH
Three times per week
3aINH/RIFThree times weekly for
78 (26 wk)B (I)B (II)
4INH
4aINH/RIF7 d/wk for 217 doses
273–195 (39 wk)C (I)C (II)
4bINH/RIFTwice weekly for 62
118–102 (39 wk)C (I)C (II)
*Reprinted with permission from the Centers for Disease Control and Prevention from MMWR Morb Mortal Wkly Rep 2003:


patients with extrapulmonary disease. However,
for individuals with HIV infection with a CD4
L, daily or intermittent
therapy three times a week is recommended instead
of biweekly therapy as the result of reports of the
development of relapse with rifampin-monoresistant
disease. In addition, children with miliary TB,
bone/joint TB, or tuberculous meningitis should
receive a minimum of 9 to 12 months of therapy.
If pyrazinamide cannot be administered for the
rst 2 months, a reasonable alternative is INH and
rifampin administered for 9 months. A 4-month
regimen of isoniazid and rifampin is acceptable
therapy for adults who have active TB and negative
results of smears and cultures (
, culture-negative
It is essential to treat pregnant women who
shown to be safe for use in pregnant women and
should be administered. Pyrazinamide, although
recommended by many authorities, has not been
thoroughly studied in pregnant women and should


is recommended for all other patients. If trans-
hepatitis occur, therapy with all medications
should be discontinued. Once signs and symptoms
resolve or improve, medications should be reintro-
duced sequentially, and the patient should be
monitored for the recurrence of hepatitis. Pyrazin-
amide can also cause hepatotoxicity as well as high
uric acid levels, resulting in gout-like symptoms.


Infection Control
Given the increased number of immunosup-
pressed individuals in health-care facilities, infec-
tion control efforts to stem nosocomial outbreaks
of TB among patients and staff are essential. All
patients who are suspected of having active TB
should be immediately isolated and remain so until
they are no longer infectious or until TB has been
ruled out.
Airborne infection isolation rooms should
have negative air pressure to prevent infected air
from entering hallways and should use at least
six air exchanges per hour. Health-care workers
who are caring for these individuals should wear
N95 masks to avoid inhaling infectious particles
while working in the enclosed room. The obser-
vance of these guidelines is especially important
in rooms in whim cough-inducing procedures are
performed. Patients in health-care facilities can
be removed from isolation once they have received
medications for 10 to 14 days, they are responding
clinically, and their AFB smear results are nega-
tive. Patients may be discharged from the hospital
before they are removed from respiratory isola-


whereas most from the
NTM disease is not reportable in the United States,
Severely immunosuppressed (CD4 counts of
100
L) individuals with HIV infection are par-
ticularly susceptible to disseminated disease
Before the widespread use of


commonly found in nature, the contamination of
culture material or transient infection does occur.
Thus, a single positive sputum culture 
nding,
especially with a small numbers of organisms, is
not always suf cient to diagnose NTM disease. The
previous notion that individuals had true coloniza-
, no tissue invasion) is now
thought to probably be rare. Given the changing
ATS published an of cial statement concerning the
diagnostic criteria of NTM lung disease in HIV-
seropositive and HIV-seronegative hosts. These
because too little is known about other
with in ltrate, nodular, or cavitary disease, or high-
resolution CT scans that show multifocal bronchi-
NTMs are recovered that are either infrequently
encountered or usually represent environmental
NTMs is discouraged, but such testing is war-
ranted to obtain baseline data for unresponsive
disease or when relapses occur.
Treatment
of therapy, which is a decision based on the poten-
tial risks and bene ts of therapy for individual
Treatment for pulmonary disease
caused by this organism was disappointing
before the advent of rifampin therapy. With the
introduction of rifamycins, the rate of treatment
failures has decreased. The recommended treat-
ment for adults consists of a regimen of daily


300 mg/d). Therapy should be continued for life
until more data become available. Prophylaxis
should be administered to adults with AIDS with
presence of a history of previous opportunistic
infections, consisting of rifabutin, 300 mg/d, clar-
ithromycin, 500 mg bid, azithromycin, 1,200 mg
once weekly and azithromycin, 1,200 mg once
weekly, plus rifabutin, 300 mg/d.
Annotated Bibliography


TB and Other Mycobacterial Diseases (Ashkin)


635
 Describe the salient epidemiologic, clinical, physiologic,
and radiographic features of idiopathic pulmonary 
brosis,
c interstitial pneumonia/ brosis, and sarcoid-
 Discuss the salient features seen on high-resolution CT
scans and their impact on prognosis
 Review the characteristic histopathologic features of each
of these disorders and the role of transbronchial or surgical
 Discuss the clinical role (if any) of ancillary studies such as
radionuclide scanning or BAL to stage or follow up these
disorders
 Review therapeutic strategies
cryptogenic  brosing alveolitis; idiopathic pulmo-
brosis; nonspeci
c interstitial pneumonia; sarcoidosis;
Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF), also
brosing alveolitis
form of chronic interstitial lung pneumonia associ-
1–5
Although UIP is a distinct
this histologic pattern is not
c for IPF and can also be found in other
, connective tissue diseases [CTDs]),
asbestosis, and diverse occupational, environmen-
tal, or drug exposures.
2–4,7
A diagnosis of IPF can
and the histologic pattern of UIP.
3,4,8
9,10
; respiratory bronchiolitis interstitial
10; nonspeci c intersti-
1114
15,16
17,18
; cryptogenic organizing pneumonia
19; and chronic hypersensitivity pneumo-
20,21
) are distinct entities with differing clinical
expression and prognoses.
3,4
A de
nitive diagnosis
of UIP requires surgical lung biopsy (SLB),
but the
diagnosis of UIP can be af rmed with con
by thin-section high-resolution CT (HRCT) scans
2225
IPF is one of the most frustrat-
ing disorders to manage because treatment is
largely ineffective.
2,2628
IPF is rare, but precise data regarding incidence
and prevalence are lacking.
2931
29,3235
were based on
clinical diagnosis, death certi cates, or diagnostic
rmation; such
studies included a mixture of ILDs, including dis-
orders other than UIP. Studies from Europe
3133,35
cited prevalence rates of IPF ranging
from 3 to 8 cases per 100,000 population. In the
United States, prevalence rates range from 13 to 42
29,30
to be increasing. The incidence of IPF increased


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
trast, the prevalence exceeded 175 per 100,000 in
Rates of mortality from IPF
are markedly increased in the elderly. In the United
States, projected deaths (per million) in 2008 were
of idiopathic UIP is a rare occurrence in chil-
dren.
3,38,39
Despite its rarity, IPF accounts for
; this
mortality rate is greater than a number of malig-
nancies, including bladder cancer, multiple
Risk Factors for IPF
The cause of idiopathic UIP is unknown, but
environmental and occupational exposures likely


ILD may progress to symptomatic IPF during a
Interestingly, gene expression pro les of lung
tissues from patients with familial IP (either UIP
or NSIP) exhibit striking similarities but differ from
gene expression pro les in sporadic IPF.
6567
tions in genes encoding proteins involved in
chronic inflammation (
broblasts); and/or
matrix mobilization and resolution
6567
may be


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
the underlying disease process.
95,103106
90%). For this reason,
mechanical ventilation is usually ill-advised in
patients with severe IPF. Unfortunately, medical
therapy has not been shown to alter the course of
Lung Cancer Complicating UIP
IPF.
102,107109
The risk is greater in smokers,
107,109
body and antibodies to SSA, SSB, Scl-70 [sclero-
derma], Sm, RNP, Jo-1, double-stranded DNA) and
hypersensitivity pneumonitis (HP) to rule out
those disorders. Elevations of the glycoprotein
115,116
and lung surfactant proteins A and D
116118
have been noted in serum and BAL  uid in patients
with IPF and may have prognostic value. These
assays are available in only a few research labora-
tories, and additional studies are required to assess
their speci city and clinical role.
Chest Radiographs
Chest radiographs in IPF typically reveal bilat-
IPF/UIP. Posteroanterior chest radiograph from
a 61-year-old man with IPF/UIP demonstrates extensive


(including old  lms) may be used to gauge the pace
Thin-Section HRCT Scans
HRCT Features and Value in the Differential Diag-
without the use of contrast, are far more accurate
the extent and nature of the disease.
123,124
HRCT has
24,125,126
and prognostic
98,123,124,127
should be part of the initial evaluation of suspected
ILD. The HRCT features of IPF/UIP are stereotypic
HRCT from a 53-year-old man with UIP con
on open-lung biopsy specimen. Note extensive areas of GGOs
with air-bronchograms in the lower lobes. Despite extensive
involvement of the posterior regions of both lower lobes, the
anterior portion of the left lower lobe is relatively normal,
emphasizing the patchy nature of the disease.
HRCT from a 63-year-old woman with UIP
rmed on open-lung biopsy specimen. HC is evident,
particularly in the peripheral (subpleural) regions. Dilated
bronchi, indicating traction bronchiectasis, are also present.
There are no GGOs.
UIP. HRCT demonstrates foci of GGOs in the sub-
pleural regions of the lower lobes (arrows). A few small hon-
eycomb cysts are also present. The central portions of the
lung are relatively spared.


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
that increase in LNE over time was associated with
progression of  brosis in UIP or NSIP.
Differential Diagnosis by HRCT:
Focal GGOs
may be observed in UIP, but the presence of pre-
tive diagnosis such as DIP,
136
HP,
4,137,138
cellular
NSIP,
4,11,13,139
COP,
19
chronic eosinophilic pneumo-
140
or pulmonary alveolar proteinosis.
141
a cardinal feature of UIP
121
but is absent in AIP
and DIP.
4,136
Honeycombing is not a prominent
feature in NSIP, but focal HC may be seen in 
brotic
variants of NSIP.
22,139
observed in other disorders (
, Langerhans-cell
142
sarcoidosis,
143
144
chronic HP,
145
LIP,
sis), but the distribution of lesions and presence of
concomitant abnormalities differentiates these
disorders from UIP.
146.
HRCT may obviate the need for SLB, provided the
CT features are classical for UIP (including pres-
22,24,98,125
dent diagnosis of UIP by a trained observer
22,24,98, 125
However, classical features of UIP
dent diagnosis by CT) are present in only 34
UIP.
2,24,125,127
Interobserver and intraobserver vari-
ability may be problematic
reached when extensive HC and subpleural pre-
dominance are deemed to be present.
CT patterns
HRCT from a 44-year-old man with severe UIP
radiolucencies (some cysts are
HRCT from a 48-year-old woman with UIP, with
extensive cystic radiolucencies (honeycomb cysts) scattered
throughout the lung parenchyma. Despite treatment with
corticosteroids, AZA, and CP, she died of progressive respi-
ratory failure.


correlates roughly with severity of functional
, FVC and diffusing capacity of the
Dlco])128,150
; the pattern
150
When serial CT scans were per-
formed, changes in CT were concordant with


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
factors were included in the multivariate model.
Given the potential for  brosis to evolve over time,
the value of CT in predicting long-term prognosis
Physiology
Characteristic physiologic aberrations in IPF
include reduced lung volumes (FVC and total lung
capacity [TLC]) consistent with a restrictive defect;
normal or increased expiratory  ow rates; impaired
oxygenation, and impaired gas exchange.
3,159
is reduced, often disproportionately to other
129,150,159
is an indirect re
tion of the pulmonary vasculature; reductions
re
ect destruction or loss of alveolar walls or cap-
illaries. In nonsmokers with IPF, expiratory 
rates are preserved, and the ratio of FEV
is increased. When emphysema also is present,
, FVC and TLC) are preserved, and
is disproportionately reduced.
128,129,131,150
The measurement of the
/lung volume ratio, does not improve the
predictive value of
and is not necessary.
159
Reduced compliance and alterations in pressure-
volume curves are characteristic of IPF,
sophisticated studies require an esophageal bal-
loon and lack clinical value. Impaired oxygenation,
which is accentuated with exercise, is a cardinal
feature of IPF.
28,159,160
may be preserved at rest but invariably
worsens with exercise. As the disease advances,
hypoxemia at rest is a nearly universal feature.


643


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
systems in 30 patients with UIP who underwent
exercise testing. The CPI was a superior predictor
of outcome compared with the physiologic com-
ponent of the original CRP score (p
ed CRP score
0.009). The CPI score is promising but may not
measurements of FVC,


IPF,
183,185,189
vasoconstriction may play contributory roles.
183
patients with advanced IPF, PAH was noted in 20
131,182,187,190193
However, one pro-
186
noted PAH (mean pulmonary artery pressure
[mP�AP]


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
70.5% vs 23.7%; mean survival 11.0 months vs 22.5
months, respectively). The combination of both
PAH and BNP was a more robust marker of mortal-
188,194
that plasma BNP concentration may be a useful a
noninvasive marker to screen for PAH.
The impact of treating PAH in patients with
IPF has not been elucidated. Favorable responses
to sildena l (a phosphodiesterase inhibitor),
192,196
prostacyclin,
182
iloprost,
197
CRP Diagnosis
UIPIPF/cryptogenic 
brosing
NSIP (provisional)
OPCOP
Diffuse alveolar damageAIP
Repiratory bronchiolitisRB-ILD
DIPDIP
LIPLIP
*Adapted from Amer J Respir Crit Care Med.


647
Top
: Photomicrograph of UIP in open-lung biopsy
specimen. Patchy subpleural  brosis with dense scarring
Photomicrograph of IPF. Open-lung biopsy speci-
men reveals end-stage honeycomb lung. The large cystic air-
spaces represent destroyed and coalescent alveolar septae.
Minimal in ammatory cells are present at this late phase


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
Top
: Photomicrograph of DIP. Open-lung biopsy
specimen demonstrates extensive and diffuse  lling of the al-
veolar spaces with alveolar macrophages. A single lymphoid
aggregate is present. The alveolar architecture is preserved


reveal reduced
ow obstruction;
lung volumes are variable.
prognosis is generally excellent. However, data are


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
and radiographic features overlap with IPF, it is
highly likely that examples of NSIP were included
in historical series of IPF. However, NSIP and IPF
Top
: Photomicrograph of NSIP. Open-lung biopsy
specimen shows patchy interstitial  brosis that lacks the


Furthermore, the prognosis of 
brotic NSIP
patients with severe functional impairment is poor.
Among NSIP patients with
35% of pre-
172
Korean inves-
221
cited 5-year survival rates of 56% among
48 patients with  brotic NSIP and 34% among 131
patients with UIP. Further, early studies
147,203,226,227
cited favorable responses to corticosteroids (alone
or combined with immunosuppressive agents) in
60 to 83% of patients, whereas subsequent stud-
98,148,204
were less sanguine (response rates of 25
, 2-year) survival rates
underestimate long-term mortality associated with
NSIP.
172,204,221
Additional studies are required to
further elucidate the clinical features, outcomes
and rate of progression associated with NSIP and
lower lobes of the same lung); representative areas
, avoid normal or very
brotic areas).
97,98,164,206
c histologic features
or subtypes of IIPs have prognostic value.
6,98,164,204
Establishing the histologic diagnosis of UIP is a
strong predictor of increased mortality and poor
response to therapy when compared with other
6,27,9698
In one prospective study,
164
survival was worse in patients with greater degrees
of FF, whereas the degree of alveolar cellularity or
brosis did not affect survival. In a
cohort of 53 patients with UIP, British investiga-
163
con rmed that increasing FF correlated with
0.006) and decreases in FVC
extent of established  brosis nor intra-alveolar
macrophage accumulation correlated with out-
163
idiopathic UIP, we
found that the extent of
FF, established  brosis, or intra-alveolar macro-
phage accumulation did not predict survival.


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
patients who have a prolonged course (
and clinical, physiologic, and HRCT features that
are characteristic of IPF/UIP.
3,125
Moreover, the risk
of VATS lung biopsy is excessive in elderly (
years old) or debilitated patients, particularly when
clinical and HRCT features strongly suggest UIP.
activity of IPF.
166,238
Radionuclide Scans
Ga citrate scanning has been used as a surro-
ammation (alveolitis) in
ammatory pulmonary disorders.
Increased intrapulmonary uptake of
Ga was asso-
ciated with a more cellular biopsy in some early
studies. However, even with careful quanti
67
Ga scans failed to predict responsiveness to
therapy.
Ga scans are expensive and
inconvenient
Tc-DTPA aerosol is accelerated in IPF and is
a marker of increased lung
permeability.
166,239,240
239
found that normal DTPA
, reduced
F) was an independent predic-
tor of mortality in patients with idiopathic UIP.
166
In that study,
166
were the most impor-
tant predictors of survival, followed by percentage
of predicted TLC and
F.
Thus, the incremental practical value of
appears to be small. Further, increased clearance
of DTPA occurs in smokers and patients with other
ammatory lung disorders; its prognostic value
240
(an aerosol of
Tc-labeled carbon particles) is
increased (compared with normal control subjects)
in IPF, HP, and CTD-associated PF but not sarcoid-
consistent with increased alveolar capillary


(cytokines) produced by fibroblasts and AECs


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
ments conclude that existing therapies are of
unproven bene
t but acknowledge that physi-
rst 6 weeks and then every 4 to 8 weeks thereaf-
ter. Signi cant anemia, leukopenia (
3,500/µL)
or thrombocytopenia (
120,000/µL) warrants
dose reduction. Azathioprine should be used with
caution in patients receiving allopurinol, and the
dose should be reduced by at least 50%.
265
After
cacy should be examined. Unless
there is unequivocal and objective improvement,
we discontinue therapy after a 6-month trial. Fur-
ther, treatment is discontinued among patients
experiencing side effects or disease progression.
265


that down-regulates the expression of TGF-
brotic effects.
201
270,271
employing recombinant
-IFN-1b were encourag-
patients with mild-to-moderate IPF to recombinant
t. The study was ended because of “futility” in
March 2007 (InterMune, Brisbane, CA).
NAC is an antioxidant that stimulates
glutathione synthesis, attenuates  brosis in ani-
272
and augments glutathione levels
in BAL in patients with IPF.
A phase III multi-
center, double-blind, placebo-controlled trial
(European Idiopathic Pulmonary Fibrosis Inter-
national Group Exploring
cance. The bene t if any of NAC as therapy for
277280
are insuf
cacy of pirfenidone but support the
has been approved for use in Japan based on a
randomized trial, but published data are not avail-
able. Currently, pirfenidone is not commercially
available elsewhere. Two placebo-controlled
DBRCTs evaluating pirfenidone as therapy for IPF


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
baseline in FVC at 12 months were
6.4% and
7.7% in the bosentan and placebo groups, respec-
tively. Mean changes from baseline in
months were
placebo groups, respectively. A trend in favor of
time to death or disease progression (hazard ratio,
0.12). A larger DBRCT (BUILD-3) assess-
progress. Further, a DBRCT assessing ambrisentan


Secondary PAH is not a contraindication to LT,
but its presence may in


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
Figure 11.
Sarcoidosis. Photomicrograph of TBB specimen.
Multinucleated giant-cell in the center of a granuloma, sur-
rounded by lymphocytes and mononuclear cells in the pe-
riphery (hematoxylin-eosin) [reproduced with permission


specimens from both the upper and lower lobes
at the time of initial diagnostic bronchoscopy.
When TBBs are nondiagnostic, mediastinoscopic
nosis, provided that enlarged mediastinal lymph
nodes are present. However, mediastinoscopy as
a routine, initial diagnostic procedure for hilar
lymphadenopathy is not cost-effective and has a
potential for patient morbidity.
340
Percutaneous needle aspiration may be an
alterative to surgical biopsies. In one study
341
patients with suspected sarcoidosis, endosonogra-
phy-guided fine-needle aspiration (FNA) of
enlarged mediastinal lymph nodes demonstrated
nonnecrotizing granulomas in 100%; 1 patient had
tuberculosis (sensitivity and speci
city rates of
100% and 94%, respectively). Experience with this
transbron-
chial FNA (TBFNA) with a 26-gauge needle
revealed cytological features consistent with sar-
coidosis in 88 of 116 patients (76%) with mediasti-
nal or hilar adenopathy. Sensitivity of TBFNA
city was
92%. Complications of TBFNA include the follow-
ing: pneumothoraces (10 to 60%) or hemoptysis
343
Sarcoidosis. Photomicrograph of TBB specimen,
showing “burned out” granuloma demonstrating nonnecro-
epithelioid cells in the center. In the periphery, no signi
ammatory cells are present, but concentric rings of colla-
gen encircle the granuloma (hematoxylin-eosin) [reproduced
Sarcoidosis. Photomicrograph of endobronchial
lung biopsy specimen showing prominent multinucleated
giant cells within the submucosa underlying the bronchi-
oles (hematoxylin-eosin) [reproduced with permission from


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
active histoplasmosis and other granulomatous
processes. The use of serum ACE as a surrogate
marker of disease activity is discussed later.
Chest Radiographs
Abnormalities are present on chest radiographs
90% of patients with sarcoidosis.
BHL, often
associated with enlargement of right paratracheal
lymph nodes, is the classic radiographic feature,
observed in more than two thirds of patients (Fig
143,303
Pulmonary parenchymal in
ltrates are
present in 25 to 50% of patients.
Pulmonary
parenchymal in
ltrates are typically bilateral and
patchy, with a predilection for the mid- and upper
lung zones (Fig 15). Multiple focal nodular or
tuberculosis and fungal pneumonia. Other disor-
ders that preferentially involve the upper lobes
include LCG, cystic  brosis, silicosis, and chronic
eosinophilic pneumonia. Cavitation is rare.
346
ral effusions occur in
thickening on plain chest radiographs is rare and
usually re ects longstanding chronic disease. Dif-
Sarcoidosis (stage I). Chest radiograph dem-
lymphadenopathy.
Stage II sarcoidosis. Chest radiograph demon-
brosis preferentially affecting upper lobes of both lungs.
Linear  brotic strands and volume loss are noted through-
out. In addition, BHL is present.
Stage III sarcoidosis. Chest radiograph demon-


). With
Top
: Stage IV sarcoidosis. Posteroanterior chest


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
bundles, central bronchovascular thickening and
nodularity, con
uent nodular opacities with air
HRCT scan from a 48-year-old man with severe,
chronic pulmonary sarcoidosis. Cuts at the level of the main
carina show areas of bronchial thickening and consolida-
tion centrally, in an axial distribution. Large cystic, bullous
changes are evident in the posterior lung  elds. The lung
architecture is distorted.


sarcoidosis.
Airway obstruction, with reduced
and expiratory  ow rates, occurs in 9 to 40%
355,357
A prospective study
358
noted air-
ow limitation (de
ned as
/FVC ratio)
in 20 of 228 (8.8%) consecutive Japanese patients
with sarcoidosis. Airflow limitation was more
ed as radiographic stage IV. Air
ow obstruction
may re ect submucosal or endobronchial in
mation, parenchymal distortion, bronchostenosis,
or exaggerated bronchial reactivity.
303,355,359,360
Increased airway hyperreactivity in response to
sarcoidosis and obtain serial levels in selected
patients when clinical criteria are inadequate to
judge disease activity.
Ga citrate scans were used
as a surrogate marker of disease activity in sar-
coidosis and other in ammatory pulmonary dis-
orders.
Ga is taken up avidly by activated
alveolar macrophages, and intrapulmonary uptake
mation (alveolitis). Characteristic patt erns of
uptake have been noted in sarcoidosis (
increased uptake in lacrimal, salivary, and parotid
364,365
However,
Ga scans are expensive, inconvenient,
difficult to quantitate, and lack prognostic
364,365
I see no role for
the initial staging or longitudinal follow-up of
patients with sarcoidosis. However,
may have a limited role in patients with normal
chest radiographs and suspected sarcoidosis to


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
neural sites
369


infiltrates after an initial 6-month observation
period was associated with improved lung func-
tion, chest radiographs, and symptoms compared
with untreated controls.
347
nary sarcoidosis eligible for the study, 33 patients
required immediate corticosteroid therapy for
control of symptoms and were excluded. In addi-
tion, 58 patients whose chest radiographs improved
an untreated observation group. The remaining
58 untreated patients with persistent radiographic
ltrates after 6 months were randomly assigned
to be administered routine corticosteroids for
27) or selective therapy only (to
suppress or reverse the disease in some cases. Cor-
ticosteroids are warranted for myocardial,
309
312
, uveitis) complications of
sarcoidosis.
304,307
Corticosteroids are also indicated
for chronic hypercalcemia (to avert late complica-
tions of nephrocalcinosis and nephrolithiasis) and
for severe or progressive pulmonary or extrapul-
individualized. Chronic disease of mild-to-moder-
ate severity can be treated with modest dosages
subsequent taper). Greater doses (
, prednisone
1 mg/kg/d for 4 weeks, with a gradual taper) are
appropriate for myocardial or CNS manifestations.
to be individualized according to clinical response
and presence or absence of adverse effects. A
3-month trial of corticosteroids is usually adequate
to judge ef cacy. If no objective response has been
shown within this time, corticosteroids can be
tapered and discontinued. In contrast, among
responders, corticosteroids should be continued,
albeit in a tapering regimen, for 12 to 18 months.
Relapses may occur as the steroid dosage is
reduced or discontinued. In such cases, escalation
of the dose may be ef cacious. Long-term cortico-
steroids are indicated only for patients who have


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
radiograph findings compared with treated


Serious adverse effects are rare (
but side effects requiring cessation of therapy occur
265


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
Alkylating Agents
Published data regarding alkylating agents (
cyclophosphamide, chlorambucil) for the treat-
ment of sarcoidosis are limited to sporadic case


412
in patients with sarcoidosis, but
the value of these agents is unproven. Pentoxifyl-
cance. Treatment with TNF inhibitors
heightened risk of tuberculosis,
nistic infections, and other adverse effects,
431434
435
Currently,
additional studies are required to establish the role


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
6. Katzenstein AL, Myers JL. Idiopathic pulmonary
brosis: clinical relevance of pathologic classi
tion. Am J Respir Crit Care Med 1998; 157:1301–
7. Lai CK, Wallace WD, Fishbein MC. Histopa-
thology of pulmonary  brotic disorders. Semin
Respir Crit Care Med 2006; 27:613–622
8. King TE Jr. Clinical advances in the diagnosis
and therapy of the interstitial lung diseases. Am J
Respir Crit Care Med 2005; 172:268–279


33. Harris JM, Cullinan P, McDonald JC. Occupa-
deaths certi ed to be cryptogenic 
brosing alveo-
litis in England and Wales. Chest 2001; 119:428–


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
strategies for treating gastroesophageal re
disease in a high-risk population. Thorac Surg


84. Young LM, Hopkins R, Wilsher ML. Lower occur-
rence of idiopathic pulmonary  brosis in Maori
and Paci c Islanders. Respirology 2006; 11:467–
85. Churg A. The uptake of mineral particles by pul-
monary epithelial cells. Am J Respir Crit Care
Med 1996; 154:1124–1140


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)


pneumonitis: prevalence, correlation with dis-


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)


182. Nathan SD, Noble PW, Tuder RM. Idiopathic pul-
monary  brosis and pulmonary hypertension:
connecting the dots. Am J Respir Crit Care Med


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)


232. The diagnosis, assessment and treatment of dif-
fuse parenchymal lung disease in adults. Intro-


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
258. Lynch JP 3rd, White E, Flaherty K. Corticoste-
roids in idiopathic pulmonary  brosis. Curr Opin


antagonist. Am J Respir Crit Care Med 1997;


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
February 1999 [review]. Am J Respir Crit Care
307. Judson MA. Extrapulmonary sarcoidosis. Semin
Respir Crit Care Med 2007; 28:83–101
308. Judson MA. Hepatic, splenic, and gastrointesti-
nal involvement with sarcoidosis. Semin Respir
Crit Care Med 2002; 23:529–541
309. Deng J, Baughman R, Lynch III JP. Cardiac
involvement in sarcoidosis. Semin Respir Crit
Care Med 2002; 23:513–528
310. Kidd D, Beynon HL. The neurological complica-
tions of systemic sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 2003; 20:85–94
311. Allen RK, Sellars RE, Sandstrom PA. A prospec-
tive study of 32 patients with neurosarcoidosis.
Sarcoidosis Vasc Diffuse Lung Dis 2003; 20:118–


683


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
364. Mediwake R, Wells A, Desai D. Radiological
imaging in sarcoidosis. In: Baughman RP, ed.
Sarcoidosis (Vol 210). New York: Taylor and
Francis Group, 2006; 365–398
365. Mana J, Vankroonenburgh M. Nuclear imaging
techniques in sarcoidosis. Eur Respir Monograph
366. Tanabe Y, Ohuchi Y, Ogawa T. Muscular and
myocardial involvement in sarcoidosis: the use-


391. Baughman RP, Lower EE. Le unomide for chronic
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
392. Moudgil A, Przygodzki RM, Kher KK. Success-
ful steroid-sparing treatment of renal limited


IPF, NSIP/Fibrosis, and Sarcoidosis (Lynch)
factor-alpha therapy. Ann Intern Med 2001;
420. Baughman RP, Lower EE. In iximab for refrac-
tory sarcoidosis. Sarcoidosis Vasc Diffuse Lung
421. Baughman RP, Iannuzzi M. Tumour necrosis fac-


687
Review the spectrum of pulmonary vasculitides and their
Describe the clinical spectrum of antineutrophil cytoplasmic
antibody (ANCA)-associated vasculitis and review treat-
Review the clinical presentation and management of
Churg-Strauss syndrome (CSS)
Discuss the differential diagnosis of diffuse alveolar
hemorrhage (DAH)
Review speci c diseases that can cause DAH
alveolar hemorrhage; antibasement membrane
1,2
of the American College of
Rheumatology for the classi cation of vasculitis
were developed to allow the separation of patients
with one form of vasculitis from those with another
nomenclature and de nitions put forth by the Cha-
pel Hill consensus conference
edge the presence of ANCA and separate classic
polyarteritis nodosa from microscopic polyangiitis
and ANCA-associated vasculitis. It is important to
recognize that not all respiratory symptoms occur-
ring in patients with vasculitis are caused by the
in ammation of pulmonary vessels.
Urticarial Vasculitis
order characterized by urticaria associated with
glomerulonephritis in 5% of patients. Angioedema,
fever, uveitis, episcleritis, and seizures may also
occur.
4,5
Hypocomplementemia is present in 38%
of patients, and this hypocomplementemic form of
cations not directly caused by vasculitis. Obstruc-
tive pulmonary disease, which occurs in up to
two thirds of these patients, is thought to result
from a combination of smoking and an unknown
immunologic process. Emphysematous changes
in the basal regions may occur in some patients.
UV with or without hypocomplementemia can
Giant Cell Arteritis
is a generalized in ammatory disorder involving
large- and medium-sized arteries.
sphere, and it appears to affect predominantly
elderly patients. The typical features of the disease
Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes


Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes (Specks)


the bronchial or bronchiolar arteries. Most cases
of classic PAN diagnosed are associated with viral
infections, speci cally hepatitis B and C. Conse-
quently, antiviral therapy plays a prominent role
in the management of such cases in addition to
immunosuppression. Classic PAN is far less likely
to reoccur than microscopic polyangiitis and there-
fore can generally be treated with a shorter course
of immunosuppression.
ANCA-Associated Vasculitis
are WG, microscopic polyangiitis (MPA), and the
CSS. In contrast to the other forms of systemic
vasculitis with predilections for larger vessels,
most patients with active WG and MPA and more
than half of patients with active CSS have ANCA.
Of all systemic vasculitides, the ANCA-associated
vasculitides are most likely to cause respiratory
manifestations. WG and MPA will be discussed


Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes (Specks)
the PR3 molecule as well as its expression on neu-
trophils may in
uence the induction and course
sure serum creatinine because early renal involve-


Standard therapy for WG and MPA currently


Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes (Specks)
For some patients with WG and MPA, the com-
bination of glucocorticoids and cyclophosphamide
may not be suf cient to induce a remission quickly.
Plasma exchange (PLEX) should be considered early
in patients who present with rapidly progressive
glomerulonephritis and renal failure as well as in
patients who present with DAH. PLEX is currently
46,47
The EUVAS investi-


exhibit a single point on the vascular damage index
(which was developed from 61 various items)
after 1 year of study enrollment.


Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes (Specks)
oral glucocorticoid therapy. There is no evidence


Proliferative and necrotizing glomerulonephritis is
usually mild. A similar type of renal lesion is seen in
patients with infective subacute bacterial endocardi-
tis, WG, SLE, PAN, and Goodpasture syndrome.
uorescence microscopy shows large
deposits of IgA in the skin and kidney. Although
HSP is more common in children (mean age of
patients, 17 years), adults may also be affected. Pal-
pable purpura, which are usually distributed over
the buttocks and lower extremities, and fever are
generally the  rst signs. The purpura may precede,
accompany, or follow arthralgias and abdominal
colic. The triad of purpura, arthritis, and abdominal
pain is present in approximately 80% of patients.
transient, involves the large joints, and causes pain
that is out of proportion to the objective evidence
of synovitis. Peritonitis and melena are common.
Pulmonary manifestations of HSP are rare. Only 26
cases have been reported to date, and capillaritis
IgA deposits along the pul-
in vessels of the skin and glomeruli of affected
kidneys, are pathognomonic for HSP.
Secondary Vasculitis
Many of the rheumatologic diseases exhibit
a secondary vasculitic process in the organs
involved. Infectious processes, particularly second-
ary to infection with Aspergillus and Mucor sp,
invade vascular structures and produce secondary
vasculitis. Certain drugs and chemicals can induce
granulomatosis, bronchocentric granulomatosis,
and necrotizing sarcoid angiitis.
AH Syndromes
Diffuse hemorrhage into the alveolar spaces is


Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes (Specks)
involvement (CBC, chemistry group, urine
specimen needs to be considered carefully, with
one weighing the risks of the biopsy procedure,
the likelihood of obtaining a diagnostic piece
ndings
to alter the therapeutic approach, and the risks
associated with the chosen therapy.
The AH syndromes can be broadly separated
into those in which AH is caused by or associ-
ated with pulmonary capillaritis and those that
lack pulmonary capillaritis (bland histology).
Pulmonary capillaritis refers to the speci
c his-
topathologic  nding of alveolar wall in
ltration
with inflammatory cells centered on capillary
ammatory cells
are predominantly neutrophils, but eosinophils or
monocytes may also be encountered. Capillaritis
brinoid necrosis of alveolar and
vessel walls and may culminate in the destruction
of the underlying lung architecture.
ltration by neutrophils seen in the context
of capillaritis needs to be distinguished from the
predominant intra-alveolar neutrophilic in
Another hallmark of capillaritis is the presence of
pyknotic cells and nuclear fragments from neutro-
phils undergoing apoptosis. This feature, referred
, allows the distinction of true
capillaritis from neutrophil margination related to
surgical trauma, which can simulate capillaritis.
Most of the syndromes associated with pulmonary
capillaritis leading to AH have been discussed in
the “Pulmonary Vasculitis” section of this chapter.
The subsequent paragraphs will describe a few
unique syndromes or conditions that may also be
associated with AH.
Anti-Basement Membrane Antibody Disease
(Goodpasture Syndrome)
Anti-basement membrane antibody disease
pasture syndrome,
is a rare autoimmune disease
characterized by the presence of autoantibodies
directed against the NC1-domain of the
3 chain of
basement membrane collagen type IV. This epitope
is only accessible for autoantibodies in the basement
Diffuse AH
occurs in about one half of patients with ABMA.
It is thought to require an additional inhalational
injury, particularly smoking, for the development
80,81
Isolated AH in the absence of renal disease is rare
in ABMA. Circulating autoantibodies to basement


697
of pulmonary capillaritis in SLE is thought to be
necessarily associated with hemoptysis. Iron de
to be caused by recurrent lung hemorrhage or
malabsorption of iron in the GI tract or both. IPH
can occur in children or young adults. Patients
antibodies, particularly because GI symptoms may


Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes (Specks)
attributable to celiac disease respond to a gluten-


699


Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes (Specks)


antithymocyte globulin (ATG): an open study in


Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes (Specks)
79. Salama AD, Pusey CD. Immunology of anti-glo-
merular basement membrane disease. Curr Opin
Nephrol Hypertens 2002; 11:279–286


703


Pulmonary Vasculitis and Alveolar Hemorrhage Syndromes (Specks)


705
 Review the normal respiratory and cardiovascular physiol-
ogy of pregnancy
 Review the management of asthma in pregnancy
 Review the management of venous thromboembolism in
pregnancy
 Review the management of tuberculosis and other respira-
tory infections in pregnancy
 Review the causes and management of acute respiratory
failure in pregnancy
 Discuss the statistics regarding smoking and the epidemiol-
 Review disorders unique to women,
, catamenial diseases
acute respiratory failure; asthma; lung cancer;
pregnancy; venous thromboembolism; women
This chapter will focus on pulmonary diseases
unique to women, including issues surrounding
pregnancy, as well as diseases that may have dif-
ferent epidemiology and/or prognosis in women.
Common pulmonary problems with different treat-
ment plans in the pregnant or lactating woman and
causes and management of acute respiratory failure
in the pregnant patient will be reviewed. Other dis-
eases that occur exclusively or are more prevalent
in women, such as lymphangioleiomyomatosis
(LAM), are discussed, but they are primarily cov-
ered elsewhere in this course.
Physiology of Pregnancy
During pregnancy, the body undergoes ana-
tomic and physiologic changes affecting both the
respiratory and cardiovascular systems. It is impor-
normal physiologic changes (Tables 1, 2).
Respiratory
The upper respiratory tract undergoes changes
during pregnancy, including hyperemia of the
Womens Issues in Pulmonary Medicine
Table 1.
Normal Respiratory Physiologic Changes in Pregnancy
Variables Changes
Expiratory reserve
Decreased
Decreased
Functional residual
Decreased
Total lung capacity
Mildly decreased
Increased
Vital capacity
Tidal volume
Increased
Respiratory rate
No change, mild increase
Increased
No change
Lung compliance No change
Total respiratory Decreased
Diffusion capacity Increase followed by
decrease
Decreased to 28 to
32 mm Hg
Increase followed
by decrease
pH Increased to 7.40 to 7.45
Serum bicarbonate Decreased to 18 to
21 mEq/L
Alveolar-arterial gradient Mildly increased
Oxygen consumption Increased
Carbon dioxide production Increased
Table 2.
in Pregnancy
Variables Change
Cardiac output Increased
Heart rate Increased
Stroke volume Increased
Systemic vascular resistance Decreased
Pulmonary vascular resistance Decreased
BP Decreased
Blood volume Increased
RBC volume Increased, but less
than blood volume
Hematocrit Dilutional decrease
Serum protein levels Decreased


Women’s Issues in Pulmonary Medicine (Levine)
and mucosal edema, particularly accentuated
in the third trimester. Patients can have upper
respiratory tract symptoms secondary to the
aforementioned, including epistaxis, nasal stuf
yposis and allergic rhinitis can begin or become
exacerbated during pregnancy. These changes are
primarily caused by the production of estrogen.
The health-care provider should be aware of these
changes when performing procedures such as
endotracheal intubation and/or nasopharyngeal
The thoracic cage also undergoes anatomic
changes during pregnancy. The diaphragm becomes
elevated up to an average of 4 cm above normal at
full-term pregnancy. However, diaphragmatic dys-
function caused by pregnancy is unusual because,
concurrent with these changes, there is a widening
of the lower rib cage and alteration of the abdominal
muscles; thus, diaphragmatic excursion is actually
maintained or increased.
Pulmonary Function Tests:
pulmonary function testing in pregnancy is a pro-
gressive decrease in the expiratory reserve volume
by 8 to 40% and a decrease in residual volume by 7
to 22%, both changes attributable to the enlarging
uterus and diaphragmatic elevation. Because of
these changes, functional residual capacity is, in
turn, decreased by 10 to 25% by the third trimester
of pregnancy. Total lung capacity may decrease
slightly, inspiratory capacity increases, and vital
capacity does not change significantly during
pregnancy. The decrease in residual volume with a
relatively maintained total lung capacity results in
a low ratio of residual volume to total lung capac-
ity. Closure of the small airways during normal
tidal breathing caused by the reduction in func-
tional residual capacity can result in changes in
discussed below.
Tidal volume increases significantly during
pregnancy by 150 mL to a  nal value of 450 to 600
mL, or a 30 to 50% increase in the average patient.
This increase is most likely to the result of a direct
progesterone-mediated increase in central respira-
tory drive and enhancement of the hypercapnic
ventilatory drive. There is little or no change in
respiratory rate during pregnancy, and tachypnea
is an unusual  nding. Because of the increase in
tidal volume, there is a signi cant increase in resting
minute ventilation from 6 L in the nonpregnant state
to 9 L at full term (or 20 to 50% above baseline).
There are no signi cant changes in peak 
, airway resistance, or maximum vol-
untary ventilation during pregnancy. Although
lung compliance does not change significantly
during pregnancy, there is a reduction in total
respiratory compliance caused by a reduction
diaphragm caused by uterine enlargement by the
third trimester. Diffusion capacity of the lung for
carbon monoxide may increase slightly in the 
trimester, followed by a slight decrease later in
pregnancy, likely the result of alterations in pul-
Gas exchange in pregnancy is
characterized by a mild compensated respiratory
alkalosis secondary to an increase in minute ven-
tilation out of proportion to maternal needs. Thus,
values are lower, 28 to 32 mm Hg, and
serum bicarbonate is compensatorily decreased to
Hg, with a slight decrease at term to 100 mm Hg.
There is normally an increase of 5 to 10 mm Hg in
in alveolar-arterial gradient above baseline, espe-
increases by 20 to 30% during pregnancy, with a
concomitant increase in carbon dioxide production
by 30 to 35%. These changes are attributable to in-


Cardiovascular
The cardiovascular system probably undergoes
the most signi cant changes during pregnancy,
including an increase in cardiac output, beginning
in the  rst trimester and peaking at about the 25th
to 32nd week at 30 to 50% above normal. This
increased is attributable to both a change in heart
rate as well as stroke volume and a decrease in
systemic vascular resistance, partially as the result
of shunting of blood to the low-resistance placental
bed and perhaps increased levels of vasodilator
mediators. Pulmonary vascular resistance also
decreases. Both systolic and particularly diastolic
pressures are reduced. Postural hypotension may
be apparent, particularly in the third trimester
when the uterus can compress the inferior vena


Women’s Issues in Pulmonary Medicine (Levine)


protein binding of the drug. There are few data
examining the use of leukotriene receptor antago-
nists during pregnancy, but montelukast and
rlukast can be used in patients demonstrat-
ing a previous response to these agents. Both are
and should be avoided. Terbutaline and other
parenteral
-agonists administered near term can
cause tocolytic pulmonary edema and are often
avoided, although terbutaline is a category B agent.
Prostaglandin F
used for uterine atony should be
avoided in asthmatics because it can cause broncho-
constriction. Omalizumab, an IgE inhibitor, is rated
pregnancy category B, and can be considered for
improved control of poorly controlled asthma.
asthmaticus is the same as in the nonpregnant asth-
matic. For acute asthma, anticholinergic agents are
normal compensated respiratory alkalosis of preg-
nancy, when evaluating the pregnant asthmatic in
tory failure. Intubation should be considered with
of approximately 42 mm Hg consistently


Women’s Issues in Pulmonary Medicine (Levine)
it is often performed if Doppler study results are
when indicated as the “gold standard” test for the


711
pregnancy should undergo surveillance or receive
prophylaxis for VTE in subsequent pregnancies
in addition to postpartum anticoagulation pro-
phylaxis (grade 2C) because the recurrence rate
two or more episodes of VTE should receive anti-
coagulation during pregnancy and be converted
to long-term anticoagulation postpartum (grade
2C). Patients requiring long-term warfarin antico-
agulation before pregnancy should be converted
to UFH or LMWH when pregnancy is planned, or
as early in pregnancy as possible if not planned.


Women’s Issues in Pulmonary Medicine (Levine)
result is negative. At that time, the PPD should
be repeated. If the PPD result remains negative,
INH can be discontinued; if results are positive,
9 months of INH prophylaxis should be admin-
istered.
Pneumonia in Pregnancy
nia in the pregnant woman is similar to that in the
nonpregnant woman. Pneumonia may complicate
1.2 to 2.7 per 1,000 deliveries and may be more


low systemic vascular resistance, can be confused
Mechanical Ventilation
pregnant patient are similar to those in the non-
pregnant woman. Intubation may be more dif
cult
because of edema of the upper airway, a reduced
airway caliber, and an increased risk for aspira-
tion and bleeding; therefore, smaller endotracheal
tubes may be required. Tidal volumes may have
to be reduced as the result of reduced chest wall
compliance from the gravid uterus, and greater
peak pressures may be required to overcome chest
wall stiffness. Gas exchange goals should be to
in the pregnant eucapnic range of
90 mm Hg to pre-


Women’s Issues in Pulmonary Medicine (Levine)
tachycardia, and diaphoresis. Respiratory arrest
soon follows, and the rate of mortality can increase
to 90%. The classic but rarely heard cardiac mill-
wheel murmur audible over the precordium is sup-
ARDS may develop. Other  ndings include mental
status changes, coma, seizures, stroke, myocardial
infarction, and thrombocytopenia. Bubbles may be


aspiration as the result of uncorrectable hypoxemia.
contents are aspirated, symptoms may be delayed
Treatment is supportive. As in the nonpregnant
patient, there is no role for prophylactic antibiot-
ics or corticosteroids when treating this aspiration
syndrome. Resolution usually occurs over the
develops. Bronchoscopy may be indicated when
witnessed aspiration with large food particles has
occurred. The chances of aspiration can be reduced
by the use of regional anesthesia, restricting oral
intake at the time of delivery and cricoid pressure
if endotracheal intubation is required.
ARDS is de ned similarly in the pregnant as
in the nonpregnant individual. In addition to the
causes of ARDS discussed elsewhere in this course,


Women’s Issues in Pulmonary Medicine (Levine)
However, in the early 20th century, with the advent
of the suffrage movement, numerous ad campaigns
promoted the use of tobacco by women, includ-
slogan “You’ve come a long way, baby.” Tobacco
and/or liberated American woman, a concept fur-
ther promoted by the advertising of the tobacco
industry. The use of tobacco products by women
increased dramatically after World War II and
peaked in 1965, when the prevalence of smoking
among women approached 35%. Currently, 18.1%
The initial 1964 landmark US Public Health Sur-
marily addressed smoking and respiratory health
in men. However, in 1980, the Surgeon General’s
for Women was released. This report concluded
that women demonstrate the same dose—response


DNA level (CP450), greater levels of DNA adducts,
and decreased capacity for DNA repair have been
In addition, hormones (estrogens) and hor-
monal replacement may play a role in the variable
susceptibility to tobacco carcinogens, particularly
with adenocarcinoma. In never-smokers, age
adjusted incidence rate is greater for women 14.4
to 20.8/100,000 person years as compared with
men 4.8 to 13.7/100,000. Other risk factors for lung
cancer in women include a family history of lung
cancer; occupational exposures to compounds such
as asbestos, cadmium, beryllium, silicosis, radon;
and previous lung disease as are found in men. In


Women’s Issues in Pulmonary Medicine (Levine)
Catamenial hemoptysis is thought to occur


discontinuation of treatment. An interesting sec-
ondary  nding in the study was an improvement


Women’s Issues in Pulmonary Medicine (Levine)
This article includes a section on sleep-disordered breathing
in pregnancy.
Deblieux PM, Summer WR. Acute respiratory failure in


Tan KS, Thomson NC. Asthma in pregnancy. Am J Med
This is a good review of this subject.


Women’s Issues in Pulmonary Medicine (Levine)


723
 Provide a clinical de nition of occupational asthma
 Show the relationship of occupational asthma to the larger
realm of adult asthma
 Outline mechanisms by which asthma develops from
after years of being asymptomatic when they
are challenged with an irritant or allergen in the
and, from the point of view of medical man-
Because the workplace environment contrib-
utes to the severity of asthma in these patients,


In some cases, patients will have had childhood
asthma that remitted in adolescence, but for others,


 Measurement of peak expiratory  ow rate with




on-line at ÒASMAPRO,Ó which includes links to PubMed
and references to the medical literature.
Mechanisms of Occupational Asthma




729
 Understand the physiology and pathophysiology of
diving and high-altitude pulmonary-related problems
 Describe the main diseases related to high altitude, their
diagnosis, management, and prevention
 Discuss the different types of diving, contraindications to
medical problems of diving
 Explain the pathophysiology of drowning and near-
drowning
 Appreciate the mechanisms of hyperbaric oxygen therapy
altitude; barotrauma; decompression; diving;
drowning; high-altitude diseases; hyperbaric oxygen;
medical problems of diving
Diseases Related to High Altitude
High-Altitude Physiology
The adjustments of the cardiovascular system
to high altitude include increases in cardiac
output and pulmonary artery pressure, improved
selective
vasodilatation and vasodilatation that improves
oxygen delivery to the brain and heart. In the brain,
hypoxia induces cerebral vasoconstriction, which
is attenuated by hypocapnia-induced cerebral
vasoconstriction. The  nal result is small increase
in cerebral blood flow in proportion to tissue


vomiting, and dif culty sleeping. Findings from
the physical examination may include tachycar-
dia, mild crackles in the chest with auscultation,
and peripheral edema. These  ndings are non-
c and are not necessary to make a diagno-
sis of AMS. The diagnosis of AMS is established


arteries and patchy or homogenous in
ltrates that


Diseases Related to High Altitude and Diving (Aksenov and Strauss)


clearheaded are essential for safe diving. Individu-


membrane separates the middle ear space from
the external ear canal. The Eustachian tube pro-
vides a passage to the middle ear space from the
back of the nasopharynx, whereas the ostia of the
sinuses provide connections to the sinus cavities
and make it possible to equilibrate pressures in
these structures. Problems arise when these chan-
equilibrate pressure in the middle-ear spaces and
sinus cavities as the ambient pressures change
es these pressure-volume effects, stating that as
pressures of a con ned gas increase, the volumes
decrease and vice versa.
The ear and sinus cavities are lined with well-
vascularized respiratory epithelium. As a pressure
differential develops, the vessels dilate and the ear
drum distends inward (stage 1 of ear barotrauma).
progression is leakage of  uid from the vessels into
hearing. In stage 3, rupture of blood vessels with
bleeding into the middle-ear space occurs. Sputum
drum is the  nal step (stage 4) in the progression.
Because water may then  ll the ear canal, pain may
resolve because the middle-ear space becomes a
lled cavity and the pressure differential is
obliterated. However, cold water entering the
entation, and generate uncontrollable panic. Dur-
ing ascent, reverse ear squeezes may occur as the
result of expansion of the air in closed space. Diz-
ziness and vertigo may be associated with this
especially if unilateral. This condition is termed
The diver himself or herself should be respon-
sible for  rst-line interventions for ear and sinus
squeezes. At the first sign of ear pain, descent


to manage these problems. Rarely, these conditions
interfere with breathing. If so, oxygen inhalation
should be instituted. For pneumothorax and AGE,
breathing of pure oxygen should be initiated imme-


rates to 1 foot every 2 s; (2) taking a 3-min rest stop
oxygen, nitrox [enriched air nitrox] or helium-
oxygen mixtures). A summary of these conditions
is presented in Table 2.
Near-Drowning and Drowning:
Any time con-
sciousness is lost in the water, the victim is at
risk of drowning. Aspiration often is associated
with drowning because the breathing re
exes are
usually the last to remain after a hypoxic injury
to the brain. If the victim is rescued and resusci-
near-drowning
Whereas aspiration and the resulting lung injury
can be managed effectively with appropriate
injury are usually irreversible and can range from


possible, the interruption of the perfusion of the
brain for more than a moment or so, for example,
in a third-degree heart block, leads to immediate
loss of consciousness. Conversely, loss of con-
“protective effects” in terms of preservation of
serving effects of the diving re ex and hypothermia
from immersion in cold water. Remarkable recov-
eries have been reported from near-drowning, even
30 min.
Consequently, the adage “never say drowned”
is very appropriate for two reasons: 
rst, remark-
able recoveries that have been observed; and sec-
ond, the primary cause of the patient’s presentation
should be identi ed. Once the primary cause is
ed, appropriate management becomes logi-
while at the bottom phase of the dive, then hyper-
baric oxygen recompression therapy is essential to
oad the inert gas present in the tissues and pre-
vent complications of decompression illness (
DCS and/or AGE
). In addition, concurrent optimal
management of the pulmonary and brain injuries
from near-drowning must be administered.
Basics of HBOT
Mechanisms of Hyperbaric Oxygen


1. Untreated pneumothorax: Air in the pleu-
ral space can increase in size as pressure de-
creases during ascent.
2. The concomitant administration of doxoru-
bicin or cis-platinum: HBOT can increase the
cytotoxic effect of these medications.
ram: This medication blocks the pro-
duction of superoxide dismutase, a protective
antioxidant against oxygen toxicity.
4. Bleomycin: This drug increase pulmonary
toxicity in patient undergoing HBOT.







Приложенные файлы

  • pdf 18416940
    Размер файла: 6 MB Загрузок: 0

Добавить комментарий