Restrictive Lung Disease

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Background

Restrictive lung diseases are characterized by reduced lung volumes, either because of an alteration in lung parenchyma or because of a disease of the pleura, chest wall, or neuromuscular apparatus. Unlike obstructive lung diseases, including asthma and COPD, which show a normal or increased total lung capacity (TLC), restrictive disease are associated with a decreased TLC. Measures of expiratory airflow are preserved and airway resistance is normal. If caused by parenchymal lung disease, restrictive lung disorders are accompanied by reduced gas transfer, which may be marked clinically by desaturation after exercise.

The many disorders that cause reduction or restriction of lung volumes may be divided into 2 groups based on anatomical structures.

The first is intrinsic lung diseases or diseases of the lung parenchyma. The diseases cause inflammation or scarring of the lung tissue (interstitial lung disease) or result in filling of the air spaces with exudate and debris (pneumonitis). These diseases can be characterized according to etiological factors. They include idiopathic fibrotic diseases, connective-tissue diseases, drug-induced lung disease, and primary diseases of the lungs (including sarcoidosis).

The second is extrinsic disorders or extra-pulmonary diseases. The chest wall, pleura, and respiratory muscles are the components of the respiratory pump, and they need to function normally for effective ventilation. Diseases of these structures result in lung restriction, impaired ventilatory function, and respiratory failure (eg, nonmuscular diseases of the chest wall, neuromuscular disorders).

The mnemonic "PAINT" has been used to divide the causes of restrictive lung disease into pleural, alveolar, interstitial, neuromuscular, and thoracic cage abnormalities.


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Pathophysiology

Air flows to and from the alveoli as lungs inflate and deflate during each respiratory cycle. Lung inflation is accomplished by a contraction of respiratory, diaphragmatic, and external intercostal muscles, whereas deflation is passive at rest. FRC is the volume of air in the lungs when the respiratory muscles are fully relaxed and no airflow is present. The volume of FRC is determined by the balance of the inward elastic recoil of the lungs and the outward elastic recoil of the chest wall. Restrictive lung diseases are characterized by a reduction in FRC and other lung volumes because of pathology in lungs, pleura, or the structures of the thoracic cage.

The distensibility of the respiratory system is called compliance, the volume change produced by a change in the distending pressure. Lung compliance is independent of the thoracic cage, which is a semirigid container. The compliance of an intact respiratory system is an algebraic sum of the compliances of both of these structures; therefore, it is influenced by any disease of the lungs, pleura, or chest wall.

In cases of intrinsic lung disease, the physiological effects of diffuse parenchymal disorders reduce all lung volumes by the excessive elastic recoil of the lungs, in comparison to the outward recoil forces of the chest wall. Expiratory airflow is reduced in proportion to lung volume.

Arterial hypoxemia in disorders of pulmonary parenchyma is primarily caused by ventilation-perfusion mismatching, with further contribution from an intrapulmonary shunt. Decreased diffusion of oxygen contributes significantly to exercise-induced desaturation.

Hyperventilation at rest and exercise is caused by the reflexes arising from the lungs and the need to maintain minute ventilation by reducing tidal volume and increasing respiratory frequency.

In cases of disorders of the pleura and thoracic cage, the total compliance by the respiratory system is reduced, and, hence, lung volumes are reduced. As a result of atelectasis, gas distribution becomes nonuniform, resulting in ventilation-perfusion mismatch and hypoxemia. In kyphoscoliosis, lateral curvature, anteroposterior angulation, kyphosis, or several of these conditions are present. The Cobb angle, an angle formed by 2 limbs of a convex prime curvature of the spine, is an indication of the severity of disease. An angle greater than 100° is usually associated with respiratory failure.

Neuromuscular disorders affect an integral part of the respiratory system, a vital pump. The respiratory pump can be impaired at the level of the central nervous system, spinal cord, peripheral nervous system, neuromuscular junction, or respiratory muscle. The pattern of ventilatory impairment is highly dependent on the specific neuromuscular disease.

Obesity is becoming a major cause of restrictive lung disease in the developed world. Over 30% of American adults are classified as obese, with a BMI greater than 30. There is an inverse relationship between BMI and lung volumes. Jones et al[34] showed that FRC and ERV were the parameters most dramatically reduced by increasing BMI, but that VC and TLC decrease as well. FRC and ERV can even be significantly reduced in the overweight, with BMI of 25-30.

Epidemiology

Frequency

United States

For intrinsic lung diseases, studies cite an overall prevalence of 3-6 cases per 100,000 persons. The prevalence of idiopathic pulmonary fibrosis (IPF) is 27-29 cases per 100,000 persons. The prevalence for adults aged 35-44 years is 2.7 cases per 100,000 persons. Prevalence exceeded 175 cases per 100,000 persons among patients older than 75 years. Exposure to dust, metals, organic solvents, and agricultural employment is associated with increased risk.

International

In Sweden, the prevalence rate for sarcoidosis is 64 cases per 100,000 persons. In Japan, the prevalence rate of sarcoidosis is 10-40 cases per 100,000 persons. The prevalence of sarcoidosis is difficult to determine, and tuberculosis is common.

The worldwide prevalence of fibrotic lung diseases is difficult to determine because studies have not been performed.

Mortality/Morbidity

The mortality and morbidity from various causes of restrictive lung disease is dependent on the underlying case of the disease process.

The median survival time for patients with IPF is less than 3 years. Factors that predict poor outcome include older age, male sex, severe dyspnea, history of cigarette smoking, severe loss of lung function, appearance and severity of fibrosis on radiologic studies, lack of response to therapy, and prominent fibroblastic foci on histopathologic evaluation.

See the image below.


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Gross pathology of small and firm lungs due to restrictive lung disease from advanced pulmonary fibrosis.

Race

Although a familial variant of IPF exists, a genetic predisposition is not documented. US prevalence of sarcoidosis is estimated to be 10-17 times higher among African Americans compared to white Americans.

Sex

Lymphangioleiomyomatosis (LAM) and lung involvement in tuberous sclerosis occur primarily in premenopausal women, although a handful of cases of LAM have been reported in men. Men are more likely to have pneumoconiosis because of occupational exposure, IPF, and collagen-vascular diseases (eg, rheumatoid lung). Worldwide, sarcoidosis is slightly more common in women.

Age

IPF is rare in children. Some intrinsic lung diseases present in patients aged 20-40 years. These include sarcoidosis, collagen-vascular–associated diseases, and pulmonary Langerhans cell histiocytosis (formerly referred to as histiocytosis X). Most patients with IPF are older than 50 years.

History

The initial evaluation of patients should consist of a complete history, including a total review of past systemic conditions. A careful history of occupation, travel, habits, hobbies, exposures, and HIV risk factors is critical to help identify any etiologic agent.

Physical

Causes

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Histologic Findings

The histological findings of various interstitial pneumonias include an interstitial cellular infiltrate and interstitial fibrosis, eventually leading to an end-stage honeycomb lung. These findings are described in detail in Procedures.

Table. Contrasting Clinical, Radiologic, and Histologic Features of Acute Interstitial Pneumonia (AIP), Usual Interstitial Pneumonia (UIP), Nonspecific Interstitial Pneumonia (NSIP),[14] and COP[15]


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See the images below.


View Image

Histopathology of a case of idiopathic pulmonary fibrosis. Alveolitis with fibroblast proliferation and collagen deposition is present.


View Image

In usual interstitial pneumonitis or idiopathic pulmonary fibrosis, subpleural and paraseptal inflammation is present, with an appearance of temporal ....


View Image

Characteristic features of usual interstitial pneumonitis as described in the image below.


View Image

Cryptogenic organizing pneumonia (also called proliferative bronchiolitis) is often patchy and peribronchiolar. The proliferation of granulation tissu....


View Image

Cryptogenic organizing pneumonia, as described in the image below, showing a close-up view of fibrogranulation tissue in terminal airspaces.


View Image

Granulomatous lung diseases are marked by granulomas characterized by the accumulation of T lymphocytes, macrophages, and epithelioid cells. These may....


View Image

Multiple well-formed noncaseating granulomas secondary to sarcoidosis.


View Image

Sarcoid granulomas.


View Image

High-power view of sarcoid granuloma shows giant cells.


View Image

A patient who developed restrictive lung disease had findings of cryptogenic organizing pneumonia on an open lung biopsy specimen.


View Image

A patient who developed restrictive lung disease had findings of cryptogenic organizing pneumonia on an open lung biopsy specimen. The biopsy sample s....


View Image

Lymphocytic interstitial pneumonitis, for which the prominent finding is a lymphoid infiltrate that involves both the interstitium and alveolar spaces....


View Image

Usual interstitial pneumonitis honeycombing.

Medical Care

Treatment depends on the specific diagnosis, which is based on findings from the clinical evaluation, imaging studies, and lung biopsy.

Corticosteroids, immunosuppressive agents, and cytotoxic agents are the mainstay of therapy for many of the interstitial lung diseases. Objective data assessing the risks and benefits of immunosuppressive and cytotoxic agents to treat diverse interstitial lung disorders are sparse. Direct comparisons among these agents are lacking.

Ancillary therapies include supplemental oxygen therapy, which alleviates exercise-induced hypoxemia and improves performance.

Surgical Care

If a pleural disorder is the cause of the restriction, surgery can occasionally be curative. Trapped lung and chronic empyema may be cured with decortication. FVC and FEV1 improve after decortication for chronic empyema, and chest wall deformity may improve after surgery as well.[36]

Consultations

Medication Summary

Medications are best used for specific diagnoses. Corticosteroids, cytotoxic agents, and immunosuppressive agents have been used with varying success.

Prednisone (Sterapred)

Clinical Context:  Used as an immunosuppressant in the treatment of autoimmune disorders. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation. Oral corticosteroid with relatively less mineralocorticoid activity.

Therapy is best prescribed in consultation with a pulmonary disease specialist.

Class Summary

Have anti-inflammatory properties and can modify the body's immune response.

Cyclophosphamide (Cytoxan, Neosar)

Clinical Context:  Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells of immune system. Possible steroid-sparing medication.

Azathioprine (Imuran)

Clinical Context:  Inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins. These effects may decrease proliferation of immune cells and result in lower autoimmune activity. Possible steroid-sparing medication.

Class Summary

These agents inhibit cell growth and proliferation.

Colchicine

Clinical Context:  Decreases leukocyte motility and phagocytosis observed in inflammatory responses.

Class Summary

Reduce inflammation by inhibiting key steps of the immune system.

Deterrence/Prevention

Acute exacerbation in patients with idiopathic pulmonary fibrosis (IPF) is a recently recognized complication that occurs unpredictably and presents as worsening dyspnea. Chest radiography demonstrates bilateral mixed alveolar-interstitial infiltrates and CT scan reveals ground-glass opacities and consolidation. The treatment includes high-dose systemic corticosteroids, although these are likely not effective, and the disease portends extremely poor prognosis.

Complications

Acute exacerbation in patients with IPF is a recently recognized complication that occurs unpredictably and presents as worsening dyspnea. Chest radiography demonstrates bilateral mixed alveolar-interstitial infiltrates and CT scan reveals ground-glass opacities and consolidation. The treatment includes high-dose systemic corticosteroids, although these are likely not effective, and the disease portends extremely poor prognosis.

Prognosis

Author

Jonathan Robert Caronia, DO, Fellow, Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, North Shore LIJ Health System

Disclosure: Nothing to disclose.

Coauthor(s)

Klaus-Dieter Lessnau, MD, FCCP, Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Disclosure: Nothing to disclose.

Lalit K Kanaparthi, MD, Attending Physician, North Florida Lung Associates

Disclosure: Nothing to disclose.

Specialty Editors

Laurie Robin Grier, MD, Medical Director of MICU, Professor of Medicine, Emergency Medicine, Anesthesiology and Obstetrics/Gynecology, Fellowship Director for Critical Care Medicine, Section of Pulmonary and Critical Care Medicine, Louisiana State University Health Science Center at Shreveport

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

Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Chair of the Credentials Committee, Pulmonary and Critical Care Fellowship Program, Henry Ford Hospital; Chair, Guidelines Oversight Committee, American College of Chest Physicians

Disclosure: Nothing to disclose.

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Ryland P Byrd Jr, MD, Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Disclosure: Nothing to disclose.

Additional Contributors

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

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Gross pathology of small and firm lungs due to restrictive lung disease from advanced pulmonary fibrosis.

Approximately half of the patients with idiopathic pulmonary fibrosis develop clubbing. Clubbing is commonly seen in patients with asbestosis.

Chest radiograph of a 67-year-old man diagnosed with idiopathic pulmonary fibrosis, based on open lung biopsy findings. Extensive bilateral reticulonodular opacities are seen in both lower lobes.

A chest radiograph of stage III sarcoidosis. This stage refers to pulmonary infiltrates without evidence of mediastinal lymphadenopathy.

Chest radiograph from a 39-year-old woman with severe kyphoscoliosis who developed hypercapnic respiratory failure. Spirometry findings showed a severe restrictive lung disease, with a forced expiratory volume in one second of 0.4 L/s and a forced vital capacity of 0.5 L.

High-resolution CT scan of the same patient in the image below demonstrates peripheral honeycombing and several areas of ground-glass attenuation. Ground-glass opacification may correlate with active alveolitis and a favorable response to therapy.

A CT scan image from a 59-year-old woman shows advanced pulmonary fibrosis. Extensive honeycombing and traction bronchiectasis are present.

Restrictive lung disease may occur in stage II and stage III sarcoidosis. In this image, mediastinal lymphadenopathy is shown secondary to stage II disease.

Sarcoidosis on CT scan shows nodules in midlung zones. These nodules are predominantly along the bronchovascular bundles and in a subpleural location.

Restrictive lung disease secondary to sarcoidosis.

Lung volume is plotted against transpulmonary pressure. Compliance is the change in volume for a given change in pressure. A patient with emphysema has much higher lung compliance compared to a patient with intrinsic lung disease.

Idealized flow volume curves for normal, obstructive, and restrictive lungs.

The expiratory flow volume curves of 2 patients are depicted graphically. A is a patient with restrictive lung disease (idiopathic pulmonary fibrosis), low forced vital capacity (FVC), but an increased ratio of forced expiratory volume in 1 second (FEV1) to FVC because of increased elastic recoil. B is a patient with chronic obstructive lung disease whose FEV1/FVC ratio is low but whose lung volumes are increased.

Pulmonary function test results from a patient with restrictive lung disease.

Intrinsic lung disease may progress to extensive fibrosis, regardless of etiology. This is described as honeycomb lung.

Histopathology of a case of idiopathic pulmonary fibrosis. Alveolitis with fibroblast proliferation and collagen deposition is present.

In usual interstitial pneumonitis or idiopathic pulmonary fibrosis, subpleural and paraseptal inflammation is present, with an appearance of temporal heterogeneity. Patchy scarring of the lung parenchyma and normal, or nearly normal, alveoli interspersed between fibrotic areas are the hallmarks of this disease. Additionally, the lung architecture is completely destroyed.

Characteristic features of usual interstitial pneumonitis as described in the image below.

Cryptogenic organizing pneumonia (also called proliferative bronchiolitis) is often patchy and peribronchiolar. The proliferation of granulation tissue within small airways and alveolar ducts is excessive and is associated with chronic inflammation of surrounding alveoli.

Cryptogenic organizing pneumonia, as described in the image below, showing a close-up view of fibrogranulation tissue in terminal airspaces.

Granulomatous lung diseases are marked by granulomas characterized by the accumulation of T lymphocytes, macrophages, and epithelioid cells. These may progress to pulmonary fibrosis. This low-power image shows well-formed granuloma along the airway.

Multiple well-formed noncaseating granulomas secondary to sarcoidosis.

Sarcoid granulomas.

High-power view of sarcoid granuloma shows giant cells.

A patient who developed restrictive lung disease had findings of cryptogenic organizing pneumonia on an open lung biopsy specimen.

A patient who developed restrictive lung disease had findings of cryptogenic organizing pneumonia on an open lung biopsy specimen. The biopsy sample shows intraluminal buds of granulation tissue.

Lymphocytic interstitial pneumonitis, for which the prominent finding is a lymphoid infiltrate that involves both the interstitium and alveolar spaces.

Usual interstitial pneumonitis honeycombing.

Approximately half of the patients with idiopathic pulmonary fibrosis develop clubbing. Clubbing is commonly seen in patients with asbestosis.

Lung volume is plotted against transpulmonary pressure. Compliance is the change in volume for a given change in pressure. A patient with emphysema has much higher lung compliance compared to a patient with intrinsic lung disease.

Idealized flow volume curves for normal, obstructive, and restrictive lungs.

The expiratory flow volume curves of 2 patients are depicted graphically. A is a patient with restrictive lung disease (idiopathic pulmonary fibrosis), low forced vital capacity (FVC), but an increased ratio of forced expiratory volume in 1 second (FEV1) to FVC because of increased elastic recoil. B is a patient with chronic obstructive lung disease whose FEV1/FVC ratio is low but whose lung volumes are increased.

Pulmonary function test results from a patient with restrictive lung disease.

Gross pathology of small and firm lungs due to restrictive lung disease from advanced pulmonary fibrosis.

Intrinsic lung disease may progress to extensive fibrosis, regardless of etiology. This is described as honeycomb lung.

End-stage sarcoidosis.

Usual interstitial pneumonitis (left).

Usual interstitial pneumonitis (right).

Histopathology of a case of idiopathic pulmonary fibrosis. Alveolitis with fibroblast proliferation and collagen deposition is present.

In usual interstitial pneumonitis or idiopathic pulmonary fibrosis, subpleural and paraseptal inflammation is present, with an appearance of temporal heterogeneity. Patchy scarring of the lung parenchyma and normal, or nearly normal, alveoli interspersed between fibrotic areas are the hallmarks of this disease. Additionally, the lung architecture is completely destroyed.

Characteristic features of usual interstitial pneumonitis as described in the image below.

Cryptogenic organizing pneumonia (also called proliferative bronchiolitis) is often patchy and peribronchiolar. The proliferation of granulation tissue within small airways and alveolar ducts is excessive and is associated with chronic inflammation of surrounding alveoli.

Cryptogenic organizing pneumonia, as described in the image below, showing a close-up view of fibrogranulation tissue in terminal airspaces.

Granulomatous lung diseases are marked by granulomas characterized by the accumulation of T lymphocytes, macrophages, and epithelioid cells. These may progress to pulmonary fibrosis. This low-power image shows well-formed granuloma along the airway.

Multiple well-formed noncaseating granulomas secondary to sarcoidosis.

Sarcoid granulomas.

High-power view of sarcoid granuloma shows giant cells.

A patient who developed restrictive lung disease had findings of cryptogenic organizing pneumonia on an open lung biopsy specimen.

A patient who developed restrictive lung disease had findings of cryptogenic organizing pneumonia on an open lung biopsy specimen. The biopsy sample shows intraluminal buds of granulation tissue.

Lymphocytic interstitial pneumonitis, for which the prominent finding is a lymphoid infiltrate that involves both the interstitium and alveolar spaces.

Usual interstitial pneumonitis honeycombing.

Chest radiograph of a 67-year-old man diagnosed with idiopathic pulmonary fibrosis, based on open lung biopsy findings. Extensive bilateral reticulonodular opacities are seen in both lower lobes.

High-resolution CT scan of the same patient in the image below demonstrates peripheral honeycombing and several areas of ground-glass attenuation. Ground-glass opacification may correlate with active alveolitis and a favorable response to therapy.

A CT scan image from a 59-year-old woman shows advanced pulmonary fibrosis. Extensive honeycombing and traction bronchiectasis are present.

Restrictive lung disease may occur in stage II and stage III sarcoidosis. In this image, mediastinal lymphadenopathy is shown secondary to stage II disease.

Sarcoidosis on CT scan shows nodules in midlung zones. These nodules are predominantly along the bronchovascular bundles and in a subpleural location.

Restrictive lung disease secondary to sarcoidosis.

A chest radiograph of stage III sarcoidosis. This stage refers to pulmonary infiltrates without evidence of mediastinal lymphadenopathy.

Chest radiograph from a 39-year-old woman with severe kyphoscoliosis who developed hypercapnic respiratory failure. Spirometry findings showed a severe restrictive lung disease, with a forced expiratory volume in one second of 0.4 L/s and a forced vital capacity of 0.5 L.

The flow volume curve of a patient with lung fibrosis.

Likely case of idiopathic pulmonary fibrosis, which should be treated with prednisone.

CausesExamplesDiagnosisPFT Findings
PleuralTrapped lung, pleural scarring, large pleural effusions, chronic empyema, asbestosisRadiography, CT scanning, pleural manometry, pleural biopsyLow RV, low TLC, low FVC
AlveolarEdema, hemorrhageRadiography, CT scanning, physical examinationIncreased DLCO in hemorrhage
InterstitialInterstitial lung disease including IPF, NSIP, COPRadiography, CT scanning, physical examination, echo often shows pulmonary hypertensionLow RV, low FVC, low TLC, decreased DLCO, poor lung compliance
NeuromuscularMyasthenia gravis, ALS, myopathyPhysical examination, EMGs, serologyLow RV, low TLC, low NIF, low MMV
Thoracic/extrathoracicObesity, kyphoscoliosis, ascitesPhysical examinationLow ERV and FRC in obesity, low VC, TLC, FRC in kyphoscoliosis
FeaturesAIPUIPNSIPCOP
Pathologic
Temporal appearanceUniformHeterogeneousUniformUniform
Interstitial inflammationScantScantUsually prominentVariable
Collagen fibrosisNoPatchyVariable, diffuseNo
Fibroblast proliferationDiffuse, interstitialPatchy (fibroblast foci)OccasionalPatchy, airspace
COP areasRareNoRare--
Honeycomb changesRareYesRareNo
Hyaline membranesYes, often focalNoNoNo