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, such as asthma and chronic obstructive pulmonary disease (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 and the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio is increased. 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 two 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.

Table 1. Causes of Restrictive Lung Disease.



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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 two 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[1] 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.(I pulled some recent refs with varying numbers.[2, 3] 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.

In North America, the prevalence of sarcoidosis is 10-40 cases per 100,000 persons.

The incidence of chronic interstitial lung diseases in persons with collagen-vascular diseases is variable, but it is increasing for most diseases.

Kyphoscoliosis is a common extrinsic disorder. It is associated with an incidence of mild deformities amounting to 1 case per 1000 persons, with severe deformity occurring in 1 case per 10,000 persons.

Other nonmuscular and neuromuscular disorders are rare, but their incidence and prevalence are not well known.

According to the CDC, 35.9% of Americans older than 20 years are obese, and 69% of Americans are at least overweight (BMI 25-30).[4]

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.

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.

Prognosis

The natural history of interstitial lung diseases is variable. It depends on the specific diagnosis and the extent and severity of lung involvement based on high-resolution CT scanning and lung biopsy.[5] IPF is typically a relentless progressive disorder, and patients have a mean survival of 3-6 years after diagnosis.[6] Early recognition of IPF is important for directing patient management and predicting prognosis.[7]

Pulmonary sarcoidosis has a relatively benign self-limiting course, with spontaneous recovery or stabilization in most cases. Approximately 15% of patients develop pulmonary fibrosis and disability.

Prognosis for collagen-vascular diseases, eosinophilic pneumonia, COP, and drug-induced lung disease is generally favorable with treatment.

Patients with chest wall diseases and neuromuscular disorders develop progressive respiratory failure and succumb during an intercurrent pulmonary infection.

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.

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 or trigger.

Duration of illness

Acute disorders last days to weeks and include acute interstitial pneumonitis, eosinophilic pneumonia, and diffuse alveolar hemorrhage.

Hypersensitivity pneumonitis and cryptogenic organizing pneumonia (COP) may manifest as acute, subacute, or chronic disease.

Subacute disorders lasting weeks to months include sarcoidosis, drug-induced interstitial lung disease, alveolar hemorrhage syndrome, COP, and connective-tissue diseases.[8]

Chronic cases lasting months to years include idiopathic pulmonary fibrosis (IPF), sarcoidosis, and pulmonary Langerhans cell histiocytosis.

Smoking history

Pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonitis, IPF, and respiratory bronchiolitis occur with increased frequency among persons who smoke or those who previously smoked.

Prior medication use

A detailed history of previously used medications is needed to exclude the possibility of drug-induced lung disease. These commonly used drugs are nitrofurantoin, amiodarone, gold, chemotherapeutic agents, procainamide, and hydralazine.

Radiation may also cause pneumonitis and fibrosis.

Family history

Familial associations include IPF, sarcoidosis, and LAM.

Occupational history

Seek a strict chronological listing of the patient's lifelong employment, including specific duties and known exposures.

Inhaled inorganic dust from substances (eg, silica, asbestos, beryllium, hard metals, cobalt) can cause pneumoconiosis.[9, 10]

Inhaled organic dust may cause hypersensitivity pneumonitis.

Environmental exposure

A review of the domestic and work environment of the patient and spouse is invaluable.

Symptoms of intrinsic diseases

Progressive exertional dyspnea is the predominant symptom. Grading the level of dyspnea is useful as a method to gauge the severity of the disease and to follow its course.

A dry cough is common and may be a disturbing sign. A productive cough is an unusual sign in most patients with diffuse parenchymal lung disorders.

Hemoptysis or grossly bloody sputum occurs in patients with diffuse alveolar hemorrhage syndromes and vasculitis.

Wheezing is an uncommon manifestation but can occur in patients with lymphangitic carcinomatosis, chronic eosinophilic pneumonia, and respiratory bronchiolitis.

Chest pain is uncommon in most instances of the disease, but pleuritic chest pain can occur in patients with rheumatoid arthritis, systemic lupus erythematosus, and some drug-induced disorders.[11]

Symptoms of extrinsic disorders

Nonmuscular diseases of the chest wall affect patients with kyphoscoliosis. Patients younger than 35 years tend to be asymptomatic, whereas middle-aged patients develop dyspnea, decreased exercise tolerance, and respiratory infections.

The cause of respiratory failure is often multifactorial and is secondary to spinal deformity, muscle weakness, disordered ventilatory control, sleep disordered breathing, and airway disease.

Neuromuscular disorders occur as the respiratory muscle weakness progresses. Patients develop dyspnea upon exertion, followed by dyspnea at rest, and their condition ultimately advances to respiratory failure.

Patients with neuromuscular diseases develop significant respiratory muscle weakness and may demonstrate fatigue, dyspnea, impaired control of secretions, and recurrent lower respiratory tract infections. In these patients, the central drive is not decreased.[12] Acute and chronic respiratory failure, pulmonary hypertension, and cor pulmonale eventually ensue.

Physical Examination

Intrinsic disorders

The physical examination in patients with intrinsic lung disorders may yield distinguishing physical findings.

Velcro crackles are common in most patients with interstitial lung disorders.

Inspiratory squeaks or scattered, late, inspiratory high-pitched rhonchi are frequently heard in patients with bronchiolitis.

Cyanosis at rest is uncommon in persons with interstitial lung diseases, and this is usually a late manifestation of advanced disease.

Digital clubbing is common in those with idiopathic pulmonary fibrosis (IPF) and is rare in others (eg, those with sarcoidosis or hypersensitivity pneumonitis). See the image below.



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

Extrapulmonary findings, including erythema nodosum, suggest sarcoidosis. A maculopapular rash can occur in those with connective-tissue diseases, or it may be drug-induced. Raynaud phenomenon may be present in patients with connective-tissue diseases, and telangiectasia is present in those with scleroderma. Peripheral lymphadenopathy, salivary gland enlargement, and hepatosplenomegaly are signs of systemic sarcoidosis. Uveitis may be observed in those with sarcoidosis and ankylosing spondylitis.

Cor pulmonale occurs in the late stages of pulmonary fibrosis or advanced kyphoscoliosis. Pulmonary hypertension and cor pulmonale become evident when signs include a loud P2, right-sided precordial lift, and right-sided gallop.

Extrinsic disorders

By their very nature, severe kyphoscoliosis and massive obesity are easily recognizable. The pleural disorders are associated with decreased tactile fremitus, dullness upon percussion, and decreased intensity of breath sounds.

In cases of neuromuscular diseases, the physical examination findings may indicate accessory muscles usage, rapid shallow breathing, paradoxical breathing, and other features of systemic involvement.

Causes

Intrinsic lung diseases

Collagen-vascular diseases, including scleroderma, polymyositis, dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, and ankylosing spondylitis, are a causes of restrictive lung disease.

Other causes may include drugs and other treatments (eg, nitrofurantoin, amiodarone, gold, phenytoin [Dilantin], bleomycin, bischloroethylnitrosourea [BCNU or carmustine], cyclophosphamide, methotrexate, radiation). Also see Drug-Induced Pulmonary Toxicity.

Causes related to primary or unclassified diseases may include sarcoidosis, pulmonary Langerhans cell histiocytosis, LAM, pulmonary vasculitis, alveolar proteinosis, eosinophilic pneumonia, and COP.

Inorganic dust exposure (eg, silicosis, asbestosis, talc, pneumoconiosis, berylliosis, hard metal fibrosis, coal worker's pneumoconiosis) may cause restrictive lung disease.

Organic dust exposure (eg, farmer's lung, bird fancier's lung, bagassosis, and mushroom worker's lung, which all cause hypersensitivity pneumonitis) is another cause.

Idiopathic fibrotic disorders

These may include acute interstitial pneumonia, idiopathic pulmonary fibrosis (IPF, usually interstitial pneumonitis), lymphocytic interstitial pneumonitis, desquamative interstitial pneumonitis, and nonspecific interstitial pneumonitis.

Extrinsic disorders

Nonmuscular diseases of the chest wall, in which kyphosis can be idiopathic or secondary, may cause restrictive lung disease. The most common cause of secondary kyphoscoliosis is neuromuscular disease (eg, polio, muscular dystrophy). Fibrothorax, massive pleural effusion, morbid obesity, ankylosing spondylitis, and thoracoplasty are other causes.

Neuromuscular diseases manifest as respiratory muscle weakness and are due to myopathy or myositis, quadriplegia, or phrenic neuropathy from infectious or metabolic causes.

Pleural diseases, including trapped lung or asbestos related pleural plaques, are an underrecognized, and potentially treatable, cause of restrictive lung disease.

Complications

Acute exacerbation in patients with IPF is a 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 worsening disease portends extremely poor prognosis.

Laboratory Studies

Intrinsic lung diseases

Routine laboratory evaluations often fail to reveal positive findings. However, anemia can indicate vasculitis, polycythemia can indicate hypoxemia in advanced disease, and leukocytosis can suggest acute hypersensitivity pneumonitis.

The decision to perform additional tests should be directed by the findings of the clinical assessment. Antinuclear antibodies and rheumatoid factor should be measured to screen for collagen vascular disorders, creatine kinase for polymyositis, antineutrophilic cytoplasmic antibodies for vasculitis, and antiglomerular basement membrane antibody for Goodpasture syndrome.

The presence of precipitating antibodies to an antigen may help in diagnosing hypersensitivity pneumonitis. Serum angiotensin-converting enzyme levels are often elevated in patients with sarcoidosis, but this finding has poor specificity.

Extrinsic disorders

An elevated creatine kinase level may indicate myositis, which may cause muscle weakness and restrictive lung disease.

Imaging Studies

Chest radiography for intrinsic lung disorders

The diagnosis of an interstitial lung disorder is often initially based on abnormal chest radiograph findings, which can be normal in as many as 10% of patients. All previous chest films should be reviewed.

The most common radiographic abnormality is a reticular pattern. Nodular, reticulonodular, or mixed patterns, such as alveolar filling (ie, ground-glass appearance), and increased interstitial markings are not unusual; however, these are not predictive of a specific pathological picture. High-resolution CT scanning can be helpful in such cases by providing an accurate assessment and is recommended before lung biopsy.[13, 14]

Air-space opacities suggest pulmonary hemorrhage, eosinophilic pneumonia, and COP.

Upper-zone predominance on chest radiographs is observed in patients with sarcoidosis, pulmonary Langerhans cell histiocytosis, chronic hypersensitivity pneumonitis, pneumoconiosis, or ankylosing spondylitis. Lower-zone predominance is seen in patients with idiopathic pulmonary fibrosis (IPF), asbestosis, or collagen-vascular diseases.

The finding of honeycombing correlates with advanced fibrosis and indicates a poor prognosis. Bilateral hilar lymphadenopathy, with or without mediastinal adenopathy, suggests sarcoidosis. See the images below.



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Chest radiograph of a 67-year-old man diagnosed with idiopathic pulmonary fibrosis, based on open lung biopsy findings. Extensive bilateral reticulono....



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



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Chest radiograph from a 39-year-old woman with severe kyphoscoliosis who developed hypercapnic respiratory failure. Spirometry findings showed a sever....

CT scanning of the chest

High-resolution CT scanning of the chest can be helpful, but the expense and high dose of radiation makes it inappropriate for every patient.[14] IPF can be diagnosed clinically based on the typical clinical features and CT scan findings without the need for lung biopsy.[15, 16] Bibasilar peripheral lung zone involvement is seen in patients with IPF, asbestosis, connective-tissue disease, or eosinophilic pneumonia.

Central disease along bronchovascular bundles is indicative of sarcoidosis or lymphangitic carcinoma.

Upper-zone predominance is observed in patients with sarcoidosis, eosinophilic granuloma, or chronic hypersensitivity pneumonitis. Lower-zone predominance is seen in patients with IPF, asbestosis, or rheumatoid arthritis.

Lower-zone and peripheral infiltration is ordinarily seen in patients with IPF or asbestosis.

The presence of bilateral cysts and nodules, with preservation of lung volumes, may suggest a diagnosis of LAM or pulmonary Langerhans cell histiocytosis.

Bibasilar reticular fibrosis with coexisting retraction bronchiectasis indicates end-stage irreversible disease, and ground-glass attenuation may result from changes in the interstitium, air spaces, or redistribution of capillary blood flow.[17] See the images below.



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High-resolution CT scan of the same patient in the image below demonstrates peripheral honeycombing and several areas of ground-glass attenuation. Gro....



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



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



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



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Restrictive lung disease secondary to sarcoidosis.

Tests for extrinsic disorders

Evidence of nonmuscular diseases of the chest wall and associated deformities of the spinal column and ribs are readily appreciated on chest radiographs. The severity of kyphoscoliosis is determined by the Cobb angle, which, when greater than 100°, indicates severe deformity. Neuromuscular diseases are also diagnosed based on chest radiograph findings showing low volumes and basal atelectasis.

Fluoroscopy is used to assess for diaphragm paralysis.

A positive result from a sniff test may demonstrate paradoxical upward movement of the affected diaphragm.

Other Tests

Pulmonary function testing

Complete lung function testing includes spirometry, lung volume, diffusing capacity, and arterial blood gas measurements. Pulmonary function test findings do not indicate a specific diagnosis or help distinguish alveolitis from fibrosis. Findings from sequential tests are invaluable for monitoring the course of the disease and assessing the response to therapy.

All disorders are associated with a restrictive defect with a reduction in TLC, FRC, and residual volume (RV).

While a reduction in the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC) with a normal or increased FEV1 -to-FVC ratio suggests a restrictive pattern, the diagnosis of restriction is based on a decreased TLC. The assessment of the severity of restriction is also based on TLC.

An obstructive airflow limitation may be observed in patients with sarcoidosis, LAM, hypersensitivity pneumonitis, and pulmonary fibrosis with concomitant chronic obstructive pulmonary disease. See the images below.



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Lung volume is plotted against transpulmonary pressure. Compliance is the change in volume for a given change in pressure. A patient with emphysema ha....



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



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The expiratory flow volume curves of 2 patients are depicted graphically. A is a patient with restrictive lung disease (idiopathic pulmonary fibrosis)....



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

Tests for extrinsic lung disorders

In nonmuscular diseases of the chest wall, severe kyphoscoliosis produces a restrictive pattern. The TLC is markedly reduced, with relative preservation of the RV. The vital capacity is reduced, and the RV-to-TLC ratio is elevated. Chest wall components are reduced, and inspiratory muscle weakness may also contribute to the restrictive process. Maximal inspiratory and expiratory pressures are modestly decreased in patients with mild disease but are severely reduced in patients with advanced disease.

Hypoxemia is due to a ventilation-perfusion mismatch caused by the underlying atelectasis and shunt.

In neuromuscular diseases, the maximal inspiratory and expiratory mouth pressures vary from normal to severely reduced. When maximal inspiratory pressure falls below 30 cm of water, ventilatory failure commonly ensues.

Patients with chronic muscular diseases have a decreased vital capacity and FRC, but the RV is preserved. TLC is also moderately reduced. Breathing during sleep is often abnormal in these patients. They have nocturnal desaturation during rapid eye movement sleep, secondary to hypoventilation.

The diffusing capacity of lung for carbon monoxide (DLCO) is reduced in all patients with intrinsic lung disorders, and the severity of the reduction does not correlate well with the stage of the disease. The DLCO is the most sensitive parameter, and findings may be abnormal even when the lung volumes are preserved. A normal DLCO value excludes intrinsic lung disease and indicates a chest wall, pleural, or neuromuscular cause of restrictive lung disease.

Arterial blood gas values at rest may reveal hypoxemia. Arterial oxygen desaturation occurs with exercise, along with an excessive increase in the respiratory rate and a high ratio of dead-space gas volume to tidal gas volume.

Cardiopulmonary exercise testing with measurements of gas exchange and oxygenation is more sensitive, and findings correlate better with lung biopsy but do not help predict the prognosis. A 6-minute walk test with oximetry provides a measure of oxygen requirement and a quantifiable measure of disease progression.

Procedures

Bronchoalveolar lavage

In selected cases, bronchoalveolar lavage (BAL) cellular analysis may be helpful to narrow the differential diagnosis. However, the utility of BAL in the clinical assessment and management of interstitial lung diseases remains to be established.

Performing BAL lymphocytosis in patients with IPF may help predict steroid responsiveness. A predominance of T lymphocytes with an elevated CD4-to-CD8 ratio is characteristic but not diagnostic of sarcoidosis.

BAL fluid may contain malignant cells, asbestos bodies, eosinophils, and hemosiderin macrophages, which assist in making a diagnosis.

Lung biopsy

A lung biopsy is not always required to make a diagnosis in patients suggested to have interstitial lung diseases. A lung biopsy can provide information that may help lead to a specific diagnosis, help assess for disease activity, exclude neoplastic and infectious processes, establish a definitive diagnosis, and predict the prognosis. Open lung biopsy can be as valuable in selected patients[18] as high-resolution CT scanning, and the American Thoracic Society/European Respiratory Society (ATS/ERS) clinical criteria may misdiagnose patients with interstitial lung disease.[19]

Fiberoptic bronchoscopy with transbronchial lung biopsy is often the initial procedure of choice, especially when sarcoidosis, lymphangitic carcinomatosis, eosinophilic pneumonia, Goodpasture syndrome, pulmonary Langerhans cell histiocytosis, hypersensitivity pneumonitis, or infection is suggested based on clinical evidence.

Surgical lung biopsy

Video-assisted thoracoscopic lung biopsy is the preferred method for obtaining lung tissue samples for analysis.

Histologic patterns may be helpful in narrowing the differential diagnosis.[20] Honeycombing is seen in end-stage disease, in which the original disease process often cannot be differentiated. See the image below.



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

The common histologic patterns include interstitial pneumonitis (ie, IPF). 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 is the hallmark of this disease. Also, the lung architecture is completely destroyed.

Desquamative interstitial pneumonitis is characterized by diffuse and temporally uniform involvement of the lung parenchyma. The alveoli are filled with macrophages and hyperplastic type II pneumocytes.

COP (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.

Diffuse alveolar damage is marked by a nonspecific reaction with diffuse temporally uniform involvement and marked thickening of the alveolar septa; inflammatory cell infiltration and type II cell hyperplasia and fibroblast proliferation are present.

For acute interstitial pneumonia, the pathological appearance is identical to that of diffuse alveolar damage.

In eosinophilic pneumonia, eosinophils and macrophages are the predominant alveolar inflammatory cells, and they also extend into the interstitium.

Lymphocytic interstitial pneumonitis marked by a lymphoid infiltrate that involves both the interstitium and alveolar spaces is the prominent finding.

In nonspecific interstitial pneumonia, the lesions are characterized by a relatively uniform appearance consisting of mononuclear interstitial infiltrates associated with varying degrees of interstitial fibrosis.

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

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 2. Contrasting Clinical, Radiologic, and Histologic Features of Acute Interstitial Pneumonia (AIP), Usual Interstitial Pneumonia (UIP), Nonspecific Interstitial Pneumonia (NSIP),[21] and COP[22]



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See Table

See the images below.



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



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



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



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



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



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



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Multiple well-formed noncaseating granulomas secondary to sarcoidosis.



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Sarcoid granulomas.



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High-power view of sarcoid granuloma shows giant cells.



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



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



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



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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.

Idiopathic pulmonary fibrosis

The rate of progression of idiopathic pulmonary fibrosis (IPF) is highly variable, and controversy exists regarding the timing of treatment. The disease may be responsive to treatment in the early, so-called inflammatory stage. IPF always progresses insidiously, and documenting the changes over short periods is difficult. Initiate a trial of therapy for 6-12 weeks, starting as early as possible, with the hope of slowing disease progression. Discontinue therapy if no benefit is observed or if adverse effects develop.

The prognosis for patients with IPF who do not respond to medical therapy is poor. They usually die within 2-3 years. These and other patients with severe functional impairment, oxygen dependency, and a deteriorating course should be listed for lung transplantation.

Conventional therapies (corticosteroids, azathioprine,[23] cyclophosphamide) provide only marginal benefit to patients with IPF. Intermittent intravenous cyclophosphamide given to IPF patients surviving 6 months improved pulmonary function and reduced prednisone dosage in one study.[24]

Lung transplantation should be considered for patients with IPF refractory to medical therapy.[25] Acute exacerbations may not respond to high-dose corticosteroid therapy.[26]

Because of a lack of response to available anti-inflammatory therapy, alternative approaches to therapy are being pursued.[27] Emerging strategies to treat patients with IPF include agents that inhibit epithelial injury or enhance repair, anticytokine approaches, agents that inhibit fibroblast proliferation or induce fibroblast apoptosis, and other novel approaches.[28]

Corticosteroids

Corticosteroids are a first-line therapy but are associated with myriad adverse effects. Corticosteroids, the most commonly used drugs, halt or slow the progression of pulmonary parenchymal fibrosis with variable success.

Questions about which patients should be treated, when therapy should be started,[29] and what constitutes the best therapy receive uncertain answers at present.

Although subjectively most patients with IPF feel better, an objective improvement occurs in 20-30% patients. A favorable response is a reduction in symptoms; the clearing of radiographs; and improvements in FVC, TLC, and DLCO. The optimal duration of therapy is not known, but treatment for 1-2 years is suggested.

Cytotoxic therapy

Immunosuppressive cytotoxic agents may be considered for patients who do not respond to steroids, experience adverse effects, or have contraindications to high-dose corticosteroid therapy. The failure of steroid therapy is defined as a fall in FVC or TLC by 10%, a worsened radiographic appearance, and a decreased gas exchange at rest or with exercise.

Azathioprine is less toxic than methotrexate or cyclophosphamide and may be preferred as a corticosteroid-sparing agent for disorders that are not life threatening. A response to therapy may not occur for 3-6 months.

Because of potentially serious toxicities, cyclophosphamide is reserved for fulminant or severe inflammatory disorders refractory to alternate therapy.

Antifibrotic therapies

These therapies, including colchicine, are suggested for a variety of fibrotic disorders, including IPF.

IPF subjects given high-dose prednisone had an increased incidence of serious adverse effects and shortened survival compared with those given colchicine in a prospective randomized study[30] ; therefore, a trial of therapy with colchicine is reasonable in less symptomatic patients or those who are experiencing adverse effects with steroid therapy.

One study showed that in patients with idiopathic pulmonary fibrosis, interferon gamma-1b did not affect progression-free survival, pulmonary function, or quality of life. No survival benefit was demonstrated in this trial.[31]

Collagen-vascular disease

Therapy for pulmonary fibrosis associated with collagen-vascular disease is controversial because the course may be indolent. Because these diseases begin as an alveolitis, an aggressive approach may be warranted.

Patients with severe disease or those who have a deteriorating course must be treated with corticosteroids, cytotoxic therapy, or both.

Sarcoidosis

Because the disease remits spontaneously, patients with respiratory symptoms and radiographic or pulmonary function evidence of extensive disease may benefit from corticosteroids. Patients with hypercalcemia or extrapulmonary involvement generally require treatment. Therapy should be continued for 6 months or longer; however, even after prolonged treatment, up to 50% of patients relapse after therapy is discontinued.

For patients who do not respond to corticosteroids, alternate therapies (eg, chloroquine, methotrexate, azathioprine) may be used; however, data are limited.

Treatment of extrinsic lung disorders

Patients with nonmuscular chest wall disorders and neuromuscular disease may develop problems with ventilation and gas exchange during sleep. The effect of decreased chest wall and lung compliance or decreased muscle strength is hypercapnia and hypoxemia, which occurs initially during sleep. Identify and treat the cause of muscle weakness.

Treatment of neuromuscular diseases includes preventive therapies to minimize the impact of impaired secretion clearance and the prevention and prompt treatment of respiratory infections.

Patients who develop respiratory failure or have severe gas exchange abnormalities during sleep may be treated with noninvasive positive-pressure ventilation via a nasal or oronasal mask. Patients in whom these devices fail may require a permanent tracheotomy and ventilator assistance with a portable ventilator.

Noninvasive ventilation with body-wrap ventilators or positive-pressure ventilation has been proven beneficial because it helps relieve dyspnea and pulmonary hypertension and helps improve RV and gas exchange. Also, hospitalization rates are markedly reduced and the activities of daily living are enhanced.

Treatment for massive obesity consists of weight loss, which causes dramatic improvement in pulmonary function test findings but is harder to achieve. These patients require polysomnographic study because of the high incidence of nocturnal hypoventilation or upper airway obstructions. Either continuous positive airway pressure or noninvasive pressure ventilation helps correct hypoventilation and upper airway obstruction.

In advanced disease, when respiratory failure develops, these patients are treated with mechanical ventilation. If they have copious secretions, cannot control their upper airway, or are not cooperative, then invasive ventilation with a tracheotomy tube is indicated. In other patients, eg, those who have good airway control and minimal secretions, use noninvasive ventilation, initially nocturnal, and then intermittently.

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.[32]

Consultations

Consultation with a pulmonologist is helpful for diagnosis and management.

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.

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:  Prednisone is used as an immunosuppressant in the treatment of autoimmune disorders. By reversing increased capillary permeability and suppressing PMN activity, it may decrease inflammation. It is an oral corticosteroid with relatively less mineralocorticoid activity. Therapy is best prescribed in consultation with a pulmonary disease specialist.

Class Summary

These agents have anti-inflammatory properties and can modify the body's immune response.

Cyclophosphamide (Cytoxan, Neosar)

Clinical Context:  Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, its mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells of the immune system. It is a possible steroid-sparing medication.

Azathioprine (Imuran)

Clinical Context:  Azathioprine inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting the synthesis of DNA, RNA, and proteins. These effects may decrease the proliferation of immune cells and result in lower autoimmune activity. It is a possible steroid-sparing medication.

Class Summary

These agents inhibit cell growth and proliferation.

Colchicine

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

Class Summary

These agents reduce inflammation by inhibiting key steps of the immune system.

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

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.

Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Chair of the Clinical Competency Committee, Pulmonary and Critical Care Fellowship Program, Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Health System; Chair, Guideline Oversight Committee, American College of Chest Physicians

Disclosure: Nothing to disclose.

Chief Editor

John J Oppenheimer, MD, Clinical Professor, Department of Medicine, Rutgers New Jersey Medical School; Director of Clinical Research, Pulmonary and Allergy Associates, PA

Disclosure: Received consulting fee from AZ for consulting; Received consulting fee from Glaxo, Myelin, Meda for consulting; Received grant/research funds from Glaxo for independent contractor; Received consulting fee from Merck for consulting; Received honoraria from Annals of Allergy Asthma Immunology for none; Partner received honoraria from ABAI for none. for: Atlantic Health System.

Additional Contributors

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.

Acknowledgements

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 a higher lung compliance compared with a patient with no lung disease, while a patient with restrictive lung disease has a reduction in compliance.

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 a higher lung compliance compared with a patient with no lung disease, while a patient with restrictive lung disease has a reduction in compliance.

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.

Causes Examples Diagnosis PFT 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 (Intrapulmonary hemoglobin absorbs the carbon monoxide, thus increasing the DLCO reading.)
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
Features AIP UIP NSIP COP
Pathologic
Temporal appearanceUniformHeterogeneousUniformUniform
Interstitial inflammationScantScantUsually prominentVariable
Collagen fibrosisNoPatchyVariable, diffuseNo
Fibroblast proliferationDiffuse, interstitialPatchy (fibroblast foci)OccasionalPatchy, airspace
COP areasRareNoRare--
Honeycomb changesRareYesRareNo
Hyaline membranesYes, often focalNoNoNo