REVIEW
DIAGNOSIS OF INTERSTITIAL LUNG DISEASES
Diagnosis of Interstitial Lung Diseases
JAY H. RYU, MD; CRAIG E. DANIELS, MD; THOMAS E. HARTMAN, MD; AND EUNHEE S. YI, MD
Interstitial lung diseases (ILDs), a broad heterogeneous group of
parenchymal lung disorders, can be classified into those with
known and unknown causes. The definitions and diagnostic crite-
ria for several major forms of ILDs have been revised in recent
years. Although well over 100 distinct entities of ILDs are recog-
nized, a limited number of disorders, including idiopathic pulmo-
nary fibrosis, sarcoidosis, and connective tissue disease–related
ILDs, account for most ILDs encountered clinically. In evaluating
patients with suspected ILD, the clinician should confirm the
presence of the disease and then try to determine its underlying
cause or recognized clinicopathologic syndrome. Clues from the
medical history along with the clinical context and radiologic find-
ings provide the initial basis for prioritizing diagnostic possibilities
for a patient with ILD. High-resolution computed tomography of the
chest has become an invaluable tool in the diagnostic process. A
confident diagnosis can sometimes be made on the basis of high-
resolution computed tomography and clinical context. Serologic
testing can be helpful in selected cases. Histopathologic findings
procured through bronchoscopic or surgical lung biopsy are often
needed in deriving a specific diagnosis. An accurate prognosis and
optimal treatment strategy for patients with ILDs depend on an
accurate diagnosis, one guided by recent advances in our under-
standing of the causes and pathogenetic mechanisms of ILDs.
Mayo Clin Proc. 2007;82(8):976-986
BAL = bronchoalveolar lavage; CTD = connective tissue disease; HRCT =
high-resolution computed tomography; ILD = interstitial lung disease;
IPF = idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia
I nterstitial lung diseases (ILDs), also called diffuse infil-
trative lung diseases, are a heterogeneous group of disor-
ders that predominantly affect the lung parenchyma and
vary widely in etiology, clinicoradiologic presentation, his-
topathologic features, and clinical course.1-4 Although ILDs
are more commonly seen in adults, some forms such as
hypersensitivity pneumonitis and idiopathic interstitial
pneumonias are encountered in children as well.5 Intersti-
tial lung diseases are characterized by infiltration of cellu-
lar or noncellular material into the lung parenchyma. Ana-
tomic distribution of these processes may affect not only
the interstitial compartment but also alveolar airspaces,
blood vessels, and distal airways.1,6 Despite this histopatho-
logic description and established definition for ILD, the
distinction between ILDs and other diseases that can affect
From the Division of Pulmonary and Critical Care Medicine (J.H.R., C.E.D.),
Department of Radiology (T.E.H.), and Department of Laboratory Medicine
and Pathology (E.S.Y.), Mayo Clinic, Rochester, MN.
Individual reprints of this article are not available. Address correspondence to
Jay H. Ryu, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic,
200 First St SW, Rochester, MN 55905 (ryu.jay@mayo.edu).
© 2007 Mayo Foundation for Medical Education and Research
976 Mayo Clin Proc. • August 2007;82(8):976-986
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
the lung diffusely can be difficult. The major physiologic
consequence of ILDs is impaired gas exchange. Thus, pro-
gressive ILD results in worsening respiratory insufficiency
and ultimately death due to respiratory failure.
CLASSIFICATION OF
INTERSTITIAL LUNG DISEASES
No universally accepted classification of ILDs exists. Vari-
ous classification schemes have been proposed with strati-
fication based on parameters such as clinical presentation
(eg, acute vs chronic), histopathologic findings, radiologic
patterns, and response to corticosteroid therapy (responsive
vs nonresponsive to corticosteroids). Perhaps the most
practical classification of ILDs for clinicians is a scheme
based on cause, ie, those with known vs unknown cause
(Table 1). This classification scheme appropriately reflects
the diagnostic approach in that the clinician begins by
trying to identify a cause through history taking and physi-
cal examination followed by diagnostic testing. Known
causes of ILDs include inhaled organic and inorganic sub-
stances, drugs, radiation, and systemic disorders, for ex-
ample, connective tissue diseases (CTDs).
For some ILDs the cause is unknown despite a well-
recognized clinicopathologic syndrome, eg, idiopathic
pulmonary fibrosis (IPF) and sarcoidosis. In most ILDs
of unknown cause, a major component of the case defini-
tion is the underlying histopathologic pattern. Thus, when
no cause can be identified for the ILD, a lung biopsy is
often pursued. However, some histopathologic patterns of
ILD are nonspecific, for example organizing pneumonia
or noncaseating granulomas. Because histopathologic
findings alone may not yield a specific diagnosis, they
should always be correlated with the clinical and radio-
logic context.
The diagnosis of ILD has become more complex in
recent years, in part because of revisions to the definitions
and diagnostic criteria of several major forms of ILDs,
particularly the idiopathic interstitial pneumonias.7,8 These
modifications occurred because of new insights into the
etiology, pathogenesis, and clinicoradiologic correlates of
these disorders. These advances have resulted in part from
refinements in the histopathologic interpretation of lung
biopsy findings and improvements in diagnostic tools, par-
ticularly high-resolution computed tomography (HRCT).
For example, IPF, defined imprecisely by traditional crite-
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ria, is actually composed of a heterogeneous mix of disor-
ders with varying prognosis and response to corticosteroid
therapy.8-10 In particular, earlier studies of IPF likely in-
cluded patients with nonspecific interstitial pneumonia,
which responds better to corticosteroid therapy and has a
more favorable prognosis than IPF as currently defined.9
Lumping of similar entities into a single disorder impairs
recognition of distinct diseases that may be associated with
important differences in pathogenesis, response to therapy,
and clinical course.
Although well over 100 distinct entities of ILDs are
recognized, a limited number of disorders account for most
ILDs encountered clinically. The most common form of
ILD seen in clinical settings is IPF, also called cryptogenic
fibrosing alveolitis, which accounts for approximately 25%
to 35% of ILD cases.8,10-12 In our experience, approximately
three quarters of patients seen with ILD have IPF, sarcoido-
sis, or CTD-related ILDs.
According to current criteria, a “definite” diagnosis of
IPF requires evidence of usual intersitial pneumonia (UIP)
on a surgical lung biopsy specimen in the presence of
appropriate clinicoradiologic context, ie, diffuse lung dis-
ease in the absence of an identifiable cause.7,8,11 Usual
interstitial pneumonia refers to a histopathologic pattern of
lung injury characterized by patchy collagen fibrosis with
associated scarring distributed in a peripheral, subpleural
fashion with honeycomb changes. The histopathologic pat-
tern of UIP is not specific for IPF and can also be seen in
CTD-related ILD, asbestosis, drug-induced lung disease,
and chronic hypersensitivity pneumonitis.7 A “probable”
diagnosis of IPF can be made without surgical lung biopsy
confirmation if the typical HRCT findings are present in
the appropriate clinical context, ie, ILD of unknown cause in
a middle-aged or older patient with gradually worsening
exertional dyspnea, bibasilar inspiratory crackles (“Velcro”-
like in quality), and restrictive lung disease or impaired gas
exchange.8 Typical HRCT findings of IPF include the pres-
ence of bilateral peripheral reticular opacities and subpleu-
ral honeycombing with basal predominance (Figure 1),8,13
all of which correlate strongly to surgical lung biopsy
findings of UIP.14,15 Bronchoscopic biopsy cannot be used
to confirm the diagnosis of IPF because the recognition of
the UIP pattern requires a larger specimen than can be
obtained by bronchoscopy.8
The second most common ILD is sarcoidosis, a multi-
system disorder of unknown cause characterized by the
presence of noncaseating epithelioid granulomas.16 In con-
trast to IPF, sarcoidosis tends to affect adults younger than
40 years.16 High-resolution computed tomograms of the
chest in patients with sarcoidosis reveal nodular infiltrates
in a perilymphatic distribution with an upper- and mid-lung
predominance (Figure 2).17 A perilymphatic distribution
Mayo Clin Proc. • August 2007;82(8):976-986
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DIAGNOSIS OF INTERSTITIAL LUNG DISEASES
TABLE 1. Classification of ILDs*
Known cause
Connective tissue disease–associated ILDs (eg,
rheumatoid arthritis, polymyositis, scleroderma)
Hypersensitivity pneumonitis (eg, farmer’s lung
“hot tub lung,” bird fancier’s lung)
Pneumoconioses (eg, asbestosis, silicosis, coal
worker’s pneumoconiosis)
Drug-induced ILDs (eg, chemotherapeutic agents,
amiodarone, nitrofurantoin)
Smoking-related ILDs
Pulmonary Langerhans cell histiocytosis
Respiratory bronchiolitis–associated ILD
Desquamative interstitial pneumonia
Acute eosinophilic pneumonia
Radiation-induced ILDs
Toxic inhalation–induced ILDs (eg, cocaine, zinc
chloride [smoke bomb], ammonia)
Unknown cause
Idiopathic pulmonary fibrosis
Sarcoidosis
Other idiopathic interstitial pneumonias
Cryptogenic organizing pneumonia
Nonspecific interstitial pneumonia
Lymphocytic interstitial pneumonia
Acute interstitial pneumonia
Eosinophilic pneumonias
Pulmonary vasculitides
Pulmonary lymphangioleiomyomatosis
Pulmonary alveolar proteinosis
Many other rare disorders
*ILDs = interstitial lung diseases.
involves the peribronchovascular regions, the interlobular
septa, and the pleural surface. Thus, the type of parenchy-
mal abnormality and the pattern of distribution identified
using HRCT are distinctly different from those associated
with IPF. Mediastinal and bilateral hilar lymphadenopathy
are also common findings. Sarcoidosis should not be con-
sidered as a diagnosis until the many potential causes of
granulomatous inflammation, especially infections, have
been excluded. Tissue biopsy specimens, most commonly
obtained by bronchoscopy, are necessary to document the
presence of noncaseating granulomas.
Connective tissue diseases, environmental inhalants,
and drugs are the most common causes of ILDs of known
etiology. Although some authors may argue that CTD is
not a specific “cause” of ILD, identification of an underly-
ing CTD clearly is relevant to evaluating, treating, and
determining a prognosis for patients with ILDs. Respira-
tory manifestations occur commonly in patients with CTDs
and may result from involvement of the lung parenchyma,
pleura, airways, vasculature, or respiratory muscles. Con-
nective tissue disease–related ILD can manifest various
histopathologic patterns that are similar to those described
in idiopathic interstitial pneumonias.7,18 These patterns
include nonspecific interstitial pneumonia, organizing
pneumonia, UIP, lymphocytic interstitial pneumonia, and
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DIAGNOSIS OF INTERSTITIAL LUNG DISEASES
FIGURE 1. High-resolution computed tomogram of a 67-year-old man
with idiopathic pulmonary fibrosis/usual interstitial pneumonia
(IPF/UIP). The image, which was taken at the level of the bronchus
intermedius, shows extensive subpleural honeycombing bilaterally,
allowing for the confident diagnosis of UIP. Also noted are subpleu-
ral reticular opacities with associated ground-glass attenuation and
traction bronchiectasis in the lower lobes posteriorly.
diffuse alveolar damage. The underlying histopathologic
pattern appears to have a similar prognostic significance
for patients with CTD-related ILD as for patients with
idiopathic interstitial pneumonias.18-23 For example, CTD-
associated organizing pneumonia and nonspecific intersti-
tial pneumonia tend to respond better to corticosteroid
therapy than do UIP and diffuse alveolar damage. How-
ever, the prognosis for patients with CTD-related ILDs is
determined not only by the underlying histopathologic pat-
FIGURE 2. High-resolution computed tomogram of a 41-year-old man
with sarcoidosis. Image of the left lung at the level of the carina
shows the perilymphatic distribution of nodules characteristic of
sarcoidosis. Nodules are seen along the bronchovascular bundles
(arrow), along the interlobular septa (arrowhead), and along the
fissures.
978 Mayo Clin Proc. • August 2007;82(8):976-986
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tern of ILD but also by the CTD itself, associated extra-
pulmonary manifestations, as well as the age and comor-
bidities of the individual patient.18
Pneumoconioses result from inhalation of inorganic
dusts such as silica and asbestos.24 Radiologic features may
be sufficient for diagnosing pneumoconioses such as sili-
cosis in the appropriate clinical context, eg, one that in-
cludes known exposure.24,25 The features revealed by
HRCT vary depending on the specific pneumoconiosis and
are often distinctive.25
Hypersensitivity pneumonitis refers to immunologically
induced inflammatory disease involving the lung paren-
chyma and terminal airways secondary to repeated inhala-
tion of an inciting agent in a sensitized host.26,27 Common
forms of hypersensitivity pneumonitis in the United States
include bird fancier’s disease, farmer’s lung disease and
“hot tub lung.”26-28 Typically, HRCT features are character-
ized by centrilobular nodules, ground-glass opacities, a
mosaic pattern, air trapping on expiratory images, or some
combination of these features (Figure 3).29,30 Most patients
with suspected hypersensitivity pneumonitis undergo bron-
choscopy or surgical lung biopsy to confirm the diagnosis.
Drugs can cause a variety of pleuropulmonary reactions
including ILD. Drugs most commonly associated with
ILD include chemotherapeutic agents (eg, bleomycin), car-
diovascular drugs (eg, amiodarone), and antibiotics (eg,
nitrofurantoin).31,32 Diverse findings from HRCT can be
expected, because drug-induced ILD has numerous histo-
pathologic manifestations,32,33 including diffuse alveolar
damage, nonspecific interstitial pneumonia, eosinophilic
pneumonia, and pulmonary hemorrhage.33 A single drug
may cause different histologic reactions in different pa-
tients.34 For example, nitrofurantoin has been associated
with histopathologic patterns of organizing pneumonia,
nonspecific interstitial pneumonia, desquamative intersti-
tial pneumonia, and giant cell pneumonia.35 The histologic
responses to various drugs can overlap considerably. In
most cases of drug-induced ILD, the histopathologic find-
ings will be nonspecific, and the diagnosis will require
correlation with clinicoradiologic features as well as exclu-
sion of other potential causes.
Smoking has been associated with several forms of
ILDs including respiratory bronchiolitis–associated ILD,
desquamative interstitial pneumonia, pulmonary Langer-
hans cell histiocytosis, and acute eosinophilic pneumo-
nia.36-38 Smoking may also be a risk factor for IPF. Approxi-
mately 80% to 100% of pulmonary Langerhans cell histio-
cytosis, desquamative interstitial pneumonia, and respira-
tory bronchiolitis–associated ILDs occur in those with a
smoking history.36 However, cigarette smoking has been
linked to only a subset of patients with acute eosinophilic
pneumonia.38-41 Respiratory bronchiolitis–associated ILD
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and desquamative interstitial pneumonia appear to repre-
sent varying degrees of severity of the pulmonary reaction
to cigarette smoke. Accordingly, the HRCT features of
these 2 disorders tend to overlap and are characterized
predominantly by the presence of ground-glass opacities.42
Pulmonary Langerhans cell histiocytosis is characterized
by proliferation of Langerhans cells in the lung with de-
struction of lung parenchyma (cystic changes on HRCT)
and architectural distortion.43,44 Extrapulmonary manifesta-
tions may occur in patients with pulmonary Langerhans
cell histiocytosis including involvement of the bone, skin,
pituitary gland, liver, lymph nodes, and thyroid gland.37,43,44
DIAGNOSTIC PROCESS
Most patients with ILD present with a nonspecific respira-
tory complaint such as a cough or dyspnea. Therefore, the
first suggestion of ILD is usually chest radiography that
reveals diffuse parenchymal infiltrates. In other situations,
abnormal pulmonary function test results such as reduced
lung volumes or diffusing capacity or exercise-induced
oxygen desaturation may be the initial clue. For approxi-
mately 10% of patients with ILDs, a chest radiograph may
look normal, particularly early in the course of disease.45-47
In our experience, hypersensitivity pneumonitis has been
the most common ILD associated with a normal-appearing
chest radiograph and occasionally even normal HRCT.
Thus, a normal chest radiograph should not dissuade the
clinician from pursuing the diagnostic possibility of ILD in
the appropriate clinical context.
Perhaps the most important advance in the past 20 years
for the diagnosis of ILD has been HRCT.48-56 In contrast to
the low-resolution, 2-dimensional summation of overlap-
ping shadows offered by chest radiography, HRCT pro-
vides a detailed depiction of the lung parenchyma that can
be used to focus and prioritize diagnostic possibilities in a
patient with suspected ILD. High-resolution computed to-
mography uses a high-spatial-frequency reconstruction al-
gorithm and 0.75- to 1.5-mm slices (collimation) rather
than 5- to 10-mm slices as in a standard CT study. Scans are
done at full inspiration and with the patient supine. The
addition of prone views may clarify the clinical importance
of infiltrates in dependent lung zones. Expiratory images
can be helpful in evaluating a mosaic attenuation pattern
(geographic patchwork of alternating lung regions of var-
ied radiologic attenuation) and assessing the presence of air
trapping. High-resolution computed tomography is more
sensitive and also allows for a more confident and specific
interpretation than chest radiography in the diagnosis of
ILD.4,49,55,56 For example, chest radiography may show pre-
dominantly linear opacities in a patient who actually proves
to have diffuse cystic lung disease as revealed on HRCT.
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DIAGNOSIS OF INTERSTITIAL LUNG DISEASES
FIGURE 3. High-resolution computed tomogram of a 47-year-old man
with subacute hypersensitivity pneumonitis showing diffuse ground-
glass attenuation infiltrates. Some of the infiltrates are centrilobular
nodules of ground-glass attenuation; in other areas, the ground-
glass attenuation is more confluent.
The finding of diffuse cystic lung disease facilitates the
diagnostic process because this radiologic pattern is associ-
ated with a limited number of diagnostic possibilities.57
CLINICAL CONTEXT
At this point in the evaluation of a patient with suspected
ILD, summarizing the gathered data using 3 pivotal param-
eters will help to determine subsequent diagnostic steps.4
These key parameters are the clinical context, tempo of the
disease process, and radiologic findings. The clinical con-
text includes the age and sex of the patient, smoking his-
tory, occupational and environmental exposures, medica-
tions, family history, coexisting medical disorders, and the
clinical setting in which the patient is encountered (Table
2). As previously discussed, several ILDs tend to occur in
particular demographic groups. Pulmonary lymphangio-
leiomyomatosis, a form of diffuse cystic lung disease, al-
most exclusively affects women.58 Smoking and other in-
halational exposures as well as drugs may have etiologic
relevance in patients with ILD. Many systemic disorders,
particularly CTDs, can involve the lung. Family history is
important in diagnosing hereditary ILDs, including famil-
ial pulmonary fibrosis, pulmonary lymphangioleiomyo-
matosis associated with tuberous sclerosis complex, Her-
mansky-Pudlak syndrome, Gaucher disease, and other
metabolic storage diseases.59 Current and previous illnesses
are relevant because the lung disease may be a manifesta-
tion of such illnesses or a treatment-related adverse effect.
The presence or absence of certain physical findings
may be diagnostically helpful. “Velcro” crackles are nearly
universal in patients with IPF and can be present in other
ILDs but are uncommon in sarcoidosis.8,10,11,16 Similarly,
digital clubbing is observed in up to two thirds of pa-
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DIAGNOSIS OF INTERSTITIAL LUNG DISEASES

TABLE 2. Diagnosis of Interstitial Lung Disease* RADIOLOGIC FINDINGS

History In the diagnosis of ILD, HRCT provides critical data
Demographics needed to determine whether specific blood tests, broncho-
Pulmonary and extrapulmonary manifestations
Temporal course of symptoms scopic procedures, and surgical lung biopsy are necessary.
Smoking Early in the evaluation of nearly all patients with suspected
Environmental/occupational exposures ILD, an HRCT scan should be obtained unless the diagno-
Drugs
Previous and concurrent illnesses sis is obvious based on the clinical context and chest radio-
Familial disorders graphic findings alone.
Physical examination The components of the HRCT findings that are helpful
Lung auscultation
Digital clubbing in the diagnosis of ILD include the pattern of parenchymal
Extrapulmonary signs abnormality (eg, consolidation, reticular pattern), the ana-
Laboratory tests tomic distribution (upper vs lower, central vs peripheral),
Complete blood cell count
Chemistry panel and associated findings (eg, mediastinal lymphadenopa-
Urinalysis thy) (Table 3). Combining the tempo of the disease process
Hypersensitivity pneumonitis serologic tests† with the radiologic findings helps narrow the differential
Connective tissue disease serologic tests†
Antineutrophil cytoplasmic antibodies† diagnosis further.4
Brain natriuretic peptide level† A reticular pattern, characterized by interlacing linear
Imaging studies opacities that suggest a mesh, is the most common radio-
Chest radiography
CT of the chest with high resolution logic finding seen in patients with ILDs, particularly
Previous chest radiographs and chest CT studies those with IPF.4,13 In patients with IPF, the reticular pat-
Echocardiography† tern is often associated with the presence of subpleural
Pulmonary function tests
Spirometry, lung volumes, diffusing capacity, and oximetry honeycombing.13 Honeycombing is defined as a cluster or
Arterial blood gas study† row of cysts (usually <5 mm in diameter) with shared
Cardiopulmonary exercise testing† walls.
Bronchoscopy†
Surgical lung biopsy† Nodules, defined as round, discrete, parenchymal opaci-
ties, can be classified according to size, density, definition
*CT = computed tomography.
†These tests are used in selected cases according to the clinical context. (distinctness of the margin), and distribution. Among ILDs,
sarcoidosis is the most common disease associated with a
nodular pattern.4,16 In sarcoidosis, these nodules are most
tients with IPF but is rare in sarcoidosis and most other prominent along the bronchovascular bundles (perilym-
ILDs.8,10,11,16 Recurrent pneumothoraces are common in pa- phatic distribution) and are seen predominantly in the up-
tients with pulmonary lymphangioleiomyomatosis and pul- per- and mid-lung zones.
monary Langerhans cell histiocytosis.58,60,61 Extrathoracic Cysts in the lung are enlarged airspaces surrounded by a
findings such as skin lesions may sometimes provide es- wall of variable thickness and composition.57 Among the
sential diagnostic clues. relatively few ILDs that are characterized by a diffuse
cystic pattern on HRCT are lymphangioleiomyomatosis
TEMPO OF DISEASE (Figure 4) and pulmonary Langerhans cell histiocyto-
Most ILDs, eg, IPF, present with an insidious onset of sis.43,44,57,58,64,65 The morphological characteristics and dis-
respiratory symptoms and slowly worsening lung infil- tribution of these cystic lesions can help radiologically
trates over a course of months to years. Acute presentation distinguish these 2 diseases.57 Scattered cystic airspaces
(lasting <4-6 weeks) of ILD is uncommon but can be seen can also be seen in other ILDs, including desquamative
in several ILDs, including hypersensitivity pneumonitis, interstitial pneumonia,66 hypersensitivity pneumonitis,67
acute reactions to drug or inhalational exposure, diffuse lymphocytic interstitial pneumonia,68 lymphoproliferative
alveolar hemorrhage syndromes, cryptogenic organizing diseases,69 light chain deposition disease,70 and Birt-Hogg-
pneumonia, acute eosinophilic pneumonia, and acute in- Dubé syndrome.71
terstitial pneumonia (also called Hamman-Rich syn- A radiologic pattern of ground-glass opacity is charac-
drome).4,62 Acute exacerbations can occur in patients with terized by a hazy increase in lung attenuation through
IPF and CTD-related ILD and may occasionally be the which pulmonary vessels may still be seen; in a pattern of
initial presentation for some of these patients.22,63 The avail- consolidation, those vessels are obscured (Figure 5).4,49
ability of previous chest radiographs or CT scans allows a Infections, pulmonary edema, and alveolar hemorrhage
more accurate assessment of the tempo of the pathologic cause alveolar filling and typically show consolidation as
process. well as ground-glass opacity.4 Ground-glass opacities may

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 DIAGNOSIS OF INTERSTITIAL LUNG DISEASES

TABLE 3. Differential Diagnosis of ILDs Based on

Radiologic Findings and Tempo*
Pattern
Consolidation
Acute: diffuse alveolar hemorrhage syndromes, acute interstitial
pneumonia, acute eosinophilic pneumonia, acute reactions to
drug or inhalational exposure, cryptogenic organizing pneumonia
(also consider infections, pulmonary edema, aspiration)
Chronic: chronic eosinophilic pneumonia, cryptogenic organizing
pneumonia, lymphoproliferative diseases, pulmonary alveolar
proteinosis, sarcoidosis (also consider chronic infections,
chronic aspiration, lymphoma, bronchoalveolar cell carcinoma)
Reticular pattern
Acute: consider infections, pulmonary edema
Chronic: IPF, connective tissue disease–associated ILD, asbestosis,
sarcoidosis, hypersensitivity pneumonitis, drug-induced lung FIGURE 4. High-resolution computed tomogram of a 34-year-old
disease woman with lymphangioleiomyomatosis showing cystic lesions ran-
Nodular pattern (nodules <1 cm in diameter) domly distributed throughout both lungs.
Acute: hypersensitivity pneumonitis, sarcoidosis (also consider
infections, eg, tuberculosis, fungal infections)
Chronic: sarcoidosis, hypersensitivity pneumonitis, silicosis,
coal worker’s pneumoconiosis, respiratory bronchiolitis, be caused by partial filling of the alveolar spaces or thick-
alveolar microlithiasis (also consider metastatic disease) ening of the interstitium due to inflammation or fibrosis.
Cystic airspaces Thus, the differential diagnosis of ground-glass opacities in
Acute: consider Pneumocystis pneumonia, septic embolism
Chronic: pulmonary Langerhans cell histiocytosis,
ILDs is broad and includes nonspecific interstitial pneumo-
lymphangioleiomyomatosis, lymphocytic interstitial pneumonia, nia, respiratory bronchiolitis–associated ILD, desquama-
honeycomb lung caused by IPF tive interstitial pneumonia, drug-induced lung diseases,
Ground-glass opacities
pulmonary alveolar proteinosis, diffuse alveolar hemor-
Acute: diffuse alveolar hemorrhage, hypersensitivity pneumonitis,
acute inhalational exposures, drug-induced lung diseases, acute rhage syndromes, hypersensitivity pneumonitis, acute in-
interstitial pneumonia (also consider infections, pulmonary halational injuries, drug-induced lung diseases, and acute
edema) interstitial pneumonia.4
Chronic: nonspecific interstitial pneumonia, hypersensitivity
pneumonitis, respiratory bronchiolitis–associated ILD, Chronic septal thickening can be seen in several ILDs
desquamative interstitial pneumonia, drug-induced lung including IPF, sarcoidosis, and pulmonary alveolar
diseases, pulmonary alveolar proteinosis proteinosis but is not the main radiologic abnormality in
Thickened interlobular septa
Acute: consider congestive heart failure, pulmonary edema these disorders.4,50 Septal thickening can also be caused by
Chronic: pulmonary alveolar proteinosis, sarcoidosis lymphangitic spread of tumor and generally has a nodular
Distribution or beaded character.50 Acute smooth septal thickening is
Upper lung predominance: sarcoidosis, pulmonary Langerhans cell usually caused by pulmonary edema.
histiocytosis, silicosis, coal worker’s pneumoconiosis, Aside from the radiologic patterns of parenchymal ab-
carmustine-related pulmonary fibrosis (also consider tuberculosis,
Pneumocystis pneumonia) normalities revealed on HRCT, the anatomic distribution
Lower lung predominance: IPF, connective tissue disease–associated of these findings can offer important information that in-
ILD, asbestosis (also consider chronic aspiration) fluences the differential diagnosis. Upper vs lower lung
Central predominance: sarcoidosis, berylliosis, pulmonary alveolar
proteinosis predominance is a useful distinction because several ILDs,
Peripheral predominance: IPF, nonspecific interstitial pneumonia, including sarcoidosis, pulmonary Langerhans cell his-
chronic eosinophilic pneumonia, cryptogenic organizing tiocytosis, silicosis, coal worker’s pneumoconiosis, and
pneumonia (also consider pulmonary infarctions, septic pulmonary
embolism)
carmustine-related pulmonary fibrosis, preferentially af-
fect upper- and mid-lung zones.1,4 In contrast, IPF, asbesto-
Associated findings
Traction bronchiectasis: IPF, asbestosis, other chronic fibrotic sis, and most CTD-related ILDs tend to be predominant in
disorders the lower lobes.1,4 Radiologic abnormalities can also be
Lymphadenopathy: sarcoidosis, silicosis, berylliosis (also consider usefully categorized as centrally vs peripherally predomi-
infections, lymphangitic carcinomatosis or metastases, lymphoma)
Air trapping: hypersensitivity pneumonitis, respiratory nant. Chronic eosinophilic pneumonia, IPF, and crypto-
bronchiolitis–associated ILD, desquamative interstitial pneumonia, genic organizing pneumonia usually involve the peripheral
sarcoidosis lung zones.1,4 In contrast, sarcoidosis and berylliosis tend to
Pleural effusion or thickening: drug-induced ILDs, connective tissue
disease–associated ILDs, asbestosis, lymphangioleiomyomatosis
affect the central lung zones, particularly along the bron-
(also consider lymphangitic carcinomatosis, lymphoma) chovascular bundles.1,4
*ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis. Associated radiologic findings may also prove useful in
Adapted from Mayo Clin Proc.4 the differential diagnosis. Traction bronchiectasis/bronchi-

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DIAGNOSIS OF INTERSTITIAL LUNG DISEASES
FIGURE 5. High-resolution computed tomogram of a 54-year-old
woman with chronic eosinophilic pneumonia showing consolidation
in the right lower lobe.
olectasis, which refers to dilatation and distortion of the
bronchi and bronchioles in areas of parenchymal fibro-
sis,50,55 is usually seen with reticular opacities and provides
reliable evidence for the presence of surrounding fibrosis.
Although most commonly encountered in IPF, it can be
seen in any chronic fibrotic disorders such as asbestosis,
many CTD-related ILDs, and radiation fibrosis. Commonly
associated with sarcoidosis, intrathoracic lymphadenopathy
is also seen with silicosis, berylliosis, and lymphocytic
interstitial pneumonia. However, mildly enlarged mediasti-
nal lymph nodes are not uncommonly seen with other ILDs
such as IPF.55 A nonspecific mosaic attenuation can be
observed in ILDs, airway diseases, or pulmonary vascular
diseases.50 Air trapping as demonstrated on expiratory views
can be characteristic of ILDs that have a prominent bronchi-
olar involvement, ie, bronchiolitis,72 such as hypersensitivity
pneumonitis, desquamative interstitial pneumonia, respira-
tory bronchiolitis–associated ILD, and sarcoidosis.72
Pleural effusion or thickening commonly occurs in
ILDs that are induced by drugs or associated with CTD. In
addition, pleural plaques, one of the characteristic pul-
monary manifestations after asbestos exposure, can be
seen together with asbestosis. Chylothorax occurs in ap-
proximately 20% to 40% of patients with pulmonary
lymphangioleiomyomatosis.73
LABORATORY TESTS
Laboratory tests performed in patients with suspected ILD
should include a complete blood cell count with differential
leukocyte counts, renal and liver function tests, and uri-
nalysis (Table 2). Patients with a pulmonary hemorrhage
syndrome, eg, microscopic polyangiitis, may have iron
deficiency anemia. Peripheral eosinophilia may occur in
eosinophilic pneumonias, Churg-Strauss syndrome, and
some drug reactions. Hypercalcemia is not uncommon in
982 Mayo Clin Proc. • August 2007;82(8):976-986
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
sarcoidosis.16 Abnormal urine sediment may suggest renal
involvement in systemic vasculitis or CTD.
Certain serologic tests can be diagnostically helpful in
the evaluation of patients with suspected ILD. Autoim-
mune markers such as anti-cyclic citrullinated peptide anti-
bodies and antinuclear antibodies raise the possibility of an
underlying CTD. Antineutrophil cytoplasmic antibody and
antiglomerular basement membrane antibody assays are
helpful in the diagnosis of Wegener granulomatosis and
Goodpasture syndrome, respectively. The serum angio-
tensin–converting enzyme level is frequently elevated in
sarcoidosis but is not specific for this disorder and is not
diagnostically useful. Detection of a serum precipitin to
an antigen in a patient with suspected hypersensitivity
pneumonitis indicates sensitization of the host but does
not prove the diagnosis.26 The brain natriuretic peptide
level may be useful in screening for pulmonary hyperten-
sion in patients with ILDs and as a prognostic marker.74
We recommend ordering selective serologic tests depend-
ing on the clinical context and the differential diagnosis
being considered.
PULMONARY FUNCTION TESTING
Pulmonary function testing is needed in the evaluation of
patients with suspected ILD and should include spirometry,
diffusing capacity for carbon monoxide, lung volumes, and
oximetry (oxygen saturation at rest and with exercise).
Pulmonary function testing in patients with ILDs typically
reveals a restrictive pattern with reduced diffusing capac-
ity. In early ILD, however, the only abnormality, if any, on
pulmonary function testing may be a mildly reduced diffus-
ing capacity. Obstructive findings are uncommon in pa-
tients with suspected ILD but can be seen in patients with
sarcoidosis, hypersensitivity pneumonitis, silicosis, pulmo-
nary Langerhans cell histiocytosis, and pulmonary lymph-
angioleiomyomatosis.75 Interstitial lung disease occurring
in patients with a preexisting obstructive lung disease, such
as chronic obstructive pulmonary disease or emphysema,
may present with pulmonary function features of obstruc-
tion, restriction, or normal lung volumes because of op-
posing effects on lung compliance. Patients with IPF and
emphysema may have normal lung volumes but a low dif-
fusing capacity and are more likely to be male smokers with
worse dyspnea and poorer prognosis than patients with only
IPF or emphysema.76,77 An arterial blood gas study should
be performed in patients with moderate to severe pulmo-
nary impairment or significant exertional dyspnea.
ECHOCARDIOGRAPHY
Echocardiographic evaluation should be considered for pa-
tients with ILDs who experience exertional dyspnea or fa-
tigue, particularly if the degree of these symptoms seems to
• www.mayoclinicproceedings.com

be disproportionate to the severity of the lung disease. Pul-
monary hypertension, which is common in patients with IPF
and pulmonary Langerhans cell histiocytosis, does not ap-
pear to correlate necessarily with the severity of impairment
in pulmonary function or gas exchange.74,78-81 Some ILDs
may be associated with an intrinsic vasculopathy. For ex-
ample, Fartoukh et al82 described a proliferative pulmonary
vasculopathy involving muscular arteries and veins in pul-
monary Langerhans cell histiocytosis.
OTHER TESTS
Depending on the clinical context, other tests and proce-
dures may be useful in the diagnostic evaluation. Testing
for gastroesophageal reflux should be considered in pa-
tients with suggestive symptoms. Gastroesophageal reflux
may play a role in the pathogenesis of some ILDs such as
IPF.83 In addition, aspiration-related lung diseases may be
confused with ILD.84 Patients with ILD who present with
diarrhea or abnormal hepatic function may have inflamma-
tory bowel disease, eg, Crohn disease or ulcerative colitis;
ILDs caused by inflammatory bowel disease may be char-
acterized by granulomatous inflammation of the lung.85
Immune suppression due to therapy or underlying systemic
disease is common in ILD, and lung infection in such
patients can have diverse clinicoradiologic presentations.
Thus, the clinician needs to be mindful of potential pulmo-
nary infections and pursue vigilant testing when clinically
indicated.
BRONCHOSCOPY AND LUNG BIOPSY
When a specific diagnosis can be made confidently on the
basis of the clinical context, the tempo of the pathological
process, and the findings on HRCT, a lung biopsy is usu-
ally not required. For example, a diagnosis of IPF is highly
likely for a middle-aged patient presenting with slowly
progressive exertional dyspnea, bibasilar inspiratory crack-
les, and HRCT features typical for IPF including subpleu-
ral honeycombing in the lower lung zones in the absence of
relevant inhalational exposures, fibrogenic drugs, or CTD.
However, if the combination of these parameters is not
distinctive enough to achieve a specific diagnosis, a lung
biopsy needs to be considered but only after several related
issues are addressed.
Lung biopsies are performed to establish a specific diag-
nosis that will aid in assessing prognosis and guiding treat-
ment. In some situations, biopsy of an extrapulmonary site
such as a skin lesion may allow for a specific diagnosis.
The diagnostic possibilities being considered will largely
determine whether a bronchoscopic or surgical lung biopsy
is performed. Bronchoscopy with transbronchoscopic lung
biopsy and bronchoalveolar lavage (BAL) may provide
sufficient evidence to diagnose sarcoidosis, hypersensitiv-
Mayo Clin Proc. • August 2007;82(8):976-986
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
DIAGNOSIS OF INTERSTITIAL LUNG DISEASES
ity pneumonitis, eosinophilic pneumonias, organizing
pneumonia, pulmonary Langerhans cell histiocytosis,
desquamative interstitial pneumonia, lymphocytic intersti-
tial pneumonia, pulmonary lymphangioleiomyomatosis,
and pulmonary alveolar proteinosis, as well as infections
and neoplastic processes presenting with interstitial lung
infiltrates.2,3,6 Most of these disorders are associated with
distinctive histopathologic features that can be discerned
even in small lung biopsy specimens, allowing for a di-
agnosis to be made independently of the underlying his-
topathologic architecture. The finding of “interstitial
pneumonitis and fibrosis” on transbronchial lung biopsy is
nonspecific and does not confirm the diagnosis of IPF.
Bronchoalveolar lavage findings can be helpful in diag-
nosing ILDs such as pulmonary alveolar proteinosis and
pulmonary Langerhans cell histiocytosis.2-4,86 In pulmonary
alveolar proteinosis, BAL yields a cloudy effluent that
contains large amounts of periodic acid-Schiff–positive
lipoproteinaceous material, as evidenced by light micros-
copy.86,87 The presence of 5% or more CD1a-positive cells
in the BAL fluid is highly specific for the diagnosis of pul-
monary Langerhans cell histiocytosis.43,86 BAL findings may
sometimes be helpful in the diagnosis of pulmonary hemor-
rhage, eosinophilic pneumonias, berylliosis, hypersensitivity
pneumonitis, and some pneumoconioses.86 BAL cell profiles
are not diagnostic in idiopathic interstitial pneumonias.86
The number of recognizable histopathologic reaction
patterns in ILDs is limited,1,6 and their morphological
specificity in the diagnosis of ILDs is variable.1,6,88 Some
biopsy specimens may provide specific clues that are diag-
nostic of the underlying disease, whereas others reveal only
nonspecific abnormalities.
Currently, most surgical lung biopsies are performed by
video-assisted thoracoscopic surgery.89-91 When pleural ad-
hesions or other complicating factors interfere with the
performance of this procedure, the biopsy is obtained in-
stead by thoracotomy. Although the diagnostic yield of
surgical lung biopsy specimens is approximately 90% or
higher, this rate depends on what types of histologic find-
ings are considered diagnostic. The distribution of the ab-
normalities on HRCT is used to determine the sites of lung
biopsy. Although biopsies from 2 separate sites are usually
preferred, a generous specimen from a site that is represen-
tative of the underlying process can suffice. In some disor-
ders, the histology of specimens from different lobes may
vary.92 Areas of end-stage honeycomb fibrosis should be
avoided because samples from these sites reveal advanced
fibrotic changes that are of no diagnostic use.
Surgical lung biopsy in patients with ILDs poses rela-
tively low risk. The mortality rate is less than 2% in most
reports,89-91 and complication rates generally range from
5% to 10%.89-91 However, the risks of a surgical lung biopsy
• www.mayoclinicproceedings.com 983
DIAGNOSIS OF INTERSTITIAL LUNG DISEASES
may be increased in some situations.93-96 For example, Utz
et al93 reported a 21.7% mortality rate within 30 days of
biopsy in patients with IPF. Similarly, Caples et al94 noted a
20% in-hospital mortality rate after surgical lung biopsy in
patients with rheumatoid-related ILD. These higher than
expected mortality rates associated with surgical lung bi-
opsy likely reflect, at least in part, a selection bias, eg, lung
biopsy performed in patients with acutely worsening lung
infiltrates. However, these reports reinforce the need for a
careful assessment of risks and benefits in the selection of
patients for surgical lung biopsy.
Histopathologic findings must be interpreted within the
context of clinical, radiologic, and physiologic features in
the diagnostic evaluation of patients with ILDs. For ex-
ample, the histopathologic pattern of nonspecific intersti-
tial pneumonia may be encountered on lung biopsy speci-
mens from patients with hypersensitivity pneumonitis,
drug-induced lung disease, CTD-associated ILD, and pul-
monary infections, as well as in those with idiopathic ILD,
ie, idiopathic nonspecific interstitial pneumonia.7 Simi-
larly, other histopathologic patterns of interstitial pneu-
monias can be seen in association with known causes as
well as idiopathic ILD.7
Only a limited number of ILDs can be diagnosed by
histologic findings alone, and even then, the clinical con-
text and radiologic findings cannot be ignored in formulat-
ing management decisions. If significant discrepancies ex-
ist between histopathologic findings and clinicoradiologic
context, a careful review of the available data is required to
arrive at a clinically meaningful diagnosis. In some cases,
histopathologic findings on a surgical lung biopsy speci-
men may not be representative of the underlying pathologic
process because of a surgical sampling problem. In others,
the biopsy findings may not represent a histopathologic
pattern that lends itself to a clear-cut pattern diagnosis.97
Even when the ILD has not been adequately character-
ized, surgical lung biopsy may not be an option in some
situations because of surgical risk, cost, or limitations in
potential therapies. Main management options in this sce-
nario are observation alone vs empiric treatment based on a
presumptive diagnosis. The pros and cons of these ap-
proaches need to be discussed with the patient, and a deci-
sion should be made according to the individual patient’s
preferences. The decision regarding surgical lung biopsy
may need to be revisited during the subsequent clinical
course, particularly if signs of progressive lung disease
appear.
CONCLUSION
Interstitial lung diseases are a diverse collection of parenchy-
mal lung diseases that vary widely in etiology, pathogenesis,
984 Mayo Clin Proc. • August 2007;82(8):976-986
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
histopathology, clinicoradiologic presentation, and clinical
course. Diagnosis of these diseases is facilitated by an orga-
nized formulation of the clinical context, tempo of the dis-
ease process, and radiologic findings, as well as a selective
use of serologic tests, echocardiography, bronchoscopy, and
surgical lung biopsy. When a lung biopsy specimen is ob-
tained, a correlation of histopathologic findings with the
clinical context and radiologic findings is essential. As our
understanding of these disorders advances and new thera-
peutic agents aimed at specific molecular targets are devel-
oped, it becomes increasingly important to achieve a specific
diagnosis to facilitate the optimal management for patients
with ILDs.
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