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Molecular Basis of Pulmonary Disease
RESPIRATORY MEDICINE
Sharon R. Rounds, MD,SERIES EDITOR
Molecular Basis of Pulmonary Disease, edited by Francis X. McCormack, Ralph J. Panos
and Bruce C. Trapnell, 2010
Pulmonary Problems in Pregnancy, edited by Ghada Bourjeily and Karen Rosene-Montella, 2009
Molecular Basis of Pulmonary
Disease
Insights from Rare Lung Disorders
Edited by
Francis X. McCormack, MD
Department of Internal Medicine,
University of Cincinnati Medical Center, Cincinnati, OH, USA
Ralph J. Panos, MD
Department of Internal Medicine, University of Cincinnati School of Medicine
and Cincinnati VA Medical Center, Cincinnati, OH, USA
Bruce C. Trapnell, MD
Department of Pediatrics and Department of Internal Medicine,
University of Cincinnati School of Medicine and Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH, USA
Editors
Francis X. McCormack
University of Cincinnati
Division of Pulmonary & Critical Care
231 Albert Sabin Way
Cincinnati OH 45267
Mail Location 0564
USA

Bruce C. Trapnell

or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the
material contained herein.
Printed on acid-free paper
Humana Press is part of Springer Science+Business Media (www.springer.com)
Preface
Dr. Sharon Rounds, the editor for this series who invited us to write a book on rare
lung diseases, developed the idea after attending the 2004 Lymphangioleiomyomatosis
(LAM) Foundation annual research meeting. She was a keynote speaker at that event
(during her tenure as the president of the American Thoracic Society) and was wit-
ness to the power of patient advocacy and the mission-based scientific effort that had
brought this rare disease of women from obscurity to clinical trials with targeted molec-
ular therapies in under a decade. The progress in pulmonary alveolar proteinosis (PAP),
pulmonary alveolar microlithiasis (PAM), inherited disorders of surfactant metabolism,
and pulmonary arterial hypertension, to name a few, has been no less astounding.
Advances have come from the most surprising directions; fruit flies for LAM, genet-
ically engineered mice made for other purposes for PAP, and groundbreaking high-
density SNP (single-nucleotide polymorphism) analyses done on a handful of families
for PAM. In many cases, insights into biology gained from rare diseases have informed
research approaches and treatment strategies for more common diseases; for example,
knowledge gained from the study of PAP about the role of GM-CSF in the lung has
sparked interest in the use of anti GM-CSF approaches to control both pulmonary and
extrapulmonary inflammation in a variety of diseases. The finding that interstitial lung
disease develops in families with cytotoxic mutations in surfactant protein C (SP-C),
a gene which is expressed only in alveolar type cells, has underscored the importance
of the integrity of the alveolar epithelium in the pathogenesis of parenchymal fibrosis.
Opportunities to approach lung disease pathogenesis from the vantage point of a pri-
mary molecular defect are gifts from nature that are uniquely abundant among the rare
lung disorders.
We salute the NIH and the National Center for Research Resources for their vision in
facilitating the translation of basic research advances in rare lung diseases into clinical

Jean M. Elwing, Gail H. Deutsch, William C. Nichols,
andTimothyD.LeCras
4 Lymphangioleiomyomatosis 85
Elizabeth P. Henske and Francis X. McCormack
5 Autoimmune Pulmonary Alveolar Proteinosis . 111
Bruce C. Trapnell, Koh Nakata, and Yoshikazu Inoue
6 Mutations in Surfactant Protein C and Interstitial Lung Disease 133
Ralph J. Panos and James P. Bridges
7 Hereditary Haemorrhagic Telangiectasia . . . 167
Claire Shovlin and S. Paul Oh
8 Hermansky–Pudlak Syndrome 189
Lisa R. Young and William A. Gahl
9 Alpha-1 Antitrypsin Deficiency . . . 209
Charlie Strange and Sabina Janciauskiene
vii
viii Contents
10 The M arfan Syndrome . 225
Amaresh Nath and Enid R. Neptune
11 Surfactant Deficiency Disorders: SP-B and ABCA3 247
Lawrence M. Nogee
12 Pulmonary Capillary Hemangiomatosis . . 267
Edward D. Chan, Kathryn Chmura, and Andrew Sullivan
13 Anti-glomerular Basement Disease: Goodpasture’s Syndrome 275
Gangadhar Taduri, Raghu Kalluri, and Ralph J. Panos
14 Primary Ciliary Dyskinesia 293
Michael R. Knowles, Hilda Metjian, Margaret W. Leigh,
and Maimoona A. Zariwala
15 Pulmonary Alveolar Microlithiasis 325
Koichi Hagiwara, Takeshi Johkoh, and Teruo Tachibana
16 CysticFibrosis 339

Yoshikazu Inoue, MD, PhD, Department of Diffuse Lung Diseases and Respiratory
Failure, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai,
Osaka, Japan
Sabina Janciauskiene, PhD, Department of Clinical Sciences, University Hospital,
Malmo, Sweden
ix
x Contributors
Takeshi Jokoh, MD, Department of Radiology, Osaka University Hospital, Osaka,
Japan
Raghu Kalluri, PhD, Department of Medicine and Biological Chemistry and Molecular
Pharmacology, Center for Matrix Biology, Beth Israel Deaconess, Boston, MA
Brent W. Kinder, MD, Department of Internal Medicine, University of Cincinnati
School of Medicine, Cincinnati, OH
Michael R. Knowles, MD, Department of Medicine, University of North Carolina,
Chapel Hill, NC
Jeffrey Krischer, PhD, Department of Pediatrics, Pediatric Epidemiology Center, Uni-
versity of South Florida, Tampa Bay, FL
Timothy D. LeCras, PhD, Department of Pediatrics, University of Cincinnati School of
Medicine and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Margaret W. Leigh, MD, Department of Pediatrics, University of North Carolina,
Chapel Hill, NC
Francis X. McCormack, MD, Department of Internal Medicine, University of
Cincinnati Medical Center, Cincinnati, OH
Hilda Morillas, MD, Department of Internal Medicine, The University of North
Carolina, Chapel Hill, NC
Koh Nakata, MD, PhD, Bioscience Medical Research Center, Niigata University
Medical Hospital, Japan
Amaresh Nath, MD, Department of Internal Medicine, University of Cincinnati School
of Medicine, Cincinnati, OH
Enid R. Neptune, MD, Department of Internal Medicine, John Hopkins University

Maimoona A. Zariwala, PhD, Department of Pathology and Laboratory Medicine, The
University of North Carolina, Chapel Hill, NC
1
A Clinical Approach to Rare Lung
Diseases
Ralph J. Panos
When you hear hoofbeats behind you, don’t expect to see a zebra.
Theodore E. Woodward, MD, University of Maryland, Circa 1950 (1)
Abstract The National Institutes of Health Office of Rare Diseases (ORD) defines a
rare or orphan disease as a disorder with a prevalence of fewer than 200,000 affected
individuals within the United States whereas in Europe, rare diseases are defined as
those disorders that affect 1 or fewer individuals per 2,000 persons. Several consortia
exist for the compilation of rare lung disorders: the British orphan lung disease (BOLD)
registry, the British pediatric orphan lung disease (BPOLD) registry, the French Groupe
d’Etudes et de Recherche sur les Maladies Orphelines Pulmonaires (GERM”O”P”)
database, and the Rare Lung Disease Consortium (RLDC) in the United States. The
National Organization for Rare Diseases (www.raredisease.org) is a nongovernmental
federation of organizations to assist individuals with rare diseases that seeks to expand
recognition and treatment of individuals with these rare illnesses. This chapter presents
an approach to pulmonary medicine that aims to go beyond the usual respiratory disor-
ders to examine the evaluation and understanding of rare lung diseases that have pro-
vided extraordinary insights into not only lung function i n health and disease but also
human biology in general. The respiratory history, physical examination, chest imaging,
and related studies are reviewed. The emphasis of this chapter is the formulation of a
differential diagnosis that encompasses r are noninfectious, nonmalignant lung diseases
of adults and is based on the presence or absence of associated signs and symptoms.
Keywords: rare lung disease, respiratory history, respiratory physical examination,
chest imaging
Introduction
In medicine, “zebra” is a common idiom for a rare disease or condition that may be

of over 7,000 rare diseases with links to various information sources. The National
Organization for Rare Diseases (www.raredisease.org) is a nongovernmental federation
of organizations to assist individuals with rare diseases that seeks to expand recog-
nition and treatment of individuals with these rare illnesses. In Europe, rare diseases
are defined as those disorders that affect 1 or fewer individuals per 2,000 persons.
Orphanet is a European database of nearly 6,000 rare disorders (www.orphan.net).
In addition to these general collections of rare diseases, there are several databases
limited to rare lung disorders: the British orphan lung disease (BOLD) register was
established in 2000 for adult rare lung diseases in the United Kingdom (www.brit-
thoracic.org.uk/ClinicalInformation/RareLungDiseasesBOLD/tabid/110/Default.aspx);
the British pediatric orphan lung disease (BPOLD) is a registry of nine rare pedi-
atric lung disorders in the United Kingdom (www.bpold.co.uk); and the Groupe
d’Etudes et de Recherche sur les Maladies Orphelines Pulmonaires (GERM”O”P”) has
established a database of patients with rare lung diseases in France (v-
lyon1.fr/). In the United States, the Rare Lung Disease Consortium (RLDC)
(www.rarediseasesnetwork.epi.usf.edu/rldc/index.htm) was founded in 2003 with
collaborating centers throughout the United States and Japan. The RLDC has ongoing
clinical trials in several rare lung diseases including lymphangioleiomyomatosis,
alpha-1 antitrypsin deficiency, and idiopathic pulmonary fibrosis.
This chapter is an introduction to a safari in pulmonary medicine that aims to go
beyond the usual pulmonary disorders to examine the evaluation and understanding of
rare lung diseases – the zebras – that have provided extraordinary insights into not only
lung function in health and disease but also human biology in general. The evaluation
of all patients begins with the history and physical examination. For those individuals
1 A Clinical Approach to Rare Lung Diseases 3
with respiratory symptoms, chest imaging and physiologic studies provide further
information to discern the underlying process. The role of the clinical history and pul-
monary signs and symptoms as well as chest imaging in the evaluation and diagnosis
of respiratory disorders has been reviewed in most textbooks of pulmonary medicine
and radiology. We will briefly review the respiratory history, physical examination,

of breathlessness. The astute clinician must often delve beyond the initial presenting
symptoms to determine whether the patient is attempting to compensate for insidiously
progressive respiratory processes. Not infrequently, patients are referred for pulmonary
evaluations for an abnormal chest imaging or physiologic study. These patients may or
may not have respiratory symptoms.
4 R.J. Panos
Breathlessness
Dyspnea is a subjective sensation of abnormal, awkward, or uncomfortable breathing
that integrates the subjective perception of breathing (4). Terms used by patients to
describe dyspnea include breathlessness, heavy breathing, suffocation, chest tightness,
air hunger, and choking. Self-limited, expected breathlessness occurs normally. After
strenuous exertion most individuals experience mild shortness of breath that is subse-
quently relieved with rest. In an individual patient, it may be difficult to discern expected
from unanticipated breathlessness. Severity of breathlessness may be difficult to assess
as the perception of breathlessness may vary between individuals and over time in a
single i ndividual.
The chronicity and onset of breathlessness are important variables in discerning
the etiology of dyspnea. Breathlessness that occurs with sudden onset is often due to
infections, pulmonary embolism, pneumothorax, or bronchospasm. Breathlessness that
develops slowly over time is most often associated with progressive pulmonary pro-
cesses such as interstitial lung disease, pulmonary vascular disease, or obstructive lung
disease. Provocative factors such as plants, pets, or odors may suggest bronchospasm
or asthma.
Causes of breathlessness include many non-pulmonary processes including cardiac,
metabolic, and hematologic disorders (5). In two-thirds of 85 patients who presented to
a pulmonary subspecialty clinic, breathlessness was due to asthma, chronic obstructive
pulmonary disease, or cardiomyopathy (6). Interestingly, the clinical impression based
on the history, physical examination, and chest X-ray was accurate in 81% of patients
when the cause of dyspnea was one of these processes but decreased to 33% for less
common causes.

flow during sleep. Wheezing is a high-pitched musical sound that is more frequently
heard during expiration than inspiration. It usually indicates obstructive airway disease
including asthma and chronic obstructive pulmonary disease. Localized wheezes sug-
gest endobronchial obstruction. Stridor is a loud, harsh sound that may occur either dur-
ing inspiration or expiration. Inspiratory stridor suggests an extrathoracic cause whereas
expiratory stridor suggests an intrathoracic etiology. Obstruction of airflow due to intra-
bronchial lesions, edema of the upper airway, or dynamic airway collapse may cause
stridor.
Medical History
The past medical history is an important source of information about systemic processes
that may also involve the lung. Associated previous or concurrent systemic medical
conditions may also help formulate the differential diagnosis. Some processes intermit-
tently involve different systems or are in evolution and require serial observation.
Family/Social History
The family history and social history may elicit genetic factors or other triggers that
might cause the development of lung disease. The family history is an important
source of information about familial processes that may affect the lungs. These dis-
eases include cystic fibrosis, alpha-1 antitrypsin deficiency, hereditary telangiectasia,
pulmonary fibrosis, and surfactant protein mutations (discussed in detail in Chapters
6, 7, 9, 11, and 16).
Occupational/Environmental History
Particular emphasis should be placed on the patient’s occupational and environmental
exposures and, occasionally, the spouse’s occupational history (8). Obtaining a chrono-
logic listing of all positions held by a patient generates a comprehensive employment
resume. The occupational history elicits not just the job title but the actual duties and
tasks as well as a comprehensive list of all vapors, gases, dust, or fumes in the work
environment. Occasionally a spouse may be exposed to particles such as asbestos fibers
that are transported from the job place to the home on the partner’s work clothes. The
home environment including pets, mold, mildew, down bedding or chemical, fumes, or
dusts generated while performing hobbies may also be the source of exposures that may

ing inspiration. Asymmetry may suggest an abnormality of the underlying chest wall,
pleura, or lung. Palpation can also determine the presence of chest wall masses, lesions,
or other abnormalities such as a flail chest. Pneumothorax, pleural effusion, or medi-
astinal mass may cause lateral deviation of the trachea. Vibratory palpation or tactile
fremitus is increased with pulmonary consolidation due to pneumonia or atelectasis
but is reduced with pleural effusions or pneumothorax. Percussion is dulled by the
loss of aerated pulmonary parenchyma caused by pleural effusion, consolidation, or
atelectasis. Hyperresonance or tympany may occur with emphysema, large bullae, or
pneumothorax.
1 A Clinical Approach to Rare Lung Diseases 7
Auscultation
Movement of air throughout the tracheobronchial tree produces sounds that range from
60 to 3,000 Hz. Auscultation should be performed in the upper and lower lung zones,
anteriorly, posteriorly, and laterally. Breath sounds include tracheal, bronchial, bron-
chovesicular, and vesicular sounds. Vesicular sounds have a long inspiratory compo-
nent and a short expiratory phase whereas bronchial sounds have a short inspiratory
phase and a long expiratory component. Adventitial sounds include rales or crackles,
wheezes, and rhonchi. Crackles are irregular, short, explosive sounds and may be classi-
fied as fine or coarse. Fine-end inspiratory crackles are strongly suggestive of interstitial
processes, whereas expiratory crackles suggest pulmonary edema or fluid accumulation
within the lungs. Wheezes are continuous, musical sounds that may occur during inspi-
ration or expiration but are most common during expiration and suggest obstructive
lung disease. Rhonchi are continuous low-pitched sounds that are frequently called dry,
coarse rales. Sounds may also emanate from the pleura and include friction rubs which
are loud coarse sounds with a raspy quality. These suggest thickening or inflammation
of the pleura.
Imaging Studies
Chest imaging studies, especially the chest X-ray and CT scan, are increasingly essen-
tial in the evaluation and diagnosis of unusual respiratory conditions. The posterior–
anterior and lateral chest roentgenogram is most frequently the initial imaging study

sound (EBUS) is performed using a probe incorporated into the bronchoscope or passed
through the working channel (15). The diagnostic yield of EBUS-guided transbronchial
aspiration is significantly increased for solitary pulmonary nodules (<2 cm) and hilar
and mediastinal lymph nodes compared with conventional bronchoscopy (15). Echocar-
diography provides functional and anatomic assessment of the heart and great vessels.
Doppler echocardiography provides a noninvasive measurement of pulmonary artery
pressures f or the diagnosis and monitoring of pulmonary hypertension.
Although ventilation perfusion scans have been largely replaced by CT scans using
a pulmonary angiogram protocol, nuclear studies are preferred for the diagnosis of
pulmonary hypertension due to chronic thromboembolism (16). PET scans utilizing flu-
orodeoxyglucose are increasingly used to determine whether thoracic lesions are neo-
plastic (17).
Physiologic Studies
Physiologic studies including spirometry, lung volumes, and diffusing capacity (DLCO)
as well as measurement of respiratory muscle strength may be helpful in limiting
the differential diagnosis of a complex pulmonary process. Pulmonary function test-
ing determines whether a physiologic abnormality of lung function is present. The
major categories of physiologic impairment are obstruction, reduced expiratory flows,
and restriction, diminished lung volumes. Obstruction may be caused by asthma,
emphysema, or chronic bronchitis. Restriction may be due to interstitial lung disease
(ILD), pleural processes, or thoracic wall abnormalities. Lung compliance is normal in
thoracic wall processes but reduced in ILD. Increases in DLCO suggest increased
intrathoracic blood volume or hemorrhage into the lung parenchyma, whereas reduction
in DLCO may be due to decreased surface area for gas exchange caused by interstitial
lung disease, loss of lung parenchyma (surgery or emphysema), or pulmonary vascu-
lar disease. Provocative studies such as methacholine challenge may be used to incite
bronchospasm. Measurement of maximal inspiratory and expiratory pressures provides
a global assessment of respiratory muscle strength t hat may be reduced by neuromus-
cular disease or thoracic wall abnormalities. Other useful studies include arterial blood
gases and oximetry that can be performed in different positions or at rest and with

establish a histopathologic diagnosis.
Skin testing is performed to determine reactivity to various allergens that might cause
atopy, asthma, or allergic rhinitis. Reactivity to Aspergillus is a diagnostic criterion
for allergic bronchopulmonary aspergillosis (ABPA). Current or prior Mycobacterium
tuberculosis infection may cause a delayed hypersensitivity reaction to purified protein
derivative (PPD). Other skin tests are used to diagnose fungal infections. Cystic fibrosis
is diagnosed by sweat chloride measurement.
Serologic testing is used to diagnose connective tissue disorders that may have
pulmonary manifestations (see Chapter 19), infections especially caused by fungal
pathogens, viral infections including human immunodeficiency or hepatitis viruses that
are associated with pulmonary hypertension (see Chapter 3). Elevation of IgE levels
may suggest atopy, asthma, ABPA, and reductions in complement or immunoglobulin
levels may determine the cause of recurrent respiratory infections or bronchiectasis.
Other serologic titers include anti-neutrophil cytoplasmic antibody, PR3, MPO, and
antiglomerular basement membrane antibody (see Chapter 13).
As the genetic mutations underlying many pulmonary processes are discovered,
increasing numbers of molecular genetic studies are available to diagnose pulmonary
processes (see Chapters 6, 9, 11, 15, and 16).
Bronchoscopy permits a direct visual inspection of the upper and lower airway and
can be used for obtaining samples from the lower respiratory tract by bronchoalveo-
lar lavage, brushings, and biopsy. Bronchoscopy is most useful for the diagnosis of
infections and neoplasms and is usually less informative in diffuse lung diseases other
than granulomatous processes. Endobronchial ultrasound improves the yield and safety
of transbronchial needle aspiration of mediastinal and hilar adenopathy and nodules
and frequently obviates the need for mediastinoscopy (29). Open lung biopsy i s often
required for the diagnosis of diffuse parenchymal lung disease and is frequently
10 R.J. Panos
performed by video-assisted thoracoscopic surgery. Nasal epithelial biopsies and ultra-
structural imaging may diagnose ciliary disorders.
Pulmonary Differential Diagnosis of Rare or Unusual Conditions

Arteriovenous malformation
Pulmonary specific
Systemic (hereditary hemorrhagic telangiectasia, Osler–Weber–Rendu disease)
Combined parenchymal–vascular
Hypogenetic lung (Scimitar syndrome)
Bronchopulmonary sequestration
Intralobar
Extralobar
Other
Congenital diaphragmatic hernia
Posterior (Bochdalek)
1 A Clinical Approach to Rare Lung Diseases 11
Table 1.1 (continued)
Anterior (Morgagni)
Musculoskeletal
Airway/bronchial processes
Upper airway disorders
Vocal cord dysfunction
Saber-sheath trachea
Tracheobronchopathia osteochondroplastica
Tracheomalacia
Tracheal polyps
Obstructive sleep apnea
Upper airway resistance syndrome
Bronchial processes
Respiratory bronchiolitis
Respiratory bronchiolitis interstitial lung disease
Peribronchiolar metaplasia–interstitial lung disease
Proliferative bronchiolitis
Bronchiolitis obliterans organizing pneumonia

12 R.J. Panos
Table 1.1 (continued)
Pulmonary calcification and ossification
Pulmonary alveolar microlithiasis
Pulmonary alveolar proteinosis
Surfactant abnormalities
SP-B mutations
SP-C mutations
ABCA3 mutations
Granulomatous infiltration
Sarcoidosis
Necrotizing sarcoid granulomatosis
Berylliosis
Hypersensitivity pneumonitis
Talc granulomatosis
Wegener’s granulomatosis
Churg–Strauss disease
Bronchocentric granulomatosis
Hypocalciuric hypercalcemia and interstitial lung disease
Mixed cellular and noncellular infiltration or accumulation
Idiopathic pulmonary fibrosis
Acute interstitial pneumonitis
Nonspecific interstitial pneumonia (cellular and fibrotic)
Cryptogenic organizing pneumonia (bronchiolitis obliterans organizing pneumonia)
Respiratory bronchiolitis interstitial pneumonia
Peribronchiolar metaplasia–interstitial lung disease
Hypersensitivity pneumonitis
Radiation pneumonitis/fibrosis
Pneumoconiosis
Inhalational lung injury

Table 1.2 Cutaneous–pulmonary associations.
Disease Cutaneous manifestation
Pulmonary
manifestation
General
Atopy Eczema Asthma
Yellow nail syndrome Yellow discolored nails that are
thicker than normal, excessive
curvature on the long axis
Onycholysis
Lymphedema
Exudative pleural effusion
Recurrent sinusitis
Bronchiectasis
Recurrent pneumonia
Costello syndrome Redundant skin
Papillomata
Lipoid pneumonia
Alpha-1 antitrypsin
deficiency
Necrotizing panniculitis Emphysema, especially
panacinar
Obstructive lung disease
Infiltrative/accumulative
Sarcoid Erythema nodosum
Lupus pernio
Erythematous or pigmented
papules
Annular plaque
Lymphadenopathy