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The radiological spectrum of small-airway diseases
The Radiological Spectrum of Small-Airway Diseases Vineet Sharma, Akram M. Shaaban, Grant Berges, and Marc Gosselin The small airways of the lungs are an often misunderstood and confusing anatomic location teeming with an array of similar-appearing disease processes that can be daunting even to the most experienced radiologist. This article shows that an understanding of small-airway anatomy and accurate pattern recognition can allow one to determine useful clinical differential diagnoses. The ability to recognize mosaic lung attenuation, and the presence of centrilobular nodules and reticular opacities (tree-in-bud), with or without ground glass, is of critical importance in evaluating this portion of the lung. In addition, we attempt to further show how high-resolution computed tomography (HRCT) scanning has opened the deep recesses of the lung to the thoracic radiologist, allowing for a more meaningful radiologic contribution to the clinical care of patients with unexplained pulmonary symptomatology.
Copyright 2002, Elsevier Science (USA). All rights reserved.
HE SMALL AIRWAYS of the lungs, aptly named, represent the anatomic dead end, so to speak, of the complex network of air transporting tubes that are the pulmonary bronchi and bronchioles (Fig 1). Devoid of the cartilaginous matrix that is so abundant proximally in the bronchi, the bronchioles are the most compliant elements of the lungs and are the primary area of gas exchange. The small airways include the subsegmental bronchi, terminal bronchioles, respiratory bronchioles, and the alveolar sacs. The second-order respiratory bronchioles, in conjunction with the alveolar sacs, comprise what is known as the secondary pulmonary lobule. An understanding of the primary pulmonary lobule, which is the smallest and most distal aspect of the airways, is vital to full comprehension of the physiology and patterns of disease in this often misunderstood area of the lung. Consisting of a terminal bronchiole, a number of respiratory bronchioles, innumerable interconnected alveolar sacs, and intricate matrices of lymphatics and capillaries, it is no surprise that the pulmonary lobule holds the key to unlocking the pathologic processes that afflict the small airways. In addition, the connections between the alveoli--via the pores of Kohn--are crucial to understanding and distinguishing among disease processes, as is discussed later. In any event, the full array of the microscopic anatomy is obviously impossible to image by using current radiographic techniques, though characteristic patterns can emerge to the trained eye--both on plain chest radiographs and high-resolution computed tomography (HRCT) scans--when the radiologist is armed with an accurate knowledge and understanding of this region of the lung.
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PATTERNS OF DISEASE
Perhaps the most difficult aspect of the thoracic radiologist's job is to determine the pattern of disease. Whether it is on a chest radiograph or a
HRCT, an interpretive conclusion, let alone a differential diagnosis, cannot be made unless one can first recognize the pattern of pathology that is present. In the small airways, as in other parts of the lung and body, the anatomy governs the pathology. Unlike other causes of diffuse lung disease, the small airways often show only subtle imaging abnormalities, even with extensive involvement. The radiologists should consider smallairways diseases when patients show chronic or worsening respiratory symptoms such as dyspnea, hypoxia, or nonproductive cough. The pretest probability for an underlying disease process increases with the chronicity of symptoms and, despite a normal-appearing chest radiograph, further evaluation with pulmonary function tests, alveolar diffusion measurements, and/or HRCT should be considered. Small-airways disease is manifest on radiographs and HRCT as mosaic lung attenuation and centrilobular nodular opacities (Table 1). As is discussed in more detail later in this article, mosaic lung attenuation refers to subtle differences in density seen in neighboring portions of the lung that are the result of a variety of causes: airtrapping and pulmonary arterial hypertension being the most prominent. The second manifestation of small-airways disease--centrilobular nodular opacities--can be divided further into "tree-inbud" opacities and ill-defined nodular ground-glass
From the Department of Radiology, University of Utah Medical Center, Salt Lake City, UT; and the Department of Radiology, Oregon Health Sciences University, Portland, OR. Address reprint requests to Marc V. Gosselin, MD, OHSU Department of Radiology, Mail Code L 340, 3181 SW Sam Jackson Park Road, Portland, OR. Copyright 2002, Elsevier Science (USA), All rights reserved. 0887-2171,/02/2304-0001535.00/0 doi:10.1053/sult.2002.34000
Seminars in Ultrasound, CT, and MRI, Vol 23, No 4 (August), 2002: pp 339-351
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iratory
:hioles 31i ar at .~vel) ucts iFsac Jveoli o~tung suppfled byterminal t bronchioIe -5 Respiratory "~ bronchioles ~l _J (3-8orders)
I Acinus
Alveolar sacsand I alveoli woresOTt~orln (interalveolarchannels) Fig 1. Anatomy of small airways.
opacities. These manifestations of the small-airways disease are unique. Hence, careful recognition of the aforementioned patterns (tree-in-bud and ground glass) is paramount to accurately diagnose and treat the underlying pulmonary process. Once small-airways disease is recognized, it is not unusual to then see bronchial or bronchiolar wall thickening, as well as radiographic evidence of
Table 1. Summary of Small-Airway Diseases and Their Predominant Manifestations
Manifestations
Diseases
Mosaic lung attenuation
Emphysema Asthma BO Bacterial bronchopneumonia Mycoplasma Aspiration pneumonia Endobronchial tuberculosis Mycobacterium avium complex Airway invasive aspergillus BOOP Diffuse panbronchiolitis RB-ILD NSIP EAA Follicular bronchiolitis LIP
Centrilobular nodules (tree-in-bud)
Ground-glass opacities with ill-defined centrilobular nodules
long-standing hypoxia (ie, pulmonary arterial hypertension or cor pulmonale). MOSAIC LUNG ATTENUATION AND AIR TRAPPING
An irdaomogeneous pattern of lung attenuation, often described as mosaic, is one of the cardinal manifestations of small-airway diseases as seen on HRCT (Fig 2). The appearance describes patchy areas of increased and decreased lung attenuation. The presence of mosaic lung attenuation may be the result of a number of different disease processes, and always represents an abnormal imaging pattern. Mosaic attenuation may be secondary to ground-glass opacities, vascular obstruction, or airway abnormalities. Once this imaging pattern is recognized on HRCT, the next decision is what regions are the abnormal areas. If the more dense region is abnormal, then the disease process is manifesting as ground-glass opacities. If the more lucent regions are abnormal, then the disease is likely secondary to either small-airways disease or pulmonary arterial abnormalities. The caliber of the pulmonary vessels on inspiratory HRCT scans often allows the radiologist to determine whether the ground glass or more lucent areas is the primary abnormality. A uniform caliber
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air trapping suggests the lucent regions are secondary to a primary arterial abnormality, especially pulmonary arterial hypertension, with plexigenic obliteration of the distal arterials. Several lung diseases primarily involving the small airways are manifested either by mosaic lung attenuation or air trapping. These include emphysema, asthma, and bronchiolitis obliterans (BO), which are discussed in more detail later. EMPHYSEMA
Fig 2. Mosaic lung attenuation. This 55-year-old woman with undiagnosed asthma shows a dramatic example of mosaic lung attenuation on expiratory HRCT. Note the extensive air trapping as evidenced by the black areas (B).
of the vessels is normally seen in the lung; therefore, when ground-glass opacities are seen in conjunction with vessels of normal caliber it can be inferred that the mosaic lung attenuation is not from redistribution of vascular perfusion, but rather a superimposed inflammatory process. Often, patients with this constellation of findings will have concurrent systemic symptoms, such as malaise, low-grade fever, and nonproductive cough. On the other hand, when reduced vessel caliber is seen in areas of low lung attenuation, the resultant mosaic perfusion is caused by vascular or airway abnormalities. The low lung attenuation in such cases is the result of vascular redistribution to the normally ventilated and/or perfused lung. Airway abnormalities, and particularly those leading to bronchiolar obstruction, are especially prone to producing the typical HRCT appearance of mosaic lung attenuation. The presence of bronchiolectasis in areas of low attenuation favors mosaic perfusion owing to an airway abnormality, rather than vascular abnormalities. However, expiratory scans are very sensitive in the detection of air trapping, which is the hallmark of bronchiolar obstruction. Air trapping is considered abnormal on HRCT when it affects a volume of lung equaling or exceeding a pulmonary segment, and is not limited to the superior segment of the lower lobe or the lingular tip (areas prone to physiologic air trapping). 1 The presence of air trapping helps distinguish small-airways disease from arterial diseases as the primary abnormality. The absence of
Emphysema, which is the leading cause of pulmonary mortality in the United States, is characterized by an abnormal, permanent dilatation of the air spaces distal to the terminal bronchioles, without areas of fibrosis. Emphysema is irrefutably associated with cigarette smoking, though it also can occur as a result of other underlying conditions, such as c~-I antitrypsin disease or intravenous Ritalin abuse. 2 It is precisely the relationship with smoking (with particles <3 mm in size) that links emphysema to the small airways. 2 The disease revolves around the concepts of compliance and expiratory airflow limitation--hypercompliant lungs result from alveolar destruction, whereas expiratory airflow limitation predominantly occurs in the small airways. 2 Moreover, emphysema can be characterized into 4 different subgroups based on its predilection for the different parts of the secondary pulmonary lobule. Centrilobular (or centriacinar) emphysema is by far the most common form of the disease--likely a result of its firm association with cigarette smoking. Pathologically, centrilobular emphysema is the end product of alveolar destruction around the proximal respiratory bronchiole. The process most often arises in the upper lobes of the lung and makes its way toward the lower lobes with disease progression. This particular characteristic of the centrilobular form of emphysema can explain its relatively silent nature, given the fact that the lower lobes play a far greater role in gas exchange. 3 It is not unusual to find incidental radiographic evidence (HRCT in particular) of centrilobular emphysema in the upper lobes in long-term cigarette smokers with no immediate pulmonary complaints or any pulmonary function test evidence of obstructive disease. Panlobular (or panacinar) emphysema--the form of the disease associated with a-1 antitrypsin deficiency--as its name implies, characteristically
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destroys the alveoli throughout the entire primary pulmonary lobule and proximal to the terminal bronchiole. It has a predilection for the lower lobes of the lungs, and hence is a far more severe form of the disease, as evidenced by greater obstructive pulmonary functional abnormalities. Panlobular emphysema occurs earlier in life and has a much more rapid progression than smoking-related emphysema. 3 Paraseptal emphysema tends to involve the periphery of the pulmonary lobule; therefore, it principally occurs adjacent to the connective tissue septa, fissures, and other areas or pleural reflections. The disease can be focal or multifocal, and confluence of the different areas of disease frequently leads to bullae (cystic air cavities) formation. Often linked with the centrilobular form of the disease, paraseptal emphysema can be associated with spontaneous pneumothorax, especially when there is extensive bullae formation. Clinical manifestations are similar to those of centrilobular emphysema. Although the anteroposterior and lateral chest radiograph is useful in showing the abnormalities associated with emphysema, it is the HRCT scan that provides the most valuable information for the radiologist in distinguishing emphysema from the other manifestations of small-airway disease. Classic findings on plain radiographs include costophrenic angle blunting and an angle exceeding 90 ° between the hemidiaphragm and sternum on the lateral projection. Hyperexpansion of the lungs (a result of increased compliance of the small airways) results in increased lucency of the most affected regions. This is secondary to destruction of the capillary beds, resulting in attenuation of the vasculature. Vascular destruction often is associated with increased branching angles of pulmonary vessels, approaching up to 90 °. The vasculature may also be affected by concurrent small-airway obstruction, leading to air trapping and reactive vasoconstriction of the pulmonary arterials in the most affected regions. 3 Furthermore, the physiologic consequences of long-standing emphysema, such as cor pulmonale, are easily identified on plain radiographs, with right ventricular and central pulmonary arterial enlargement being the most readily apparent findings. It is the HRCT scan, however, that has revolutionized the examination of the small airways, with emphysema being no exception, HRCT is far more
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Fig 3. Centrilobular emphysema. A 53-year-old man presented with worsening shortness of breath and hemoptysis. CT exhibits extensive emphysema (centrilobular) throughout the lungs, particularly with large bullous changes seen involving the apices. Note the presence of vessels (arrows) coursing within the large bullae.
sensitive than plain films in exhibiting the findings described earlier. It occasionally is used to diagnose emphysema, along with the clinical findings and pulmonary function tests, in patients with obstructive pulmonary physiology. HRCT clearly shows the areas of markedly low lung attenuation that is the hallmark of the disease. The distinctive areas are observed as round, black lucencies, with the characteristic absence of discernible walls. 4 A centrilobular vessel may be seen within the lucent area, helping to distinguish an emphysematous area from a lung cyst (Fig 3). HRCT can also be used to evaluate the large bullae often seen in paraseptal emphysema. This is especially important when surgery is considered and detailed anatomic definition is needed. In addition, the pulmonary vessels are visibly smaller in areas of extensive emphysematous disease, which is the end result of the shunting of blood flow to parts of the lung more amenable to gas exchange (the body's attempt to match ventilation and perfusion). This shunting is one of the factors explaining why the lower lobes appear so busy in patients with predominantly upper lobe emphysema. The combination of increased blood volume in the lower lobes and bronchial and bronchiolar wall thickening accentuates the difference of opacity of upper and lower lobes, resulting in the characteristic upper lobe lucency seen on chest radiographs in advanced centrilobular emphysema.
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ASTHMA
Asthma is a puhnonary disease that is characterized by reversible airway obstruction, inflammation, and hyperresponsiveness. 3 It is often the result of an environmental insult to the small airways that triggers inflammatory mediators from mast cells, macrophages, and epithelial cells. These mediators eventually lead to smooth muscle contraction and airway obstruction. The environmental triggers can include exercise, cold air, chemical irritants, allergens, or infection. Pulmonary function tests often yield an obstructive pattern, and the degree of abnormality typically correlates with the degree to which the disease is controlled with bronchodilatory therapy. Although often thought of as a benign, treatable, and self-limiting process, asthma can also present as a chronic, incapacitating process, eventually leading to irreversible obstructive pulmonary disease. Typically, however, the lungs in patients with asthma are conspicuously devoid of emphysema, unless there is comorbidity related to cigarette smoking. A representative abnormal chest radiograph of a patient with asthma would show signs consistent wig----but not distinctive of--the disease. These include airway thickening, hyperaerafion, atelectasis, and, in some cases, complications of disease, such as pneumothorax and pneumomediastinum. Asthma exacerbations are closely linked to pneum o n i a - u s u a l l y viral--and care should be taken to evaluate the chest radiograph closely for the increased reticular opacities or consolidative patterns typical, respectively, for viral and bacterial pneumonia. HRCT yields yet more clues that may lead to the diagnosis of asthma because it often shows the presence of bronchial wall thickening and mosaic lung attenuation with air trapping. Less common findings include a centrilobular tree-in-bud appearance from mucus plugging, and bronchiectasis or bronchiolectasis. 3 Furthermore, allergic bronchopulmonary aspergillosis is often seen with asthma, and is easily discernible on chest radiograph or CT scan by the typical appearance of filled central bronchiectasis, or the gloved fingers sign (bronchoceles). The degree of air trapping in asthma can vary considerably, depending on the severity of the disease and the success of pharmacologic control. Mosaic lung attenuation is emphasized on the expiratory HRCT, and can undoubtedly be mistaken for other diseases that exhibit
Fig 4. Asthma. (A) This patient with asthma has subtle mosaic lung attenuation on the inspiratory HRCT scan. (B) Extensive air trapping (AT) is shown only on the expiratory scan, a typical finding in patients with asthma,
forms of air trapping, such as BO (Fig 4). The feature that distinguishes asthma from other similar obstructive diseases, however, is reversible obstructive physiology (usually in response to steroids or bronchodilators). The sensitivity of HRCT for asthma is likely superior to pulmonary function tests because the latter are relatively insensitive to small-airways disease and are also primarily a global measurement of lung function. Patchy subsegmental involvement can be detected with HRCT, even when pulmonary function tests are normal. BRONCHIOLITIS OBLITERANS
Bronchiolitis is a descriptive and pathologic term used to show an inflammatory process that affects the small airways, and can eventually lead to fibrosis and irreversible airway obstruction. Re-
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sulting from a vast array of infectious and inflammatory disorders, bronchiolitis presents clinically with cough, dyspnea, and fatigue. The clinical criterion used for the diagnosis of BO is irreversible airflow limitation. BO is defined by a forced expiratory volume in I second that is less than 60% of the predicted value, in the absence of emphysema, chronic bronchitis, asthma, or other cause of airway obstruction. Etiologic factors include the following: (1) any cause of respiratory bronchiolitis (usually viral, with respiratory syncytial virus and adenovirus being the most common), (2) Swyer-James Syndrome (BO after a viral infection in children), (3) collagen vascular diseases (such as RA), (4) inhalation injury (with ammonia, nitrous oxide, and gastric acid being common), (5) graftversus-host disease (bone marrow transplant), (6) chronic lung rejection, and (7) idiopathic causes. 3 The pathogenesis of bronchiolitis involves vigorous infiltration of terminal and respiratory bronchioles with lymphocytes, histiocytes, and plasmacytes. This inflammatory attack on the distal airways essentially squeezes shut the terminal airways, which leads to air trapping in the alveoli beyond the affected area. Ultimately, the inflammatory process leads to irreversible fibrosis of the proximal bronchioles. The alveoli, however, are continuously provided more air from adjacent unaffected alveoli via the terminal conducting airways (pores of Kohn and canals of Lambert), further exacerbating the degree of air trapping. As the number of terminal conducting airways increases, bronchiolectasis and air trapping become prominent on imaging studies. Ultimately, in severe cases, lung transplantation is the only alternative. This is a poorly understood disease because it simply represents scarring. Scar involving the skin would be analogous. We do not regard a skin scar as a disease, but simply a normal reaction to a moderate or severe injury. If we were to consider a differential for a skin scar, the list would be long. Similar to the skin, the terminal bronchiole mucosal surface is limited in the number of reactions it has to various different forms of injury. Therefore, it may be preferable to refer to the earlier-mentioned characteristic imaging findings as a BO-like reaction, knowing there are many different potential ways to injure the mucosal surfaces. This injury is actually quite common and underdiagnosed. Numerous patients are labeled with chronic obstructive pulmonary disease and emphysema
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Fig 5. BO. A 62-year-old man presents with a history of rheumatoid arthritis and refractory asthma that does not respond to therapy, HRCT shows a mosaic lung perfusion pattern and diffuse air trapping (AT)throughout the lungs with the presence of bronchial wall thickening, most likely representing BO.
who actually have extensive BO. HRCT can often distinguish between the 2 by confirming or excluding the presence of extensive emphysema. The radiographic features of BO are quite variable; nevertheless, many causes share common features that allow grouping of diseases causing BO. The distribution pattern of these abnormalities, and the presence of any additional features, may allow recognition of specific disease entities. Not surprisingly, as with most diseases involving the small airways, the chest radiograph is usually unremarkable in BO. 3 Having said that, the experienced eye looking at a plain chest film may be able to discern hyperinflation that results from air trapping, vessel attenuation, and bronchial wall thickening, all of which suggest BO. However, it is HRCT, and expiratory HRCT in particular, that can be especially useful in delineating the disease. The following are the common radiologic features as detected mainly on HRCT: (1) mosaic lung attenuation, with significant pulmonary vascular attenuation in dark areas; (2) prominent air trapping (as evidenced by the striking similarity of the inspiratory and expiratory scans); and (3) perhaps the presence of bronchiectasis (seen in many forms of small-airway disease) (Fig 5). CENTRILOBULAR NODULES (TREE-IN-BUD) The lobular bronchioles measure less than 1 mm in diameter and their walls are less than 0.1-mm thick. These bronchioles cannot be seen on HRCT in normal individuals because they are below its spatial resolution. However, bronchi as small as 2
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becomes evident. Endobronchial spread of bacterial pneumonia is an important differential consideration in virtually all patients--immunocomproraised or otherwise--presenting with fever, cough, purulent sputum, and radiographic findings of thick reticular opacities with 3-4 mm nodules and bronchial wall thickening. Although each of the aforementioned findings are found repeatedly in every one of the entities to follow, recognition is crucial to guide the clinical course of the diseases.
Mycoplasma
Fig 6. Tree-in-bud. This 35-year-old patient with AML presented with fever, HRCT shows innumerable centrilobular nodules with branching lines (tree-in-bud) as a result of widespread Streptococa[ pneumonia (arrowheads).
mm in diameter can, in fact, be seen on HRCT. Inflammation of the lobular bronchioles results in thickening of the bronchiolar wall, peribronchial infiltration with inflammatory cells, and/or filling of the dilated bronchioles with granulation tissue, pus, or mucus. These diseased bronchioles appear as small centrilobular nodules on HRCT, when they course perpendicular to the CT plane of section, and they appear as branching, linear opacities when they course parallel to the plane of section (Fig 6). These 2 configurations merge to form the characteristic tree-in-bud pattern that is so often seen in the diseases that afflict the secondary pulmonary lobule. The tree-in-bud presence often indicates an active inflammatory disease process within the small airways, either acute or more indolent. Usually, there is concurrent involvement of the more central airways, represented on imaging studies by thickening of the bronchial walls. The diseases in which centrilobular nodules are prominent are considered later.
Bacterial Bronchopneumonia Community-acquired pneumonia can spread within the lungs by traveling distally through the airways. When the purulent material becomes impacted within the terminal bronchioles of the small airways, the distinctive tree-in-bud disease pattern
An important form of community-acquired pneumonia affecting the small airways is that caused by the organism Mycoplasma pneumoniae. A somewhat indolent infection with a good prognosis in most afflicted individuals, Mycoplasma pneumonia is seen on the chest radiograph as areas of patchy consolidation, bronchial wall thickening, and reticular opacities, all of which translate to the characteristic tree-in-bud appearance on HRCT. The features of mycoplasma infection, namely linear septal thickening (pseudo Kerley lines), centrilobular nodules, and peribronchial inflammation, tend to predominate in the lower lobes, though they can be seen throughout the lungs. The distribution and manifestations within the lung are rather indistinguishable from those seen with bacterial bronchopneumonia; therefore, diagnosis is again ultimately made on the basis of clinical presentation. 5
Aspiration Pneumonia Aspiration of gastric or pharyngeal contents can lead to a similar picture as described previously. The dependant portions of medial basal segments of both lungs are typically involved (though the fight lobe is affected more often than the left) and bronchiolar impaction leading to the tree-in-bud appearance can be recognized on chest radiographs. Recognizing the tree-in-bud appearance in aspiration pneumonia is useful in distinguishing it from bibasilar atelectasis, which is usually more linear, without centrilobular nodules, and is associated with volume loss.
Endobronchial Tuberculosis When the Mycobacterium tuberculosis organism spreads via the tracheobronchial tree (most often seen with the primary or postprimary forms of the disease) the tree-in-bud pattern is again manifested
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samples, and the acumen of the radiologist. It characteristically presents on the plain radiograph only with hilar adenopathy, though when it affects the small airways, ill-defined centrilobular nodules, reticular opacities, and bronchial wall thickening are seen. HRCT usually shows a tree-in-bud pattern, along with patchy consolidation, and perhaps even the presence of thin-walled cysts. The recognition of mycobacterium avium-intracellulare complex on plain films and HRCT, with subsequent confirmatory diagnosis via sputum sampling or bronchoalveolar lavage, is important given the nature of the disease, which normally requires the patient to undergo long-term antibiotic treatment (usually 6-12 too), or even lobectomy for locally recurrent disease. 7
Airway Invasive Aspergillus Fig 7. Tuberculosis. A 23-year-old human immunodeficiency virus-positive man presents with a cavitary mass in left upper lobe (not shown). Diffuse tree-in-bud appearance is seen throughout the lungs (seen here in RUL) as a result of endobronchial spread of TB. This patient also had necrotic mediastinal lymphadenopathy (not shown).
(Fig 7). The presence of 2- to 4-mm centrilobular nodules with linear reticular opacities is often seen in this form of the disease. Again, these findings are somewhat indistinguishable from the other disease processes described in this section. In addition, mural thickening and narrowing of the bronchi are also seen. 6 The secondary presence of lymphadenopathy, as well as areas of cavitation or consolidation in characteristic locations, can clue the radiologist in to the possibility of tuberculosis infection. Overall, endobronchial spread of tuberculosis (TB) occurs in only a small percentage of patients with pulmonary TB. 6 The earlier-mentioned findings in the setting of human immunodeficiency virus allow a more definitive diagnosis of TB.
Mycobacterium A vium-IntracelIulare Complex Most often seen in the elderly, and more recently as an important pathogen in patients with human immunodeficiency virus, mycobacterium aviumintracellulare complex can also manifest itself within the small airways. Either asymptomatic or fulminant in its presentation, mycobacterium avium-intracellulare complex is diagnosed by using a combination of clinical suspicion, sputum
Indistinguishable from bronchopneumonia of any cause, airway invasive aspergillus is most often seen in immunocompromised patients, such as those with acquired immune deficiency syndrome (end-stage, neutropenic acquired immune deficiency syndrome), or others with immune-suppressed neutropenia. Patients may exhibit a new onset of cough and flu-like symptoms, along with bronchospasm. 3 Sputum samples are often teeming with the Aspergillus species Aspergillusfumigatus. The chest radiograph shows ill-defined areas of patchy consolidation accompanied by centrilobular nodular opacities, s HRCT clearly identifies the tree-in-bud pattern seen with this disease, though definitive diagnosis cannot be made, given the obvious overlap of findings with BO organizing pneumonia (see later), bacterial bronchopneumonia, and endobronchial spread of TB. In addition, enlargement of the bronchi and bronchioles can be seen along with a picture of postobstructive atelectasis secondary to mucus plugging--a hallmark of allergic bronchopulmonary aspergillosis that is closely related and sometimes confused with the airway invasive form of aspergillus. 8
Bronchiolitis Obliterans Organizing Pneumonia Bronchiolitis obliterans organizing pneumonia (BOOP), also known as cryptogenic organizing pneumonia (COP), is characterized as a relatively indolent process (1-6 mo in duration) occurring primarily in individuals aged 30 to 50 years, and presenting with a clinical picture of dyspnea, cough, and low-grade fever. 3 Pulmonary function
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tests reveal a restrictive lung pattern. The cause of the disease process ranges from idiopathic, to postinfectious, to posttransplantation. BOOP can also result from collagen vascular disease, inhalation injury, or drug toxicity. 3 Regardless of the cause, BOOP is pathologically described as masses of granulation tissue within the small airways-first affecting the terminal bronchioles, and then spreading distally to involve the alveoli (organizing pneumonia). 9 Many textbooks and articles list a long differential of causes of BOOP/COP. It is best, however, not to consider BOOP/COP a unique pulmonary disease, but rather as a lung reaction to various injuries that primarily involve the respiratory bronchioles and also extend into the alveolar spaces. An example would be a BOOP/ COP-like reaction secondary to chronic graft-versus-host disease in an allogenic bone marrow transplant recipient. Therefore, this disease should be considered more of a reaction to a known or unknown (idiopathic BOOP) injury. Histopathology shows minimal, if any, fibrosis initially, but without treatment, progression of the BOOP/COPlike reaction can eventually lead to fibrosis. This can explain the common imaging presentations of consolidations, without much reticular opacity or fibrosis (until advanced disease). In some rare cases, BOOP can become a fulminate process leading to respiratory failure or adult respiratory distress syndrome if left untreated or unrecognized. The treatment, as with most inflammatory lung processes, is corticosteroids, and though recurrence can occur, most patients recover completely. BOOP manifests itself quite similarly on both chest radiography and HRCT (Fig 8). Chronic, patchy areas of consolidation, with a tendency to follow (or highlight) the airways, are the hallmarks of BOOP. BOOP often presents as multifocal areas of consolidation. Concurrent with consolidation, areas of ground-glass opacity, ill-defined nodules, and tree-in-bud opacities may be present. However, these later manifestations usually do not dominate the image, but are associated with the more common consolidative opacities. Bronchial dilation also is seen commonly in the areas of consolidation, which over time may evolve into fibrosis and traction bronchiolectasis. This is not a unique feature of BOOP/COP because many chronic inflammatory pulmonary diseases can result in fibrosis and traction bronchiolectasis if allowed to progress. Thus, the differential includes
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infectious processes, such as tuberculosis or fungal disease, chronic eosinophilic pneumonia, or cellular nonspecific interstitial pneumonia (NSIP). Chronic eosinophilic pneumonia is radiographically very similar to BOOP because both tend to consist of peribronchial consolidation and concurrent areas of ground-glass opacities. Occasionally, reticular opacities or septal markings may be present in advanced disease. 9 According to a recent study, the presence of parenchymal nodules or mass-like opacities is the most significant differentiating factor between BOOP and eosinophilic pneumonia--these findings occur far more often in BOOP, and only rarely with eosinophilic pneumonia. 9 The mass-like opacities (often 1-10 mm in size, and peripherally located), in combination with septal thickening, can present as spiculated lesions resembling the appearance of bronchogenic carcinoma or lymphoma. The presence of lymphadenopathy and pleural effusions is uncommon, helping to distinguish BOOP from its mimics, such as TB or fungal disease.
Diffuse Panbronchiolitis Diffuse panbronchiolitis, an important cause of progressive obstructive lung disease in Japan and the Far East, represents a distinctive sinobronchial syndrome, with typical radiologic and histologic features. Rare cases are now being identified in Europe, as well as South and North America. 1°-12 Patients often have a history of sinusitis, present with dyspnea on exertion, and show a restrictive pattern on pulmonary function tests. Histologically, there is transmural, chronic inflammation centered on the terminal bronchioles, with lymphocytic, plasma cell, and foamy macrophage infiltration. 11,13Chest radiographs of patients with diffuse panbronchiolitis usually show small nodular shadows throughout both lungs. Several patterns of lung involvement are seen on HRCT and may represent different stages of evolution. The following patterns may be seen: (1) small centrilobular nodules connected by small branching linear opacities (tree-in-bud); (2) nodules accompanied by ring-shaped or small ductal opacities connected to proximal bronchovascular bundles, representing bronchiolectasis; and (3) large cystic opacities accompanied by dilated proximal bronchi (bronchiectasis) (Fig 9). 14'15
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Fig 8, BOOP. (A and B) This 76-year-old man presents with chest radiographs showing bilateral, patchy, eonsolidativs opacities that seem to follow a bronehovascular distribution, (C) CT scan confirms the findings seen on chest films, and also reveals a peribronchovascular distribution of the consolidative opacities (white arrow), as well as a small right anterior pneumothorax (black arrow). BOOP was diagnosed via transbronchial biopsy.
GROUND-GLASS OPACITIES WITH ILL-DEFINED CENTRILOBULAR NODULES
Ground-glass opacities may be seen in some cases of bronchiolitis, and result from reaction of the alveoli to the same insults that cause bronchiolitis. Diffuse ground-glass opacities can be difficult to appreciate on HRCT, but the dark bronchus sign may be helpful (Fig 10). As is discussed in further detail later, ground-glass opacity is often
seen in acute infectious bronchiolitis, extrinsic allergic alveolitis, respiratory bronchiolitis, follicular bronchiolitis, lymphocytic interstitial pneumonia (LIP), and occasionally in BOOP-like reactions. RESPIRATORY BRONCHIOLITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE
Respiratory bronchiolitis is a distinct clinicopathologic disease described almost exclusively in
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Fig 9. Diffuse Asian panbronchiolitis. A 49-year-old Japanese woman with diffuse Asian panbronchiolitis exhibits extensive tree-in-bud opacities bilaterally (dark arrows).
cigarette smokers. The disease usually presents with mild symptoms and is associated with a good prognosis. Pathologically, it is characterized by mild chronic inflammation of the bronchioles, associated with the accumulation of pigmented macrophages in respiratory bronchioles and alveoli. Heyneman et a116 found significant overlap between the CT findings of respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), mad desquamative interstitial pneumonia (DIP), which is consistent with the concept that they represent different degrees of severity of small-airway disease and parenchymal
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Fig 11. RB-ILD. A 32-year-old man with no past medical history except that he is a heavy smoker. CT exhibits illdefined centrilobular nodules (arrows) with ground-glass opacities.
reaction to cigarette smoke. On HRCT, respiratory bronchiolitis presents with small, ill-defined centrilobular nodules and ground-glass attenuation accompanied by areas of air trapping, with upper lobe predominance (Fig 11). 16"17 Note that upper lobe predominance is a common feature in nearly all smoking-related lung diseases. Mild imaging evidence of fibrosis may be seen with RB-ILD, and is even more likely to be seen with DIP, but does not occur with respiratory bronchiolitis alone. The centrilobular nodular opacities likely represent the precursors of centrilobular emphysema because both processes have the same distribution and upper lobe predominance. This spectrum of smokingrelated injury may be useful for clinicians to know because they can use these imaging findings to help motivate patients to quit smoking. RB-ILD represents inflammation that is potentially and partially reversible, as opposed to centrilobular emphysema. NSIP
Fig 10. Ground glass. A 44-year-old man with extensive smoking history shows diffuse, bilateral areas of groundglass opacities (GG) with the presence of centrilobular nodules. This patient was diagnosed with DIP with areas of RB-ILD.
Originally used as a wastebasket term to describe an entity that did not meet the pathologic criteria of usual interstitial pneumonia, DIP, acute interstitial pneumonia, or BOOP, the cellular form of NSIP is now seen as a discrete pathologic diagnosis that, unfortunately, exhibits HRCT findings that significantly overlap those of the other interstitial pneumonias, BOOP, and extrinsic allergic alveolitis. The presence of ground-glass opacities, with or without ill-defined centrilobular nodules, is the typical HRCT finding of cellular NSIP, though a vast spectrum of manifestations are seen, from emphysematous changes to frank honeycombing. Needless to say, familiarity with the
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ing related), and because treatment options differ between the 2 entities. The consolidative form of EAA can be confused with BOOP radiographically. Once again, these conditions may be distinguished on the basis of history, though treatment for both entities is corticosteroid therapy.
Follicular Bronchiolitis
Fig 12. EAA. This patient is a 56-year-old woman who presented with a gradual history of progressively worsening symptoms of shortness of breath and dyspnea on exertion. HRCT showed ill-defined centrilobular nodules (arrows) with groundglass opacities, without evidence of fibrosis or lymphadenopathy. Biopsy specimen revealed extrinsic allergic alveolitis.
radiologic presentations of the other interstitial pneumonias is crucial in identifying NSIP by exclusion on chest radiographs or HRCT. The variable presentation of NSIP should be considered the classic presentation, and close communication with the pathologist and the clinical team defines the course of action, is
Extrinsic Allergic Alveolitis Hypersensitivity pneumonitis, or extrinsic allergic alveolitis (EAA), refers to a broad spectrum of inflammatory processes that occur within the lung parenchyma and airways secondary to an identifiable pathogen or insult. Such agents include airborne occupational hazards (eg, wood dust, bird proteins), fungi, or bacteria. Once the inciting agent makes its way to the small airways, a cascade of inflammatory mediators are triggered, resulting in a characteristic radiographic response to the insult. Depending on the presentation (acute versus chronic), plain radiographs in EAA patients can show subtle nodular opacities, well-defined nodules, larger focal areas of consolidation, or a combination of findings in the face of a diffuse groundglass picture. HRCT further delineates the subtle ground-glass opacity and ill-defined nodules that are suspected on plain films, and tends to show predominance within the mid-upper lobes (Fig 12). 19 An accurate smoking or environmental exposure history is paramount when EAA is suspected because its radiographic findings overlap considerably with those of RB-ILD (clearly smok-
Follicular bronchiolitis is a distinct clinicopathologic form of bronchiolitis seen with rheumatoid arthritis, mixed collagen vascular disorders, autoimmune disorders, and the acquired immunodeficiency syndrome. Histologically, this disease shows lymphoid hyperplasia along the bronchioles, accompanied by peribronchiolar lymphocytic infiltration. On HRCT, the cardinal feature of follicular bronchiolitis is the presence of small centrilobular nodules variably associated with peribronchial nodules and areas of ground-glass opacity (Fig 13). 2o However, patients with follicular bronchiolitis may show no evidence of bronchiolitis in the presence of severe limitation of airflow. 21
LIP LIP is a disease of diffuse infiltration of lymphocytes and plasma cells within the airways and parenchyma of the lungs. Often described in children infected with the human immunodeficiency virus, LIP is characterized by bilateral diffuse areas of ground-glass opacity, along with reticular opacities and small, ill-defined centrilobular nodules (representing areas of lymphocytic infiltration within the small airways) usually predominant in the lower lobes. 22 In rare cases, focal areas of
Fig 13. Follicular bronchiolitis. A 66-year-old woman with rheumatoid arthritis shows a pattern of ill-defined centrilobular nodules on HRCT (arrows).
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consolidation and bronchiectasis can be seen. Radiographic improvement of LIP in children with acquired immune deficiency syndrome has been identified as a harbinger of worsening immunosuppression, depicting inability to mount a cell-mediated response to insults. LIP is also associated with autoimmune thyroid disease, rheumatologic disorders (Sjogrens syndrome), and Castlemen's disease. 23 It is thought to represent a more severe form of follicular bronchiolitis. SUMMARY
In this article, we have attempted to show that recognizing mosaic lung attenuation, tree-in-bud, and ill-defined centrilobular nodules with groundglass opacities is the first step in identifying disease processes occurring within the small airways.
Unless the plain chest radiograph is scrutinized for these patterns, they will be missed, and the findings will be called nonspecific, given the vast overlap of radiographic findings. This form of pattern recognition-most accurate on HRCT, but just as evident on plain radiographs--allows for a greater understanding of the pathogenesis of the disease processes, and this understanding can focus treatment options. The examination of the small airways is only limited by the resolution of available modalities. Further pathologic secrets, and patterns, may be discovered once the deeper recesses of the lungs are more accurately explored. Until that time, however, the radiologist must use the modalities available--including the knowledge of the referring clinician--in order to be a meaningful and critical part of the clinical team.
REFERENCES 1. Leung AN, Fisher K, Valentine V, et al: Bronchiolitis obliterans after lung transplantation: Detection using expiratory HRCT. Chest 113:365-370, 1998 2. Gelb AS, Zamel N, Hogg JC, et al: Pseudophysiologic emphysema resulting from severe small-airways disease. Am J Respir Crit Care Med 158:815-819, 1998 3. Collins J, Blankenbaker D, Stern EJ: CT patterns of bronchiolar disease: What is "tree-in-bud"? AJR Am J Roentgenol 171:365-370, 1998 4. Kazerooni E: High-resolution CT of the lungs. AJR Am J Roentgenol 177:501-519, 2001 5. Reittner P, Muller N, Heyneman L: Mycoplasma pneumoniae pneumonia. Radiographic and high-resolution CT features in 28 patients. AJR Am J Roentgenol 174:37-41, 2000 6. Leung A: Pulmonary tuberculosis: The essentials. Radiology 210:307-322, 1999 7. Erasmus J, McAdams P, Farrell M: Pulmonary nontuberculous mycobacterial infection: Radiologic manifestations. Radiographics 19:1487-1503, 1999 8. Franquet T, Muller N, Gimenez A, et al: Spectrum of pulmonary aspergillosis: Histologic, clinical and radiologic findings. Radiographics 21:825-837, 2001 9. Arakawa H, Kurihara Y, Niimi H, et al: Bronchiolitis obliterans with organizing pneumonia versus chronic eosinophilic pneumonia: High-resolution CT findings in 81 patients. AJR Am J Roentgenol 176:1053-1058, 2001 10. Gulhan M, Erturk A, Kurt B, et al: Diffuse panbronchiolitis observed in a white man in Turkey. Sarcoidosis Vasc Diffuse Lung Dis 17:292-296, 2000 11. Fitzgerald JE, King TE Jr, Lynch DA, et al: Diffuse panbronchiolitis in the United States. Am J Respir Crit Care Med 154:497-503, 1996 12. Martinez JA, Guimaraes SM, Ferreira RG, et al: Diffuse panbronchiolitis in Latin America. Am J Med Sci 319:183-185, 2000 13. Fisher MS Jr, Rush WL, Rosado-de-Christenson ML, et
al: Diffuse panbronchiolitis: Histologic diagnosis in unsuspected cases involving North American residents of Asian descent. Arch Pathol Lab Med 122:156-160, 1998 14. Akira M, Kitatani F, Lee YS, et al: Diffuse panbronchiolitis: Evaluation with high-resolution CT. Radiology 168:433438, 1988 15. Nishimura K, Kitaichi M, Izumi T, et al: Diffuse panbronchiolitis: Correlation of high-resolution CT and pathologic findings. Radiology 184:779-785, 1992 16. Heyneman LE, Ward S, Lynch DA, et al: Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: Different entities or part of the spectrum of the same disease process? AJR Am J Roentgenol 173:1617-1622, 1999 17. Essadki O, Chartrand-Lefebvre C, Briere J, et al: Respiratory bronchiolitis: Radiographic and CT findings in a pathologically proven case. Eur Radiol 8:1674-1676, 1998 18. Hartman T, Swenson S, Hansell D: Nonspecific interstitial pneumonia: Variable appearance at high-resolution chest CT. Radiology 217:701-705, 2000 19. Matar L, McAdams HP, Sporn T: Hypersensitivity pneumonitis. AJR Am J Roentgenol 174:1061-1066, 2000 20. Howling SJ, Hansell DM, Wells AU, et al: Follicular bronchiolitis: Thin-section CT and histologic findings. Radiology 212:637-642, 1999 21. Kagamu H, Hasegawa T, Kurashige K, et al: [Bronchiolitis obliterans and no radiographic abnormalities in a patient with rheumatoid arthritis]. Nihon Kyobu Shikkan Gakkai Zasshi 35:524-529, 1997 22. Takeshi J, Muller N, Pickford H: Lymphocytic interstitial pneumonia: Thin-section CT findings in 22 patients. Radiology 212:567-572, 1999 23. Lee ES, Gotway MB, Reddy GP, et al: Early bronchiolitis obliterans following lung transplantation: Accuracy of expiratory thin-section CT for diagnosis. Radiology 216:472477, 2000
Copyright 2002, Elsevier Science (USA). All rights reserved.
HE SMALL AIRWAYS of the lungs, aptly named, represent the anatomic dead end, so to speak, of the complex network of air transporting tubes that are the pulmonary bronchi and bronchioles (Fig 1). Devoid of the cartilaginous matrix that is so abundant proximally in the bronchi, the bronchioles are the most compliant elements of the lungs and are the primary area of gas exchange. The small airways include the subsegmental bronchi, terminal bronchioles, respiratory bronchioles, and the alveolar sacs. The second-order respiratory bronchioles, in conjunction with the alveolar sacs, comprise what is known as the secondary pulmonary lobule. An understanding of the primary pulmonary lobule, which is the smallest and most distal aspect of the airways, is vital to full comprehension of the physiology and patterns of disease in this often misunderstood area of the lung. Consisting of a terminal bronchiole, a number of respiratory bronchioles, innumerable interconnected alveolar sacs, and intricate matrices of lymphatics and capillaries, it is no surprise that the pulmonary lobule holds the key to unlocking the pathologic processes that afflict the small airways. In addition, the connections between the alveoli--via the pores of Kohn--are crucial to understanding and distinguishing among disease processes, as is discussed later. In any event, the full array of the microscopic anatomy is obviously impossible to image by using current radiographic techniques, though characteristic patterns can emerge to the trained eye--both on plain chest radiographs and high-resolution computed tomography (HRCT) scans--when the radiologist is armed with an accurate knowledge and understanding of this region of the lung.
T
PATTERNS OF DISEASE
Perhaps the most difficult aspect of the thoracic radiologist's job is to determine the pattern of disease. Whether it is on a chest radiograph or a
HRCT, an interpretive conclusion, let alone a differential diagnosis, cannot be made unless one can first recognize the pattern of pathology that is present. In the small airways, as in other parts of the lung and body, the anatomy governs the pathology. Unlike other causes of diffuse lung disease, the small airways often show only subtle imaging abnormalities, even with extensive involvement. The radiologists should consider smallairways diseases when patients show chronic or worsening respiratory symptoms such as dyspnea, hypoxia, or nonproductive cough. The pretest probability for an underlying disease process increases with the chronicity of symptoms and, despite a normal-appearing chest radiograph, further evaluation with pulmonary function tests, alveolar diffusion measurements, and/or HRCT should be considered. Small-airways disease is manifest on radiographs and HRCT as mosaic lung attenuation and centrilobular nodular opacities (Table 1). As is discussed in more detail later in this article, mosaic lung attenuation refers to subtle differences in density seen in neighboring portions of the lung that are the result of a variety of causes: airtrapping and pulmonary arterial hypertension being the most prominent. The second manifestation of small-airways disease--centrilobular nodular opacities--can be divided further into "tree-inbud" opacities and ill-defined nodular ground-glass
From the Department of Radiology, University of Utah Medical Center, Salt Lake City, UT; and the Department of Radiology, Oregon Health Sciences University, Portland, OR. Address reprint requests to Marc V. Gosselin, MD, OHSU Department of Radiology, Mail Code L 340, 3181 SW Sam Jackson Park Road, Portland, OR. Copyright 2002, Elsevier Science (USA), All rights reserved. 0887-2171,/02/2304-0001535.00/0 doi:10.1053/sult.2002.34000
Seminars in Ultrasound, CT, and MRI, Vol 23, No 4 (August), 2002: pp 339-351
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iratory
:hioles 31i ar at .~vel) ucts iFsac Jveoli o~tung suppfled byterminal t bronchioIe -5 Respiratory "~ bronchioles ~l _J (3-8orders)
I Acinus
Alveolar sacsand I alveoli woresOTt~orln (interalveolarchannels) Fig 1. Anatomy of small airways.
opacities. These manifestations of the small-airways disease are unique. Hence, careful recognition of the aforementioned patterns (tree-in-bud and ground glass) is paramount to accurately diagnose and treat the underlying pulmonary process. Once small-airways disease is recognized, it is not unusual to then see bronchial or bronchiolar wall thickening, as well as radiographic evidence of
Table 1. Summary of Small-Airway Diseases and Their Predominant Manifestations
Manifestations
Diseases
Mosaic lung attenuation
Emphysema Asthma BO Bacterial bronchopneumonia Mycoplasma Aspiration pneumonia Endobronchial tuberculosis Mycobacterium avium complex Airway invasive aspergillus BOOP Diffuse panbronchiolitis RB-ILD NSIP EAA Follicular bronchiolitis LIP
Centrilobular nodules (tree-in-bud)
Ground-glass opacities with ill-defined centrilobular nodules
long-standing hypoxia (ie, pulmonary arterial hypertension or cor pulmonale). MOSAIC LUNG ATTENUATION AND AIR TRAPPING
An irdaomogeneous pattern of lung attenuation, often described as mosaic, is one of the cardinal manifestations of small-airway diseases as seen on HRCT (Fig 2). The appearance describes patchy areas of increased and decreased lung attenuation. The presence of mosaic lung attenuation may be the result of a number of different disease processes, and always represents an abnormal imaging pattern. Mosaic attenuation may be secondary to ground-glass opacities, vascular obstruction, or airway abnormalities. Once this imaging pattern is recognized on HRCT, the next decision is what regions are the abnormal areas. If the more dense region is abnormal, then the disease process is manifesting as ground-glass opacities. If the more lucent regions are abnormal, then the disease is likely secondary to either small-airways disease or pulmonary arterial abnormalities. The caliber of the pulmonary vessels on inspiratory HRCT scans often allows the radiologist to determine whether the ground glass or more lucent areas is the primary abnormality. A uniform caliber
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air trapping suggests the lucent regions are secondary to a primary arterial abnormality, especially pulmonary arterial hypertension, with plexigenic obliteration of the distal arterials. Several lung diseases primarily involving the small airways are manifested either by mosaic lung attenuation or air trapping. These include emphysema, asthma, and bronchiolitis obliterans (BO), which are discussed in more detail later. EMPHYSEMA
Fig 2. Mosaic lung attenuation. This 55-year-old woman with undiagnosed asthma shows a dramatic example of mosaic lung attenuation on expiratory HRCT. Note the extensive air trapping as evidenced by the black areas (B).
of the vessels is normally seen in the lung; therefore, when ground-glass opacities are seen in conjunction with vessels of normal caliber it can be inferred that the mosaic lung attenuation is not from redistribution of vascular perfusion, but rather a superimposed inflammatory process. Often, patients with this constellation of findings will have concurrent systemic symptoms, such as malaise, low-grade fever, and nonproductive cough. On the other hand, when reduced vessel caliber is seen in areas of low lung attenuation, the resultant mosaic perfusion is caused by vascular or airway abnormalities. The low lung attenuation in such cases is the result of vascular redistribution to the normally ventilated and/or perfused lung. Airway abnormalities, and particularly those leading to bronchiolar obstruction, are especially prone to producing the typical HRCT appearance of mosaic lung attenuation. The presence of bronchiolectasis in areas of low attenuation favors mosaic perfusion owing to an airway abnormality, rather than vascular abnormalities. However, expiratory scans are very sensitive in the detection of air trapping, which is the hallmark of bronchiolar obstruction. Air trapping is considered abnormal on HRCT when it affects a volume of lung equaling or exceeding a pulmonary segment, and is not limited to the superior segment of the lower lobe or the lingular tip (areas prone to physiologic air trapping). 1 The presence of air trapping helps distinguish small-airways disease from arterial diseases as the primary abnormality. The absence of
Emphysema, which is the leading cause of pulmonary mortality in the United States, is characterized by an abnormal, permanent dilatation of the air spaces distal to the terminal bronchioles, without areas of fibrosis. Emphysema is irrefutably associated with cigarette smoking, though it also can occur as a result of other underlying conditions, such as c~-I antitrypsin disease or intravenous Ritalin abuse. 2 It is precisely the relationship with smoking (with particles <3 mm in size) that links emphysema to the small airways. 2 The disease revolves around the concepts of compliance and expiratory airflow limitation--hypercompliant lungs result from alveolar destruction, whereas expiratory airflow limitation predominantly occurs in the small airways. 2 Moreover, emphysema can be characterized into 4 different subgroups based on its predilection for the different parts of the secondary pulmonary lobule. Centrilobular (or centriacinar) emphysema is by far the most common form of the disease--likely a result of its firm association with cigarette smoking. Pathologically, centrilobular emphysema is the end product of alveolar destruction around the proximal respiratory bronchiole. The process most often arises in the upper lobes of the lung and makes its way toward the lower lobes with disease progression. This particular characteristic of the centrilobular form of emphysema can explain its relatively silent nature, given the fact that the lower lobes play a far greater role in gas exchange. 3 It is not unusual to find incidental radiographic evidence (HRCT in particular) of centrilobular emphysema in the upper lobes in long-term cigarette smokers with no immediate pulmonary complaints or any pulmonary function test evidence of obstructive disease. Panlobular (or panacinar) emphysema--the form of the disease associated with a-1 antitrypsin deficiency--as its name implies, characteristically
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destroys the alveoli throughout the entire primary pulmonary lobule and proximal to the terminal bronchiole. It has a predilection for the lower lobes of the lungs, and hence is a far more severe form of the disease, as evidenced by greater obstructive pulmonary functional abnormalities. Panlobular emphysema occurs earlier in life and has a much more rapid progression than smoking-related emphysema. 3 Paraseptal emphysema tends to involve the periphery of the pulmonary lobule; therefore, it principally occurs adjacent to the connective tissue septa, fissures, and other areas or pleural reflections. The disease can be focal or multifocal, and confluence of the different areas of disease frequently leads to bullae (cystic air cavities) formation. Often linked with the centrilobular form of the disease, paraseptal emphysema can be associated with spontaneous pneumothorax, especially when there is extensive bullae formation. Clinical manifestations are similar to those of centrilobular emphysema. Although the anteroposterior and lateral chest radiograph is useful in showing the abnormalities associated with emphysema, it is the HRCT scan that provides the most valuable information for the radiologist in distinguishing emphysema from the other manifestations of small-airway disease. Classic findings on plain radiographs include costophrenic angle blunting and an angle exceeding 90 ° between the hemidiaphragm and sternum on the lateral projection. Hyperexpansion of the lungs (a result of increased compliance of the small airways) results in increased lucency of the most affected regions. This is secondary to destruction of the capillary beds, resulting in attenuation of the vasculature. Vascular destruction often is associated with increased branching angles of pulmonary vessels, approaching up to 90 °. The vasculature may also be affected by concurrent small-airway obstruction, leading to air trapping and reactive vasoconstriction of the pulmonary arterials in the most affected regions. 3 Furthermore, the physiologic consequences of long-standing emphysema, such as cor pulmonale, are easily identified on plain radiographs, with right ventricular and central pulmonary arterial enlargement being the most readily apparent findings. It is the HRCT scan, however, that has revolutionized the examination of the small airways, with emphysema being no exception, HRCT is far more
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Fig 3. Centrilobular emphysema. A 53-year-old man presented with worsening shortness of breath and hemoptysis. CT exhibits extensive emphysema (centrilobular) throughout the lungs, particularly with large bullous changes seen involving the apices. Note the presence of vessels (arrows) coursing within the large bullae.
sensitive than plain films in exhibiting the findings described earlier. It occasionally is used to diagnose emphysema, along with the clinical findings and pulmonary function tests, in patients with obstructive pulmonary physiology. HRCT clearly shows the areas of markedly low lung attenuation that is the hallmark of the disease. The distinctive areas are observed as round, black lucencies, with the characteristic absence of discernible walls. 4 A centrilobular vessel may be seen within the lucent area, helping to distinguish an emphysematous area from a lung cyst (Fig 3). HRCT can also be used to evaluate the large bullae often seen in paraseptal emphysema. This is especially important when surgery is considered and detailed anatomic definition is needed. In addition, the pulmonary vessels are visibly smaller in areas of extensive emphysematous disease, which is the end result of the shunting of blood flow to parts of the lung more amenable to gas exchange (the body's attempt to match ventilation and perfusion). This shunting is one of the factors explaining why the lower lobes appear so busy in patients with predominantly upper lobe emphysema. The combination of increased blood volume in the lower lobes and bronchial and bronchiolar wall thickening accentuates the difference of opacity of upper and lower lobes, resulting in the characteristic upper lobe lucency seen on chest radiographs in advanced centrilobular emphysema.
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ASTHMA
Asthma is a puhnonary disease that is characterized by reversible airway obstruction, inflammation, and hyperresponsiveness. 3 It is often the result of an environmental insult to the small airways that triggers inflammatory mediators from mast cells, macrophages, and epithelial cells. These mediators eventually lead to smooth muscle contraction and airway obstruction. The environmental triggers can include exercise, cold air, chemical irritants, allergens, or infection. Pulmonary function tests often yield an obstructive pattern, and the degree of abnormality typically correlates with the degree to which the disease is controlled with bronchodilatory therapy. Although often thought of as a benign, treatable, and self-limiting process, asthma can also present as a chronic, incapacitating process, eventually leading to irreversible obstructive pulmonary disease. Typically, however, the lungs in patients with asthma are conspicuously devoid of emphysema, unless there is comorbidity related to cigarette smoking. A representative abnormal chest radiograph of a patient with asthma would show signs consistent wig----but not distinctive of--the disease. These include airway thickening, hyperaerafion, atelectasis, and, in some cases, complications of disease, such as pneumothorax and pneumomediastinum. Asthma exacerbations are closely linked to pneum o n i a - u s u a l l y viral--and care should be taken to evaluate the chest radiograph closely for the increased reticular opacities or consolidative patterns typical, respectively, for viral and bacterial pneumonia. HRCT yields yet more clues that may lead to the diagnosis of asthma because it often shows the presence of bronchial wall thickening and mosaic lung attenuation with air trapping. Less common findings include a centrilobular tree-in-bud appearance from mucus plugging, and bronchiectasis or bronchiolectasis. 3 Furthermore, allergic bronchopulmonary aspergillosis is often seen with asthma, and is easily discernible on chest radiograph or CT scan by the typical appearance of filled central bronchiectasis, or the gloved fingers sign (bronchoceles). The degree of air trapping in asthma can vary considerably, depending on the severity of the disease and the success of pharmacologic control. Mosaic lung attenuation is emphasized on the expiratory HRCT, and can undoubtedly be mistaken for other diseases that exhibit
Fig 4. Asthma. (A) This patient with asthma has subtle mosaic lung attenuation on the inspiratory HRCT scan. (B) Extensive air trapping (AT) is shown only on the expiratory scan, a typical finding in patients with asthma,
forms of air trapping, such as BO (Fig 4). The feature that distinguishes asthma from other similar obstructive diseases, however, is reversible obstructive physiology (usually in response to steroids or bronchodilators). The sensitivity of HRCT for asthma is likely superior to pulmonary function tests because the latter are relatively insensitive to small-airways disease and are also primarily a global measurement of lung function. Patchy subsegmental involvement can be detected with HRCT, even when pulmonary function tests are normal. BRONCHIOLITIS OBLITERANS
Bronchiolitis is a descriptive and pathologic term used to show an inflammatory process that affects the small airways, and can eventually lead to fibrosis and irreversible airway obstruction. Re-
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sulting from a vast array of infectious and inflammatory disorders, bronchiolitis presents clinically with cough, dyspnea, and fatigue. The clinical criterion used for the diagnosis of BO is irreversible airflow limitation. BO is defined by a forced expiratory volume in I second that is less than 60% of the predicted value, in the absence of emphysema, chronic bronchitis, asthma, or other cause of airway obstruction. Etiologic factors include the following: (1) any cause of respiratory bronchiolitis (usually viral, with respiratory syncytial virus and adenovirus being the most common), (2) Swyer-James Syndrome (BO after a viral infection in children), (3) collagen vascular diseases (such as RA), (4) inhalation injury (with ammonia, nitrous oxide, and gastric acid being common), (5) graftversus-host disease (bone marrow transplant), (6) chronic lung rejection, and (7) idiopathic causes. 3 The pathogenesis of bronchiolitis involves vigorous infiltration of terminal and respiratory bronchioles with lymphocytes, histiocytes, and plasmacytes. This inflammatory attack on the distal airways essentially squeezes shut the terminal airways, which leads to air trapping in the alveoli beyond the affected area. Ultimately, the inflammatory process leads to irreversible fibrosis of the proximal bronchioles. The alveoli, however, are continuously provided more air from adjacent unaffected alveoli via the terminal conducting airways (pores of Kohn and canals of Lambert), further exacerbating the degree of air trapping. As the number of terminal conducting airways increases, bronchiolectasis and air trapping become prominent on imaging studies. Ultimately, in severe cases, lung transplantation is the only alternative. This is a poorly understood disease because it simply represents scarring. Scar involving the skin would be analogous. We do not regard a skin scar as a disease, but simply a normal reaction to a moderate or severe injury. If we were to consider a differential for a skin scar, the list would be long. Similar to the skin, the terminal bronchiole mucosal surface is limited in the number of reactions it has to various different forms of injury. Therefore, it may be preferable to refer to the earlier-mentioned characteristic imaging findings as a BO-like reaction, knowing there are many different potential ways to injure the mucosal surfaces. This injury is actually quite common and underdiagnosed. Numerous patients are labeled with chronic obstructive pulmonary disease and emphysema
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Fig 5. BO. A 62-year-old man presents with a history of rheumatoid arthritis and refractory asthma that does not respond to therapy, HRCT shows a mosaic lung perfusion pattern and diffuse air trapping (AT)throughout the lungs with the presence of bronchial wall thickening, most likely representing BO.
who actually have extensive BO. HRCT can often distinguish between the 2 by confirming or excluding the presence of extensive emphysema. The radiographic features of BO are quite variable; nevertheless, many causes share common features that allow grouping of diseases causing BO. The distribution pattern of these abnormalities, and the presence of any additional features, may allow recognition of specific disease entities. Not surprisingly, as with most diseases involving the small airways, the chest radiograph is usually unremarkable in BO. 3 Having said that, the experienced eye looking at a plain chest film may be able to discern hyperinflation that results from air trapping, vessel attenuation, and bronchial wall thickening, all of which suggest BO. However, it is HRCT, and expiratory HRCT in particular, that can be especially useful in delineating the disease. The following are the common radiologic features as detected mainly on HRCT: (1) mosaic lung attenuation, with significant pulmonary vascular attenuation in dark areas; (2) prominent air trapping (as evidenced by the striking similarity of the inspiratory and expiratory scans); and (3) perhaps the presence of bronchiectasis (seen in many forms of small-airway disease) (Fig 5). CENTRILOBULAR NODULES (TREE-IN-BUD) The lobular bronchioles measure less than 1 mm in diameter and their walls are less than 0.1-mm thick. These bronchioles cannot be seen on HRCT in normal individuals because they are below its spatial resolution. However, bronchi as small as 2
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becomes evident. Endobronchial spread of bacterial pneumonia is an important differential consideration in virtually all patients--immunocomproraised or otherwise--presenting with fever, cough, purulent sputum, and radiographic findings of thick reticular opacities with 3-4 mm nodules and bronchial wall thickening. Although each of the aforementioned findings are found repeatedly in every one of the entities to follow, recognition is crucial to guide the clinical course of the diseases.
Mycoplasma
Fig 6. Tree-in-bud. This 35-year-old patient with AML presented with fever, HRCT shows innumerable centrilobular nodules with branching lines (tree-in-bud) as a result of widespread Streptococa[ pneumonia (arrowheads).
mm in diameter can, in fact, be seen on HRCT. Inflammation of the lobular bronchioles results in thickening of the bronchiolar wall, peribronchial infiltration with inflammatory cells, and/or filling of the dilated bronchioles with granulation tissue, pus, or mucus. These diseased bronchioles appear as small centrilobular nodules on HRCT, when they course perpendicular to the CT plane of section, and they appear as branching, linear opacities when they course parallel to the plane of section (Fig 6). These 2 configurations merge to form the characteristic tree-in-bud pattern that is so often seen in the diseases that afflict the secondary pulmonary lobule. The tree-in-bud presence often indicates an active inflammatory disease process within the small airways, either acute or more indolent. Usually, there is concurrent involvement of the more central airways, represented on imaging studies by thickening of the bronchial walls. The diseases in which centrilobular nodules are prominent are considered later.
Bacterial Bronchopneumonia Community-acquired pneumonia can spread within the lungs by traveling distally through the airways. When the purulent material becomes impacted within the terminal bronchioles of the small airways, the distinctive tree-in-bud disease pattern
An important form of community-acquired pneumonia affecting the small airways is that caused by the organism Mycoplasma pneumoniae. A somewhat indolent infection with a good prognosis in most afflicted individuals, Mycoplasma pneumonia is seen on the chest radiograph as areas of patchy consolidation, bronchial wall thickening, and reticular opacities, all of which translate to the characteristic tree-in-bud appearance on HRCT. The features of mycoplasma infection, namely linear septal thickening (pseudo Kerley lines), centrilobular nodules, and peribronchial inflammation, tend to predominate in the lower lobes, though they can be seen throughout the lungs. The distribution and manifestations within the lung are rather indistinguishable from those seen with bacterial bronchopneumonia; therefore, diagnosis is again ultimately made on the basis of clinical presentation. 5
Aspiration Pneumonia Aspiration of gastric or pharyngeal contents can lead to a similar picture as described previously. The dependant portions of medial basal segments of both lungs are typically involved (though the fight lobe is affected more often than the left) and bronchiolar impaction leading to the tree-in-bud appearance can be recognized on chest radiographs. Recognizing the tree-in-bud appearance in aspiration pneumonia is useful in distinguishing it from bibasilar atelectasis, which is usually more linear, without centrilobular nodules, and is associated with volume loss.
Endobronchial Tuberculosis When the Mycobacterium tuberculosis organism spreads via the tracheobronchial tree (most often seen with the primary or postprimary forms of the disease) the tree-in-bud pattern is again manifested
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samples, and the acumen of the radiologist. It characteristically presents on the plain radiograph only with hilar adenopathy, though when it affects the small airways, ill-defined centrilobular nodules, reticular opacities, and bronchial wall thickening are seen. HRCT usually shows a tree-in-bud pattern, along with patchy consolidation, and perhaps even the presence of thin-walled cysts. The recognition of mycobacterium avium-intracellulare complex on plain films and HRCT, with subsequent confirmatory diagnosis via sputum sampling or bronchoalveolar lavage, is important given the nature of the disease, which normally requires the patient to undergo long-term antibiotic treatment (usually 6-12 too), or even lobectomy for locally recurrent disease. 7
Airway Invasive Aspergillus Fig 7. Tuberculosis. A 23-year-old human immunodeficiency virus-positive man presents with a cavitary mass in left upper lobe (not shown). Diffuse tree-in-bud appearance is seen throughout the lungs (seen here in RUL) as a result of endobronchial spread of TB. This patient also had necrotic mediastinal lymphadenopathy (not shown).
(Fig 7). The presence of 2- to 4-mm centrilobular nodules with linear reticular opacities is often seen in this form of the disease. Again, these findings are somewhat indistinguishable from the other disease processes described in this section. In addition, mural thickening and narrowing of the bronchi are also seen. 6 The secondary presence of lymphadenopathy, as well as areas of cavitation or consolidation in characteristic locations, can clue the radiologist in to the possibility of tuberculosis infection. Overall, endobronchial spread of tuberculosis (TB) occurs in only a small percentage of patients with pulmonary TB. 6 The earlier-mentioned findings in the setting of human immunodeficiency virus allow a more definitive diagnosis of TB.
Mycobacterium A vium-IntracelIulare Complex Most often seen in the elderly, and more recently as an important pathogen in patients with human immunodeficiency virus, mycobacterium aviumintracellulare complex can also manifest itself within the small airways. Either asymptomatic or fulminant in its presentation, mycobacterium avium-intracellulare complex is diagnosed by using a combination of clinical suspicion, sputum
Indistinguishable from bronchopneumonia of any cause, airway invasive aspergillus is most often seen in immunocompromised patients, such as those with acquired immune deficiency syndrome (end-stage, neutropenic acquired immune deficiency syndrome), or others with immune-suppressed neutropenia. Patients may exhibit a new onset of cough and flu-like symptoms, along with bronchospasm. 3 Sputum samples are often teeming with the Aspergillus species Aspergillusfumigatus. The chest radiograph shows ill-defined areas of patchy consolidation accompanied by centrilobular nodular opacities, s HRCT clearly identifies the tree-in-bud pattern seen with this disease, though definitive diagnosis cannot be made, given the obvious overlap of findings with BO organizing pneumonia (see later), bacterial bronchopneumonia, and endobronchial spread of TB. In addition, enlargement of the bronchi and bronchioles can be seen along with a picture of postobstructive atelectasis secondary to mucus plugging--a hallmark of allergic bronchopulmonary aspergillosis that is closely related and sometimes confused with the airway invasive form of aspergillus. 8
Bronchiolitis Obliterans Organizing Pneumonia Bronchiolitis obliterans organizing pneumonia (BOOP), also known as cryptogenic organizing pneumonia (COP), is characterized as a relatively indolent process (1-6 mo in duration) occurring primarily in individuals aged 30 to 50 years, and presenting with a clinical picture of dyspnea, cough, and low-grade fever. 3 Pulmonary function
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tests reveal a restrictive lung pattern. The cause of the disease process ranges from idiopathic, to postinfectious, to posttransplantation. BOOP can also result from collagen vascular disease, inhalation injury, or drug toxicity. 3 Regardless of the cause, BOOP is pathologically described as masses of granulation tissue within the small airways-first affecting the terminal bronchioles, and then spreading distally to involve the alveoli (organizing pneumonia). 9 Many textbooks and articles list a long differential of causes of BOOP/COP. It is best, however, not to consider BOOP/COP a unique pulmonary disease, but rather as a lung reaction to various injuries that primarily involve the respiratory bronchioles and also extend into the alveolar spaces. An example would be a BOOP/ COP-like reaction secondary to chronic graft-versus-host disease in an allogenic bone marrow transplant recipient. Therefore, this disease should be considered more of a reaction to a known or unknown (idiopathic BOOP) injury. Histopathology shows minimal, if any, fibrosis initially, but without treatment, progression of the BOOP/COPlike reaction can eventually lead to fibrosis. This can explain the common imaging presentations of consolidations, without much reticular opacity or fibrosis (until advanced disease). In some rare cases, BOOP can become a fulminate process leading to respiratory failure or adult respiratory distress syndrome if left untreated or unrecognized. The treatment, as with most inflammatory lung processes, is corticosteroids, and though recurrence can occur, most patients recover completely. BOOP manifests itself quite similarly on both chest radiography and HRCT (Fig 8). Chronic, patchy areas of consolidation, with a tendency to follow (or highlight) the airways, are the hallmarks of BOOP. BOOP often presents as multifocal areas of consolidation. Concurrent with consolidation, areas of ground-glass opacity, ill-defined nodules, and tree-in-bud opacities may be present. However, these later manifestations usually do not dominate the image, but are associated with the more common consolidative opacities. Bronchial dilation also is seen commonly in the areas of consolidation, which over time may evolve into fibrosis and traction bronchiolectasis. This is not a unique feature of BOOP/COP because many chronic inflammatory pulmonary diseases can result in fibrosis and traction bronchiolectasis if allowed to progress. Thus, the differential includes
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infectious processes, such as tuberculosis or fungal disease, chronic eosinophilic pneumonia, or cellular nonspecific interstitial pneumonia (NSIP). Chronic eosinophilic pneumonia is radiographically very similar to BOOP because both tend to consist of peribronchial consolidation and concurrent areas of ground-glass opacities. Occasionally, reticular opacities or septal markings may be present in advanced disease. 9 According to a recent study, the presence of parenchymal nodules or mass-like opacities is the most significant differentiating factor between BOOP and eosinophilic pneumonia--these findings occur far more often in BOOP, and only rarely with eosinophilic pneumonia. 9 The mass-like opacities (often 1-10 mm in size, and peripherally located), in combination with septal thickening, can present as spiculated lesions resembling the appearance of bronchogenic carcinoma or lymphoma. The presence of lymphadenopathy and pleural effusions is uncommon, helping to distinguish BOOP from its mimics, such as TB or fungal disease.
Diffuse Panbronchiolitis Diffuse panbronchiolitis, an important cause of progressive obstructive lung disease in Japan and the Far East, represents a distinctive sinobronchial syndrome, with typical radiologic and histologic features. Rare cases are now being identified in Europe, as well as South and North America. 1°-12 Patients often have a history of sinusitis, present with dyspnea on exertion, and show a restrictive pattern on pulmonary function tests. Histologically, there is transmural, chronic inflammation centered on the terminal bronchioles, with lymphocytic, plasma cell, and foamy macrophage infiltration. 11,13Chest radiographs of patients with diffuse panbronchiolitis usually show small nodular shadows throughout both lungs. Several patterns of lung involvement are seen on HRCT and may represent different stages of evolution. The following patterns may be seen: (1) small centrilobular nodules connected by small branching linear opacities (tree-in-bud); (2) nodules accompanied by ring-shaped or small ductal opacities connected to proximal bronchovascular bundles, representing bronchiolectasis; and (3) large cystic opacities accompanied by dilated proximal bronchi (bronchiectasis) (Fig 9). 14'15
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Fig 8, BOOP. (A and B) This 76-year-old man presents with chest radiographs showing bilateral, patchy, eonsolidativs opacities that seem to follow a bronehovascular distribution, (C) CT scan confirms the findings seen on chest films, and also reveals a peribronchovascular distribution of the consolidative opacities (white arrow), as well as a small right anterior pneumothorax (black arrow). BOOP was diagnosed via transbronchial biopsy.
GROUND-GLASS OPACITIES WITH ILL-DEFINED CENTRILOBULAR NODULES
Ground-glass opacities may be seen in some cases of bronchiolitis, and result from reaction of the alveoli to the same insults that cause bronchiolitis. Diffuse ground-glass opacities can be difficult to appreciate on HRCT, but the dark bronchus sign may be helpful (Fig 10). As is discussed in further detail later, ground-glass opacity is often
seen in acute infectious bronchiolitis, extrinsic allergic alveolitis, respiratory bronchiolitis, follicular bronchiolitis, lymphocytic interstitial pneumonia (LIP), and occasionally in BOOP-like reactions. RESPIRATORY BRONCHIOLITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE
Respiratory bronchiolitis is a distinct clinicopathologic disease described almost exclusively in
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Fig 9. Diffuse Asian panbronchiolitis. A 49-year-old Japanese woman with diffuse Asian panbronchiolitis exhibits extensive tree-in-bud opacities bilaterally (dark arrows).
cigarette smokers. The disease usually presents with mild symptoms and is associated with a good prognosis. Pathologically, it is characterized by mild chronic inflammation of the bronchioles, associated with the accumulation of pigmented macrophages in respiratory bronchioles and alveoli. Heyneman et a116 found significant overlap between the CT findings of respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), mad desquamative interstitial pneumonia (DIP), which is consistent with the concept that they represent different degrees of severity of small-airway disease and parenchymal
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Fig 11. RB-ILD. A 32-year-old man with no past medical history except that he is a heavy smoker. CT exhibits illdefined centrilobular nodules (arrows) with ground-glass opacities.
reaction to cigarette smoke. On HRCT, respiratory bronchiolitis presents with small, ill-defined centrilobular nodules and ground-glass attenuation accompanied by areas of air trapping, with upper lobe predominance (Fig 11). 16"17 Note that upper lobe predominance is a common feature in nearly all smoking-related lung diseases. Mild imaging evidence of fibrosis may be seen with RB-ILD, and is even more likely to be seen with DIP, but does not occur with respiratory bronchiolitis alone. The centrilobular nodular opacities likely represent the precursors of centrilobular emphysema because both processes have the same distribution and upper lobe predominance. This spectrum of smokingrelated injury may be useful for clinicians to know because they can use these imaging findings to help motivate patients to quit smoking. RB-ILD represents inflammation that is potentially and partially reversible, as opposed to centrilobular emphysema. NSIP
Fig 10. Ground glass. A 44-year-old man with extensive smoking history shows diffuse, bilateral areas of groundglass opacities (GG) with the presence of centrilobular nodules. This patient was diagnosed with DIP with areas of RB-ILD.
Originally used as a wastebasket term to describe an entity that did not meet the pathologic criteria of usual interstitial pneumonia, DIP, acute interstitial pneumonia, or BOOP, the cellular form of NSIP is now seen as a discrete pathologic diagnosis that, unfortunately, exhibits HRCT findings that significantly overlap those of the other interstitial pneumonias, BOOP, and extrinsic allergic alveolitis. The presence of ground-glass opacities, with or without ill-defined centrilobular nodules, is the typical HRCT finding of cellular NSIP, though a vast spectrum of manifestations are seen, from emphysematous changes to frank honeycombing. Needless to say, familiarity with the
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ing related), and because treatment options differ between the 2 entities. The consolidative form of EAA can be confused with BOOP radiographically. Once again, these conditions may be distinguished on the basis of history, though treatment for both entities is corticosteroid therapy.
Follicular Bronchiolitis
Fig 12. EAA. This patient is a 56-year-old woman who presented with a gradual history of progressively worsening symptoms of shortness of breath and dyspnea on exertion. HRCT showed ill-defined centrilobular nodules (arrows) with groundglass opacities, without evidence of fibrosis or lymphadenopathy. Biopsy specimen revealed extrinsic allergic alveolitis.
radiologic presentations of the other interstitial pneumonias is crucial in identifying NSIP by exclusion on chest radiographs or HRCT. The variable presentation of NSIP should be considered the classic presentation, and close communication with the pathologist and the clinical team defines the course of action, is
Extrinsic Allergic Alveolitis Hypersensitivity pneumonitis, or extrinsic allergic alveolitis (EAA), refers to a broad spectrum of inflammatory processes that occur within the lung parenchyma and airways secondary to an identifiable pathogen or insult. Such agents include airborne occupational hazards (eg, wood dust, bird proteins), fungi, or bacteria. Once the inciting agent makes its way to the small airways, a cascade of inflammatory mediators are triggered, resulting in a characteristic radiographic response to the insult. Depending on the presentation (acute versus chronic), plain radiographs in EAA patients can show subtle nodular opacities, well-defined nodules, larger focal areas of consolidation, or a combination of findings in the face of a diffuse groundglass picture. HRCT further delineates the subtle ground-glass opacity and ill-defined nodules that are suspected on plain films, and tends to show predominance within the mid-upper lobes (Fig 12). 19 An accurate smoking or environmental exposure history is paramount when EAA is suspected because its radiographic findings overlap considerably with those of RB-ILD (clearly smok-
Follicular bronchiolitis is a distinct clinicopathologic form of bronchiolitis seen with rheumatoid arthritis, mixed collagen vascular disorders, autoimmune disorders, and the acquired immunodeficiency syndrome. Histologically, this disease shows lymphoid hyperplasia along the bronchioles, accompanied by peribronchiolar lymphocytic infiltration. On HRCT, the cardinal feature of follicular bronchiolitis is the presence of small centrilobular nodules variably associated with peribronchial nodules and areas of ground-glass opacity (Fig 13). 2o However, patients with follicular bronchiolitis may show no evidence of bronchiolitis in the presence of severe limitation of airflow. 21
LIP LIP is a disease of diffuse infiltration of lymphocytes and plasma cells within the airways and parenchyma of the lungs. Often described in children infected with the human immunodeficiency virus, LIP is characterized by bilateral diffuse areas of ground-glass opacity, along with reticular opacities and small, ill-defined centrilobular nodules (representing areas of lymphocytic infiltration within the small airways) usually predominant in the lower lobes. 22 In rare cases, focal areas of
Fig 13. Follicular bronchiolitis. A 66-year-old woman with rheumatoid arthritis shows a pattern of ill-defined centrilobular nodules on HRCT (arrows).
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consolidation and bronchiectasis can be seen. Radiographic improvement of LIP in children with acquired immune deficiency syndrome has been identified as a harbinger of worsening immunosuppression, depicting inability to mount a cell-mediated response to insults. LIP is also associated with autoimmune thyroid disease, rheumatologic disorders (Sjogrens syndrome), and Castlemen's disease. 23 It is thought to represent a more severe form of follicular bronchiolitis. SUMMARY
In this article, we have attempted to show that recognizing mosaic lung attenuation, tree-in-bud, and ill-defined centrilobular nodules with groundglass opacities is the first step in identifying disease processes occurring within the small airways.
Unless the plain chest radiograph is scrutinized for these patterns, they will be missed, and the findings will be called nonspecific, given the vast overlap of radiographic findings. This form of pattern recognition-most accurate on HRCT, but just as evident on plain radiographs--allows for a greater understanding of the pathogenesis of the disease processes, and this understanding can focus treatment options. The examination of the small airways is only limited by the resolution of available modalities. Further pathologic secrets, and patterns, may be discovered once the deeper recesses of the lungs are more accurately explored. Until that time, however, the radiologist must use the modalities available--including the knowledge of the referring clinician--in order to be a meaningful and critical part of the clinical team.
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