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Chest Imaging and Pathology for Clinicians: Special Feature |

Bronchiolar Disorders: A Clinical-Radiological Diagnostic Algorithm FREE TO VIEW

Arun Devakonda, MD; Suhail Raoof, MD, FCCP; Arthur Sung, MD, FCCP; William D. Travis, MD, FCCP; David Naidich, MD, FCCP
Author and Funding Information

From Integris Southwest Medical Center (Dr Devakonda), Oklahoma City, OK; New York Methodist Hospital (Drs Raoof and Sung), Brooklyn, NY; Memorial Sloan Kettering Cancer Center (Dr Travis), New York, NY; and NYU Langone Medical Center (Dr Naidich), New York, NY.

Correspondence to: Suhail Raoof, MD, FCCP, Division of Pulmonary and Critical Care Medicine, New York Methodist Hospital, 506 Sixth St, Brooklyn, NY 11215. e-mail: sur9016@nyp.org


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;137(4):938-951. doi:10.1378/chest.09-0800
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Bronchiolar disorders are generally difficult to diagnose because most patients present with nonspecific respiratory symptoms of variable duration and severity. A detailed clinical history may point toward a specific diagnosis. Pertinent clinical questions include history of smoking, collagen vascular disease, inhalational injury, medication usage, and organ transplant. It is important also to evaluate possible systemic and pulmonary signs of infection, evidence of air trapping, and high-pitched expiratory wheezing, which may suggest small airways involvement. In this context, pulmonary function tests and plain chest radiographs may demonstrate abnormalities; however, they rarely prove sufficiently specific to obviate bronchoscopic or surgical biopsy. Given these limitations, in our experience, high-resolution CT (HRCT) scanning of the chest often proves to be the most important diagnostic tool to guide diagnosis in these difficult cases, because different subtypes of bronchiolar disorders may present with characteristic image findings. Three distinct HRCT patterns in particular are of value in assisting differential diagnosis. A tree-in-bud pattern of well-defined nodules is seen primarily as a result of infectious processes. Ill-defined centrilobular ground-glass nodules point toward respiratory bronchiolitis when localized in upper lobes in smokers or subacute hypersensitivity pneumonitis when more diffuse. Finally, a pattern of mosaic attenuation, especially when seen on expiratory images, is consistent with air-trapping characteristic of bronchiolitis obliterans or constrictive bronchiolitis. Based on an appreciation of the critical role played by HRCT scanning, this article provides clinicians with a practical algorithmic approach to the diagnosis of bronchiolar disorders.

Figures in this Article

Bronchiolitis is a nonspecific inflammatory and/or fibrotic process involving the respiratory and membranous bronchioles that may also involve the alveoli.1 It is relatively common and occurs in a variety of clinical conditions, including infections, connective tissue diseases and other immunologic disorders, drug reactions, inhalational injuries, and posttransplant (bone marrow, lung, and heart-lung), among others.2 Numerous classification schemes have been previously proposed, using a variety of clinical, histopathologic, and radiologic features; yet, no single classification is widely accepted.3-5 The purpose of this article is to alert the clinician of the possible diagnosis of bronchiolar disease in patients presenting with nonspecific respiratory complaints and, usually, disproportionate shortness of breath with reduced diffusing capacity of the lung for carbon monoxide and reduced midexpiratory flows. This article summarizes the important clinical conditions associated with bronchiolar involvement and highlights the importance of high-resolution CT (HRCT) scanning in considering the diagnosis. The three HRCT scan patterns that point toward bronchiolar involvement are discussed in detail. It should be noted that we have excluded organizing pneumonia as a predominant airways disease. In the majority of conditions, the actual airways component of this disease is minimal. Additionally, this article focuses primarily on small airways disease. However, certain conditions, mentioned in the description, involve both large and small airways. These conditions include cystic fibrosis (CF), primary ciliary dyskinesis, and allergic bronchopulmonary mycosis. The clinical signs and symptoms of large airways disease usually eclipse the symptoms produced by small airways diseases. Those bronchiolar diseases in which the presence of typical HRCT scan pattern and appropriate history and clinical features obviate tissue diagnosis are enumerated. Finally, we describe the spectrum of histologic patterns that are seen in patients with bronchiolar disease who undergo a lung biopsy.

Bronchioles are small airways < 2 mm in diameter without cartilage or submucosal glands. This includes terminal bronchioles, whose principal role is to conduct air to the respiratory bronchioles.6 The latter contain alveoli, which are the site of air conduction and gas exchange. Critical to the HRCT scan identification of bronchiolar diseases is detailed familiarity with the cross-sectional appearance of secondary pulmonary lobules. As defined by Miller,7 the secondary pulmonary lobule corresponds to the smallest morphologic unit of the lung and is limited along its perimeter by connective tissue septa. Each lobule consists of a lobular bronchiole (0.15 mm wall thickness) accompanied by a peripheral pulmonary artery, typically measuring 1 mm in diameter. At the periphery of the secondary lobule, pulmonary veins and lymphatics are identified (Fig 1). The latter are also seen in centrilobular regions. However, the lymphatics in the center of the lobule are much less profuse than at the periphery of the lobule. Therefore, although conditions affecting the lymphatics may produce centrilobular nodules, it would be rare to find these nodules without more conspicuous nodules in the interlobular septae or pleural surfaces. These structures, with the sole exception of lobular arteries, are normally < 1 mm in size and therefore lie below the resolution of HRCT scanning.9 When there is thickening or edema around the bronchioles, or intraluminal secretions, however, these findings may become recognizable. It cannot be overemphasized that optimal evaluation of small airways requires HRCT protocols that use thin (0.63-1.25 mm) collimation with images reconstructed contiguously or at most at 10-mm intervals from the apices to costophrenic angles in the supine position.10 One advantage of contiguous 1- to 1.5-mm sections is the ability to use additional advanced imaging techniques, including coronal or sagittal multiplanar reconstructions or either maximum- or minimum-intensity projection images.11 These latter, in particular, may be of value in detecting otherwise subtle foci of mucoid-impacted peripheral airways resulting in a tree-in-bud pattern (Fig 2).

Figure Jump LinkFigure 1. Anatomy of secondary pulmonary lobule. (Reproduced with permission from CHEST.8)Grahic Jump Location
Figure Jump LinkFigure 2. A 2:1 target reconstruction showing a routine 1-mm section though the left mid lung in a patient with Kartagener syndrome (note the middle lobe is collapsed on the left side) with an adjacent 5-mm maximum projection intensity image showing the tree-in-bud pattern with exquisite detail.Grahic Jump Location

HRCT scanning at full exhalation should be obtained routinely when small airways disease is suspected. Prone imaging should only be performed in select cases to distinguish gravity-dependent atelectasis from an early interstitial process. In most cases, there is little indication for the use of routine contrast enhancement, as this adds little to an evaluation of bronchiolar abnormalities. An important exception is cases in which mucoid impaction involving the central bronchi is suspected, as these fluid-filled airways will show no evidence of enhancement following administration of intravenous contrast media.11 Finally, it should be emphasized that in those cases in which primary bronchiolar disease is suspected, or those cases in which bronchiolar disease is being sequentially followed, the use of low-dose CT technique (≤ 80 mAs) is strongly advised.

Abnormalities on HRCT scan that reflect bronchiolar diseases can be categorized into direct and indirect signs (Fig 3). Signs directly pointing to bronchiolar disease primarily include the presence of centrilobular opacities, either focal or diffuse.12 When caused by inspissation of secretions in the lumen of bronchioles, as typically seen in patients with infectious bronchiolitis, the result is either branching or clustered, sharply delineated, centrilobular opacities typically demonstrating a tree-in-bud pattern. These are often seen in association with more proximal airway inflammation, including thickened bronchial walls and/or bronchiectasis. Alternatively, when abnormalities are primarily localized to inflammation in the centrilobular peribronchiolar or perivascular space in the absence of bronchiolar impaction, the result is poorly defined subcentimeter ground-glass nodules and typically absent branching or tree-in-bud configuration.13,14 Importantly, regardless of their etiology, centrilobular opacities by definition characteristically lie 5 to 10 mm distant from either pleural or fissural surfaces (Fig 4).

Figure Jump LinkFigure 3. Direct signs of bronchiolar disease include evidence of dilatation of bronchiolar lumen, thickening of bronchiolar wall, or obstruction of bronchiolar lumen. By observing mosaic attenuation, it can be inferred (indirect sign) that bronchiolar disease may be present. HRCT = high-resolution CT.Grahic Jump Location
Figure Jump LinkFigure 4. A high-resolution target reconstructed 1-mm images in a patient with classic hypersensitivity pneumonitis. Evident are multiple, small, ill-defined, ground-glass opacities. There is no evidence of peripheral branching (tree-in-bud) opacities or subpleural nodules as is seen in patients with infectious bronchiolitis or primary perilymphatic disease.Grahic Jump Location

Distinct from direct signs, the most important indirect sign is the finding of mosaic attenuation, especially on expiratory scans. Characteristically the result of obstructive small airway disease, this finding may be seen in isolation or in association with direct signs of bronchiolar disease (Fig 5). Although the reproducibility in the interpretation of plain chest radiographs for diffuse lung diseases is poor, it is significantly better for chest CT scans. In a study by Gruden et al,15 the ability of readers to identify different categories of diffuse multinodular disease was studied in 58 patients. There was an overall concordance among four readers of 79% with an additional concordance of 17% when three of four readers agreed. Very importantly, observers were correct in 218 (94%) of 232 localizations. This study, performed prior to the era of multidetector CT scans, provides sufficient proof that reader agreement is high with this modality.

Figure Jump LinkFigure 5. A four-on-one set of inspiratory and expiratory paired images showing extensive air trapping in a patient with constrictive bronchiolitis.Grahic Jump Location

The clinical presentation of patients with bronchiolar disorders depends on the cause and varies from insidious onset of cough and shortness of breath to an acute, fulminant illness. A proposed algorithmic approach that takes into consideration the history, physical findings, pulmonary function tests, and imaging studies is outlined in Figure 6.

Figure Jump LinkFigure 6. Algorithmic approach to bronchiolar disease. The algorithm takes into consideration important history and physical findings that should tip the clinician to suspect bronchiolar disease. The plain chest radiograph (CXR) may not always show evidence of hyperinflation. Small airways dysfunction on PFT should trigger a request for an HRCT scan of the chest, performed during inspiration and exhalation. Further classification is based on the pattern seen on the HRCT scan. A tree-in-bud pattern generally signifies an infectious bronchiolitis. On the other hand, centrilobular nodules in a smoker point toward RB-ILD, whereas the same pattern in nonsmokers may indicate HP. Evidence of air trapping on the HRCT scan may be due to constrictive or obliterative bronchiolitis. Finally, if histologic confirmation is required, especially in conditions such as subacute HP, constrictive or obliterative bronchiolitis, RB-ILD, or bronchoalveolar cell carcinoma, a tissue diagnosis may be obtained. Generally, surgical biopsy is preferred because of difficulty in recognizing and classifying bronchiolitis in transbronchial biopsies. Conditions diagnosed by lavage (PLCH) or where infections are suspected (Mycobacterium avium-intracellulare, bacterial, parasitic, and fungal), or BAL may be performed. In lung transplant patients suspected of having constrictive bronchiolitis, five or more pieces of tissue, obtained by transbronchial biopsy, are recommended. ABPM = allergic bronchopulmonary mycosis; BAC = bronchoalveolar cell carcinoma; CF = cystic fibrosis; CHF = congestive heart failure; HP = hypersensitivity pneumonitis; PFT = pulmonary function test; PLCH = pulmonary Langerhans cell histiocytosis; RB-ILD = respiratory bronchiolitis-interstitial lung disease; TBBx = transbronchial biopsy. See Figure 3 legend for expansion of other abbreviation.Grahic Jump Location
Step 1: Clinical History/Physical Examination

Pertinent history may suggest bronchiolar disorders. This includes, among others, inhalational exposure to toxic gases, mineral dust, and organic dust; cigarette smoke; respiratory tract infections; drug-induced reactions caused by D-penicillamine and gold; organ transplantation; and associated connective tissue diseases.16

History of hereditary conditions such as CF and dyskinetic cilia syndrome, which result in chronic inflammation and infection leading to progressive bronchial wall damage, should be included. In patients with persistent asthma, Aspergillus colonization in the proximal bronchi acts as an antigenic stimulus for the production of IgE and IgG antibodies, resulting in wide ranging bronchiolar disorders, including bronchiectasis.

Ethnic background is relevant in diffuse panbronchiolitis (DPB), especially in Japanese, Chinese, and Korean populations, where this rare, chronic inflammatory lung disease of unknown cause is prevalent. In elderly bedridden patients, especially those with significant oropharyngeal dysphagia, diffuse aspiration bronchiolitis (DAB) should be considered.

Onset of symptoms may be relatively acute in bronchiolitis from infections, inhalational injury, or drugs; subacute in organizing pneumonia; and indolent and chronic in patients with atypical mycobacterial disease. Cough with copious expectoration may be seen in infectious bronchiolitis and DPB. A detailed history of symptoms suggestive of connective tissue disease, as well as exposure to inhalational irritants, drugs, and radiation, should be elicited in order to identify a possible cause.

On physical examination, the chest may demonstrate air trapping with increased anteroposterior diameter and may be hyperresonant to percussion. Findings on auscultation include any combination of prolonged expiratory phase, expiratory wheeze, and coarse or fine crackles. It is important to highlight that the auscultatory findings are not specific for the various etiologic diagnoses included under bronchiolar disorders. However, a prolonged expiratory phase associated with expiratory wheezing favors both infectious and constrictive bronchiolitis over hypersensitivity pneumonitis (HP) and cryptogenic organizing pneumonia.

Step 2: Chest Radiographic/Pulmonary Function Correlations

Following detailed history and physical examination, posteroanterior and lateral chest radiographs (CXRs) and pulmonary function tests (PFTs) are typically obtained in no particular order.17 Unfortunately, these rarely establish specific diagnoses and often prove of only limited value in directing the diagnostic workup. CXRs in bronchiolar disorders may be normal or may demonstrate nonspecific abnormalities, including variable degrees of hyperinflation, peripheral attenuation of the vascular markings, and, sometimes, nodular or reticulonodular opacities.18,19 Increased bronchial wall thickening may also be seen (Figs 7A-C).

Figure Jump LinkFigure 7. Plain CXRs of a middle-aged man with a history of working in shipyards as a welder for 30 years. He was severely short of breath on exertion and did not show significant improvement with oral steroids. Surgical biopsy was read as peribronchiolar chronic inflammation including lymphoid aggregates, consistent with respiratory bronchiolitis. Of note, the posteroanterior film (A) shows linear opacities at both bases, but a paucity of radiographic signs, such as flattening of diaphragms, to suggest hyperinflation. On the lateral image, (B), the retrosternal air space is not significantly increased, although both images show reticular opacities. The CT images (C) show, in addition, mosaic attenuation, suggestive of air trapping. These images highlight the importance of suspecting bronchiolar diseases based on the history and symptoms elicited from patients, even in the absence of clear signs on plain CXRs. See Figure 6 legend for expansion of abbreviation.Grahic Jump Location

PFTs may yield variable results depending on the predominant physiology. Acute infectious bronchiolitis may demonstrate airway obstruction affecting mainly the small airways, often associated with air trapping.20 Similar air trapping also occurs in patients with constrictive bronchiolitis, which often shows nonreversibility with inhaled bronchodilators. In addition, these patients also demonstrate reduced diffusion capacity. Obstructive defect is the predominant abnormality in follicular constrictive bronchiolitis or DPB.21 In distinction, a restrictive or mixed obstructive/restrictive pattern is observed in patients with HP, respiratory bronchiolitis (RB), respiratory bronchiolitis-interstitial lung disease (RB-ILD), and organizing pneumonia.22

It is important to note that in some bronchiolar diseases, both the CXRs and PFTs may appear normal or only minimally abnormal. The search for bronchiolar disorders, however, should not be abandoned at this stage, if the clinical history suggests otherwise. Clinicians should maintain a high index of suspicion for bronchiolar disorders and proceed with ordering an HRCT scan of the chest to further evaluate.

Step 3: HRCT Scan Evaluation: Tree-in-Bud Opacities

The main features on HRCT scan of patients with predominant bronchiolar disorders can be classified into three distinct, easily identifiable patterns: (1) centrilobular branching or clustered nodular opacities—the latter appropriately labeled as tree-in-bud opacities; (2) poorly defined centrilobular ground-glass nodules absent tree-in-bud opacities; and (3) mosaic attenuation, especially when apparent on expiratory scans. A particular advantage of this approach is that following strict definitions of the various patterns mentioned allows consistent differentiation between these patterns.15,23

Of these, the most common is the tree-in-bud pattern. Defined by the presence of clusters of well-defined nodules attached to centrilobular branching or tubular structures, tree-in-bud opacities result from extensive bronchiolar mucoid impaction with or without the additional involvement of adjacent alveoli. The most important differential diagnosis for this pattern of disease is infectious bronchiolitis.24

It should be pointed out that endobronchial infection results in mucoid impaction with a variable degree of extension into the adjacent peribronchiolar alveolar sacs. Both these mechanisms make the nodules appear well defined, a feature that distinguishes them from the ill-defined, ground-glass, and hazy nodules (emanating from peribronchiolar inflammation without impaction) seen in HP. Other entities causing predominantly tree-in-bud opacities include immunologic disorders, such as allergic bronchopulmonary aspergillosis/mycosis25; congenital disorders, such as CF and dyskinetic cilia syndrome; juvenile laryngotracheobronchial papillomatosis26-29; DAB30; and diffuse panbronchiolitis.31 The important clinical, radiologic, and histopathologic characteristics of the diseases resulting in tree-in-bud opacities are described in Table 1. Depending on the extent of disease, this group can be further classified into focal and diffuse tree-in-bud patterns. The prototype of focal tree-in-bud pattern on HRCT scan is acute infectious bronchiolitis. Symptomatic acute bronchiolitis is relatively rare in adults and is caused by viral or bacterial infections.32-34 Localized tree-in-bud opacities are more often seen in patients with chronic infections, including those seen in patients with AIDS, for example, or especially in patients with TB and atypical Mycobacterium. In this regard, it should be noted that some patterns of distribution may suggest specific diagnoses. For example, localized tree-in-bud opacities restricted to or predominantly involving one lung apex or upper lobe are often seen in patients with Mycobacterium tuberculosis, often due to the endobronchial spread of disease, whereas similar findings predominantly involving the middle lobe and lingual are often seen in patients with atypical mycobacterial infection.35,36

Table Graphic Jump Location
Table 1 —Bronchiolar Diseases With Predominantly Tree-in-Bud Opacities

CF = cystic fibrosis; HRCT = high-resolution CT.

Rheumatoid arthritis and Sjögren syndrome may also affect the small airways resulting in focal tree-in-bud opacities with or without associated centrilobular ground-glass opacities and bronchiectasis. Not surprisingly, superimposed infections that respond to antibiotic therapy, even in these settings, are often implicated.

Diffuse tree-in-bud pattern is commonly seen in DAB, allergic bronchopulmonary aspergillosis (ABPA), diffuse panbronchiolitis, and congenital disorders, including CF and primary ciliary dyskinesia. DAB presents with recurrent episodes of bronchorrhea, bronchospasm, and dyspnea. It is characterized by diffuse bronchiolar involvement secondary to chronic aspiration.29 It occurs most commonly in elderly patients with neurologic deficits or dementia, bed-ridden patients, or patients with oropharyngeal dysphagia.30,37 DPB is a rare form of bronchiolitis mainly in Japanese and Korean adults and is characterized by bronchiolar inflammation.37-40 The most-affected individuals are middle-aged men, nonsmokers, and almost all have chronic sinusitis. Histopathology is characterized by presence of acute and chronic inflammation involving the bronchiolar wall or the lumen associated with epithelial necrosis and sloughing. There may be associated edema as well as inflammatory exudates and mucus in the bronchiolar lumen. A characteristic feature is the accumulation of foamy macrophages within the peribronchiolar interstitium (Fig 8).31 Again the pattern of distribution may provide a key to the correct diagnosis. The presence of central bronchiectasis associated with a tree-in-bud pattern is commonly seen in patients with ABPA, for example, whereas a truly diffuse pattern uniformly identifiable throughout the lungs is highly suggestive of panbronchiolitis.

Figure Jump LinkFigure 8. Diffuse panbronchiolitis: This bronchiole shows a marked chronic inflammatory infiltrate involving the bronchiolar wall and extending into the surrounding interstitium (hematoxylin-eosin, ×4). In addition to many lymphocytes and plasma cells, there are numerous foamy histiocytes in the peribronchiolar interstitium (top left).Grahic Jump Location
Step 4: HRCT Scan Evaluation: Poorly Defined Centrilobular Ground-Glass Nodules

If HRCT scan discloses centrilobular opacities appearing as ill-defined ground-glass nodules in the absence of a tree-in-bud pattern, the differential diagnosis is distinctly different than if tree-in-bud opacities are present. This is despite the fact that ill-defined centrilobular nodules as well as tree-in-bud opacities anatomically lie at least 5 to 10 mm from either the pleural and fissural surfaces and may be either focal or diffuse in distribution.14,41

The classic example of this appearance is subacute HP. HP is a disease usually found in nonsmokers, and is characterized by diffuse inflammation of lung parenchyma and terminal bronchioles in response to the inhalation of organic and inorganic antigens to which the patient has been previously sensitized.42 To date, HRCT scanning has proved of particular value in the diagnosis of subacute HP, because characteristically this is one of only a few entities that lead to the presence of diffuse centrilobular ground-glass nodules uniformly noted throughout the lungs (Fig 4). These findings in the appropriate clinical setting are sufficiently suggestive of the diagnosis to potentially obviate further diagnostic procedures, especially bronchoscopy. Parenthetically, air trapping on expiratory thin-section images may also be present, which accounts for the finding of preserved secondary lobules reported with the chronic, fibrotic form of this disease.43-45

In patients with smoking history, a substantial narrowing of the differential diagnosis is possible. RB and RB-ILD, in particular, should be considered because these entities occur, albeit rarely, in smokers and even more rarely in those with collagen vascular diseases and mineral dust-induced diseases.40,46-48 HRCT scanning of patients with RB demonstrates characteristic upper lobe-predominant, ill-defined centrilobular ground-glass nodules, which are typically smaller and less defined than those seen in HP. Although the extent of ground-glass opacities in patients with RB may be exceedingly subtle, in patients with RB-ILD, small foci of ground-glass attenuation are typically present as well, simplifying the identification of this entity.48,49 Not surprisingly, emphysema is often present also (Fig 9). Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon disorder of young adults that is also strongly associated with cigarette smoking.50,51

Figure Jump LinkFigure 9. The image was taken from a patient who had a smoking history. A diagnosis of respiratory bronchiolitis-interstitial lung disease was made. Note the focal areas of ground-glass opacities alternating with more lucent areas. The lucent areas are abnormal and represent air trapping.Grahic Jump Location

Distinct from patients with RB/RB-ILD, although scattered centrilobular nodules may also be seen in PLCH, these typically occur as isolated findings only quite early in the course of the disease and are typically better defined (Fig 10).52 Far more often, centrilobular nodules are associated with characteristic bizarre-shaped, thick-walled cysts, some of which represent cavitary nodules with characteristic sparing of the lung bases.8,51,53

Figure Jump LinkFigure 10. The image is taken from a patient with pulmonary Langerhans cell histiocytosis. Note the dilated bronchi, which are larger than the accompanying pulmonary arteries. In addition, there are thick-walled cysts in the periphery of the lungs in both upper lobes.Grahic Jump Location

It should be emphasized that the differential diagnosis of a pattern of ill-defined centrilobular ground-glass nodules, both focal and diffuse, is extensive, encompassing a number of far less common disease entities; this includes, among others, follicular bronchiolitis, mineral dust exposure, infection with human T-lymphotropic virus type 1, other early viral infections, and multifocal or lobar bronchioloalveolar cell carcinoma.8,25,54,55

In patients with human T-lymphotropic virus type 1, an etiologic retrovirus of adult T-cell leukemia or lymphoma, the most common CT scan findings are centrilobular nodules, followed by thickening of bronchovascular bundles. Centrilobular nodules correspond to the extent of lymphocytic infiltration into the wall of respiratory bronchioles extending into the adjacent peribronchiolar interstitium.54

Bronchioloalveolar carcinoma may present with a variety of appearances on HRCT scan and diffuse clusters of centrilobular nodules is least common, especially in the absence of associated parenchymal consolidation.55 Centrilobular nodules in bronchioloalveolar carcinoma, if present, are rare, likely to be associated with the airspace filling process, and not likely to be the dominant pattern.

Follicular bronchiolitis is defined as lymphoid hyperplasia in response to an extrinsic immune stimulus or altered systemic immune response. Most cases are idiopathic or occur in association with connective tissue diseases (particularly rheumatoid arthritis and Sjögren disease), immunodeficiency syndromes including AIDS, and pulmonary infections.56 Microscopically it is characterized by presence of hyperplastic lymphoid follicles with reactive germinal centers distributed along bronchovascular bundles.57 HRCT scanning demonstrates predominantly centrilobular and peribronchial nodules, with most being around 3 mm in size, but ranging from 1 to 12 mm (Fig 11).40

Figure Jump LinkFigure 11. A 1-mm axial image of a patient with documented follicular bronchiolitis showing asymmetric involvement with a few discernible centrilobular changes.Grahic Jump Location

Mineral dust airways disease occurs because of inhalation of a number of inorganic dusts, including asbestos, iron oxide, aluminum oxide, talc, mica, silica, and coal.58 Inflammatory response induced by the dust likely leads to local production of fibrogenic factors and morphogenesis of the bronchiolar lesion.58 Peribronchial infiltration of dust-laden macrophages is often noted on microscopy. Poorly defined centrilobular opacities can be seen on HRCT scans early in the course of the disease; these predominate posteriorly and at the lung bases owing to the gravitational effects of fiber deposition.

Similar to differential diagnosis in patients with tree-in-bud opacities, it is apparent that in select cases, a combination of clinical and HRCT scan findings by themselves are sufficiently specific to obviate further invasive testing. Specifically included in this group are patients with subacute HP, RB, PLCH, and mineral dust exposure. In distinction, in the absence of a suggestive history, serologic findings, and/or an appropriate smoking history, nearly all other causes of ill-defined centrilobular nodules, especially when diffuse, require at a minimum bronchoscopic, and more often, surgical lung biopsy for definitive evaluation. Since bronchiolar diseases are sometimes patchy, surgical lung biopsies should be made from multiple lobes, preferably with biopsy sites chosen after review of the HRCT scan by the surgeon obtaining diagnostic tissue. The important clinical, radiologic, and histopathologic characteristics of the diseases resulting in centrilobular nodules are described in Table 2.

Table Graphic Jump Location
Table 2 —Bronchiolar Diseases With Centrilobular Nodules

RB = respiratory bronchiolitis; RB-ILD = respiratory bronchiolitis-interstitial lung disease. See Table 1 for expansion of other abbreviations.

Step 5: HRCT Scan Evaluation: Mosaic Lung Attenuation

In patients presenting with predominant obstructive airways physiology, HRCT scan often displays a characteristic finding of mosaic attenuation in the absence of centrilobular opacities. This pattern is characterized by alternate foci of relatively increased lung density with foci of decreased lung density, frequently resulting in a geographic appearance to the lung parenchyma. The appearance is characterized by heterogeneous lung density, with the lower-density lung being abnormal because of decreased perfusion and, commonly, an element of air trapping. In the context of small airways disease, this is mainly from reflex hypoxic vasoconstriction. Mosaic perfusion is a nonspecific finding and can be seen with any airways or vascular disease. When mosaic perfusion is the only or predominant finding, it is more specific and is typically seen with constrictive bronchiolitis, HP, asthma, or chronic pulmonary embolism. The “headcheese sign” is the combination of mosaic perfusion and ground-glass opacities in the same patient. Typically in these patients three densities of lung are seen (normal, too dense [ground-glass opacity], and too lucent [mosaic perfusion]). This is indicative of a mixed obstructive/infiltrative disorder and is very suggestive of HP. Very rarely, headcheese sign may be seen with other diseases, such as RB, follicular bronchiolitis, and viral infections. Of note, the history of causative exposure is elicited in only 50% of cases, increasing the importance of HRCT scan even more. In distinction, mosaic attenuation due to diffuse infiltrative lung diseases is not characterized by attenuation of low-density regions on exhalation, as low-density regions represent normal lung. Therefore, they demonstrate an increase in density as expected on exhalation. A similar lack of persistent low density is noted on exhalation in patients with chronic thromboembolic hypertension.

The prototype for this characteristic radiologic finding is constrictive bronchiolitis, also commonly referred as bronchiolitis obliterans (BO) or obliterative bronchiolitis. In patients with constrictive or obliterative bronchiolitis, because the predominant pathologic finding is concentric narrowing or obliteration of the bronchioles caused by submucosal and peribronchiolar fibrosis (Fig 12), direct CT scan signs of bronchiolar and peribronchiolar inflammation (ie, centrilobular opacities) are characteristically absent.59

Figure Jump LinkFigure 12. The lumen of this bronchiole from a bone marrow transplant patient shows marked narrowing by prominent submucosal fibrosis (hematoxylin-eosin, × 20).Grahic Jump Location

A common cause of constrictive bronchiolitis is previous childhood infection, resulting in the so-called Swyer-James syndrome, identifiable as asymmetric hyperlucent lung on routine chest radiographs (Figs 13A, 13B). Other conditions resulting in a pattern of mosaic attenuation include connective tissue disorders, bone marrow and transplantation, toxic fume inhalation, drugs, and cryptogenic constrictive bronchiolitis (Table 3).9,60

Figure Jump LinkFigure 13. Axial (A) and coronal (B) images in a patient with mosaic attenuation due to Swyer-James syndrome with constrictive bronchiolitis. The coronal view shows the extent of disease to better advantage.Grahic Jump Location
Table Graphic Jump Location
Table 3 —Causes and/or Underlying Disorders Associated With Constrictive Bronchiolitis

Of particular note, constrictive bronchiolitis remains the most common form of chronic rejection in patients with lung transplants, occurring in up to 50% of patients.61 Because it is inappropriate to perform a biopsy on transplanted lung to make this diagnosis, the diagnosis of BO is based on clinical symptoms and spirometry.62 Constrictive bronchiolitis is seen as a manifestation of graft vs host disease in 10% of people who have received allogeneic bone marrow transplants.63 Other less common causes have also been described. Rheumatoid arthritis-associated constrictive bronchiolitis, for example, has been described as a rare pleuropulmonary complication, presumably as a result of autoimmune reaction.64,65 Most of the reported cases have marked irreversible airways obstruction and a fulminating course of the disease. Most have had long-standing rheumatoid arthritis, although in rare cases, pulmonary abnormalities antedate rheumatologic manifestations. In some cases, use of D-penicillamine therapy66 has been implicated as a potential causative factor. Silo filler’s lung (nitrogen dioxide) is a classic cause of toxic exposure-related constrictive bronchiolitis. Other toxic fumes, such as chlorine, sulfur dioxide, ammonia, and phosgene, have been reported to cause constrictive bronchiolitis.10,67 Most recently, work-related inhalation of flavoring agents (diacetyl used in making popcorn) has been found to result in a clinical presentation and imaging pattern typical of constrictive bronchiolitis.68

Other causes and associations with constrictive bronchiolitis are listed in Table 3 and include neuroendocrine cell hyperplasia or multiple carcinoid tumorlets, Sauropus androgynus ingestion,69 and drugs, such as D-penicillamine,10 gold,70 cocaine, and lomustine. Clinically, dyspnea is the most common complaint. The clinical criteria used for diagnosing constrictive bronchiolitis include evidence of severe irreversible airflow obstruction measured by spirometry, with an FEV1 of < 60% of predicted value in the absence of other pathologic causes for airway obstruction, such as emphysema or chronic bronchitis. The midexpiratory phase of forced expiratory flows is a measure of small airways disease; a marked decrease (ie, , 30% of predicted) is a particularly sensitive indicator of BO. Obtaining expiratory HRCT scans increases the likelihood of identifying areas of air trapping that are not apparent on inspiratory scans.61,71 Bankier et al72 showed that expiratory air trapping achieved a sensitivity and specificity of 87.5% for the detection of BO syndrome; in another study, Lee et al73 demonstrated a sensitivity of 74% and a specificity of 67% for air trapping in histologically proven BO in lung transplant patients.

Step 6: Role of Lung Biopsy

Histologically, bronchiolitis can have a wide variety of patterns, as summarized in Table 4.74-76 Most of these have already been mentioned here. In surgical lung biopsies, it is usually possible to recognize these patterns, and these terms can be applied when the histologic findings are clear. Bronchiolar pathology is often patchy, and severity of clinical manifestations frequently exceeds that of the histologic changes. Thus, it is important to obtain wedge biopsies from multiple lobes. It is also not uncommon for bronchiolitis to be seen among a mixture of histologic patterns of lung injury, such as an interstitial pneumonia or pleuritis. Occasionally, bronchiolar pathology may be very subtle, and on biopsy alone it is difficult to be certain if the morphologic observation is an incidental or clinically significant finding. In such cases, careful clinical and HRCT scan correlation is required.

Table Graphic Jump Location
Table 4 —Histologic Patterns of Bronchiolitis

This table summarizes the major histopathologic patterns seen in different bronchiolar diseases.

It can be difficult to recognize and classify bronchiolitis in transbronchial biopsies because of the limited sampling size. However, in certain clinical settings, such as heart-lung or bone marrow transplantation, these are the most common specimens obtained. In these patients with appropriate clinical and HRCT scan findings, the presence of submucosal fibrosis may support a diagnosis of constrictive bronchiolitis. In the heart-lung transplant setting, it is recommended to obtain at least five pieces of well-expanded alveolar parenchyma with transbronchial biopsies.76 It is also recommended to gently agitate the biopsy tissue samples in formalin to expand the airspaces, because interpretation can be compromised by specimen atelectasis. Clinical and radiologic correlation is particularly important with such small biopsies.

Bronchiolitis is a nonspecific inflammation of the respiratory bronchioles and peribronchiolar alveolar sacs that has variable causes, clinical manifestations, and evolution. However, suggestive, specific diagnoses are rarely made based on clinical history alone. As both CXR and PFT findings are also frequently nonspecific, a high index of clinical suspicion should be maintained in order to diagnose and/or exclude bronchiolar disease. Given these limitations, in our experience, HRCT scanning may play a critical role in both suggesting specific causes of bronchiolar disease and directing optimal management in select cases. Tree-in-bud opacities, for example, typically signify an infectious cause with a pattern of distribution often suggestive of particular causes, including Mycobacterium tuberculosis, atypical mycobacterial infection, CF, and ABPA. Even when nonspecific in appearance, as typically occurs in AIDS, the finding of tree-in-bud opacities is often sufficiently specific for infection to suggest empirical treatment obviating biopsy. Poorly defined centrilobular ground-glass nodules commonly indicate subacute HP in a nonsmoker, whereas RB/RB-ILD and PLCH are typically seen in smokers. In select cases, these findings, coupled with appropriate clinical history and serologic testing, also may obviate more invasive diagnostic testing. In distinction, other causes of centrilobular nodules usually require open lung biopsy rather than transbronchial biopsy for definitive diagnosis. Finally, mosaic attenuation is characteristically associated with constrictive bronchiolitis. It is anticipated that the application of the algorithmic approach presented in this article will facilitate the timely diagnosis and/or optimal management of bronchiolar disorders that may otherwise be difficult to identify. In many cases, a diagnosis may be made solely using HRCT scans in combination with the history and clinical presentation.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank Ms. Patrice Balistreri for her invaluable secretarial assistance and coordination.

ABPA

allergic bronchopulmonary aspergillosis

BO

bronchiolitis obliterans

CF

cystic fibrosis

CXR

chest radiograph

DAB

diffuse aspiration bronchiolitis

DPB

diffuse panbronchiolitis

HP

hypersensitivity pneumonitis

HRCT

high-resolution CT

PFT

pulmonary function test

PLCH

pulmonary Langerhans cell histiocytosis

RB

respiratory bronchiolitis

RB-ILD

respiratory bronchiolitis-interstitial lung disease

Ryu JH. Classification and approach to bronchiolar diseases. Curr Opin Pulm Med. 2006;122:145-151. [CrossRef] [PubMed]
 
Poletti V, Costabel U. Bronchiolar disorders: classification and diagnostic approach. Semin Respir Crit Care Med. 2003;245:457-464. [CrossRef] [PubMed]
 
Ryu JH, Daniels CE, Hartman TE, Yi ES. Diagnosis of interstitial lung diseases. Mayo Clin Proc. 2007;828:976-986. [CrossRef] [PubMed]
 
Visscher DW, Myers JL. Histologic spectrum of idiopathic interstitial pneumonias. Proc Am Thorac Soc. 2006;34:322-329. [CrossRef] [PubMed]
 
Webb WR. Thin-section CT of the secondary pulmonary lobule: anatomy and the image—the 2004 Fleischner lecture. Radiology. 2006;2392:322-338. [CrossRef] [PubMed]
 
Epler GR. Diseases of the Bronchioles. 1994; New York, NY Raven Press:1
 
Miller WS, Charles C. The Lung. 1947; Springfield, IL Thomas Ltd:39-42
 
Raoof S, Amchentsev A, Vlahos I, Goud A, Naidich DP. Pictorial essay: multinodular disease: a high-resolution CT scan diagnostic algorithm. Chest. 2006;1293:805-815. [CrossRef] [PubMed]
 
Müller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic findings. Radiology. 1995;1961:3-12. [PubMed]
 
Ryu JH, Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir Crit Care Med. 2003;16811:1277-1292. [CrossRef] [PubMed]
 
Remy J, Remy-Jardin M, Artaud D, Fribourg M. Multiplanar and three-dimensional reconstruction techniques in CT: impact on chest diseases. Eur Radiol. 1998;83:335-351. [CrossRef] [PubMed]
 
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Gruden JF, Webb WR, Naidich DP, McGuinness G. Multinodular disease: anatomic localization at thin-section CT—multireader evaluation of a simple algorithm. Radiology. 1999;2103:711-720. [PubMed]
 
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Figures

Figure Jump LinkFigure 1. Anatomy of secondary pulmonary lobule. (Reproduced with permission from CHEST.8)Grahic Jump Location
Figure Jump LinkFigure 2. A 2:1 target reconstruction showing a routine 1-mm section though the left mid lung in a patient with Kartagener syndrome (note the middle lobe is collapsed on the left side) with an adjacent 5-mm maximum projection intensity image showing the tree-in-bud pattern with exquisite detail.Grahic Jump Location
Figure Jump LinkFigure 3. Direct signs of bronchiolar disease include evidence of dilatation of bronchiolar lumen, thickening of bronchiolar wall, or obstruction of bronchiolar lumen. By observing mosaic attenuation, it can be inferred (indirect sign) that bronchiolar disease may be present. HRCT = high-resolution CT.Grahic Jump Location
Figure Jump LinkFigure 4. A high-resolution target reconstructed 1-mm images in a patient with classic hypersensitivity pneumonitis. Evident are multiple, small, ill-defined, ground-glass opacities. There is no evidence of peripheral branching (tree-in-bud) opacities or subpleural nodules as is seen in patients with infectious bronchiolitis or primary perilymphatic disease.Grahic Jump Location
Figure Jump LinkFigure 5. A four-on-one set of inspiratory and expiratory paired images showing extensive air trapping in a patient with constrictive bronchiolitis.Grahic Jump Location
Figure Jump LinkFigure 6. Algorithmic approach to bronchiolar disease. The algorithm takes into consideration important history and physical findings that should tip the clinician to suspect bronchiolar disease. The plain chest radiograph (CXR) may not always show evidence of hyperinflation. Small airways dysfunction on PFT should trigger a request for an HRCT scan of the chest, performed during inspiration and exhalation. Further classification is based on the pattern seen on the HRCT scan. A tree-in-bud pattern generally signifies an infectious bronchiolitis. On the other hand, centrilobular nodules in a smoker point toward RB-ILD, whereas the same pattern in nonsmokers may indicate HP. Evidence of air trapping on the HRCT scan may be due to constrictive or obliterative bronchiolitis. Finally, if histologic confirmation is required, especially in conditions such as subacute HP, constrictive or obliterative bronchiolitis, RB-ILD, or bronchoalveolar cell carcinoma, a tissue diagnosis may be obtained. Generally, surgical biopsy is preferred because of difficulty in recognizing and classifying bronchiolitis in transbronchial biopsies. Conditions diagnosed by lavage (PLCH) or where infections are suspected (Mycobacterium avium-intracellulare, bacterial, parasitic, and fungal), or BAL may be performed. In lung transplant patients suspected of having constrictive bronchiolitis, five or more pieces of tissue, obtained by transbronchial biopsy, are recommended. ABPM = allergic bronchopulmonary mycosis; BAC = bronchoalveolar cell carcinoma; CF = cystic fibrosis; CHF = congestive heart failure; HP = hypersensitivity pneumonitis; PFT = pulmonary function test; PLCH = pulmonary Langerhans cell histiocytosis; RB-ILD = respiratory bronchiolitis-interstitial lung disease; TBBx = transbronchial biopsy. See Figure 3 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 7. Plain CXRs of a middle-aged man with a history of working in shipyards as a welder for 30 years. He was severely short of breath on exertion and did not show significant improvement with oral steroids. Surgical biopsy was read as peribronchiolar chronic inflammation including lymphoid aggregates, consistent with respiratory bronchiolitis. Of note, the posteroanterior film (A) shows linear opacities at both bases, but a paucity of radiographic signs, such as flattening of diaphragms, to suggest hyperinflation. On the lateral image, (B), the retrosternal air space is not significantly increased, although both images show reticular opacities. The CT images (C) show, in addition, mosaic attenuation, suggestive of air trapping. These images highlight the importance of suspecting bronchiolar diseases based on the history and symptoms elicited from patients, even in the absence of clear signs on plain CXRs. See Figure 6 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 8. Diffuse panbronchiolitis: This bronchiole shows a marked chronic inflammatory infiltrate involving the bronchiolar wall and extending into the surrounding interstitium (hematoxylin-eosin, ×4). In addition to many lymphocytes and plasma cells, there are numerous foamy histiocytes in the peribronchiolar interstitium (top left).Grahic Jump Location
Figure Jump LinkFigure 9. The image was taken from a patient who had a smoking history. A diagnosis of respiratory bronchiolitis-interstitial lung disease was made. Note the focal areas of ground-glass opacities alternating with more lucent areas. The lucent areas are abnormal and represent air trapping.Grahic Jump Location
Figure Jump LinkFigure 10. The image is taken from a patient with pulmonary Langerhans cell histiocytosis. Note the dilated bronchi, which are larger than the accompanying pulmonary arteries. In addition, there are thick-walled cysts in the periphery of the lungs in both upper lobes.Grahic Jump Location
Figure Jump LinkFigure 11. A 1-mm axial image of a patient with documented follicular bronchiolitis showing asymmetric involvement with a few discernible centrilobular changes.Grahic Jump Location
Figure Jump LinkFigure 12. The lumen of this bronchiole from a bone marrow transplant patient shows marked narrowing by prominent submucosal fibrosis (hematoxylin-eosin, × 20).Grahic Jump Location
Figure Jump LinkFigure 13. Axial (A) and coronal (B) images in a patient with mosaic attenuation due to Swyer-James syndrome with constrictive bronchiolitis. The coronal view shows the extent of disease to better advantage.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Bronchiolar Diseases With Predominantly Tree-in-Bud Opacities

CF = cystic fibrosis; HRCT = high-resolution CT.

Table Graphic Jump Location
Table 2 —Bronchiolar Diseases With Centrilobular Nodules

RB = respiratory bronchiolitis; RB-ILD = respiratory bronchiolitis-interstitial lung disease. See Table 1 for expansion of other abbreviations.

Table Graphic Jump Location
Table 3 —Causes and/or Underlying Disorders Associated With Constrictive Bronchiolitis
Table Graphic Jump Location
Table 4 —Histologic Patterns of Bronchiolitis

This table summarizes the major histopathologic patterns seen in different bronchiolar diseases.

References

Ryu JH. Classification and approach to bronchiolar diseases. Curr Opin Pulm Med. 2006;122:145-151. [CrossRef] [PubMed]
 
Poletti V, Costabel U. Bronchiolar disorders: classification and diagnostic approach. Semin Respir Crit Care Med. 2003;245:457-464. [CrossRef] [PubMed]
 
Ryu JH, Daniels CE, Hartman TE, Yi ES. Diagnosis of interstitial lung diseases. Mayo Clin Proc. 2007;828:976-986. [CrossRef] [PubMed]
 
Visscher DW, Myers JL. Histologic spectrum of idiopathic interstitial pneumonias. Proc Am Thorac Soc. 2006;34:322-329. [CrossRef] [PubMed]
 
Webb WR. Thin-section CT of the secondary pulmonary lobule: anatomy and the image—the 2004 Fleischner lecture. Radiology. 2006;2392:322-338. [CrossRef] [PubMed]
 
Epler GR. Diseases of the Bronchioles. 1994; New York, NY Raven Press:1
 
Miller WS, Charles C. The Lung. 1947; Springfield, IL Thomas Ltd:39-42
 
Raoof S, Amchentsev A, Vlahos I, Goud A, Naidich DP. Pictorial essay: multinodular disease: a high-resolution CT scan diagnostic algorithm. Chest. 2006;1293:805-815. [CrossRef] [PubMed]
 
Müller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic findings. Radiology. 1995;1961:3-12. [PubMed]
 
Ryu JH, Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir Crit Care Med. 2003;16811:1277-1292. [CrossRef] [PubMed]
 
Remy J, Remy-Jardin M, Artaud D, Fribourg M. Multiplanar and three-dimensional reconstruction techniques in CT: impact on chest diseases. Eur Radiol. 1998;83:335-351. [CrossRef] [PubMed]
 
Teel GS, Engeler CE, Tashijian JH, duCret RP. Imaging of small airways disease. Radiographics. 1996;161:27-41. [PubMed]
 
Weibel ER, Taylor CR.Fishman AP. Design and structure of the human lung. Pulmonary Diseases and Disorders. 1988;2nd ed. New York, NY:11-60
 
Gruden JF, Webb WR, Warnock M. Centrilobular opacities in the lung on high-resolution CT: diagnostic considerations and pathologic correlation. AJR Am J Roentgenol. 1994;1623:569-574. [PubMed]
 
Gruden JF, Webb WR, Naidich DP, McGuinness G. Multinodular disease: anatomic localization at thin-section CT—multireader evaluation of a simple algorithm. Radiology. 1999;2103:711-720. [PubMed]
 
Hansell DM. Computed tomography of diffuse lung disease: functional correlates. Eur Radiol. 2001;119:1666-1680. [CrossRef] [PubMed]
 
Lynch DA. Imaging of small airways diseases. Clin Chest Med. 1993;144:623-634. [PubMed]
 
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