Molecular Basis of Pulmonary Disease Insights from Rare Lung Disorders pdf

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

[email protected]

Bruce C. Trapnell

Cincinnati Children’s Hospital

Medical Center

Division of Pulmonary Biology

3333 Burnet Ave.

Cincinnati OH 45229

USA

[email protected]

Ralph J. Panos

University of Cincinnati

Division of Pulmonary & Critical Care

231 Albert Sabin Way

Cincinnati OH 45267

Mail Location 0564

USA

[email protected]

ISBN 978-1-58829-963-5 e-ISBN 978-1-59745-384-4

DOI 10.1007/978-1-59745-384-4

Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2010920243

© Springer Science+Business Media, LLC 2010

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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

reality through the Rare Lung Disease Consortium, a network of 13 US and interna￾tional sites that is currently conducting clinical trials and studies in LAM, alpha one

antitrypsin deficiency, pediatric interstitial lung disease, and PAP. It has been a rare

privilege to work on such fascinating diseases with such capable investigators from all

over the world over the past 6 years.

v

vi Preface

The format for this volume is unique. Most chapters have been authored by a clini￾cian and a basic scientist who are expert in the disease topic and underlying molecular

defect, respectively. Their charge was to focus on the genetic basis and molecular patho￾genesis of disease, animal models, clinical features, diagnostic approach, conventional

management and treatment, and future therapeutic targets and directions. The intent was

not to provide a broad overview, but rather to shed light on the molecular mechanisms

that evoke the clinical presentation and engender treatment strategies for each disease.

We hope that this approach will prove useful for pulmonary clinicians and scientists

alike.

We thank our wives, Holly, Jean, and Vicky, for their support and indulgence with

late night emails and work-filled weekends, Dr. Rounds for the invitation to write the

book, and all of the authors who contributed.

Francis McCormack, MD

Ralph Panos, MD

Bruce Trapnell, MD

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

1 A Clinical Approach to Rare Lung Diseases . . .............. 1

Ralph J. Panos

2 Clinical Trials for Rare Lung Diseases . . . . . . . . . . . . . . . . . . . 31

Jeffrey Krischer

3 Idiopathic and Familial Pulmonary Arterial Hypertension . . . . . . . . 39

Jean M. Elwing, Gail H. Deutsch, William C. Nichols,

and Timothy D. Le Cras

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 Marfan 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 Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

André M. Cantin

17 Pulmonary Langerhans’ Cell Histiocytosis – Advances

in the Understanding of a True Dendritic Cell Lung Disease . . . . . . . 369

Robert Vassallo

18 Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

Ralph J. Panos and Andrew P. Fontenot

19 Scleroderma Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . 409

Brent W. Kinder

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

Contributors

James P. Bridges, PhD, Department of Neonatology in Pulmonary Biology, Children’s

Hospital Medical Center, Cincinnati, OH

André M. Cantin, MD, Department of Medicine, University of Sherbrooke,

Sherbrooke, QC, Canada

Edward D. Chan, MD, Department of Internal Medicine, National Jewish Medical and

Research Center, Denver, CO

Kathryn Chmura, BA, Department of Medicine, University of Colorado School of

Medicine, Denver, CO

Gail H. Deutsch, MD, Department of Pathology, Seattle Children’s Hospital,

Seattle, WA

Jean M. Elwing, MD, Department of Internal Medicine, University of Cincinnati

School of Medicine, Cincinnati, OH

Andrew P. Fontenot, MD, Department of Medicine, University of Colorado Health

Sciences Center, Denver, CO

William A. Gahl, MD, PhD, National Human Genome Research Institute, National

Institutes of Health, Bethesda, MD

Koichi Hagiwara, MD, Department of Respiratory Medicine, Saitama Medical School,

Saitama, Japan

Elizabeth P. Henske, MD, PhD, Department of Medicine, Harvard Medical School,

Boston, MA

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

School of Medicine, Baltimore, MD

William C. Nichols, PhD, Department of Pediatrics, University of Cincinnati School of

Medicine and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Lawrence M. Nogee, MD, Department of Pediatrics, John Hopkins University School

of Medicine, Baltimore, MD

S. Paul Oh, PhD, Department of Physiology and Functional Genomics, University of

Florida Cancer & Genetic Research Complex, Gainesville, FL

Ralph J. Panos, MD, Department of Internal Medicine, University of Cincinnati School

of Medicine, Cincinnati VA Medical Center, Cincinnati, OH

Claire Shovlin, PhD, MA, FRCP, Department of Respiratory Medicine, Imperial

College London, UK

Charlie Strange, MD, Department of Medicine, Medical University of South Carolina,

Charleston, SC

Andrew Sullivan, MD, Department of Internal Medicine, University of Colorado

School of Medicine, Denver, CO

Contributors xi

Gangadar Taduri, MD, Department of Nephrology, Nizam’s Institute of Medical

Sciences, Andhrapradesh, India

Teruo Tachibana, MD, Department of Internal Medicine, Aizenbashi Hospital, Osaka,

Japan

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

Robert Vassallo, MD, Department of Pulmonology, Mayo Clinic Rochester,

Rochester, MN

Lisa R. Young, MD, Department of Pediatrics and Department of Internal Medicine,

University of Cincinnati School of Medicine and Cincinnati Children

s Hospital Medi￾cal Center, Cincinnati, OH

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 in 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 rare 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

conspicuously noticeable among the herd of common disorders or, more frequently,

F.X. McCormack et al. (eds.), Molecular Basis of Pulmonary Disease, Respiratory Medicine, 1

DOI 10.1007/978-1-59745-384-4_1, © Springer Science+Business Media, LLC 2010

2 R.J. Panos

hidden amidst their thundering hooves. When confronted with hoof beats – a patient’s

constellation of symptoms, signs, and other studies – most physicians consider the sim￾plest and most common diagnosis as the likely cause. This principle of parsimony is

based on methodological reductionism and was developed by William of Ockham, a

14th century English logician and Franciscan friar. Ockham’s razor, Entia non sunt

multiplicanda praeter necessitatem (entities should not be multiplied beyond neces￾sity), is a central premise in medical diagnosis (1). In the current medical environment

of history and physical examination templates, the physician is frequently presented

with a delimited database that constrains the development of a comprehensive differ￾ential diagnosis – not only are zebras excluded but the hoofbeats of the herd of horses

have been muffled. The time to search for zebras in the busy, frenetic, clinical envi￾ronment is a luxury that few pulmonologists enjoy. Thus, in many ways, a clinical

approach to rare lung diseases is an oxymoron. The concept that common things hap￾pen commonly is inculcated into our medical being from medical school onward and

reinforced by regimented, templated patient assessments guided by required, bulleted,

billing-based guidelines that limit and restrict the formation of an unbiased and com￾prehensive database from which an expansive differential diagnosis is developed – one

that includes the zebras.

The vast spectrum of medical diagnoses is constantly expanding with the recognition

and publication of approximately five new disorders each week (2). In the United

States, approximately 25 million people are afflicted with over 6,000 rare diseases

(3). 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. The ORD maintains a web-based, searchable list

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 (http://germop.univ￾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,

chest imaging, and related studies. The emphasis of this chapter is the formulation of

a differential diagnosis that encompasses rare noninfectious, nonmalignant lung dis￾eases of adults and is based on the presence or absence of associated signs and symp￾toms. Environmental exposures, pneumoconioses, and drug-induced pulmonary disor￾ders are not discussed. Many processes are limited strictly or principally to the lungs,

and for these disorders, the radiographic imaging, physiologic, other laboratory stud￾ies, and genetic testing may be essential for the identification of the underlying disease.

Table 1.1 presents a listing of rare lung disorders or conditions that are limited princi￾pally to the lungs. Other disorders affect the lungs and other organ systems. For these

processes, the key to the diagnosis is the recognition of associated constellations of

symptoms that affect the lungs as well as another system or systems. Tables 1.2, 1.3,

1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, and 1.11 present differential diagnoses of lung disorders

based on associated organ involvement.

Diagnostic Evaluation

The diagnostic evaluation of a patient with suspected lung disease requires a logi￾cal sequential series of steps to distinguish the myriad potential causes of pulmonary

pathology. The initial approach should include a comprehensive history, physical exam￾ination, chest X-rays, and pulmonary function testing.

History

Although most clinicians do not initiate their clinical evaluations looking for rare pul￾monary processes, a comprehensive, logical, and sequential evaluation is essential in

the evaluation of rare or complex pulmonary disorders. The initial and most impor￾tant step in this assessment is a comprehensive clinical history to determine the pul￾monary symptoms and any associated systemic clues to the etiology of the underlying

process. The most frequent presenting respiratory symptoms include breathlessness,

cough, chest discomfort, and respiratory sounds or noises. Specific qualities of these

presenting symptoms such as onset, duration, location, quality, aggravating or alleviat￾ing factors, and associated respiratory or systemic manifestations may help establish a

specific diagnosis or limit the differential diagnosis. Occasionally, patients subtly adapt

their lifestyle, such as decreasing activity level to minimize or alleviate the sensation

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.