Sections

Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD)

Sections Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD)
Overview
Presentation
DDx
Workup
Treatment
Guidelines
Medication
Media Gallery
Tables
References

Workup

Laboratory Studies

Laboratory studies are helpful in the setting of connective tissue disease-associated (CTD) interstitial lung disease (ILD) (CTD-ILD). At least 15% of patients with ILD have evidence of underlying CTD.^[3]

Antibody testing

Various antibodies detected in the serum of patients with CTD help in determining the diagnosis and the prognosis (see Table 2 below).

Table 2. Autoantibodies in Connective Tissue Diseases (Open Table in a new window)

Autoantibody	RA	SLE	SD	SS	PM/DM	AS	MCTD	IPAF #^[10]
RF	+	+	+	+	Rare	-	+	Possible
ANA	+	+	+	+	Rare	-	+ (speckled)	Possible
ds-DNA	-	+	-	-	-	-	-	Possible
Anti centromere	-	-	+ (limited)	Rare	Rare	-	-	Possible
Scl-70	-	-	+ (diffuse)		Rare	-	-	Possible
Anti-Jo	-	-	-	Rare	+ (ILD)	-	-	Possible
ANCA	Rare	Rare	-	-	-	-	-	-
Smith antibody	-	+	-	-	-	-	-	Possible
Anti-Ro/SSA and anti-La/SSB	-	-	-	+	-	-	-	Possible
Anti-U1-RNP and anti-UN-70 kd	-	-	-	-	-	-	+	Possible
Anti-CCP	+	-	-	-	-	-	-	Possible
ANA = antinuclear antibody; ANCA = antineutrophilic cytoplasmic antibody; AS = ankylosing spondylitis; CCP = cyclic citrullinated peptide; DM = dermatomyositis; ds-DNA = double-stranded DNA antibody; ILD = interstitial lung disease; IPAF = interstitial pneumonia with autoimmune features; MCTD = mixed connective-tissue disease; PM = polymyositis; RA = rheumatoid arthritis; RF = rheumatoid factor; RNP = ribonucleoprotein; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome.

Anemia of chronic disease can be found in persons with rheumatoid arthritis (RA), whereas systemic lupus erythematosus (SLE) can cause leukopenia, lymphopenia, thrombosis, and thrombocytopenia. The erythrocyte sedimentation rate (ESR) and creatine kinase levels may be high in patients with polymyositis (PM)/dermatomyositis (DM). Total complement levels and a high ESR may be present in patients with SLE who present with an acute lupus flare.

Schirmer and Rose Bengal staining

The Schirmer test may be used to screen for dry eyes secondary to decreased tear production in patients with Sjögren syndrome (SS). Similarly, Rose Bengal staining of the cornea can detect keratitis associated with SS.

Radiology

Radiologically, connective tissue disease (CTDs) may manifest as a focal or a diffuse pulmonary abnormality. The type and frequency of the lung abnormalities vary with the specific disease (see Table 3 below).

Table 3. Radiologic Patterns of Connective Tissue Diseases (Open Table in a new window)

Radiologic Pattern	RA	SLE	SD	Secondary SS	PM/DM	AS	MCTD	IPAF ^[10]
Pleural effusion	+	+	+	±	-	-	+	May be present
Interstitial pneumonitis, fibrosis	UIP and NSIP patterns	+	LIP pattern	±	+	Upper apical fibrosis^[59]	+	NISP, OP, LIP or NISP with OP overlap pattern
BOOP	±	+	+	+	+	±	±
Pulmonary nodules	Rheumatoid pulmonary nodules; uncommon, maybe 1-5 mm, single or multiple, may cavitate	-	-	Follicular lymphoid hyperplasia or lymphoma can present as lung nodules	+	-	-
Bronchiectasis	+	+	+	+	+	+	+	unexplained airflow obstruction, bronchiolitis or bronchiectasis.
Caplan syndrome	Coal worker pneumoconiosis, rheumatoid nodules	-	-	-	-	-	±
Diffuse pulmonary hemorrhage	-	+	-	-	-	-	±
Shrinking lung syndrome	-	Loss of lung volume at bases with no parenchymal pathology	-	-	-	-	±
Diaphragmatic dysfunction	-	+	-	May be present	+	-	±
Cysts, honeycombing	10% of patients have subpleural honeycombing; compared with IPF, it is more anterior and involves upper lobes	Uncommon	+	Present, especially in LIP	+	Upper-lobe cyst may become infected with Aspergillus species	-
GGO	Present, especially in NSIP	+	+	+	+	-	±
AS = ankylosing spondylitis; BOOP = bronchiolitis obliterans organizing pneumonia; DM = dermatomyositis; GGO = ground-glass opacification; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; LIP = lymphoid interstitial pneumonia; MCTD = mixed connective-tissue disease; NSIP = nonspecific interstitial pneumonia; OP = organizing pneumonia; PM = polymyositis; RA = rheumatoid arthritis; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome; UIP = usual interstitial pneumonia.

Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma (SD), Sjögren syndrome (SS), and polymyositis/dermatomyositis (PM/DM) can cause interstitial fibrosis similar to idiopathic pulmonary fibrosis (IPF). All CTDs like IPF involve the lung bases and are subpleural, except for ankylosing spondylitis (AS), which involves the upper lobes, and RA-induced interstitial lung disease (ILD). RA-ILD is differentiated from IPF on the basis of greater upper-lobe involvement, an anterior location, and the presence of reticular infiltrates finer than those associated with IPF (see the image below).

Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). The high-resolution computed tomography scan of advanced-stage pulmonary fibrosis demonstrates reticular opacities with honeycombing in a predominantly subpleural distribution. This pattern can be present in rheumatoid arthritis–related interstitial lung disease, Sjögren syndrome, and scleroderma.

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Radiologic features of mixed connective tissue disease (MCTD) vary across different studies. Radiologic abnormalities include subpleural honeycombing, bronchiolitis obliterans organizing pneumonia (BOOP), and pleural effusion.

Chest radiography

Chest radiographs can detect ILD; however, these may be normal initially.^[60]Thus, high-resolution computed tomography (CT) scanning remains the standard when it comes to the evaluation of CTD-related ILD (CTD-ILD). Depending on the type of CTD present and the extent of lung involvement, radiography may reveal a plethora of findings, including but not limited to ground-glass opacities, reticulations, pleural effusions, pulmonary nodules, bronchiectasis, volume loss, and prominent pulmonary vessels.

SS is manifested by a reticulonodular pattern of infiltrates involving lower lung zones. This finding may reflect the presence of lymphocytic interstitial fibrosis (see the image below). HRCT scans may reveal ground-glass opacities (GGOs) and bronchiolitis obliterans.^[61]

Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This chest radiograph was obtained from a patient with lymphocytic interstitial pneumonia.

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Ultrasonography

Although not yet adopted as a gold standard, data exists to suggest a role for the use of lung ultrasonography.^{[62, 63, 64, 65]}^[66]

Echocardiography can help detect cardiac involvement, which is useful in patients presenting with heart failure and in patients with suspected pulmonary hypertension.

Computed tomography (CT) scanning

Numerous studies show high-resolution (HR) CT findings and pulmonary function test (PFT) results correlate with underlying lung histopathology in patients with CTD.^[67]GGOs and consolidation may reflect the presence of interstitial pneumonia on CT scanning of the chest (see the image below). Pulmonary fibrosis is uncommon in patients with SLE; if present, it is usually patchy. The abnormalities occur mainly at the periphery of the lung and can be associated with traction bronchiectasis and honeycombing. The HRCT findings in CTD-ILD can be indistinguishable from those found in idiopathic interstitial pneumonia.

Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Ground-glass opacification (GGO) may correlate with active alveolitis and a favorable response to therapy. GGO is among the earliest features of rheumatoid arthritis–induced interstitial lung disease.

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RA is associated with the following four CT scan patterns:

Usual interstitial pneumonia (UIP)
Nonspecific interstitial pneumonia (NSIP)
Bronchiolitis^[68]
Organizing pneumonia (OP)^[69]

The most common CT scan features of RA-related lung disease are GGOs and reticulation.^{[18, 70]}RA can manifest as rheumatoid nodules, Caplan syndrome (rheumatoid nodules ≤5 cm, mostly involving the upper lungs in coal miners and resembling coal worker pneumoconiosis).^[71]In a smoker who has RA and presents with lung nodules, lung cancer should be ruled out first.^[72]

In patients with SD, HRCT scanning frequently shows evidence of interstitial pneumonitis and fibrosis, mainly involving the lower lobes, in a predominantly peripheral and posterior distribution.

PM/DM-induced lung disease is rare (5%). The most common pattern of ILD is symmetric and predominantly basal reticulation. HRCT scanning is remarkable for revealing prominent interlobular septa, patchy consolidation, and honeycombing. Patients with an acute presentation have GGOs and consolidation, in contrast to the reticulation and honeycombing seen in patients with the chronic type of ILD.

Nuclear imaging

Gallium scanning results may be abnormal in patients with CTDs, probably as a consequence of alveolitis. However, the role of gallium scanning in the diagnosis or prognosis of CTDs is not well established.

Pulmonary Function Tests

Pulmonary function testing (PFT) includes spirometry, lung volumes, diffusion capacity of the lung for carbon monoxide (DLCO), and arterial blood gas (ABG) measurements.

Most connective tissue diseases (CTDs) cause a restrictive lung disease pattern with a decrease in total lung capacity (TLC), residual volume (RV), functional residual capacity (FRC), and DLCO.^[73]Forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) (ie, the FEV₁/FVC ratio) may be normal or increased. However, bronchiolitis obliterans may cause an obstructive ventilatory defect (reduced FEV₁/FVC ratio and FEV₁, increased RV and RV/TLC ratio).

Arterial blood gas (ABG) analysis may reveal hypoxemia at rest. Arterial oxygen desaturation may occur with exercise. A 6-minute walk test with pulse oximetry provides a measure of oxygen desaturation and helps to detect disease progression.

Bronchoalveolar Lavage

Bronchoalveolar lavage (BAL) results are not diagnostic in patients with connective tissue diseases (CTDs), but they are diagnostic in excluding infections and can help narrow a differential diagnosis.^[74]

Studies have been performed to determine the importance of cell counts in BAL samples; patients with increased neutrophil counts tend to have a worse prognosis than those with increased lymphocyte counts.^[75]BAL results seem to correlate with the underlying lung pathology.^{[76, 77]}Similarly, BAL lymphocytosis may predict responsiveness to corticosteroids. Most patients with underlying interstitial lung disease (ILD) have lymphocytosis in BAL fluid. Finally, BAL is valuable for excluding infections that can mimic CTDs.

Biopsy

As with other interstitial lung diseases (ILDs), a transbronchial biopsy is usually inadequate for diagnosis, given the often patchy distribution of histologic findings. Although lung biopsies would provide a histopathologic diagnosis, they are often not required.

High-resolution computed tomography (HRCT) scanning results correlate well with the pathology of the underlying connective tissue disease (CTD).^[78]However, open lung biopsy is needed in atypical cases,^[79]depending on the clinical and functional status of the patient. Video-assisted thoracoscopic surgery is usually preferred.

Histologic Findings

The most common histopathologic findings in patients with connective disease tissues (CTDs) are interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), follicular bronchiolitis, diffuse alveolar hemorrhage (DAH), and lymphoid interstitial pneumonia (LIP).

Usual interstitial pneumonia

Histologic findings in UIP include fibroblastic foci with alternate areas of normal lung tissue, fibrosis, and honeycombing (see the image below). The distribution is peripheral, subpleural, and basal. These findings may be seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and mixed connective tissue disease (MCTD).

Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). The histologic image is from a patient with usual interstitial pneumonitis. Subpleural and paraseptal inflammation are present, with the appearance of temporal heterogeneity. Patchy scarring of the lung parenchyma and normal (or nearly normal) alveoli interspersed between fibrotic areas are hallmarks of this disease. In addition, the lung architecture is completely destroyed. This pattern can be present in rheumatoid arthritis–induced interstitial lung disease and is generally associated with a poor prognosis.

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Nonspecific interstitial pneumonia

Histologic findings in NSIP include varying proportions of interstitial inflammation and fibrosis, which may be divided into cellular and fibrosing and are patchy with intervening normal lung tissue.^[80]The distribution is peripheral, subpleural, basal, and symmetric. These findings may be seen in SLE, RA, DM/PM, and MCTD.

Lymphoid interstitial pneumonia

Histologic findings in LIP include infiltration of T cells, plasma cells, and macrophages, as well as lymphoid hyperplasia that is usually diffuse and predominantly septal. The distribution is diffuse. These findings may be seen in Sjögren syndrome (SS) and MCTD.

Organizing pneumonia

Histologic findings in OP include patchy intraluminal organizing fibrosis in air spaces, with preservation of lung architecture. The distribution is bronchovascular. These findings may be seen in SLE, scleroderma (SD), SS, and PM/DM.

Diffuse alveolar hemorrhage

Histologic findings in DAH include hyaline membrane formation, damaged type II pneumocytes, alveolar edema, and fibroblastic proliferation. Distribution is diffuse. These findings may be seen in SLE, RA, SD, and PM/DM.

Interstitial pneumonia with autoimmune features (IPAF)

The histopathologic features included within the morphologic domain criteria for IPAF are only those considered to be highly associated with, but not diagnostic for, the presence of CTDs. These are the primary patterns of NSIP, OP and LIP and the secondary features of interstitial lymphoid aggregates with germinal centers and diffuse lymphoplasmacytic infiltration, with or without lymphoid follicles.^[10]

Treatment & Management

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Media Gallery

Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Pulmonary hypertension is a complication of various collagen vascular diseases, referred to as connective tissue diseases. This lung biopsy specimen demonstrates severe interstitial fibrosis and medial fibrosis, as well as smooth muscle hyperplasia of a pulmonary arteriole, features that are compatible with pulmonary hypertension.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Note the heliotrope rash in a woman with dermatomyositis.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This image reveals Gottron papules and nail-fold telangiectasia in a patient with dermatomyositis.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This image shows the classic malar rash (butterfly rash), with distribution over the cheeks and nasal bridge. Note that the fixed erythema (sometimes associated with mild induration, as seen here) characteristically spares the nasolabial folds.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). The high-resolution computed tomography scan of advanced-stage pulmonary fibrosis demonstrates reticular opacities with honeycombing in a predominantly subpleural distribution. This pattern can be present in rheumatoid arthritis–related interstitial lung disease, Sjögren syndrome, and scleroderma.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Ground-glass opacification (GGO) may correlate with active alveolitis and a favorable response to therapy. GGO is among the earliest features of rheumatoid arthritis–induced interstitial lung disease.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This chest radiograph was obtained from a patient with lymphocytic interstitial pneumonia.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). The histologic image is from a patient with usual interstitial pneumonitis. Subpleural and paraseptal inflammation are present, with the appearance of temporal heterogeneity. Patchy scarring of the lung parenchyma and normal (or nearly normal) alveoli interspersed between fibrotic areas are hallmarks of this disease. In addition, the lung architecture is completely destroyed. This pattern can be present in rheumatoid arthritis–induced interstitial lung disease and is generally associated with a poor prognosis.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). In reviewing a retrospective database, Odham et al (Chicago cohort), showed a significant difference in mortality for patients with and without autoimmune features. CTD-ILD = Connective tissue disease-associated interstitial lung disease; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia. Reproduced with permission of the © ERS 2019. Eur Resp J. 2016 Jun:47(6):1767-75. DOI: 10.1183/13993003.01565-2015. Published 31 May 2016. PMID: 27103387.

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Table 1. Important Physical Findings in Connective Tissue Diseases

CTD	Skin and Musculoskeletal System	Lungs	Heart	Salivary Glands	Eyes
RA^*	Subcutaneous nodules, digital ulcers, nail-fold infarcts	Bibasilar Velcro crackles, signs of pulmonary hypertension, pleural effusion	Pericarditis, myocarditis	N/A	N/A
SLE^*	Malar rash, alopecia, livedo reticularis, erythema, telangiectasia, capillary infarcts, polyarthritis	Pleural effusion or rub, pneumonitis, cor pulmonale, diaphragmatic weakness	Pericarditis, myocarditis, CAD	N/A	N/A
SD	Thickening of skin of face, fingers, and hands; Raynaud phenomenon and ischemic changes of fingertips	Cor pulmonale, inspiratory "Velcro crackles" at lung bases	Restrictive pericardial disease, conduction defects, CHF	N/A	N/A
SS^*	Secondary SS can manifest similarly to RA and SLE	Secondary SS can manifest similarly to RA and SLE	N/A	Xerostomia, parotid gland swelling	Keratoconjunctivitis sicca
PM	Proximal muscle weakness	Respiratory muscle failure	N/A	N/A	N/A
DM	Heliotrope rash of eyelids, Gottron papules	Respiratory muscle failure	N/A	N/A	N/A
AS	Sacroiliitis	Restriction in chest expansion, pulmonary apical fibrosis	Aortic insufficiency	N/A	Anterior uveitis
^* Mixed connective tissue disease (MCTD) can manifest with the signs and symptoms of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or Sjögren syndrome (SS). AS = ankylosing spondylitis; CAD = coronary artery disease; CHF = congestive heart failure; CTD = connective-tissue disease; DM = dermatomyositis; PM = polymyositis; SD = scleroderma.

Table 2. Autoantibodies in Connective Tissue Diseases

Autoantibody	RA	SLE	SD	SS	PM/DM	AS	MCTD	IPAF #^[10]
RF	+	+	+	+	Rare	-	+	Possible
ANA	+	+	+	+	Rare	-	+ (speckled)	Possible
ds-DNA	-	+	-	-	-	-	-	Possible
Anti centromere	-	-	+ (limited)	Rare	Rare	-	-	Possible
Scl-70	-	-	+ (diffuse)		Rare	-	-	Possible
Anti-Jo	-	-	-	Rare	+ (ILD)	-	-	Possible
ANCA	Rare	Rare	-	-	-	-	-	-
Smith antibody	-	+	-	-	-	-	-	Possible
Anti-Ro/SSA and anti-La/SSB	-	-	-	+	-	-	-	Possible
Anti-U1-RNP and anti-UN-70 kd	-	-	-	-	-	-	+	Possible
Anti-CCP	+	-	-	-	-	-	-	Possible
ANA = antinuclear antibody; ANCA = antineutrophilic cytoplasmic antibody; AS = ankylosing spondylitis; CCP = cyclic citrullinated peptide; DM = dermatomyositis; ds-DNA = double-stranded DNA antibody; ILD = interstitial lung disease; IPAF = interstitial pneumonia with autoimmune features; MCTD = mixed connective-tissue disease; PM = polymyositis; RA = rheumatoid arthritis; RF = rheumatoid factor; RNP = ribonucleoprotein; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome.

Table 3. Radiologic Patterns of Connective Tissue Diseases

Radiologic Pattern	RA	SLE	SD	Secondary SS	PM/DM	AS	MCTD	IPAF ^[10]
Pleural effusion	+	+	+	±	-	-	+	May be present
Interstitial pneumonitis, fibrosis	UIP and NSIP patterns	+	LIP pattern	±	+	Upper apical fibrosis^[59]	+	NISP, OP, LIP or NISP with OP overlap pattern
BOOP	±	+	+	+	+	±	±
Pulmonary nodules	Rheumatoid pulmonary nodules; uncommon, maybe 1-5 mm, single or multiple, may cavitate	-	-	Follicular lymphoid hyperplasia or lymphoma can present as lung nodules	+	-	-
Bronchiectasis	+	+	+	+	+	+	+	unexplained airflow obstruction, bronchiolitis or bronchiectasis.
Caplan syndrome	Coal worker pneumoconiosis, rheumatoid nodules	-	-	-	-	-	±
Diffuse pulmonary hemorrhage	-	+	-	-	-	-	±
Shrinking lung syndrome	-	Loss of lung volume at bases with no parenchymal pathology	-	-	-	-	±
Diaphragmatic dysfunction	-	+	-	May be present	+	-	±
Cysts, honeycombing	10% of patients have subpleural honeycombing; compared with IPF, it is more anterior and involves upper lobes	Uncommon	+	Present, especially in LIP	+	Upper-lobe cyst may become infected with Aspergillus species	-
GGO	Present, especially in NSIP	+	+	+	+	-	±
AS = ankylosing spondylitis; BOOP = bronchiolitis obliterans organizing pneumonia; DM = dermatomyositis; GGO = ground-glass opacification; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; LIP = lymphoid interstitial pneumonia; MCTD = mixed connective-tissue disease; NSIP = nonspecific interstitial pneumonia; OP = organizing pneumonia; PM = polymyositis; RA = rheumatoid arthritis; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome; UIP = usual interstitial pneumonia.

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Author

Aniruddh Kapoor, MBBS Fellow in Pulmonary Disease and Critical Care Medicine, St Louis University Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Setu K Patolia, MD, MPH Assistant Professor of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Director of Interventional Pulmonary Services, Associate Program Director for Pulmonary and Critical Care Fellowship, St Louis University School of Medicine

Setu K Patolia, MD, MPH is a member of the following medical societies: American Association for Bronchology and Interventional Pulmonology, American College of Chest Physicians, American Thoracic Society, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

David Picker, MD, MBA Attending Physician, Department of Pulmonary Disease and Critical Care Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society

Disclosure: Nothing to disclose.

Additional Contributors

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director, Pulmonary Medicine General Practice Unit (F2), Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, Society of Critical Care Medicine

Disclosure: Received research grant from: Sanofi Pharmaceutical.

Arshad Ali, MD Attending Physician, Department of Pulmonary and Critical Care Medicine, Mercy General Hospital of Sacramento

Arshad Ali, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Danilo A Enriquez, MD, FCCP Clinical Assistant Professor of Medicine, State University of New York Health Science Center at Brooklyn; Associate Program Director of Internal Medicine Residency Program, Interfaith Medical Center

Danilo A Enriquez, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association

Disclosure: Nothing to disclose.

Isabel F Pedraza, MD Director, Respiratory Intensive Care Unit, Faculty Physician, Department of Medicine, Division of Pulmonary/Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Southern California Keck School of Medicine

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Osler Society, American Thoracic Society, New York Academy of Medicine, and Royal Society of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment