Editors: Collins, Jannette; Stern, Eric J.
Title: Chest Radiology: The Essentials, 2nd Edition
> Table of Contents > Chapter 3 - Interstitial Lung Disease
Chapter 3
Interstitial Lung Disease
This chapter on interstitial lung disease (ILD) is followed by a chapter on alveolar lung disease (ALD). When the chest radiograph shows a clear pattern of ILD or ALD, one can render a differential diagnosis based on the pattern of parenchymal disease (Table 3-1). A conundrum arises when widespread small opacities are difficult to categorize into one group or the other on chest radiography, or when ILD and ALD are both present. In these cases, coming up with a differential diagnosis is not as straightforward. One must decide what the predominant pattern is, take into consideration the clinical history and any associated radiographic findings, or further define the pattern(s) and distribution of disease with a CT scan of the lungs.
Patterns of Interstitial Lung Disease
The interstitium of the lung is not normally visible radiographically; it becomes visible only when disease (e.g., edema, fibrosis, tumor) increases its volume and attenuation. The interstitial space is defined as “a continuum of loose connective tissue throughout the lung composed of three subdivisions: (i) the bronchovascular (axial), surrounding the bronchi, arteries, and veins from the lung root to the level of the respiratory bronchiole; (ii) the parenchymal (acinar), situated between the alveolar and capillary basement membranes; and (iii) the subpleural, situated beneath the pleura, as well as in the interlobular septa” (1). Any or all of these three interstitial compartments can be abnormal at any one time.
Interstitial lung disease may result in four patterns of abnormal opacity on chest radiographs and CT scans: linear, reticular, nodular, and reticulonodular (Fig. 3-1). These patterns are more accurately and specifically defined on CT. A linear pattern is seen when there is thickening of the interlobular septa, producing Kerley lines. These septal lines were first described by Kerley in patients with pulmonary edema (2). Kerley B lines are short, straight lines (1 to 2 cm) perpendicular to and abutting the lower lateral pleural edge. Kerley A lines are generally longer (2 to 6 cm), they radiate out from the hilum toward the pleura but are not contiguous with the pleura, and they are most obvious in the upper and middle lungs. The interlobular septa contain pulmonary veins and lymphatics. The most common cause of interlobular septal thickening, producing Kerley A and B lines, is pulmonary edema, as a result of pulmonary venous hypertension and distension of the lymphatics (Fig. 3-2). Other causes of Kerley lines are listed in Table 3-2. Anything that causes thickening of the interlobular septa can produce Kerley lines, including edema, inflammation, tumor, or fibrosis. Septal thickening without architectural distortion is more likely to represent pulmonary edema.

Bronchiectasis (ILD "look-alike")
Bugs (especially fungi, mycoplasma, and viruses)
Aspiration, chronic
Drug toxicity
Lymphangitic carcinomatosis
Lymphocytic interstitial pneumonia and other idiopathic interstitial pneumonias
Scleroderma and other collagen vascular diseases
Hypersensitivity pneumonitis
Heart failure
Histiocytosis (Langerhan cell histiocytosis)
ILD, interstitial lung disease
FIGURE 3-1. Diagrams illustrating the four types of ILD. A: Linear ILD is seen as Kerley lines. Kerley A lines radiate out from the hila to the periphery of the lung. Kerley B lines are shorter lines that contact and are perpendicular to the lateral pleural edge, predominantly in the lower lungs. Both A and B lines are seen as a result of interlobular septal thickening, most commonly from pulmonary edema. B: Reticular ILD is seen as a network of curvilinear opacities. When seen as a result of a reversible process, such as viral pneumonia, sarcoidosis, or hypersensitivity pneumonitis, the distribution can be patchy or diffuse. C: When reticular ILD is seen as a result of chronic, irreversible lung disease, such as usual interstitial pneumonia, honeycombing is seen. The curvilinear opacities form small cystic spaces (forming the honeycomb) in a characteristic bibasilar and subpleural distribution. D: Nodular ILD will often, but not always, have an upper and middle lung–predominant distribution. This is often the case with sarcoidosis, Langerhan cell histiocytosis, silicosis, and coal worker's lung. The nodules generally range from 1 to 10 mm in size. E: Reticulonodular ILD results from a combination of reticular and nodular opacities, or it can be caused by reticular opacities seen end-on. This pattern is often difficult to distinguish from a pure nodular or reticular pattern on chest radiography. The list of diagnostic possibilities to consider when this pattern is seen can be shortened by taking into account the acuity of the disease, the distribution of disease, and associated radiographic abnormalities.
Pulmonary edema - the most common cause
Mitral stenosis
Lymphangitic carcinomatosis
Malignant lymphoma
Congenital lymphangiectasia
Viral and mycoplasma pneumonias
Idiopathic pulmonary fibrosis
Late-stage hemosiderosis

FIGURE 3-2. Kerley lines. This patient presented with cardiogenic edema. A: PA chest radiograph shows an enlarged cardiac silhouette and bilateral reticular and linear ILD. B: Close-up view of (A), lower right lung, shows short linear opacities perpendicular to the lateral pleural edge, representing Kerley B lines. C: Close-up of (A), right upper lung, shows linear opacities (arrow) radiating outward from the hila, representing Kerley A lines. D: CT shows interlobular septal thickening (arrows), representing Kerley lines.
A reticular pattern results from the summation or superimposition of irregular linear opacities. The term reticular is defined as meshed, or in the form of a network. Reticular opacities can be described as fine, medium, or coarse, as the width of the opacities increases. A classic reticular pattern is seen with pulmonary fibrosis, in which multiple curvilinear opacities form small cystic spaces along the pleural margins and lung bases (honeycomb lung) (Fig. 3-3).
A nodular pattern consists of multiple round opacities, generally ranging in diameter from 1 mm to 1 cm, which may be difficult to distinguish from one another as individual nodules on a chest radiograph. Nodular opacities may be described as miliary (1 to 2 mm, the size of millet seeds), small, medium, or large, as the diameter of the opacities increases (Figs. 3-4 and 3-5). A nodular pattern, especially with an upper lung–predominant distribution, suggests a specific differential diagnosis (Table 3-3).
A reticulonodular pattern results from a combination of reticular and nodular opacities, or it can appear when reticular opacities are seen end-on. This pattern is often difficult to distinguish from a purely reticular or nodular pattern, and in such a case a differential diagnosis should be developed based on the predominant pattern. If there is no predominant pattern, causes of both nodular and reticular patterns should be considered. An acute appearance suggests pulmonary edema or pneumonia (Fig. 3-6). A lower lung–predominant distribution with decreased lung volumes suggests idiopathic pulmonary fibrosis, asbestosis, collagen vascular disease, or chronic aspiration. A reticulonodular pattern and larger-than-normal lung volumes can be seen with lymphangioleiomyomatosis and Langerhan cell histiocytosis (LCH). A middle or upper lung–predominant distribution suggests mycobacterial or fungal disease, silicosis, sarcoidosis, LCH, extrinsic allergic alveolitis (hypersensitivity pneumonitis), or, very rarely, ankylosing spondylitis. Kerley lines help limit the differential diagnosis (see Table 3-2). Associated lymphadenopathy suggests sarcoidosis; neoplasm (lymphangitic carcinomatosis, lymphoma, metastases); infection (viral, mycobacterial, or fungal); and silicosis. Associated pleural thickening and/or calcification suggest asbestosis. Associated pleural effusion suggests pulmonary edema, lymphangitic carcinomatosis, lymphoma, collagen vascular disease, or lymphangioleiomyomatosis (especially if the effusion is

chylous). Associated pneumothorax suggests lymphangioleiomyomatosis or LCH.
FIGURE 3-3. Farmer's lung and pulmonary fibrosis. This 50-year-old man presented with end-stage lung fibrosis from chronic exposure to inhaled antigens on his farm. A: PA chest radiograph shows medium to coarse reticular ILD with a predominant bibasilar and subpleural distribution. B: CT scan shows multiple small cysts (honeycombing) involving predominantly the subpleural peripheral regions of lung. Traction bronchiectasis, another sign of end-stage lung fibrosis, is seen in the right middle lobe (arrows).
Pulmonary Edema
Hydrostatic pulmonary edema is defined as abnormal water in the lungs secondary to elevated pulmonary venous pressure from a failing left ventricle, mitral stenosis, increased circulating blood volume (as with anemias), renal failure (causing fluid retention), or overhydration. Interstitial edema is seen on chest radiographs and CT scans as blurring of the margins of the blood vessels and bronchial walls (peribronchial cuffing), thickening of the fissures (subpleural edema), and thickening of the interlobular septae (Kerley lines) (Fig. 3-7). As capillary pressure rises and interstitial pressure increases, water is forced into the alveolar spaces through the alveolar–capillary membrane; therefore edema is often seen as a combination of both interstitial and alveolar opacities on the chest radiograph. The chest radiograph may also show associated findings of cardiomegaly, pleural effusions, widening of the vascular pedicle, enlargement of the azygos vein, and vascular redistribution (Fig. 3-8). Pulmonary edema is so common, relative to other causes of ILD, that it should often be considered the most likely diagnosis in the differential diagnosis of ILD. An uncommon pattern of edema is more common than an uncommon cause

of ILD. Uncommon patterns of pulmonary edema can result from patient positioning or underlying perfusion abnormalities in the nonedematous lung (e.g., secondary to pulmonary embolism or asymmetric emphysema). Pulmonary edema can be caused by a number of processes other than chronic heart failure, and it may present with a normal-sized heart (Table 3-4).
FIGURE 3-4. Disseminated histoplasmosis and nodular ILD. This previously healthy man living in the upper midwestern part of the United States presented with mild symptoms of shortness of breath and cough. CT scan shows multiple bilateral round circumscribed pulmonary nodules.
FIGURE 3-5. Hematogenous metastases and nodular ILD. This 45-year-old woman presented with metastatic gastric carcinoma. The PA chest radiograph shows a diffuse pattern of nodules, 6 to 10 mm in diameter.
Histiocytosis (Langerhan cell histiocytosis)
Hypersensitivity pneumonitis
Rheumatoid nodules
Infection (mycobacterial, fungal, viral)
Microlithiasis, alveolar
Pneumoconioses (silicosis, coal worker's, berylliosis)
This list excludes the relatively uncommon diagnosis of amyloidosis.
Idiopathic Interstitial Pneumonias
The idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of diffuse parenchymal lung diseases that have no well-defined cause (3). The classification is based on histologic criteria, although the diagnosis of IIP is made by correlating the clinical, imaging, and pathologic features. Each IIP "pattern" seen at histologic or CT examination is linked to a specific clinical syndrome. Clinical evaluation must prove that an interstitial pneumonia is idiopathic and exclude a recognizable cause (e.g., collagen vascular disease). Usual interstitial pneumonia (UIP) is the most common of the IIPs. Nonspecific interstitial pneumonia (NSIP) is next most frequent. Cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis–associated interstitial lung disease (RB-ILD) and acute interstitial pneumonia (AIP) are less common, and lymphoid interstitial pneumonia (LIP) is rare. Typical CT features of each IIP are distinct, but there is overlap (Table 3-5). CT features of UIP and organizing pneumonia may be diagnostic in the correct clinical context, but those of NSIP, DIP, RB-ILD, AIP, and LIP are less specific.
FIGURE 3-6. Disseminated histoplasmosis and reticulonodular ILD. A: PA chest radiograph, close-up of right upper lung, shows reticulonodular ILD. B: CT scan shows multiple circumscribed round pulmonary nodules, 2 to 3 mm in diameter.
FIGURE 3-7. Cardiogenic pulmonary edema. This 69-year-old woman presented with left ventricular failure and a predominantly interstitial pattern of pulmonary edema. CT scan shows numerous Kerley B lines (short arrows), thickening of the right major fissure from subpleural edema (arrowheads), patchy areas of ground-glass opacification (long arrows), and a right pleural effusion (curved arrows).
UIP is characterized histologically by a patchy heterogeneous pattern with foci of normal lung, interstitial inflammation, fibroblastic proliferation, interstitial fibrosis, and honeycombing. Temporal heterogeneity is an important histologic feature and helps to distinguish UIP from DIP. Although the terms UIP and idiopathic pulmonary fibrosis (IPF) are often used interchangeably, the term IPF should only be applied to the clinical syndrome associated with the morphologic pattern of UIP. The typical CT features of UIP are a predominantly basal and subpleural reticular interstitial pattern with honeycombing and traction bronchiectasis (Fig. 3-9). Ground-glass opacity and consolidation can be seen but are not dominant features. Architectural distortion, reflecting lung fibrosis, is often prominent. In the correct clinical context, the CT features of UIP are often diagnostic. The presence of honeycombing as a predominant imaging finding is highly specific for UIP and can be used to differentiate it from NSIP, particularly when

the distribution is patchy and subpleural predominant (4). The presence of predominant ground-glass and reticular opacities is highly characteristic of NSIP, but there is a subset of patients with UIP who have this pattern and may require biopsy for differentiation from NSIP. Distinction of UIP from other IIPs is important, because UIP is associated with a poorer prognosis than the other entities.
FIGURE 3-8. Cardiogenic pulmonary edema. PA chest radiograph shows enlargement of the cardiac silhouette, bilateral ILD, enlargement of the azygos vein (solid arrow), and peribronchial cuffing (dashed arrow).
NSIP is characterized histologically by spatially homogeneous alveolar wall thickening caused by inflammation, fibrosis, or both. The spatial and temporal homogeneity of this pattern is important in distinguishing NSIP from UIP. The prognosis of NSIP is substantially better than that of UIP. Patients with NSIP are more commonly female and generally have a younger mean age than patients with UIP. The typical CT feature of NSIP is predominantly basilar ground-glass and reticular opacities (Fig. 3-10). Consolidation is uncommon and honeycombing is rare. The parenchymal abnormalities of NSIP may be reversible on follow-up CT scanning. Because the CT features of NSIP may overlap with those of organizing pneumonia, DIP, and UIP, a surgical lung biopsy should be considered when the CT pattern suggests NSIP.
Central nervous system disorders
High-altitude pulmonary edema
Inhalation (e.g., carbon monoxide)
Acute myocardial infarction
Hypersensitivity reaction
Underwater, near drowning
Aspiration (gastric secretions)
Morphologic pattern Imaging features
UIP (clinical diagnosis of IPF) Basal and subpleural predominant distribution, reticular opacities (often with honeycombing), traction bronchiectasis, and architectural distortion
NSIP (clinical diagnosis of NSIP) Basal predominant distribution, ground-glass and reticular opacities
DIP (clinical diagnosis of DIP) Basal predominant distribution, ground-glass opacities, sometimes with cysts
Respiratory bronchiolitis (clinical diagnosis of RB-ILD) Centrilobular distribution, ground-glass opacity, typically nodular
Organizing pneumonia (clinical diagnosis of COP) Basal and subpleural predominant distribution, ground-glass opacity and consolidation; bronchovascular distribution is also common
Diffuse alveolar damage (clinical diagnosis of AIP) Diffuse ground-glass opacity and consolidation
LIP (clinical diagnosis of LIP) Bronchovascular distribution common, ground-glass and reticular opacities and perivascular cysts
UIP, usual interstitial pneumonia; IPF, idiopathic pulmonary fibrosis; NSIP, nonspecific interstitial pneumonia; DIP, desquamative interstitial pneumonia; RB-ILD, respiratory bronchiolitis–associated interstitial lung disease; COP, cryptogenic organizing pneumonia; AIP, acute interstitial pneumonia; LIP, lymphoid interstitial pneumonia.
DIP is characterized histologically by spatially homogeneous thickening of alveolar septa, which is associated with intra-alveolar accumulation of macrophages. The term desquamative refers to an initially incorrect belief that the intra-alveolar macrophages represented desquamated alveolar cells. The majority of patients are cigarette smokers in their fourth

or fifth decades of life (5). DIP is more common in men than in women. Most patients improve with cessation of smoking and oral corticosteroids. The histologic features of DIP are similar to those of RB-ILD (a condition seen exclusively in smokers), although the distribution of DIP is diffuse and RB-ILD has a predominantly bronchiolocentric distribution. The typical CT feature of DIP is ground-glass opacity in a predominantly lower lung distribution (Fig. 3-11). Reticulation is frequently seen but is typically limited to the lung bases. Well-defined cysts can occur within the areas of ground-glass opacity.
FIGURE 3-9. Usual interstitial pneumonia (UIP). A: PA chest radiograph shows medium to coarse reticular ILD with honeycombing, in a predominantly bibasilar and subpleural distribution. Lung volumes are decreased. B: CT scan shows bilateral subpleural honeycombing (dashed arrow), traction bronchiectasis (solid arrows), and a background of ground-glass opacity.
Respiratory bronchiolitis is a histopathologic lesion found in cigarette smokers and is characterized by the presence of pigmented intraluminal macrophages within respiratory bronchioles (3). It is usually asymptomatic. In rare cases, patients who are heavy smokers may develop RB-ILD, a condition characterized by pulmonary symptoms, abnormal pulmonary function, and imaging abnormalities, with respiratory bronchiolitis being the only histologic lesion identified on lung biopsy. Respiratory bronchiolitis, RB-ILD, and DIP are regarded as a continuum of smoking-related lung injuries. The CT features of patients with asymptomatic respiratory bronchiolitis show ground-glass centrilobular nodules and patchy areas of ground-glass opacity (Fig. 3-12). In RB-ILD the findings are more extensive (Fig. 3-13) but are at least partially reversible in patients who stop smoking. The imaging features of RB-ILD may be similar to those of hypersensitivity pneumonitis and NSIP. Patients with hypersensitivity pneumonitis often have a history of exposure to an inciting agent and are usually nonsmokers.
FIGURE 3-10. Nonspecific interstitial pneumonia (NSIP). CT scan shows bibasilar reticular and ground-glass opacities.
Although COP is primarily an intra-alveolar process, it is included in the classification of the IIPs because of its idiopathic nature and because its appearance may overlap with that of the other IIPs. The term organizing pneumonia refers to the morphologic imaging or histologic pattern (associated with a wide variety of diseases), whereas COP indicates the associated idiopathic clinical syndrome. Histologically, organizing pneumonia is distinguished by patchy areas of consolidation characterized by polypoid plugs of loose organizing connective tissue with or without endobronchiolar intraluminal polyps. The architecture of the lung is preserved. Patients with COP typically present with cough and dyspnea of relatively short duration. Consolidation is present on CT images in 90% of

patients with COP, with a subpleural or peribronchial distribution in up to 50% of cases (3) (Fig. 3-14). Air bronchograms, with mild cylindric bronchial dilatation, are common. Ground-glass opacities are present in about 60% of cases. The lower lungs are more frequently involved. Findings usually improve with steroid treatment. The differential diagnosis of COP includes bronchioloalveolar cell carcinoma, lymphoma, vasculitis, sarcoidosis, chronic eosinophilic pneumonia, and infectious pneumonia.
FIGURE 3-11. Desquamative interstitial pneumonia (DIP). CT scan shows bilateral ground-glass opacity in a predominantly lower lung distribution.
FIGURE 3-12. Respiratory bronchiolitis. This patient had a long history of cigarette smoking and no respiratory symptoms. CT scan shows numerous ground-glass nodules in a centrilobular distribution (arrows).
AIP is a rapidly progressive form of interstitial pneumonia characterized histologically by hyaline membranes within the alveoli and diffuse, active interstitial fibrosis indistinguishable from the histologic pattern found in acute respiratory distress syndrome caused by sepsis and shock. The term AIP is reserved for diffuse alveolar damage of unknown origin. Patients with AIP present with respiratory failure developing over days or weeks. Mechanical ventilation is usually required. No etiologic agent is identified. Typical CT features of early stage AIP are ground-glass opacity, bronchiolar dilatation, and dense airspace opacity. Late-stage features are honeycombing, architectural distortion, and traction bronchiectasis.
FIGURE 3-13. Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD). This patient had a long history of cigarette smoking, chronic cough, and shortness of breath. CT scan shows bilateral reticular and ground-glass opacities in a predominantly upper lung distribution.
FIGURE 3-14. Organizing pneumonia. This patient had a history of rheumatoid arthritis and presented with acute shortness of breath and nonproductive cough. CT scan shows subpleural dense airspace opacity in the left lung.
In adults, LIP is commonly associated with connective tissue disorders (particularly Sjögren syndrome), immunodeficiency syndromes, and Castleman syndrome. Idiopathic LIP is rare. The histologic feature of LIP is alveolar septal interstitial infiltration by lymphocytes and plasma cells. The typical CT findings are ground-glass and reticular opacities, sometimes associated with perivascular cysts (Fig. 3-15). Other findings may include lung nodules, dense airspace opacity, thickening of the bronchovascular bundles, and interlobular septal thickening.
Infectious Interstitial Pneumonia
Infectious pneumonia resulting in a diffuse interstitial pattern is unusual; however, viral, fungal, mycobacterial, and

Mycoplasma pneumonias may be predominantly interstitial or interstitial appearing. Fungal disease is discussed in Chapter 7. Pneumocystis pneumonia also produces a fine interstitial pattern on chest radiography and is discussed in Chapter 16.
FIGURE 3-15. Lymphocytic interstitial pneumonia (LIP). This patient had Sjögren syndrome and new respiratory symptoms. CT scan shows bilateral patchy ground-glass opacities in a peribronchovascular distribution.
FIGURE 3-16. Influenza pneumonia. This patient had a history of emphysema and acute respiratory symptoms. A: Supine chest radiograph shows bilateral reticular ILD. B: CT scan shows bilateral reticular and ground-glass opacities and areas of consolidation. "Cystic" areas represent pulmonary emphysema.
Mycoplasma pneumoniae usually affects previously healthy individuals between the ages of 5 and 40 years (6). Chest radiographs may show widespread bilateral nodular or reticular opacities, and they may take several weeks to return to normal. Alternatively, dense airspace opacity may be seen involving one or several lobes.
Viruses are the major cause of respiratory tract infection in the community, especially in children. The most common viral pneumonias in infants and young children are caused by respiratory syncytial virus, parainfluenza virus, adenovirus, and influenza; in adults, influenza and adenovirus are most common. Viruses that cause pneumonia in immunocompromised patients include Cytomegalovirus, varicella-zoster, and herpesvirus. The radiographic appearance of viral pneumonias is typically a diffuse interstitial pattern with a diffuse, patchy, often nodular appearance (Fig. 3-16).
Drug Toxicity
Numerous drugs can result in transient or permanent lung injury of varying types and severities (Fig. 3-17), some of which are listed in Table 3-6. A more complete list can be found in

the medical literature. The adverse effects of some of the drugs that can cause ILD are discussed below.
FIGURE 3-17. Methotrexate lung toxicity. A: PA chest radiograph shows bilateral ILD, predominantly in the lower lungs. B: CT scan shows subtle bilateral ground-glass opacity and subpleural reticular and dense airspace opacities.
Acetylsalicylic acid
Ornithine-ketoacid transaminase orthoclone
Bleomycin is a cytotoxic drug used in the treatment of squamous cell carcinoma, lymphoma, and testicular neoplasms. Toxicity is related to the cumulative dose, and the incidence of pulmonary toxic side effects is between 4% and 15% (7,8). The initial radiographic changes are predominantly basilar reticulonodular interstitial opacities. Progression of disease may result in dense airspace opacity.
Nitrofurantoin is an antibacterial agent used in the treatment of urinary tract infections. An acute reaction produces basilar interstitial or mixed interstitial/alveolar opacities. A chronic reaction develops after months or years of therapy, resulting in pulmonary fibrosis, with a bibasilar and subpleural distribution of reticular ILD and a gradual reduction in lung volume.
Salicylates can alter the capillary permeability of the lung, leading to noncardiogenic pulmonary edema. The radiographic features are indistinguishable from those of cardiogenic edema.
Ornithine-ketoacid transaminase orthoclone (OKT3) is a monoclonal antibody used to treat acute rejection of transplant allografts. OKT3 toxicity manifests as acute pulmonary edema, usually within hours of starting therapy. It is important to ensure that the patient does not have excess pulmonary fluid prior to starting therapy, and pretherapy chest radiographs are commonly ordered for this purpose.
Amiodarone is used to treat refractory cardiac rhythm disturbances. Because of the drug's relatively high incidence of pulmonary toxicity (5%) (9), its potential life-saving benefit must be weighed against the risks of potentially fatal pulmonary toxicity. Amiodarone is concentrated in the lung and has a long tissue half-life, which accounts for the slow appearance of toxic effects and slow clearing following cessation of therapy (months for both). The most common radiographic appearance of amiodarone toxicity is multiple peripheral areas of dense airspace opacity. Another radiographic manifestation is diffuse interstitial opacification leading to pulmonary fibrosis. Amiodarone contains 37% iodine by weight, which can result in high-attenuation pleuroparenchymal, liver, or spleen lesions that are distinctive for amiodarone toxicity on CT scans.
Lymphangioleiomyomatosis (LAM) is a disorder characterized by perilymphatic smooth muscle proliferation that later spreads to involve airways, airspaces, arterioles, and venules and that can affect pulmonary, mediastinal, and retroperitoneal lymph nodes. The histologic and radiographic findings of LAM (Table 3-7) are similar to those of tuberous sclerosis, and the two diagnoses are considered to be part of a spectrum of the same disease process. Patients with LAM are female, usually of childbearing age. Spontaneous pneumothorax is the presenting event in more than half of patients and is often recurrent (10) (Fig. 3-18). Other defining events include (a) chylous pleural effusion or ascites and (b) hemoptysis. The earliest radiographic signs of lung disease consist of subtle, diffuse, fine nodular, reticular, or reticulonodular opacities that result from the superimposition of cyst walls. The reticular pattern becomes more coarse and irregular, and cysts, bullae, and honeycombing can develop. During the end-stage of this disease, lung volumes are usually increased. The characteristic findings on CT include multiple thin-walled cysts distributed in a uniform fashion in otherwise essentially normal lung. The cysts are generally rounded and uniform in shape, although when large they can assume polygonal or bizarre shapes.
Effusion (chylous)
Reticulonodular interstitial pattern
"HER" emphasizes that this is a disorder affecting women. The addition of a P on the end ("HERP") emphasizes the frequent occurrence of pneumothorax with this disorder.
FIGURE 3-18. Lymphangioleiomyomatosis (LAM). This 42-year-old woman presented with right chest pain. A: PA chest radiograph shows a right basilar pneumothorax and two right pleural drainage catheters. The lung volumes are increased, which is characteristic of LAM, and there is diffuse reticular ILD. B: CT scan shows bilateral thin-walled cysts and a loculated right pneumothorax (P).

"Certain Cancers Spread by Plugging the Lymphatics"
Modified with permission from Dähnert W. Radiology Review Manual. Baltimore: Williams & Wilkins; 1991:237.
Lymphangitic Carcinomatosis
Lymphangitic carcinomatosis refers to infiltration of pulmonary lymphatics by neoplastic cells. The most common tumors resulting in lymphangitic carcinomatosis are listed in Table 3-8. Mechanisms of tumor dissemination include (a) blood-borne emboli that lodge in smaller pulmonary arteries, infiltrate the vessel walls, and then spread out into the lymphatic vessels; (b) expansion by way of lymph vessels to hilar nodes and then retrograde into the pulmonary lymphatics; and (c) direct invasion of the pulmonary lymphatics from primary lung neoplasms. Chest radiographs and CT scans show fine reticulonodular opacities and thickened septal lines (Kerley A and B lines). CT scans show interlobular septal thickening and irregular thickening of the bronchovascular bundles (Fig. 3-19). The appearance, especially on chest radiography, may be difficult to distinguish from pulmonary edema. A unilateral distribution suggests primary bronchogenic carcinoma as the underlying tumor; most other tumors result in bilateral lung involvement (Fig. 3-20). Central lymphatic obstruction, with distended lymphatics but no actual carcinomatosis, can have a similar appearance. The septa are usually more irregular and beaded with true carcinomatosis.
The term pneumoconiosis means "dusty lungs" and is used to describe the reactions of the lungs to inhaled dust particles. The notable inorganic dusts involved include coal, silica, and asbestos. Coal worker's pneumoconiosis and silicosis result in similar chest radiographic abnormalities and should not be confused with the findings seen with asbestosis. The reaction of lung tissue to these dusts depends on the sizes of the particles inhaled, the fibrogenicity of the dust, the amount of dust retained in the lungs, the duration of exposure, and the individual immunologic response to the dust.
The International Labour Office (ILO) classification of the radiographic appearances of the pneumoconioses is a standardized, internationally accepted system that is used to codify the roentgenographic changes of the pneumoconioses in a reproducible manner (11). The classification includes a description of small rounded opacities (nodules), irregular linear and reticular opacities, and pleural thickening (diffuse or circumscribed, such as with a plaque). After passing an examination given by the National Institute for Occupational Safety and Health, an individual becomes a "B reader," certified officially to interpret chest radiographs according to the ILO standards.
FIGURE 3-19. Lymphangitic carcinomatosis. This 68-year-old man had adenocarcinoma of the lung. He developed shortness of breath, which was initially attributed to congestive heart failure. A: PA chest radiograph shows bilateral ILD. The cardiac silhouette is chronically enlarged, but there is no pleural effusion or increase in the width of the vascular pedicle. B: CT scan shows bilateral patchy ground-glass opacities and thickening of the interlobular septae (arrows). The diagnosis of lymphangitic carcinomatosis was confirmed with lung biopsy.
Free silica is present in many rocks in the earth's crust. Silicosis refers to lung disease caused primarily by free silica, and it occurs predominantly in individuals who work in quarries, who drill or tunnel in quartz-containing rocks, who cut or polish masonry, who clean boilers or castings in iron and steel foundries, or who are exposed to sandblasting. The chronic form of the disease requires 20 or more years of exposure to high dust concentrations before radiographic changes are visible.
Silica dust particles are ingested by pulmonary macrophages. The macrophages die and release their enzymatic contents, resulting in lung fibrosis. The cycle continues even without ongoing exposure to silica from the environment, as the silica released from the death of macrophages is free to be taken up by other macrophages. Early in the course of silicosis, 1- to 3-mm nodules are seen with an upper

lung–predominant distribution (12) (Figs. 3-21 and 3-22). As the process advances, the nodules increase in size and number and can calcify. The nodules may coalesce, resulting in larger nodules (greater than 1 cm in diameter), creating masslike opacities referred to as progressive massive fibrosis, a stage of "complicated" silicosis (Fig. 3-23). Cavitation of the masses may occur, leading to superinfection with tuberculosis. Contraction of the upper lobes occurs, and cicatricial emphysema and bullae form around the areas of conglomerate masses. The conglomerate masses begin in the periphery of the lungs and slowly migrate toward the hila. Hilar and mediastinal lymph node enlargement is not uncommon, and calcification, sometimes in an "eggshell" pattern, may be seen in the nodes (13). The radiographic signs of coal worker's pneumoconiosis are similar to, and often indistinguishable from, those described for silicosis.
FIGURE 3-20. Lymphangitic carcinomatosis. This 53-year-old man presented with chronic obstructive pulmonary disease, recurrent pneumonia, chronic cough, wheezing, and large-cell bronchogenic carcinoma of the right lung. CT scan shows unilateral nodular thickening of the central and peripheral interstitial compartments (arrows) and a malignant right pleural effusion. Note nodular involvement of the subpleural lymphatics adjacent to the right major fissure (arrowhead).
Acute silicosis is a rare condition related to heavy exposure to free silica in enclosed spaces with minimal or no protection. The disease is rapidly progressive. Chest radiographs show diffuse airspace or ground-glass opacification with a perihilar distribution and air bronchograms (14). A number of connective tissue diseases have been reported to occur with increased prevalence in patients with silicosis. For example, Caplan syndrome consists of the presence of large necrobiotic nodules (rheumatoid nodules) superimposed on a background of simple silicosis. The nodules measure from 0.5 to 5.0 cm, may cavitate and calcify, and may precede the onset of arthritis by months or years.
FIGURE 3-21. Complicated silicosis. PA chest radiograph of a male foundry worker shows multiple nodules involving the upper and middle lungs, with coalescence of nodules in the left upper lobe resulting in early "progressive massive fibrosis" (arrows).
Asbestos is composed of a group of fibers that can be divided into two principal subgroups based on the physical properties of the fibers: the serpentines and the amphiboles. Serpentine asbestos has long, curly, flexible fibers and accounts for 90% of the asbestos used in the United States. The only serpentine asbestos used commercially is chrysotile. The amphiboles (including crocidolite) have straight, needlelike fibers, which have

a much greater fibrogenic and carcinogenic potential than the serpentine-form chrysotile. Benign asbestos-related pleural disease refers to any or all of the following pleural abnormalities: benign, sometimes recurrent pleural effusions; diffuse pleural thickening; and pleural plaques (with or without calcification) (15). Benign pleural effusion is the most common abnormality seen within 10 years of the onset of asbestos exposure. The amount of fluid is usually small; effusions larger than 500 mL are uncommon. Pleural plaques are usually first identified more than 20 or 30 years after the initial asbestos exposure; they occur on the parietal pleura, in typical locations over the diaphragm and along the posteromedial and anterolateral chest walls. The more benign form of asbestos fiber, chrysotile, is noted for transpleural migration, whereas the more fibrogenic and carcinogenic amphiboles, crocidolite and amosite, tend to get held up in the lung parenchyma. This difference in fiber migration accounts for the finding of asbestos-related pleural disease that can be unassociated with parenchymal fibrosis or intrathoracic malignancy. On chest radiographs, pleural plaques are irregular, smooth elevations of the pleura identified in profile along the margins of the lungs or over the diaphragm. When seen en face, the plaques are flat relative to their width, and the density of the shadow projected over the lungs is less than would be expected for a parenchymal lesion of equivalent size (Fig. 3-24). Plaques are usually multiple and fairly symmetric from side to side.

Calcification in plaques is linear when seen in profile, and when seen en face it may have an irregular, unevenly dense appearance, referred to as a "holly leaf" pattern of calcification. There is no evidence that pleural plaques degenerate into malignant mesothelioma, but there is evidence to support a small but statistically significant increased incidence of mesothelioma in individuals with occupational exposure and radiographically detectable pleural plaques (16). In addition, it was found in one study that occupationally exposed individuals with plaques (but not parenchymal disease) had increased mortality from bronchogenic carcinoma (17).
FIGURE 3-22. Simple silicosis. A: CT scan with lung windowing shows numerous circumscribed pulmonary nodules, 2 to 3 mm in diameter (arrows). B: CT scan with mediastinal windowing shows densely calcified hilar (solid arrows) and subcarinal (dashed arrow) nodes.
FIGURE 3-23. Complicated silicosis. This 61-year-old man had a 30-year exposure to silica from sandblasting. PA chest radiograph shows conglomerate upper lung masses, referred to as progressive massive fibrosis (straight arrows). The masses have a tendency to migrate from the periphery to the hila. There is tenting of the right hemidiaphragm as a result of severe contraction of the right upper lobe (curved arrow).
FIGURE 3-24. Asbestos-related pleural disease and asbestosis. A: PA chest radiograph, coned to the right lung, shows curvilinear calcified pleural plaques en face (arrows). B: CT scan with lung windowing shows bilateral lower lung ground-glass and reticular opacities. The diagnosis of asbestosis was confirmed with lung biopsy. C: CT scan with mediastinal windowing shows bilateral calcified pleural plaques (arrows). This appearance is virtually diagnostic of previous asbestos exposure.
FIGURE 3-25. Asbestos-related pleural disease and rounded atelectasis. This 62-year-old man had a 20-year history of asbestos exposure. A: PA chest radiograph shows a large right lobulated pleural fluid collection (small arrows) and a right lower lobe "mass" (large arrows). B: CT scan with intravenous contrast enhancement shows thickening and enhancement of the parietal pleura (small arrows), indicating a chronic pleural effusion. The parenchymal "mass" (large arrows), in contact with the visceral pleural surface, represents collapsed lung. The atelectatic lung has a rounded shape caused by fibrous adhesions and infolding of the visceral pleura. Air bronchograms are seen within the collapsed lung (arrowhead). C: CT scan with lung windowing shows the "vacuum cleaner effect" or "comet-tail sign," both descriptions of how the vessels leading toward the atelectatic lung diverge and arc around the undersurface of the atelectatic lung before merging with it.
Rounded atelectasis is a form of juxtapleural lung collapse that can be confused with a neoplasm or pneumonia. Always associated with chronic pleural disease (and therefore commonly associated with asbestos exposure), rounded atelectasis represents an infolding of the visceral pleura as an isolated area of atelectasis. A proposed mechanism of rounded atelectasis is collapsed lung floating on pleural effusion and development of fibrous adhesions suspending the rounded atelectatic area in an elevated and tilted position. The pleural effusion may resolve, but the sequestered atelectatic lung may not re-expand. Rounded atelectasis forms a round or oval mass, usually 2.5 to 5.0 cm in diameter, in contact with the pleural surface. The vessels leading toward the mass are crowded, and as they reach the mass they tend to diverge and arc around the undersurface of the mass before merging with it. This appearance has been called the vacuum cleaner effect and the comet tail sign (18) (Fig. 3-25). Rounded atelectasis may slowly resolve or remain unchanged on serial chest radiographs or chest CT scans. To confidently suggest the diagnosis of rounded atelectasis, three criteria must be met: (i) contiguity with chronic pleural effusion/thickening, (ii) typical appearance of crowded vessels and bronchi sweeping into and around the base of the atelectatic lung, and (iii) volume loss in the affected lobe.
The term asbestosis refers to asbestos-induced pulmonary fibrosis and is distinguished from asbestos-related pleural disease without pulmonary fibrosis. Time from exposure to evidence of development of asbestosis is generally 20 to 30 years. The chest radiograph shows reticular interstitial disease, often with evidence of honeycombing, in a subpleural and basilar distribution, identical to the UIP pattern. Pleural changes related to asbestos exposure may provide a clue to the underlying diagnosis, but they are not present in all cases. In early or mild stages, chest CT scans can show interlobular septal thickening; subpleural lines (curvilinear opacities paralleling the chest wall in a subpleural location); parenchymal

bands (linear structures up to 5 cm in length coursing into the lung from the pleural surface); ground-glass opacities (diffuse, mild alveolar wall fibrosis and edema that cannot be resolved by CT); and centrilobular nodular opacities (peribronchiolar fibrosis). Honeycombing is an end-stage finding. In some cases, when the parenchymal findings are limited to the dependent lung, CT done with prone positioning is helpful to differentiate the findings resulting from asbestosis from the obscuring and confounding effects of gravity-related dependent atelectasis.
Exposure to asbestos increases the incidence of bronchogenic carcinoma, and this risk is multiplied in cigarette smokers. Asbestos exposure also increases an individual's risk of developing malignant mesothelioma, an uncommon and fatal neoplasm of the serosal lining of the pleural cavity, peritoneum, or both. There is usually a latency period of approximately 20 to 40 years between exposure and detection of mesothelioma. This neoplasm is further discussed in Chapter 9.
Sarcoidosis is a systemic disease of unknown etiology characterized histologically by noncaseating granulomas. The disease occurs in people of all ages and both sexes but characteristically affects African American women between the ages of 20 and 40. Chest radiographs can be normal or show parenchymal opacities, adenopathy, or both. The most frequent chest radiographic pulmonary abnormality is small rounded or irregular opacities (reticulonodular opacities), with most nodules measuring 2 to 4 mm (19). These opacities are usually bilateral and symmetric, often with a predominant middle or upper and middle lung distribution. Sarcoid granulomas may resolve completely, or they may heal by fibrosis. Chest radiographic findings of sarcoid fibrosis include permanent coarse linear opacities radiating laterally from the hilum into the adjacent upper and middle lungs. The hila are pulled upward and outward, and vessels and fissures are distorted. The fibrosis can be quite extensive, occasionally resembling the progressive massive fibrosis seen with complicated silicosis. Ring opacities can be seen as a result of bronchiectasis or bullae. CT scans of sarcoidosis typically show 1- to 5-mm nodules with irregular margins in a perilymphatic distribution along bronchovascular margins, interlobular septa, and subpleural areas and in the centers of lobules (Fig. 3-26). This distribution of nodules can be identical to the pattern seen with lymphangitic carcinomatosis. Further description of the features of sarcoidosis is provided in Chapter 10.
FIGURE 3-26. Sarcoidosis. CT scan shows nodular thickening of the bronchovascular bundles (solid arrow) and subpleural nodules (dashed arrow), illustrating the typical perilymphatic distribution of sarcoidosis.
Collagen Vascular Diseases
Rheumatoid arthritis (RA) is an inflammatory polyarthropathy of unknown cause. The arthritic changes occur more commonly in women, but pulmonary manifestations occur with greater frequency in men. Pleural involvement, typically pleural effusions or pleural thickening, is the most common thoracic manifestation of RA. Pleural effusions are usually unilateral and small to moderate in size but can occasionally be large or bilateral. Pulmonary fibrosis occurs in approximately 10% to 20% of patients with RA, producing radiographic changes similar to those seen in UIP (20) (Fig. 3-27). Another pleuropulmonary abnormality associated with RA is the rare necrobiotic nodule. These nodules are pathologically identical to the subcutaneous nodules that these patients develop. Necrobiotic nodules, which usually occur in patients with established disease, are usually radiologically discrete, rounded or lobulated, and subpleural. They may be single or multiple, and they have a middle and upper lung–predominant distribution. They range in size from a few millimeters to 7 cm, and occasionally a miliary pattern is seen. The nodules cavitate in approximately 50% of cases (21). The nodules may increase in size and number, resolve completely, or remain stable for many years; they may wax and wane with the activity of subcutaneous nodules and arthritis. Systemic vasculitis occurs in patients with RA and can affect the lung in rare cases, resulting in pulmonary arterial hypertension. Other intrathoracic associations with RA include obliterative bronchiolitis, organizing pneumonia, and pericarditis.
FIGURE 3-27. Pulmonary fibrosis and rheumatoid arthritis. CT scan of the right lung shows layers of small cysts in a subpleural location (arrows). This pattern of honeycombing is diagnostic of pulmonary fibrosis. The "mass" in the anterior right lung is the liver.

FIGURE 3-28. Systemic sclerosis. This 63-year-old man presented with increasing shortness of breath. A: PA chest radiograph shows a bibasilar and subpleural distribution of fine reticular ILD. The presence of a dilated esophagus (arrows) provides a clue to the correct diagnosis. B: CT scan shows peripheral ILD and a dilated esophagus (arrow).
Systemic lupus erythematosus (SLE) is a multisystem collagen vascular disease characterized by widespread inflammatory changes, particularly in the vessels, serosa, and skin. The disease is 10 times more common in women than in men (22), with an increased prevalence among African American women of childbearing age. Pleuritis is found in 40% to 60% of patients with SLE (23). The pleuritis is dry 50% of the time; at other times it is accompanied by a pleural effusion and/or pericardial effusion. The pleural effusion is usually small or moderate in size but may be large, and unilateral and bilateral effusions occur with equal frequency.
Acute lupus pneumonitis is an unusual life-threatening condition resembling infectious pneumonia, pulmonary infarction, and pulmonary hemorrhage, all of which are associated with SLE. The chest radiographic findings in lupus pneumonitis consist of areas of dense airspace opacity, usually bilateral and basal, that represent diffuse alveolar damage mediated by immune complex deposition. Pulmonary hemorrhage is common in patients with SLE, and it is usually manifested radiographically as bilateral and diffuse airspace opacification, similar to the pattern seen with Goodpasture syndrome, another pulmonary–renal syndrome. Pulmonary fibrosis occurs in approximately 3% of patients (24), with a pattern that is radiographically and pathologically identical to that seen in other collagen vascular diseases. Bilateral diaphragm elevation is commonly seen in patients with SLE, and in some reports this has been shown to be the most common radiologic pleuropulmonary abnormality in SLE. As the diaphragm rises, lung volumes decrease, referred to as the "shrinking lungs" sign (25). Pulmonary hypertension and vasculitis, pulmonary embolism (caused by circulating lupus anticoagulant), lymphocytic interstitial pneumonia, obliterative bronchiolitis, and organizing pneumonia are also seen in patients with SLE. Secondary thoracic manifestations of SLE include atelectasis, infectious pneumonia (simple or opportunistic owing to steroid treatment), cardiac failure, pericarditis, and drug-induced changes.
Systemic sclerosis (SS) is a generalized connective tissue disorder characterized by tightening, induration, and thickening of the skin (scleroderma); Raynaud phenomenon; musculoskeletal manifestations; and visceral involvement, especially of the gastrointestinal tract, lungs, heart, and kidneys. The pathogenesis is not completely understood. SS occurs more commonly in women in the third to fifth decades of life. The most common radiologic abnormality is pulmonary fibrosis, which causes a symmetric, diffuse, basally predominant reticulonodular pattern with associated loss of lung volume (26) (Fig. 3-28). The CT findings are similar to those of other diseases with a UIP histologic pattern. Pneumonia can occur, particularly after aspiration as a result of esophageal involvement. Esophageal dilatation seen on a chest radiograph or CT scan can provide a clue to the diagnosis of SS.
Sjögren syndrome (sicca syndrome) is an autoimmune disorder characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). A disease of middle-aged women, it can result in many of the pleural, parenchymal, and diaphragmatic complications associated with other collagen vascular diseases, including pulmonary fibrosis.
Langerhan Cell Histiocytosis
Also known as histiocytosis X and eosinophilic granuloma of lung, LCH is a granulomatous disorder of unknown cause characterized by the presence within the granulomas of a histiocyte, the Langerhan cell. LCH represents a spectrum of diseases, with lung involvement seen either in infancy as part of a serious multisystem disorder (Letterer-Siwe disease), in older children as part of a more indolent disorder involving one organ system or a few organs (Hand-Schüller-Christian disease), or as a primary lung disease in adults. LCH is equally prevalent in both sexes, and 95% of adult patients have a history of cigarette smoking (27). Pneumothorax is a classic initial or presenting manifestation of LCH, as it is in LAM. Pneumothoraces occur in 6% to 25% of patients with LCH and are commonly bilateral and recurrent. The characteristic radiographic appearance of LCH is a diffuse, symmetric, reticulonodular pattern or, less commonly, a solely nodular pattern, with a middle and upper lung–predominant distribution (Fig. 3-29). The nodules are usually ill defined, varying in size from 1 to 15 mm, and are usually innumerable. Progression to cystic lung disease results in increased lung volume. The radiographic findings clear in one third of patients, remain stable in one third, and show

deterioration in one third (28). CT scan findings consist of cysts and nodules, often in combination. When only cysts are seen, the appearance can resemble that of LAM or emphysema. The cysts range in diameter from 1 to 30 mm. Nodule margins tend to be indistinct, and some cavitate. Serial CT scans show progression from nodules, to cavitary nodules, to cysts, to an end stage of destruction resembling generalized emphysema.
FIGURE 3-29. Langerhan cell histiocytosis. This 50-year-old man had a 30 pack-year history of cigarette smoking. A: PA chest radiograph shows hyperinflation of the lungs and fine bilateral reticular ILD. B: CT scan shows multiple cysts (solid arrow) and nodules (dashed arrow).
Unilateral Interstitial Lung Disease
Most disorders discussed in this chapter result in bilateral chest radiograph changes. The four processes that can characteristically result in unilateral ILD are listed in Table 3-9. Recognizing a unilateral distribution can help narrow the differential diagnosis.
Lymphangitic carcinomatosis (primary bronchogenic carcinoma)
Atypical edema (large contralateral pulmonary embolism)
Aspiration pneumonia
X-ray therapy changes
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