Applied Radiology

Dr. Collins is an Associate Professor of Radiology and Medicine, University of Wisconsin Hospital and Clinics, Clinical Science Center, Madison, WI; Dr. Stern is a Professor of Radiology and Medicine, Director of Thoracic Imaging, and Director for Faculty Development, Harborview Medical Center, University of Washington, Seattle, WA; and Dr. Franquet is an Associate Professor of Radiology and Director of Thoracic Imaging, Hospital de Sant Pau, Barcelona, Spain.

This article will define bronchiolar anatomy, present an optimal method for computed tomography (CT) scanning of the chest when bronchiolar disease is suspected, describe the direct and indirect CT findings of bronchiolar disease, and review the main causes of bronchiolar disease.

Bronchiolar anatomy

The division of the trachea gives rise to the left and right mainstem bronchi, which further divide into lobar and segmental bronchi. Segmental bronchi divide, and after 6 to 20 divisions they no longer contain cartilage in their walls and are referred to as bronchioles. The bronchioles divide, and the last of the purely conducting airways is referred to as the terminal bronchiole. Beyond the terminal bronchioles lie the acini, the gas exchange units of the lung. The central bronchi down to the segmental level can be identified routinely with 10-mm collimation CT sections, and 8th order branching airways can be seen with thin sections.

The secondary pulmonary lobule refers to the smallest unit of lung structure marginated by connective tissue septa, and it is easily visible on the surface of the lung. The size of secondary pulmonary lobules varies from about 1 to 2.5 cm in diameter in most locations, and each is supplied by a central small bronchiole (<1 mm in diameter) and a pulmonary artery. The lobules are marginated by connective tissue interlobular septa that contain pulmonary vein and lymphatic branches (figure 1). ^1,2 Because visibility on CT is limited to bronchi >2 mm in diameter, normal lobular bronchioles cannot be seen on CT scans. ³ However, centrilobular arteries and diseased bronchioles can be easily resolved using the high-resolution CT (HRCT) technique.

CT patterns of bronchiolar disease

When bronchiolar disease is suspected, CT scanning should be performed using thin collimation (1.0 to 1.5 mm), image reconstruction with a high-spatial frequency "sharp" algorithm (i.e., "bone" algorithm), short scan time (1 to 2 seconds), and increased kVp (120 to 140) and mA (140 to 240) technique. Thicker sections do not characterize the bronchiolar disease as well. Windowing may need to be customized, although in general, window width between 1200 and 2000 and level between -500 to -750 is recommended for viewing pleuro-parenchymal disease. Scanning should include the entire lungs, at 1.0-cm intervals during full inspiration. Expiratory scanning should be performed at the same levels, or every 2 to 3 cm throughout the lungs. The presence of air trapping on expiratory scanning may be the only finding of bronchiolar disease, and, therefore, scans obtained during expiration are especially important when the inspiratory scans are normal.

Direct CT findings of bronchiolar disease include bronchiolar wall thickening, bronchiolar dilatation, and luminal impaction (figure 2). ⁴ Bronchiolar impaction with pus, mucus, granulomas, inflammatory exudate, or fibrotic material all have similar appearances, and manifest as 2- to 4-mm nodular and linear branching centrilobular opacities on CT. Usually, abnormal bronchioles can be distinguished from normal centrilobular vessels by their more irregular appearance, a lack of tapering, or a knobby or bulbous appearance at the tips of small branches. ⁵ The "tree-in-bud" pattern represents a form of bronchiolar impaction. The term "tree-in-bud" dates back to the bronchogram descriptions of normal respiratory bronchioles by Twining and Kerley ⁶ and Reid and Simon ⁷ (figure 3), and has been popularized by Im et al ⁸ to describe the CT appearance of the endobronchial spread of Mycobacterium tuberculosis . This pattern is analogous to the "finger-in-glove" appearance of bronchial impaction, but on a much smaller scale. Because of its similar appearance to the metal "jack" used in the childhood game played with a rubber ball, the "tree-in-bud" pattern has also been described as resembling "jacks." ⁹

Indirect or secondary CT signs of bronchiolar disease include subsegmental atelectasis and air trapping. Air trapping appears as focal or diffuse areas of decreased lung attenuation, often forming a "mosaic" pattern of lung attenuation, which is best seen (or only seen) on expiratory scanning. Lung parenchyma normally increases in CT attenuation as lung volume is reduced during expiration. This change can be recognized on CT as an increase in lung opacity. Normally, the lungs of people without bronchiolar disease can show occasional lobular-sized areas of focal lucency on expiratory CT scans; in these regions, the lung does not increase normally in attenuation, probably due to physiologic air trapping. ¹⁰ This is limited to a small proportion of lung volume, and when more than a few secondary pulmonary lobules are involved, pathologic air trapping should be considered.

Bronchiolar diseases

"Bronchiolitis" is a term used to describe a spectrum of inflammatory disorders affecting small bronchioles. These disorders show great heterogeneity in regard to cause, clinical features, and histopathologic changes. Myers and Colby ¹¹ classified these conditions into 8 types: 1) constrictive bronchiolitis; 2) cryptogenic organizing pneumonia; 3) infectious bronchiolitis; 4) adult bronchiolitis; 5) respiratory bronchiolitis; 6) mineral dust airways disease; 7) diffuse panbronchiolitis; and 8) follicular bronchiolitis. The causes of bronchiolitis are similar to the causes of bronchiectasis, as most of the causes of bronchiectasis can also involve the bronchioles, leading to bronchiolectasis and other direct CT signs of bronchiolar disease. Causes of bronchiolectasis include infection, aspiration of gastric or other irritant substances, impaired host defenses/immunologic deficiencies, cigarette smoking, and idiopathic causes.

Infection

Endobronchial spread of infectious organisms can result in centrilobular nodules and linear branching opacities on CT and is the most common cause of the "tree-in-bud" pattern. ¹² Bacterial organisms are the most common cause of a bronchiolar pattern of disease on CT (figures 4 through 6), and viral, parasitic, mycobacterial (figures 7 and 8), and fungal organisms are the less common causes.

The term "tree-in-bud" is commonly associated with endobronchial spread of M tuberculosis , though this pattern is not pathognomonic for tuberculosis. The "tree-in-bud" appearance is characteristic of active and likely contagious tuberculosis, especially when associated with adjacent cavitary nodules in the lungs (figure 9). The presence of multiple cavitary lesions on CT in the absence of the "tree-in-bud" pattern, however, makes the diagnosis of active and potentially contagious tuberculosis much less likely. In addition to the "tree-in-bud" pattern, CT findings that can be seen with tuberculosis include air space consolidation, cavitation, small, well-defined nodules indicative of miliary or hematogenous spread of infection, pleural effusion, and lymph node enlargement with central necrosis. Reactivation tuberculosis has a propensity for predominantly involving the posterior segments of the upper lobes and the superior segments of the lower lobes. Histologically, the terminal tufts of the "tree-in-bud" pattern represent lesions in the bronchioles and alveolar ducts, whereas the stalk represents a lesion affecting the last-order bronchus in the secondary pulmonary lobule. ⁸

Non-tuberculous mycobacterial infections can appear similar to tuberculosis, or can manifest in a "nonclassical" way on CT. This nonclassical nontuberculous mycobacterial infection is typically produced by infection with Mycobacterium avium-intracellulare complex. ¹³ The typical patients are women in their 70s who lack predisposing conditions. This phenomenon has been termed the "Lady Windermere Syndrome." ¹⁴ It has been hypothesized that habitual voluntary suppression of cough may lead to the development of nonspecific inflammatory processes in poorly draining lung regions, upon which the mycobacterial organisms grafted. Computed tomography shows patchy bronchiectasis and other direct signs of bronchiolar disease, commonly in the middle lobe and lingula (figure 10).

Aspergillus involvement of the airways may take the form of colonization, as in allergic bronchopulmonary aspergillosis (ABPA), or, in the immunosuppressed patient, as an invasive bronchitis and tracheobronchitis. Allergic bronchopulmonary aspergillosis is an immunologic hyperimmune response to airway colonization with Aspergillus , usually seen in patients with asthma. The fungus proliferates in the proximal bronchi, acting as an antigenic stimulus for the production of IgE and IgG antibodies. The inflammatory reaction causes mucoid impaction in the central airways, which leads to damage of the bronchial wall and subsequent bronchiectasis. The CT findings include central bronchiectasis with an upper-lobe predominance and mucoid impaction. ¹⁵ This mucoid impaction can extend into the bronchioles, resulting in a "tree-in-bud" pattern on CT (figure 11).

Predominant airway involvement is seen in 14% to 34% of cases of invasive aspergillosis. The CT findings include peribronchial areas of consolidation, centrilobular nodules, and the "tree-in-bud" pattern. ¹⁶ Histologically, the peribronchial areas represent bronchopneumonia and the nodules represent bronchiolitis caused by Aspergillus , often with fungal hyphae found in the airway lumen.

Aspiration

Bronchiolar changes can be seen on CT after aspiration of infected oral secretions, other irritant material, or inert material (i.e., barium). With barium aspiration, the nodular and linear branching opacities seen on CT are composed of high-attenuation material. ⁴ Aspiration can occur during periods of altered consciousness or in persons with neuromuscular disorders. The clinical features of a large amount of aspirated gastric contents are abrupt in onset and consist of cough, wheezing, cyanosis, dyspnea, and tachypnea. Initially, pathologic changes consist of a chemical tracheobronchitis and pneumonia. Secondary bacterial infection is common, however, and the clinical course may be further complicated by acute respiratory distress syndrome. The severity of the pulmonary changes depends on the volume of fluid aspirated and the pH of the aspirate. ¹⁷ The CT findings can include areas of consolidation, small irregular shadows, and small nodular and linear branching opacities (figure 12). The distribution of the abnormalities is generally perihilar or bibasilar, although this can vary depending on the patient's position during the time of aspiration. The abnormal opacities can even be entirely unilateral.

Impaired host defenses/immunologic deficiencies

Cystic fibrosis is a genetic disorder affecting the upper and lower respiratory tracts, pancreas, liver, gallbladder, intestines, and genital tract. An abnormally low water content of airway mucus is at least partially responsible for decreased mucous clearance, mucus plugging of small and large airways, and an increased incidence of bacterial airway infection. Bronchial wall inflammation progressing to bronchiectasis and bronchiolectasis is eventually seen on CT, in addition to nodular and tubular areas of mucus plugging, bronchial/bronchiolar wall thickening, and areas of lung collapse or consolidation. The "tree-in-bud" pattern is seen with extensive mucus plugging of bronchioles or airway spread of infected organisms (figure 13).

Dyskinetic cilia syndromes are inherited disorders of ciliary structure and function. They can be characterized by bronchiectasis, situs inversus, sinusitis (the triad defining Kartagener's syndrome), and infertility. Abnormal ciliary motion in the respiratory tract results in recurrent bronchial infections and subsequent bronchiectasis, bronchiolectasis, air trapping, and the "tree-in-bud" pattern on CT. Numerous other genetic abnormalities affecting mucociliary clearance, immune deficiency, or structural abnormalities of the bronchus or bronchial wall can result in bronchiolar disease.

Cigarette smoking

Respiratory bronchiolitis is a clinicopathologic syndrome that is seen in current heavy cigarette smokers. Pathologic findings consist of an excess of pigmented macrophages in respiratory bronchioles and adjacent alveolar ducts and alveoli, a membranous and respiratory mononuclear bronchiolitis, fibrous scarring extending outward from airways into alveolar walls, and an abnormal airway epithelium. CT findings include centrilobular nodules (figure 14), ground-glass opacities, and intralobular and interlobular septal thickening. ¹⁸

Idiopathic causes

Diffuse panbronchiolitis is a disorder characterized by chronic sinusitis and bronchial inflammation, and is found most commonly in patients with Japanese, Chinese, or Korean heritage. In a late stage, the disorder is characterized by repeated bacterial infections, resulting in bronchiectasis and bronchiolectasis. The histologic findings involve the respiratory bronchioles, and include dense peribronchial and intraluminal infiltrate of acute and chronic inflammatory cells, particularly mononuclear cells, with hyperplasia of lymphoid follicles. High-resolution CT scans can be quite striking, showing diffuse centrilobular nodules, thin, branching linear opacities, thickened bronchiolar walls, and air trapping (figure 15). ¹⁹

Follicular bronchiolitis is a condition most commonly described in patients with rheumatoid arthritis and Sjögren's syndrome, and represents a form of lymphoid hyperplasia characterized by coalescent germinal centers distributed along airways. ³ The hyperplastic lymphoid follicles narrow airways by external compression. Findings on CT include small nodular opacities in a bronchiolar distribution.

Asthma is characterized by reversible airway narrowing from bronchoconstriction, edema of the airway wall, and mucus hypersecretion. Computed tomography shows nonspecific findings consisting of some or all of the following: bronchial/bronchiolar wall thickening, bronchiolar dilatation, air trapping, atelectasis, and centrilobular nodules (figure 16).

Bronchiolitis obliterans is characterized histologically by plugs of granulation tissue that fill and obstruct the centrilobular terminal or respiratory bronchioles and by a variable intraluminal and peribronchiolar inflammatory response. Although often idiopathic, bronchiolitis obliterans is associated with viral infection of the airways, toxic fume inhalation, collagen vascular diseases, complication of drug therapy, chronic graft-versus-host disease following bone marrow transplantation, or chronic rejection in patients with lung transplantation. Computed tomography findings can include bronchiectasis/ bronchiolectasis, bronchial/bronchiolar wall dilatation, centrilobular nodular and linear branching opacities, and often severe air trapping (figure 17).

Conclusion

When bronchiolar disease is suspected, HRCT should be performed, in both inspiration and expiration. Direct computed tomography (CT) signs of bronchiolar disease include bronchiolar wall thickening, bronchiolar dilatation, and bronchiolar luminal impaction. Indirect signs include subsegmental atelectasis, and air trapping. The term "tree-in-bud" is used to describe a severe form of bronchiolar disease with mucoid impaction of dilated bronchioles. The most common cause of the CT "tree-in-bud" pattern is infectious bronchiolitis. A specific infectious organism is not implied when this pattern is seen, although the presence of adjacent cavitary lesions on CT suggests tuberculosis. AR