CHEST Chest Imaging and Pathology for Clinicians: Special Feature

Bronchiolar Disorders
A Clinical-Radiological Diagnostic Algorithm
Arun Devakonda, MD; Suhail Raoof, MD, FCCP; Arthur Sung, MD, FCCP;
William D. Travis, MD, FCCP; and David Naidich, MD, FCCP

Bronchiolar disorders are generally difficult to diagnose because most patients present with non-
specific 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 centrilobu-
lar 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 algo-
rithmic approach to the diagnosis of bronchiolar disorders. CHEST 2010; 137(4):938–951

Abbreviations: ABPA 5 allergic bronchopulmonary aspergillosis; BO 5 bronchiolitis obliterans; CF 5 cystic fibrosis;

CXR 5 chest radiograph; DAB 5 diffuse aspiration bronchiolitis; DPB 5 diffuse panbronchiolitis; HP 5 hypersensitivity
pneumonitis; HRCT 5 high-resolution CT; PFT 5 pulmonary function test; PLCH 5 pulmonary Langerhans cell histio-
cytosis; RB 5 respiratory bronchiolitis; RB-ILD 5 respiratory bronchiolitis-interstitial lung disease

Bronchiolitis is a nonspecific inflammatory andⲐor

fibrotic process involving the respiratory and mem-
branous bronchioles that may also involve the alveoli.1
It is relatively common and occurs in a variety of clini-
cal conditions, including infections, connective tissue
Manuscript received March 31, 2009; revision accepted October
15, 2009.
Affiliations: 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
© 2010 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (www.chestpubs.orgⲐ
siteⲐmiscⲐreprints.xhtml).
DOI: 10.1378Ⲑchest.09-0800
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 bronchi-
olar 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 midexpira-
tory flows. This article summarizes the important clin-
ical conditions associated with bronchiolar involve-
ment and highlights the importance of high-resolution
CT (HRCT) scanning in considering the diagnosis. The
three HRCT scan patterns that point toward bronchi-
olar involvement are discussed in detail. It should be

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 noted that we have excluded organizing pneumonia as
a predominant airways disease. In the majority of condi-
tions, 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 clin-
ical 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.
HRCT Scan—Anatomic Correlations: Imaging
the Secondary Pulmonary Lobule
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 connec-
tive 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,
Figure 1. Anatomy of secondary pulmonary lobule. (Reproduced
with permission from CHEST.8)
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pulmonary veins and lymphatics are identified (Fig 1).
The latter are also seen in centrilobular regions. How-
ever, the lymphatics in the center of the lobule are much
less profuse than at the periphery of the lobule. There-
fore, 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 struc-
tures, 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 thick-
ening or edema around the bronchioles, or intralumi-
nal secretions, however, these findings may become
recognizable. It cannot be overemphasized that opti-
mal evaluation of small airways requires HRCT pro-
tocols 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).
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 enhance-
ment, as this adds little to an evaluation of bronchiolar
abnormalities. An important exception is cases in which
mucoid impaction involving the central bronchi is
Figure 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.
CHEST / 137 / 4 / APRIL, 2010 939
 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 fol-
lowed, the use of low-dose CT technique (ⱕ 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 bronchioli-
tis, the result is either branching or clustered, sharply
delineated, centrilobular opacities typically demon-
strating a tree-in-bud pattern. These are often seen in
association with more proximal airway inflammation,
including thickened bronchial walls andⲐor bronchiec-
tasis. Alternatively, when abnormalities are primarily
localized to inflammation in the centrilobular peri-
bronchiolar 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).
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
HRCT Signs of Bronchiolar Disorders
Direct signs In- direct signs
Bronchial wall Bronchiectasis or Luminal impaction Mosaic attenuation
thickening Bronchiolar (on expiratory CT)
dilatation
Centrilobular nodules Tree in bud Pattern
Figure 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 atten-
uation, it can be inferred (indirect sign) that bronchiolar disease
may be present. HRCT 5 high-resolution CT.
940
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Figure 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 sub-
pleural nodules as is seen in patients with infectious bronchiolitis
or primary perilymphatic disease.
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.
Stepwise Approach to Bronchiolar
Disorders
The clinical presentation of patients with bronchi-
olar 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.
Step 1: Clinical HistoryⲐPhysical Examination
Pertinent history may suggest bronchiolar disor-
ders. This includes, among others, inhalational expo-
sure 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 connec-
tive tissue diseases.16
History of hereditary conditions such as CF and dys-
kinetic cilia syndrome, which result in chronic inflam-
mation and infection leading to progressive bronchial
wall damage, should be included. In patients with per-
sistent asthma, Aspergillus colonization in the proximal
Chest Imaging and Pathology for Clinicians: Special Feature
 Figure 5. A four-on-one set of inspiratory and expiratory paired images showing extensive air trapping
in a patient with constrictive bronchiolitis.
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 panbronchi-
olitis (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 bronchi-
olitis (DAB) should be considered.
Onset of symptoms may be relatively acute in bron-
chiolitis 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 ausculta-
tory findings are not specific for the various etiologic
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diagnoses included under bronchiolar disorders. How-
ever, a prolonged expiratory phase associated with expi-
ratory wheezing favors both infectious and constrictive
bronchiolitis over hypersensitivity pneumonitis (HP)
and cryptogenic organizing pneumonia.
Step 2: Chest RadiographicⲐPulmonary Function
Correlations
Following detailed history and physical examina-
tion, posteroanterior and lateral chest radiographs
(CXRs) and pulmonary function tests (PFTs) are typ-
ically 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 nor-
mal or may demonstrate nonspecific abnormalities,
including variable degrees of hyperinflation, peri-
pheral attenuation of the vascular markings, and,
sometimes, nodular or reticulonodular opacities.18,19
Increased bronchial wall thickening may also be seen
(Figs 7A-C).
PFTs may yield variable results depending on the
predominant physiology. Acute infectious bronchi-
olitis may demonstrate airway obstruction affecting
mainly the small airways, often associated with air
trapping.20 Similar air trapping also occurs in patients
CHEST / 137 / 4 / APRIL, 2010 941
 Step 1: History & Physical Examination
(Infection, inhalation exposure, drug reactions, organ transplantation)

Step 2: Chest radiograph & PFT

(Hyperinflation with airflow obstruction)

Step 3: HRCT
Predominant Tree-in-bud opacities
YES NO Step 4: Predominant
Centrilobular nodules
YES NO

Focal Diffuse Smokers Non-smokers

Step 5: Mosaic
Infectious bronchiolitis Diffuse aspiration RB/RB-ILD Sub-acute HP attenuation/
Viral bronchiolitis expiratory airtrapping
Bacterial Diffuse pan bronchiolitis Less common:
Mycobacterial Constrictive
PLCH bronchiolitis
Parasitic Congenital diseases CHF
Fungal CF Obliterative
Lymphoma bronchiolitis
Dyskinetic cilia syndrome BAC
Less common:
Juvenile laryngo tracheo-
bronchial Papillomatosis
ABPM, rheumatoid arthritis, collagen vascular disease

Step 6: Consider tissue diagnosis

(surgical biopsy preferred; however, BAL+TBBx may suffice in some conditions)

Figure 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 air-
ways dysfunction on PFT should trigger a request for an HRCT scan of the chest, performed dur-
ing 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, cen-
trilobular 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 oblit-
erative 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 5 allergic bronchopulmonary mycosis; BAC 5 bronchoalveolar cell carcinoma; CF 5 cystic
fibrosis; CHF 5 congestive heart failure; HP 5 hypersensitivity pneumonitis; PFT 5 pulmonary
function test; PLCH 5 pulmonary Langerhans cell histiocytosis; RB-ILD 5 respiratory bronchiolitis-
interstitial lung disease; TBBx 5 transbronchial biopsy. See Figure 3 legend for expansion of other
abbreviation.

with constrictive bronchiolitis, which often shows
nonreversibility with inhaled bronchodilators. In
addition, these patients also demonstrate reduced
diffusion capacity. Obstructive defect is the predomi-
nant abnormality in follicular constrictive bronchi-
olitis or DPB.21 In distinction, a restrictive or mixed
obstructiveⲐrestrictive 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 nor-
mal or only minimally abnormal. The search for
bronchiolar disorders, however, should not be aban-
doned 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) centri-
lobular branching or clustered nodular opacities—
the latter appropriately labeled as tree-in-bud opac-
ities; (2) poorly defined centrilobular ground-glass

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 Figure 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, con-
sistent 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.

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 impac-
tion 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 infec-
tion results in mucoid impaction with a variable
degree of extension into the adjacent peribronchiolar
alveolar sacs. Both these mechanisms make the nod-
ules appear well defined, a feature that distinguishes
them from the ill-defined, ground-glass, and hazy
nodules (emanating from peribronchiolar inflamma-
tion without impaction) seen in HP. Other entities
causing predominantly tree-in-bud opacities include
immunologic disorders, such as allergic bronchopul-
monary aspergillosisⲐmycosis25; congenital disorders,

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

Characteristic Clinical Causes andⲐor Associated

Features Conditions HRCT Features Histopathologic Features
Infection Wheezing with Viral, bacterial, parasitic, Tree-in-bud pattern, Acute and chronic
concomitant signs of mycobacterial, fungal centrilobular nodules, inflammation of small
respiratory dense consolidation bronchioles with
tractinfection epithelial necrosis and
sloughing
Immunologic Cough, fever, wheezing; Asthma Tree-in-bud pattern, central Mucoid impaction of
disorders (allergic recurrent episodes of bronchiectasis, mucoid bronchi, eosinophilic
bronchopulmonary bronchial obstruction impaction, upper lobe infiltration, bronchocentric
aspergillosis) predominance granulomatosis
Congenital disorders Recurrent purulent cough, Genetic predisposition, Tree-in-bud pattern, bronchial Cellular infiltration
(CF, dyskinetic cilia airway hyperactivity multisystem disease wall thickening,
syndrome) bronchiectasis,
bronchiolectasis
Neoplasms Symptoms and signs Juvenile Tree-in-bud pattern, Varies from multiple
of upper respiratory laryngotracheobronchial multiple solid or clusters of squamous
tract obstruction papillomatosis cystic nodules cells within alveoli to
(hoarseness, stridor) large cavitary lesions
Diffuse aspiration Nonspecific Elderly, bed bound Tree-in-bud pattern, Foreign body giant cell
bronchiolitis centrilobular nodules reaction
Idiopathic diffuse Mainly in Japanese Associated sinusitis, Tree-in-bud pattern, Infiltration of lymphocytes,
panbronchiolitis adults; subacute HLABw54 antigen thickened ecstatic bronchi, plasma cells, and foamy
onset of cough, centrilobular nodules macrophages at the
dyspnea level of respiratory
bronchiole
CF 5 cystic fibrosis; HRCT 5 high-resolution CT.

such as CF and dyskinetic cilia syndrome; juvenile
laryngotracheobronchial papillomatosis26-29; DAB30;
and diffuse panbronchiolitis.31 The important clin-
ical, 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 proto-
type 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 Local-
ized tree-in-bud opacities are more often seen in
patients with chronic infections, including those
seen in patients with AIDS, for example, or espe-
cially in patients with TB and atypical Mycobacte-
rium. In this regard, it should be noted that some
patterns of distribution may suggest specific diag-
noses. 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
Rheumatoid arthritis and Sjögren syndrome may
also affect the small airways resulting in focal tree-
in-bud opacities with or without associated centrilob-
ular 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 dif-
fuse 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 charac-
terized 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 slough-
ing. 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 inter-
stitium (Fig 8).31 Again the pattern of distribution
may provide a key to the correct diagnosis. The pres-
ence of central bronchiectasis associated with a tree-
in-bud pattern is commonly seen in patients with
ABPA, for example, whereas a truly diffuse pattern

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 Figure 8. Diffuse panbronchiolitis: This bronchiole shows a marked
chronic inflammatory infiltrate involving the bronchiolar wall and
extending into the surrounding interstitium (hematoxylin-eosin, 34).
In addition to many lymphocytes and plasma cells, there are numerous
foamy histiocytes in the peribronchiolar interstitium (top left).
uniformly identifiable throughout the lungs is highly
suggestive of panbronchiolitis.
Step 4: HRCT Scan Evaluation: Poorly Defined
Centrilobular Ground-Glass Nodules
If HRCT scan discloses centrilobular opacities appear-
ing 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 cen-
trilobular 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 paren-
chyma 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 pres-
ence of diffuse centrilobular ground-glass nodules uni-
formly noted throughout the lungs (Fig 4). These find-
ings in the appropriate clinical setting are sufficiently
suggestive of the diagnosis to potentially obviate fur-
ther 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 nar-
rowing of the differential diagnosis is possible. RB and
RB-ILD, in particular, should be considered because
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Figure 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.
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 scan-
ning of patients with RB demonstrates characteris-
tic upper lobe-predominant, ill-defined centrilobu-
lar 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 pre-
sent also (Fig 9). Pulmonary Langerhans cell histio-
cytosis (PLCH) is an uncommon disorder of young
adults that is also strongly associated with cigarette
smoking.50,51
Figure 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.
CHEST / 137 / 4 / APRIL, 2010 945
 Distinct from patients with RBⲐRB-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 typi-
cally better defined (Fig 10).52 Far more often, centri-
lobular 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
It should be emphasized that the differential diag-
nosis 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 bron-
chiolitis, mineral dust exposure, infection with human
T-lymphotropic virus type 1, other early viral infec-
tions, 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 cor-
respond 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 bronchi-
oloalveolar 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
Figure 11. A 1-mm axial image of a patient with documented
follicular bronchiolitis showing asymmetric involvement with a
few discernible centrilobular changes.
946
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idiopathic or occur in association with connective tis-
sue diseases (particularly rheumatoid arthritis and
Sjögren disease), immunodeficiency syndromes
including AIDS, and pulmonary infections.56 Micro-
scopically it is characterized by presence of hyper-
plastic lymphoid follicles with reactive germinal cen-
ters distributed along bronchovascular bundles.57
HRCT scanning demonstrates predominantly centri-
lobular and peribronchial nodules, with most being
around 3 mm in size, but ranging from 1 to 12 mm
(Fig 11).40
Mineral dust airways disease occurs because of
inhalation of a number of inorganic dusts, including
asbestos, iron oxide, aluminum oxide, talc, mica, sil-
ica, and coal.58 Inflammatory response induced by the
dust likely leads to local production of fibrogenic fac-
tors and morphogenesis of the bronchiolar lesion.58
Peribronchial infiltration of dust-laden macrophages
is often noted on microscopy. Poorly defined centri-
lobular opacities can be seen on HRCT scans early in
the course of the disease; these predominate posteri-
orly 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 sug-
gestive history, serologic findings, andⲐor 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.
Step 5: HRCT Scan Evaluation: Mosaic Lung
Attenuation
In patients presenting with predominant obstruc-
tive airways physiology, HRCT scan often displays a
characteristic finding of mosaic attenuation in the
absence of centrilobular opacities. This pattern is char-
acterized 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 het-
erogeneous lung density, with the lower-density lung
being abnormal because of decreased perfusion and,
Chest Imaging and Pathology for Clinicians: Special Feature
 Table 2—Bronchiolar Diseases With Centrilobular Nodules

Characteristic Causes and or

Clinical Features Associated Conditions HRTC Features Histopathologic Features
Hypersensitivity Subacute onset of Organic and inorganic Ground-glass centrilobular Patchy peribronchiolar
pneumonitis dyspnea, fever, inhalation nodules, low attenuation and lymphocytic infiltration,
malaise mosaic perfusion, tree-in-bud poorly formed granulomas
pattern (uncommon)
RBⲐRB-ILD Inspiratory crackles, Cigarette smoke Ill-defined ground-glass Pigmented macrophages
digital clubbing centrilobular nodules, and interstitial
upper lobe predominance inflammation around
respiratory bronchioles
Follicular Progressive dyspnea, Connective tissue Centrilobular nodules, Peribronchiolar lymphoid
bronchiolitis cough disease (Sjögren, diffuse and bilateral aggregates
rheumatoid arthritis),
immunodeficiency
Mineral dust Progressive dyspnea Inhalation of inorganic Ill-defined panacinar Peribronchial infiltration of
airway disease dusts, asbestosis, centrilobular nodules, dust laden macrophages
talc, aluminum calcification
oxide, silica, coal
Pulmonary Dyspnea, cough, Immune mediated, Centrilobular nodules, Cellular interstitial infiltrates
Langerhans cell chest pain predominantly in macronodules, eccentric composed of Langerhans
histiocytosis females, smokers and bizarre cysts cells, lymphocytes,
macrophages, and
fibroblasts
RB 5 respiratory bronchiolitis; RB-ILD 5 respiratory bronchiolitis-interstitial lung disease. See Table 1 for expansion of other abbreviations.

commonly, an element of air trapping. In the context tive bronchiolitis. In patients with constrictive or
of small airways disease, this is mainly from reflex obliterative bronchiolitis, because the predominant
hypoxic vasoconstriction. Mosaic perfusion is a non- pathologic finding is concentric narrowing or oblit-
specific finding and can be seen with any airways or eration of the bronchioles caused by submucosal
vascular disease. When mosaic perfusion is the only and peribronchiolar fibrosis (Fig 12), direct CT scan
or predominant finding, it is more specific and is typ- signs of bronchiolar and peribronchiolar inflamma-
ically seen with constrictive bronchiolitis, HP, asthma, tion (ie, centrilobular opacities) are characteristi-
or chronic pulmonary embolism. The “headcheese cally absent.59
sign” is the combination of mosaic perfusion and A common cause of constrictive bronchiolitis
ground-glass opacities in the same patient. Typically is previous childhood infection, resulting in the
in these patients three densities of lung are seen (nor- so-called Swyer-James syndrome, identifiable as
mal, too dense [ground-glass opacity], and too lucent
[mosaic perfusion]). This is indicative of a mixed
obstructiveⲐinfiltrative 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, increas-
ing the importance of HRCT scan even more. In
distinction, mosaic attenuation due to diffuse infil-
trative lung diseases is not characterized by attenua-
tion 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 den-
sity is noted on exhalation in patients with chronic
thromboembolic hypertension.
The prototype for this characteristic radiologic
Figure 12. The lumen of this bronchiole from a bone marrow
finding is constrictive bronchiolitis, also commonly transplant patient shows marked narrowing by prominent submu-
referred as bronchiolitis obliterans (BO) or oblitera- cosal fibrosis (hematoxylin-eosin, 3 20).

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 Figure 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.

asymmetric hyperlucent lung on routine chest radio- 50% of patients.61 Because it is inappropriate to per-
graphs (Figs 13A, 13B). Other conditions resulting in form a biopsy on transplanted lung to make this diag-
a pattern of mosaic attenuation include connective nosis, the diagnosis of BO is based on clinical symp-
tissue disorders, bone marrow and transplantation, toms and spirometry.62 Constrictive bronchiolitis is
toxic fume inhalation, drugs, and cryptogenic con- seen as a manifestation of graft vs host disease in 10%
strictive bronchiolitis (Table 3).9,60 of people who have received allogeneic bone marrow
Of particular note, constrictive bronchiolitis transplants.63 Other less common causes have also
remains the most common form of chronic rejection been described. Rheumatoid arthritis-associated
in patients with lung transplants, occurring in up to constrictive bronchiolitis, for example, has been
described as a rare pleuropulmonary complication,
presumably as a result of autoimmune reaction.64,65
Table 3—Causes andⲐor Underlying Disorders
Most of the reported cases have marked irreversible
Associated With Constrictive Bronchiolitis
airways obstruction and a fulminating course of the
Postinfectious disease. Most have had long-standing rheumatoid
Viral (adenovirus, respiratory syncytial virus, influenza, arthritis, although in rare cases, pulmonary abnor-
parainfluenza)
malities antedate rheumatologic manifestations. In
Mycoplasma
Collagen vascular diseases some cases, use of D-penicillamine therapy66 has been
Rheumatoid arthritis implicated as a potential causative factor. Silo filler’s
Systemic lupus erythematosus lung (nitrogen dioxide) is a classic cause of toxic
Eosinophilic fasciitis exposure-related constrictive bronchiolitis. Other
Transplant related toxic fumes, such as chlorine, sulfur dioxide, ammo-
Graft vs host disease
Allograft recipients
nia, and phosgene, have been reported to cause
Bone marrow transplant constrictive bronchiolitis.10,67 Most recently, work-
Heart-lung transplant related inhalation of flavoring agents (diacetyl used in
Toxic fume exposure making popcorn) has been found to result in a clinical
Nitrogen dioxide presentation and imaging pattern typical of con-
Sulfur dioxide
Ammonia
strictive bronchiolitis.68
Chlorine Other causes and associations with constrictive
Phosgene bronchiolitis are listed in Table 3 and include neuro-
Diacetyl (popcorn workers) endocrine cell hyperplasia or multiple carcinoid
Ingested toxins tumorlets, Sauropus androgynus ingestion,69 and
Sauropus androgynus
Drugs
drugs, such as D-penicillamine,10 gold,70 cocaine,
D-penicillamine and lomustine. Clinically, dyspnea is the most com-
Gold mon complaint. The clinical criteria used for diag-
Cocaine nosing constrictive bronchiolitis include evidence of
Carmustine severe irreversible airflow obstruction measured by
Cryptogenic constrictive bronchiolitis
spirometry, with an FEV1 of , 60% of predicted

948 Chest Imaging and Pathology for Clinicians: Special Feature

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 Table 4—Histologic Patterns of Bronchiolitis
Cellular bronchiolitis
Follicular bronchiolitis
Organizing pneumoniaⲐ bronchiolitis obliterans with intraluminal
polyps
Constrictive bronchiolitis
Respiratory bronchiolitis
Diffuse panbronchiolitis
Bronchiolitis with peribronchiolar metaplasia
This table summarizes the major histopathologic patterns seen in
different bronchiolar diseases.
value in the absence of other pathologic causes for
airway obstruction, such as emphysema or chronic
bronchitis. The midexpiratory phase of forced expi-
ratory flows is a measure of small airways disease; a
marked decrease (ie, , 30% of predicted) is a par-
ticularly sensitive indicator of BO. Obtaining expira-
tory HRCT scans increases the likelihood of identi-
fying 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 demon-
strated 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 vari-
ety of patterns, as summarized in Table 4.74-76 Most
of these have already been mentioned here. In sur-
gical lung biopsies, it is usually possible to recognize
these patterns, and these terms can be applied when
the histologic findings are clear. Bronchiolar pathol-
ogy is often patchy, and severity of clinical manifes-
tations 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 histo-
logic 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 observa-
tion is an incidental or clinically significant finding.
In such cases, careful clinical and HRCT scan corre-
lation is required.
It can be difficult to recognize and classify bron-
chiolitis in transbronchial biopsies because of the
limited sampling size. However, in certain clinical
settings, such as heart-lung or bone marrow trans-
plantation, these are the most common specimens
obtained. In these patients with appropriate clinical
and HRCT scan findings, the presence of submuco-
sal fibrosis may support a diagnosis of constrictive
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bronchiolitis. In the heart-lung transplant setting, it
is recommended to obtain at least five pieces of
well-expanded alveolar parenchyma with transbron-
chial 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.
Conclusions
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 andⲐor 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 opac-
ities, for example, typically signify an infectious cause
with a pattern of distribution often suggestive of par-
ticular 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 RBⲐRB-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 andⲐor optimal
management of bronchiolar disorders that may other-
wise be difficult to identify. In many cases, a diagnosis
may be made solely using HRCT scans in combina-
tion with the history and clinical presentation.
Acknowledgments
FinancialⲐnonfinancial disclosures: The authors have reported
to CHEST that no potential conflicts of interest exist with any
companiesⲐorganizations whose products or services may be dis-
cussed in this article.
Other contributions: We thank Ms. Patrice Balistreri for her
invaluable secretarial assistance and coordination.
CHEST / 137 / 4 / APRIL, 2010 949
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